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Full text of "Report of program activities : National Cancer Institute"

NATIONAL CANCER INSTITUTE 

ANNUAL REPORT 

July 1, 1976 through September 30, 1977 

Part I 

OFFICE OF THE DIRECTOR 



. iw ,. ^.>^.M,v?? 



US- NATIONAL CANCER INSTITUTE, 

ANNUAL REPORT appro^ray^ ^ac^/^/'/i^ 
July 1, 1976 through September 30, 1977 
TABLE OF CONTENTS 



OFFICE OF THE DIRECTOR 



Page 



Introduction 1 

Staff Changes, Activities, Honors and Awards 3 

Journal of the National Cancer Institute 

Summary Report 5 

Associate Director for International Affairs 

Introduction 7 

The International Cancer Research Data Bank Program 9 

Interagency Agreements 15 

Scientist to Scientist Communication 19 

Bilateral Agreements 25 

Exchange of Personnel Under Auspices of Bilateral 

Agreement 35 

Collaborative Research with Foreign Nationals 39 

NCI International Contracts and Grants 41 

Summary 49 

Associate Director for Administrative Management 

Research Contracts Branch 51 

General 51 

Management of Workload and Manpower 51 

Frederick Cancer Research Center 51 



Small Business 

Equal Employiaent Opportunity Contract Compliance 
Contract Management System 
Associate Director for Program Planning and Analysis 

Office of the Associate Director 

Analysis and Formulation 

National Cancer Program Scientific Analysis 
Scientific and Managerial Formulation Activities 
Documentation 

Planning 

National Cancer Program Planning Effort 
Support of Department Level Planning 
Support of the Office of the Director, NCI 
Research and Cancer Control Program Planning 
Management Information System 
Presentation and Publications 

Contract Narratives 
Associate Director for Cancer Communications 

Summary Report 

Educational Activities 

Public and Congressional Inquiries 

News Media 

Program Liaison Branch 

Publications and Audiovisuals 

Computerized Information System 



II 



Other Activities 

Appendixes 

APPENDIX I: "Ongoing Research Projects o£ Memorial Sloan- 
Kettering Cancer Center, January 1976. 

APPENDIX II: ICRDB Cancergram, "Oncofetal Proteins," 
17 June 1977. 

APPENDIX III: Special Listing on "Clinical Aspects o£ 
Leukemia, Lymphomas and Other Lymphopro- 
liferative Disorders, and Myeloma," 8 April 
1977. 



Page 
85 



87 



107 



117 



III 



NATIONAL CANCER INSTITUTE 
ANNUAL REPORT 
Introduction 



Fiscal 1977 saw the first major change in leadership of the National Cancer 
Institute since passage of the National Cancer Act of 1971. Dr. Frank J. 
Rauscher, Jr., first Director of the expanded National Cancer Institute, 
National Cancer Program resigned in November of 1976. Pending the appoint- 
ment by the President of Dr. Arthur C. Upton, Dean of Basic Health Sciences, 
State University of New York at Stony Brook, as Director in July of 1977, 
Dr. Guy R. Newell, Jr. served as Acting Director. 

The Division of Cancer Control and Rehabilitation underwent further 
refinements in its organization with the abolishment of its Resources, 
Liaison, Evaluation, Communication and Planning Branches and the establishment 
of an Office of Planning and Analysis within the Office of DCCR's Director. 

In April of 1977 the Division of Cancer Treatment was significantly reorganized 
through realignment of its Experimental Therapeutics and Drug Research and 
Development Programs into a newly created Developmental Therapeutics Program. 
Concurrently functions of the Laboratory of Experimental Chemotherapy was 
transferred to the Laboratory of Chemical Pharmacology. 

Plans to reemphasize the bioassay of chemical carcinogens through creation 
in the Division of Cancer Cause and Prevention of a Carcinogenesis Testing 
Program were under review in the Office of the Secretary as this report was 
written. Chemical bioassay activities were strengthened during the year 
through allocation of additional personnel resources and the improvement 
of contractor-managed testing processes. The Clearinghouse on Environmental 
Carcinogens, established in FY 1976 made significant contributions to 
improvement of this important activity. 

The 50th anniversary of the NCI was marked by a special program held in 
Masur Auditorium, August 5. Senator Warren Magnuson, one of the signers 
of the NCI Act of 1937, and other Congressmen who were in Congress at that 
time were special guests. 



Staff Changes, Activities, Honors and Awards 
IIH Directors Award 



Mrs. Norma R. Golumbic 
Dr. Jeffrey Schlom 
Dr. Maxine F. Singer 
Mrs. Elizabeth W. Stroud 

PHS Commendation Awards 

Dr. Peter J. Fischinger 

Dr. Mitchell H. Gail 

Dr. Richard J. Hodes 

NIH EEO Award 

Dr. George M. Wil lis 

Meritorious Service Medal 



Dr. Robert F. Goldberger, Laboratory of Biochemistry, DCBD 

Jeffrey Gottlieb Award 

Dr. Vincent T. DeVita, Jr., DCT 

1976 Albion 0. Bernstein, M.D. Award 
Dr. Vincent T. DeVita, Jr., DCT 



staff Changes, Activities, Honors and Awards 

Dr. Nicholas R. Bachur, Sr. was appointed Chief, Laboratory of Clinical 
Biochemistry, DCT 

Dr. Edward Bird was appointed Chief, Community Special Projects Branch 
DCCR 

Dr. Vincent H. Bono was appointed Chief, Investigation Drug Branch DCT 

Dr. Bruce Chabner was appointed Chief, Clinical Pharmacology Branch DCT 

Dr. Richard Costlow was appointed Chief, Detection, Diagnosis & Pretreatment 
Evaluation Branch, DCCR 

Mr. Jean P. Davignon was appointed Chief, Pharmaceutical Resources Branch 
DCT 

Dr. John D. Douros was appointed Chief, Natural Products Branch, DCT 

Dr. Abraham Goldin was appointed Associate Director for International 
Treatment Research, DCT 

Dr. Roger Halterman was appointed Chief, Diagnosis and Treatment Branch 
DCRRC 

Ms. Ruby Isom was appointed Chief, Community Resources Development Branch 
DCCR 

Dr. David Joftes was appointed Chief, Review & Referral Branch, DCRRC 

Dr. Winfred Malone was appointed Chief, Prevention Branch, DCCR 

Dr. Vincent T. Oliverio was appointed Associate Director, DCT 

Dr. William Roberson was appointed Chief, Cancer Centers Branch, DCRRC 

Dr. Barbara Sanford was appointed Chief, Cancer Biology Branch, DCRRC 

Dr. Saul A. Schepartz was appointed Deputy Director, DCT 

Dr. Edward M. Scolnick was appointed Chief, Laboratory of Tumor Virus 
Genetics, DCCP 

Dr. Arthur C. Upton was appointed Director of the National Cancer Program, 
National Cancer Institute 

Dr. Peter H. Wiernik was appointed Chief, Clinical Oncology Branch, DCT 



Program Activities Report 

Fiscal Year 1976-77 

Editorial Office of the National Cancer Institute 



The Board of Editors reviewed 2,452 items for publication during the 
15-month period April 1, 1976, to June 30, 1977. Of this total number, 
1,033 manuscripts and 318 abstracts were intended for publications other 
than the Journal of the National Cancer Institute (JNCI). The 1,101 
manuscripts submitted for publication in JNCI were from the following 
sources: 

National Cancer Institute: 87 (58 accepted, 

9 rejected, 20 pending) 
Other research institutions: 1,014 (394 

accepted, 370 rejected, 250 pending or 

withdrawn) 

Of the 1,014 manuscripts received from sources outside the National 
Cancer Institute, 305 were from authors in other countries, including 
Belgium, Bulgaria, Canada, China, Czechoslovakia, Denmark, England, 
Federal Republic of Germany, Finland, France, Greece, Hungary, India, 
Ireland, Israel, Italy, Japan, Mexico, Russia, Scotland, Singapore, Spain, 
Sweden, Switzerland, The Netherlands, Wales, and Yugoslavia; and the 
continents of Africa, Australia, and South America. 

Volume 56 (Jan-June 1976) totaled 1,287 pages, whereas volumes 57 
(July-Dec 1976) and 58 (Jan- June 1977) contained 1,429 and 1,878 pages, 
respectively. The increase in number of printed pages in volumes 57 and 
58 over that in volume 56 does not represent a higher acceptance rate, but 
rather, a successful effort by the JNCI staff to eliminate the backlog of 
accepted papers. These efforts by the staff, who continued to maintain a 
high quality of editing while reducing the backlog, were recognized by a 
group achievement award presented in May 1977. In addition, the 
Washington, D.C. chapter of the Society for Technical Communication granted 
an award of achievement to the Journal in January 1977 for "superior writing, 
editing, graphics, and total integration." 

The printing and binding of volumes 57 and 58 were contracted out by 
the Government Printing Office to Waverly Press, Easton, Maryland. Begin- 
ning with volume 58, No. 2, the contractor also handled all the mailing and 
distribution each month. 

Monographs 

Several Monographs were processed during FY 76, and some have been 
completed. The status of each Monograph follows: 

Advances in Neuroblastoma Research (unnumbered) : 
Printed in Sept 1976 Journal; 122 pp. 



S3miposiiim on Pneumocystis carinii Infection 

(No. 43): Completed Dec 1976; 223 pp. 
Symposium on Spontaneous Regression of Cancer 

(No. 44): Completed Dec 1976; 150 pp. 
Methods of Development of New Anticancer Drugs , 

a joint USA-USSR publication (No. 45): 

Completed May 1977; 262 pp. 
Modern Concepts in Brain Tumor Therapy ; 

Laboratory and Clinical Investigations 

(No. 46): In press; approximately 206 pp. 
Epidemiology and Cancer Registries in the 

Pacific Basin (No. 47): In press; 

approximately 140 pp. 
Third Decennial Review Conference; Cell , 

Tissue, and Organ Culture (No. 48); 

Being edited; approximately 380 pp. 
Workshop on Genitourinary Cancer Immunology 

(No. 49): Manuscripts currently being 

received; approximately 300 pp. 

Of the above publications, the editing for Advances in Neuroblastoma 
Research and for Monographs 45, 46, and 47 was done by outside contractors. 



ASSOCIATE DIRECTOR FOR INTERNATIONAL AFFAIRS 



INTERNATIONAL ACTIVITIES OF THE NATIONAL CANCER INSTITUTE 



INTRODUCTION ; 

Among Americans and other English-speaking people of the world it is "cancer." 
The French speak of cancer, too, but pronounce it as "kahnsair." The Germans 
use the word "krebs" and the Italians say "kahnkrow" (cancro). In the Soviet 
Union and Poland it is "rak" (rruck). The Japanese refer to it as "gann" 
(gahn) and the Spanish-speaking people utter "cangrejo" (kahngreho). 
Regardless of the variation in ethnic pronunciation, the meaning of the word, 
its nature and its consequences are one and the same. The people of the world 
acknowledge that the disease is an international threat to the health of 
millions of persons each year. 

Through pioneering efforts by the National Cancer Institute for international 
cooperation toward eradication of this pernicious affliction of the human, 
overwhelming evidence has been accrued concerning variations in cancer levels 
that exist among countries of the world as well as among population groups 
within a nation. This, therefore, makes the need more urgent for filling in 
the large gaps in our knowledge of cancer etiology, morbidity and mortality 
at the international level, especially for those cancers in population groups 
displaying high-risks. Conversely, it is essential to know why other 
populations are of low-risk to certain cancers. 

For instance, stomach cancer is diminishing in the United States whereas in 
the Soviet Union it is the number one cancer problem of the adult population. 
Cancer of the liver is a major problem in Africa and Southeast Asia. Still 
rare in China and Japan is cancer of the prostate, however, it is the one that 
occurs most frequently in Sweden. 

Thus, international collaboration in cancer is essential because cancer is a 
disease of undefined coirplexity, undetermined origin and, certainly, is not 
an exclusionist-type disease. And, pursuing its mandate in the National 
Cancer Act of 1971 (ly74), the NCI is playing, very capably, its position on 
the international team, in return for which, information is being received 
that will ensure more rapid advances in basic research, the clinical 
management, control and/or prevention of cancer. 

NCI's effort, spearheaded by its Office of International Affairs in consonance 
with the NCI operating divisions, has led to the establishment of effective 
communication on cancer problems as v/ell as collaborative cancer research 
programs with scientists throughout the world. 



THE INTERNATIONAL CANCER RESEARCH DATA BANK PROGRAM: 



One of NCI ' s modes of communication on the cancer problem is through the 
International Cancer Research Data Bank (ICRDB) Program. Since it 
became operational in ly74, the ICRDB Program has been actively 
promoting and facilitating, on a world-wide basis, the exchange of 
information between cancer scientists and the dissemination of 
information (through cancer centers and other organizations) to 
physicians for the good of the cancer patient. 

The resources of this vast, international cancer information system 
are dispersed throughout the world by means of a computerized retrieval 
system which contains three data bases, collectively referred to as 
CANCERLINE, Figure 1. 

One of these data bases, CANCERLIT ( Can cer Lit erature) , contains more than 
9U,00U abstracts of published literature dealing with all aspects of cancer. 
Currently, more than 2,U00 biomedical and scientific journals, as well as 
books, monographs, technical reports and theses are screened and abstracted 
for CANCERLIT. Meticulous search of the literature allows for a monthly 
update by some 2,500 abstracts and an annual growth of the base at the rate 
of 30,000. 

CANCERPROJ (Cancer Proj ects), another data base, contains approximately 
16,000 descriptions of cancer research projects in progress during the 
past two years. Project descriptions, contributed by scientists through- 
out the world, include those supported by government and private 
organizations, APPENDIX I. For instance, in Appendix I, one can find 
abstracts of 75 ongoing cancer research projects currently active in the 
Memorial Sloan-Kettering Cancer Center. Each abstract describes the 
objective, the approach and a capsule of acconplishments. 

The third data base, CLINPROT (Clinical Cancer Prot ocols) , contains about 
1,000 summaries of clinical investigations of new therapeutic agents and 
procedures . Although most of the protocols are those supported by NCI ' s 
Division of Cancer Treatment, several hundred have been provided by major 
American cancer centers and foreign oncologic institutes. 

The information from these data bases can be tailored to the specific needs 
of scientists. Searches can be performed and are facilitated via terminals 
in some 500 institutions connected via a world-wide telecommunications 
network to the central computer facility in the National Library of Medicine. 

As indicated by Figure 2, there has been an increasing use of the CANCERLINE 
data base since January of 1976. Over the entire year, user terminals were 
connected to CANCERLINE for some 1,«76 hours. Use of The CANCERPROJ system 
in December, amounted to some 367 hours. CANCERPROJ allowed free access 
in December, and usage soared to almost 1000 hours. 






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Direct access to CANCERLINE is amplified by the ICRDB's Clinical 
Information Dissemination and Analysis Centers (CIDAC). Three CIDACs 
now exist for Carcinogenesis information. Cancer Therapy and Cancer 
Virology, Immunology and Biology. The information products of these 
facilities are actively disseminated by two major types of service. 
These are a Current Awareness Service (CANCERGPiAMS) and Oncology 
Overviews. The latter consist of comprehensive listings of abstracts 
of papers published in recent years on selected, high-interest subjects 
of special interest to researchers. CANCERGRAMS are regularly 
published collections of abstracts of newly published results 
in specific cancer research areas APPENDIX II. Sixty to eighty 
topics are covered with automatic distribution, every few weeks, 
to researchers working in areas corresponding to a CANCERGRAM 
topic. A quick analysis of APPENDIX II shows a conpilation of 35 abstracts 
on a specific research topic, "Oncofetal Proteins." Further inspection of 
the abstracts brings out the international flavor associated with research 
on this topic. Although the majority of the abstracts are of American 
origin, 5 represent the work of Japanese scientists, 2 by those in Italy 
and France and one each from scientists in Australia, Belgium, Canada, 
the Federal Republic of Germany, Israel, the Republic of South Africa and 
Sweden. 

Exemplary of the responses from recipients of CANCERGRAMS are: 

"I want to convey my appreciation for your publication 
(Cancergram on Avian Tumor Viruses). I find it extremely 
useful ." University of Rochester. 

"This regular listing (Cancergram on Nitroso Connpounds) 

is extremely useful to both me and my colleagues.... 

woula certainly appreciate continuation of this service...." 

Christie Hospital and Holt Radium Institute, Manchester, England. 

"The Cancergram on Oncofetal Proteins contained much useful 
information and is of definite value.... in my laboratory...." 
University of Vermont. 

"I would like to inform you that I am very pleased with this 
form of information dissemination...." Oak Ridge National 
Laboratory. 

"I just received the Cancergram on Oncofetal Proteins and 
discovered some papers I originally missed in the literature." 
City of Hope National Medical Center, Duarte, California. 

"I have found your first Cancergram extremely valuable in 

my carcinogenesis studies. This type of service is extremely 

important to researchers ." University of Hawaii. 



12 



"These periodic compilations are of extreme value in the 
planning and operation of our own research on the development 
of tumors with nitrosamines and nitrosamides. . . ." University 
of Toronto. 

"It is quite valuable, particularly for the investigators in 
the remote area where the original publications are not always 
available".... Mahidol University, Bangkok, Thailand. 

"I found it extremely interesting and useful due to the large 
amount of data excerpted from so many publications...." 
Institute of Oncology of Cluj, Cluj, Romania. 

Another activity which serves as an ICRDB information source is the CCRESPAC 
or the Current Cancer Research Project Analysis Center. Here, descriptions 
of ongoing research projects are collected and processed for inclusion 
in the CANCERPROJ data base and for compilation into SPECIAL LISTINGS. 
These contain descriptions of ongoing projects in specific cancer research 
areas and are intended for promoting the exchange of information between 
cancer scientists through an awareness of active projects throughout the 
world that are related to their own research, APPENDIX III. SPECIAL 
LISTINGS deal with some 6U specific research areas. APPENDIX III, for 
example, is a "Special Listing on Clinical Aspects of Leukemia, 
Lymphomas and other Lynphoproliferative Disorders, and Myeloma." 
The abstracts — 4b 1 in number — have been screened from the two-year 
accumulation of the ICP^DB data base, and cover the literature 
of iy75 and iy76. 

The foregoing illustrate the magnitude of the ICRDB Program and the 
systematic and comprehensive implementation of the broad spectrum of 
operations required for the integration of the variety of scientific 
information systems and services for the community of international 
scientists. Certainly the current success that has been achieved in 
meeting the ICRDB mission mandated in the National Cancer Act could 
not have been achieved without the excellent association and collaboration 
of international organizations. As evident in Figure 1, a superior degree 
of rapport exists between NCI/ICRDB and the World Health Organization (WHO), 
the International Union Against Cancer (UICC), the International Agency 
for the Cancer Research (lARC), the Pan American Health Organization (PAHO), 
and the International Medical Information Center (IMIC) in Japan. There 
is strong association between ICRDB and other information collection centers 
such as the German Cancer Research Center in Heidelberg. With the exception 
of the Soviet bloc community, the collaborative network of communication 
established between ICRDB and international institutions is vast. However, 
negotiations with Soviet counterparts are a continuum. 

Interagency agreements entered into by the ICRDB Program follow on pages 
5 through 8. 



13 



Interagency Agreement; National Library of Medicine (NLM) 

Title ; Establish and Operate an On-Line Cancer Information System 
CANCERLINE 

Contractor's Project Director: Dr. Henry M. Kissman 

Project Director; Dr. John H. Schneider 

Objective; 

The objective of this agreement is for the placement of cancer-related 
information (abstracts, project descriptions, clinical protocol summaries) 
into data bases generated, maintained and operated on the NLM's computer 
systems, and for the dissemination of the data so placed to institutions 
via the NLM telecommunications network or via direct mailing of necessary 
tapes . 

Major Accomplishments; 

A data base called CANCERLINE has been created from data supplied by the 
ICRDB Program. This data base currently contains more than 90,000 abstracts 
describing the results of research in all fields of cancer. 

CANCERLINE has been periodically updated and arrangements have been made 
to enter approximately 2,000 new abstracts to the data base each month. 

The entire CANCERLINE Data Base is regenerated at least once each year 
so that errors and inconsistencies in the content and format of the data 
are corrected. 

A data base called CANCERPROJ has been created from data supplied by the 
ICRDB Program. This data base currently contains more than Id, 000 
descriptions of current cancer research projects. This data base is 
completely regenerated using new data from the ICRDB Program four times 
each year. 

An experimental data base called CLINPROT has been created from data 
supplied by the ICRDB Program. This data base currently contains 
approximately luou descriptions of clinical protocols in a special 
format describing the type of cancer being treated, the agents used, 
and outlining the protocol. 

Users of the NLM system are given instruction on the use of ICRDB data 
bases as part of the standard user training courses given by NLM, 

NLM, in cooperation with the ICRDB Program, prepares user manuals and 
periodic technical bulletins for users describing the ICRDB data bases. 



15 



NLM provides NCI with basic statistics regarding the use of ICRDB 
data bases. 

NLM provides a work station and back-up services for an NCI staff 
person who is assigned to the NLM. 

NLM provides NCI staff and NCI contractors with a nuinber of free 
access codes which permit them to search ICRDB data bases without 
the usual search charges. 

Significance to the National Cancer Program; 

In consonance with the National Cancer Act of 1971, this interagency 
agreement has given the ICRDB Program the cost savings benefit of using 
an existing organization with capabilities to reformat, process, and 
make the results of cancer research available to more than 5U0 locations 
throughout the world via an existing telecommunications network resident 
at the NLM. These locations include medical schools, medical research 
institutions, regional medical libraries and hospitals throughout the 
United States, and in several countries outside the U.S. 

Proposed Course; Plans call for the continuation of this agreement 
through September 30, 1978. 

Date Agreement Initiated; July 1, 1974 

Current Agreement Level; $380,000 



16 



Interagency Agreement; Smithsonian Institution (SI) 

Title; Establish and Operate a Current Cancer Research Project Analysis 
Center (CCRESPAC) 

Contractor's Project Director; David Hersey, Ph.D. 

Project Officer; Richard H, Ainacher 

Objective; 

The overall objective of this Agreement is for the Smithsonian Institution 
to establish and maintain a Current Cancer Research Project Analysis 
Center (CCRESPAC) to support the International Cancer Research Data Bank 
(ICRDB) Program by processing research project descriptions specifying 
who is doing the research, where it is being done and what approach is 
being used. 

Major Accomplishments; 

Prepared pilot file of approximately 1000 cancer treatment protocols for 
on-line retrieval similar to CANCERLINE, part of the NLM MEDLARS computer 
system. 

Prepared 5 publications of various subsets of this protocol file for the 
NCI staff and clinicians working under NCI grants or contracts. 

Prepared for publication 60 Special Listings consisting of edited resumes 
of ongoing research in specific cancer subject areas. 

Devised a detailed cancer-related thesaurus which was used to key over 
116,000 research resumes. 

Prepared a computer file of over 15,000 cancer projects called CANCERPROJ 
which is now available for on-line searching and retrieval via the NLM 
MEDLARS computer system. 

Continued correspondence and other communications with scientists and 
clinicians in more than 40 countries. This has resulted in the 
identification of over 1,400 non-U. S. research projects previously 
unknown to the CCRESPAC information system. 

Significance to the National Cancer Program; 

In consonance with the National Cancer Act of iy71, this interagency agreement 
has given the ICRDB Program the cost savings benefit of using an existing 
organization with capabilities to collect, process, and disseminate ongoing 
cancer research project information to researchers anywhere. This Center 



17 



produces a variety of information products and services including the 
dissemination of specialized cancer catalogs and the on-line searching 
of current cancer research project information. 

Proposed Course: Plans call for the continuation of this Agreement 
through December 30, 1977 

Date Agreement Initiated; December 30, 1974 

Current Agreement Level; $498,000 



18 



SCIENTIST-TO-SCIENTIST COMMUNICATION: 



The scientist-to-scientist communication program, although managed as a 
discrete entity of NCI International Activities, is an integral conponent 
of the ICRDB Program. With funds provided by the ICRDB, the International 
Union Against Cancer (UICC), established in 1975 two major programs for 
scientific communication in the international sphere. These are the 
"International Cancer Research Technology Transfer (ICRETT)" Program and 
the "International Cancer Research Workshop (ICREW)" Program. 

The purpose of ICRETT is to enable investigators from different countries 
to carry out jointly brief research projects (for an average of three 
weeks) which will develop, improve or modify new or specialized techniques 
or methods, and will clearly contribute toward the progress of cancer 
research. Scientis':s can engage in short-term, on-the-spot collaboration 
necessary for comparing the results of parallel or related research in 
different countries. It enables such scientists to meet for intensive 
discussions and/or demonstrations, thereby promoting direct and rapid 
person-to-person transfer of information in areas of basic, clinical or 
behavioral research. 

ICREW, on the other hand, is designed to increase the frequency, speed and 
efficiency of direct information exchange between small groups of cancer 
investigators (15 persons, on the average). Although working in different 
countries, they are actively engaged in the same field of basic, clinical 
or behavior ial research related to cancer. 

In the first year of operation of the ICRETT/ICREW Programs, 51 applications 
were received for ICRETT. The applications were categorized according to 
the fifteen cancer problem areas listed in Table 1. Thirty-three of the 
51 applicants were given ICRETT awards. 

Figure 3 shows the countries of origin of the ICRETT awardees, the cancer 
problem area in which they are actively engaged, and the country of their 
choice for scientific interaction. As can be seen, the majority of the 
scientists visited the United States (13), the United Kingaom (5) and 
Sweden (4). France, Japan and the Netherlands each hosted two ICRETT 
visitors. The remaining five awardees visited Australia, Germany, Finland, 
New Zealand, and the USSR. 

As an illustration, a scientist from the Institute of Oncology in Vienna, 
Austria, spent two weeks in the Department of Pathology of the 
University of Glasgow. The purpose of her stay there was to 
compare two methods (hers and that of her host) of tumor specific 
cell-mediated immunity. She found that her host's technique 
turned out to be more sensitive as far as tumor specific immune 
reactivity of cancer patients is concerned. The Austrian scientist, as 
a result, was able to adapt her technique to the method developed by her 
host and, more importantly, their discussions resulted in establishing 
collaborative projects between the Universities of Vienna and Glasgow. 

19 



TABLE 1 - ICRETT APPLICATIONS AND AWARDS— 1976 



CANCER DISCIPLINE APPLICATIONS AWARDS 

1. Behavioral and Social Sciences 

2. Biochemistry, Molecular Biology 

and Biophysics 6 5 

3. Cell Biology and Cell Genetics 1 1 

4. Chemical Carcinogenesis 3 1 

5. Clinical Chemotherapy and 

Endocrinology 3 

6. Controlled Therapeutic Trials 1 1 

7. Detection and Diagnosis 2 1 

8. Environmental Factors and 

Prevention 2 

y. Epidemiology, Biostatistics, 

Registries 

10. Experimental Chemotherapy 6 6 

11. Experimental Pathology 6 4 

12. Immunology 7 4 

13. Radiobiology and Radiotherapy 5 5 

14. Surgery 

15. Viral Carcinogenesis 9 5 

51 33 



20 



Under ICRETT auspices, an American scientist from the University of 
California, Irvine, spent three weeks in the Institute of Oncology 
Problems (lOP) Kiev, Ukrainian SSR. His scientific mission was 
to compare normal and cancerous cells with respect to their sensitivity 
to laser microirradiation, using an lOP nitrogen laser not available 
to the American in his UC Irvine laboratory. An observation was made 
that malignant HeLa cells are much more sensitive to the nitrogen laser 
when they are grown in a medium containing phenol red (PR); indicating 
perhaps, that malignant HeLa cells take up (internalize) PR whereas 
normal cells do not. Both scientists feel that this phenomenon may 
reflect a basic physiologic difference between normal and transformed 
cells that can be useful in understanding the process of malignancy 
as well as its treatment. Collaboration in these experiments is 
continuing. 

A scientist from the Center for Radiobiology and Radioprotection in 
Warsaw, Poland, was able to participate in the "Third UICC Training 
Course in Cancer Research" through ICRETT support. "The visit to the 
Chester Beatty Research Institute in London enabled me to contact 
experts in different branches of experimental oncology with the 
excellent possibility to broaden my experience in cell kinetics, 
cell culture and experimental chemotherapy — techniques useful for 
present and future research work of our team," the Polish scientist 
stated in his report. In exchange, he delivered a lecture on the 
"effects of microwave hyperthermia" on experimental neoplasms. 

In another situation, a researcher from the University of Zagreb spent 
almost three weeks in the University of Texas Health Science Center at 
San Antonio where he was "able to clarify some methodologic problems 
and technical difficulties encountered in our work in Zagreb. .. .such 
as the problem of error due to absorption of steroids in the wall of 
polypropylene tubes; discrepencies in homogenation procedures; etc. 
I think that we shall be able to improve our laboratory work and extend 
our experience to other people and help initiate similar assays in other 
laboratories in our country." 

Finally, an Argentine biochemist was able to devote three weeks to the 
study of chromatographic techniques for nucleoside analysis in the 
Division of Chemical Carcinogenesis, Institute of Cancer Research, 
Buckinghamshire, England. Her interest is to apply these "basic" 
procedures in her laboratory where a program in chemical carcinogenesis 
is under development in the Instituto de Investigaciones Cientificas y 
Tecnicas de las Fuerzas Armadas of Buenos Aires. 

Two ICREW awards were made from a total of 15 applications. One workshop 
was organized by an American and an Australian scientist and held in 
Washington on "Standardization of Selective Cultures for Normal and 
Leukemic Cells." The other was organized by a Finnish scientist in 
Helsinki on the subject of "Thyroid Cancer in Scandinavia — Repeatability 
of the WHO Histologic Calssif ication. " 



21 



FIGURE 3: ICRETT AWARDEES AND THEIR 
SCiENTIFIC INTERACTION 




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22 



Thus, the first year of the ICRETT and ICREW Programs can be considered as 
a success because their aims are being achieved and the quality of the 
awardees has been of a high order. The scientists and projects supported 
have met the objective of the need for expeditious, rapid international 
exchange of ideas and techniques on a person-to-person basis. Certainly, 
cancer is a disease of enough complexity without adding to the research 
burden by scientists studying a problem with divergent methods resulting 
in variability in interpretation of data and arriving at differing 
and even controversial conclusions. Thus, ICRETT and ICREW appear to 
have made excellent inroads into enabling scientists to communicate 
with each other much more readily; permitting them to exchange information 
on similar techniques in an attempt to arriving at commonality in 
procedure; enabling a more standardized methodology and technology; 
and, the ultimate realization of parity in scientific pursuit of similar 
problems in different laboratories throughout the world. 



23 



BILATERAL AGREEMENTS 



THE USA-USSR AGREEMENT FOR COOPERATION IN THE FIELDS 
OF MEDICAL SCIENCE AND PUBLIC HEALTH 

23 May lbi77 marked the fifth anniversary of cooperation between scientists 
of the United States and those of the Soviet Union on problems of cancer. 
Progress continues to be achieved and the joint effort in the six cancer 
problem areas in continuing in a satisfactory manner. 

In the first of these problem areas — Cancer Chemotherapy — an intense 
effort is continuing in the exploration of drug development logic and the 
operational organization of cancer systems in both countries by which drugs 
are taken from laboratory synthesis to clinical application. From 1312 to 
ly76, a total of 154 anticancer and potential anticancer agents has been 
exchanged. Sixty-one American compounds (41 clinical drugs and 2U preclinical) 
have been given to Soviet investigators, in return for which, American 
scientists received lu3 Soviet products (4 clinical drugs, 22 preclinical 
agents and 77 preparations for screening for potential anticancer activity) . 
As a result of the exchange of anticancer drugs for clinical trials, there 
has been an acceleration in the evaluation of drug activity and behavior 
in patients. In particular, Soviet studies of the American drug, DTIC, paved 
the way for the Pharmacologic Unit of the USSR Ministry of Health to recommend 
DTIC for practical use in the USSR. What commercial effect this will have 
on the American producer of DTIC — Dome Laboratories — is not known at this 
time. In the United States, on the other hand, detailed preclinical and 
clinical studies have been carried out on the Soviet drug, ftorafur. This 
has affected the American private sector, favorably perhaps, in that a 
license for the manufacture of ftorafur in the United States has been granted 
by the USSR to Bristol Laboratories of Rochester, New York. 

During the past year, additional joint studies resulted in working out 
regimens for active, combined chemotherapy of skin melanoma and small cell 
carcinoma of the lung, using the American drug, CCNU, and the Soviet drug, 
methylnitrosourea (MNU). The Soviets have completed their study utilizing 
the combination of CCNU and/or MNU in combination with radiotherapy for 
treating this cancer. Soviet accrued information has led to their 
recommendation of this mode of therapy for practical use because of the 
prolongation of patient survival, increased significantly over that resulting 
from previously used treatment modalities. 

In May ly77, the joint USA-USSR Monograph on METHODS OF DEVELOPMENT OF NEW 
ANTICANCER DRUGS was published in English in the United States and, in 
Russian, in the USSR. Eleven chapters were contributed by American authors 
and ten were under Soviet authorship. Additionally, the results of laboratory 
study of some 5U experimental drugs in both countries now serve as a basis 
for a second joint monograph to be published in iy78 under the title of 
"Analysis of USA-USSR Preclinical Test Data and Clinical Correlation." 



25 



Joint endeavors in Cancer Immunology are considered quite satisfactory. 
American and Soviet results with the use of conbination of chemo- and 
immunotherapy show considerable promise in the clinical management of 
certain cancers. 

Clinical experience with 173 patients with various operable skin melanomas 
was obtained in five USSR institutes during ly74-iy76. Their three year 
follow-up demonstrated that the combination of surgery + imidazole 
carboxamide (American DTIC) + BCG was the most effective therapy for 
patients with melanoma of the trunk and extremities and involving four 
or more lymphatic nodes. In the combined therapy group, 16 of 35 patients 
are alive today without any notice of tumor growth. Only one control is 
living currently. In the American study of BCG conbined with DTIC, the 
chemo- immunotherapy patients with lynph node metastases had a remission 
rate of 55% compared to a rate of 18% for patients treated only with DTIC. 

Analyses were carried out in the Soviet Union on the results of chemotherapy 
alone and in combination with BCG in 1U2 patients with disseminated skin 
melanoma. It was shown that the duration of remission (7% full and 24% 
partial) was longer in the combination therapy group. It was determined, 
too, that BCG, as an immunostimulator in disseminated melanoma, did not 
alter the sensitivity of the tumor to chemotherapy, as had been hoped. 

Of significance is a joint study which is currently underway in both 
countries, of breast cancer using polychemotherapy, plus immuno-stimulation 
in disseminated forms of breast cancer. In the United States, patients will 
be treated with the combination of cyclophosphan + methotrexate + 5- 
fluorouracil (CMF) plus Adriamycin (drug produced by Farmitalia of Italy). 
In the Soviet Union, patients will receive CMF + carminomycin, the Soviet- 
produced analogue of Adriamycin. (Again, Bristol Laboratories has been 
granted a license by the USSR to produce carminomycin in the USA and its 
availability to U.S. investigators is anticipated in late 1977). In the 
patients with disseminated breast cancer, both countries will use C. parvum 
as the immunostimulator. 

Scientific exchanges during the first American-Soviet conference on "Fetal 
and Tumor Antigens" held in Tallinn, Estonia, May lb»76, were mutually 
profitable. The highlight of the meeting, however, was the presentation of 
an award from the Cancer Research Institute of New York to Professor 
G.I. Abelev of Moscow's Gamaleya Institute of Epidemiology and Microbiology. 
The prize acknowledged Abelev 's outstanding v/ork and "his observation in 
1963, that alpha-fetoprotein could be detected in the sera of adult mice 
with hepatomas (but not in normal adult mice) and by his recognition of the 
fundamental oncologic significance of this finding." His discovery "has 
opened up an area of cancer research which is now being pursued throughout 
the world." 

In Cancer Virology , data has been accrued on: (1) RNA viruses known or 
suspected to induce neoplasia in humans or in animals; (2) on virus- 
producing cell lines from cultures infected with known or suspected 



26 



oncogenic viruses; (3) viruses associated with leukemia or lymphoma in 
baboons; (4) herpesvirus-associated carcinogenesis; (5) the molecular 
biology of tumor viruses; and (6) tumor virus immunology. Much of this 
information has been published this year in articles written jointly for 
American and Soviet journals. 

Since late 1975, American and Soviet virologists have expanded their 
scientific effort to include: (1) research on the breeding of endangered 
non-human primate species essential to the basic study of tumor viruses; 
and (2) studies of oncogenic viruses that might be potentially hazardous 
to human ecology such as avian, bovine, porcine and other viruses that 
might directly or indirectly affect human well-being. 

During 1976, new directions were taken for joint USA-USSR studies in 
Mammalian Scanatic Cell Genetics Related to Neoplasia . After three years 
of exchanging information, discrete and finite projects were established 
on: (1) the genetic analysis of malignancy by means of somatic cell 
hybridization; (2) the mutagenic action of anticancer agents; (3) genetic 
disorders with predisposition to malignancy in patients with retinoblastoma 
and xeroderma pigmentosum and those with recessive diseases with chromosome 
instability; and (4) the clinical aspects of somatic cell genetics. Since 
the above programs have been adopted, Soviet scientists have demonstrated 
that Ftorafur induces chromatid breaks (predominantly single breaks) and 
chromosome rearrangements in the cells of a human colon tumor transplanted 
into experimental animals (nude or athymic mice). The study was begun during 
a visit to the NCI in 1976 by a Soviet geneticist. American colleagues 
consider the apparent selective toxic effect of this chemotherapeutic 
agent — a chemical analogue of the American 5-Fluorouracil deoxyribose — on 
malignant cells to be of great potential clinical inportance. 
Ftorafur (FT) damaged chromosomes after its conversion to 5-f luorouracil 
and then to fluorodeoxyuridine. The same biochemical mechanism 
underlies FT and 5-FU in chromosome breaking effect. 

Following mutual acceptance for a joint program in Cancer Epidemiology , an 
USA-USSR project evolved in 1976 on the epidemiology of breast cancer. 
Collaborating are NCI, the Harvard School of Public Health, Moscow's 
Cancer Research Center and the Institute of Experimental and Clinical 
Medicine in Tallinn. Two studies are being pursued jointly: (1) an analysis 
of breast cancer case-control data; and (2) feasibility studies of urinary 
estrogen profiles. In the first, the Soviet side will provide data on some 
15U0 Estonian wonen (5U0 breast cancer cases) for analysis according to 
procedures used by the American group in Harvard. The second study relates 
to the hypothesis that the pattern of a woman's estrogen metabolism during 
the earliest years of reproductive life is an inportant determinant of her 
lifetime breast cancer risk. Urine samples of Estonian women, initially, 
will be made available to American scientists for analysis. 

The American-Soviet effort in Cancer Control and Cancer Centers includes four 
projects in active stages of joint investigation. The first deals with the 
search for effective methods of early detection of breast cancer. Thousands 
of patients in both countries have been studied employing the four modalities 



27 



of history, physical examination, mammography and thermography. The 
breast cancer detection rates were 3.4 or U.34% per lUUO screenees in 
the USA and 2.7 or 0.27% per lOOU in the USSR. In the second project, 
a questionnaire was prepared jointly for determining the methodology 
and efficacy in rehabilitation programs for breast cancer patients. 
A pilot study of 50 cases in each country, has been completed and the 
data were computer processed and analyzed in NCI. Thirdly, the project 
on the evaluation of the efficacy of treatment of breast cancer is 
providing very useful information on the joint approach for comparing 
the evaluation in both countries, of histologic forms of tumors of breast 
cancer in accordance with the MOTNAC system. This study is iirplemented 
by the exchange of microscopic slides of pathologic tissue sections. A 
fourth project deals with jointly determining the operational structure 
and effectiveness of the cancer center/institute for providing optimum 
cancer control programs. 

According to the schedule agreed to during the Third USA-USSR Meeting on 
this problem (September 1976), each side completed the jointly-prepared 
questionnaires on 50 cases of breast cancer as an approach to determining 
the methodology and efficacy of American and Soviet programs for 
rehabilitation of the breast cancer patient. These were computer processed 
and analyzed by the NCI/DCCR staff, following which Soviet and American 
principals met (in early June of this year) to review the data. After 
resolution of all discrepancies, a new questionnaire was developed and 
accepted mutually. Studies are now underway to collect data on 300 
additional breast cancer cases in each country. 

In characterizing the general course of activity in cancer research under 
the USA-USSR Agreement, reflections over the past five years must be 
considered, using a variety of indicators. First , openness of Soviet 
scientists in the "give and take" of scientific information, the opinions 
rendered by Americans in general, indicate that initially Soviet attitudes 
were at worst, recalcitrant, and at best, diffident. After five years of 
cooperation and continually improving person-to-person contact, the opinion 
of most Americans is that "we are not being deluded by individual Soviet 
scientists and that the rapport between scientists continues to be 
strengthened." Secondly , the levels of research in most areas of Soviet 
biomedical science are still further advanced in the United States. In 
general, Soviet scientists still have much more to gain by spending time 
in a laboratory in the United States than would Americans spending an 
equal amount of time in USSR laboratories. There are obvious exceptions, 
however, and these should be exploited, e.g., the Institute of Molecular 
Biology, AS, USSR, Moscow. Thirdly , many Americans have a tendency to 
undersell the capabilities of Soviet scientists and to underestimate their 
capacity for scientific and technologic advances. Most of the hundred or 
so Soviet cancer researchers who have visited the United States have 
demonstrated that they do learn fast and what they learn is translated 
rapidly into practice. For instance, there is almost a consensus among 
American specialists in cancer therapy that the clinical benefits accruing 
for Soviet cancer patients have iirproved by an order of magnitude since this 



28 



Agreement has been effected. And certainly, perhaps this is what it is 
all about — collaboration is an expedient for reaffirming the interest 
and an intensification of the effort, jointly rather than unilaterally, 
against a serious disease and health malady affecting the people of 
both nations. 



THE AGREEMENT BETWEEN THE NATIONAL CANCER INSTITUTE AND 
THE JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE 

During the Third Annual Meeting of the Joint NCI-JSPS Scientific Groups 
in Kyoto, Japan from 12-13 October 1976, a consensus was expressed that 
American- Japanese cooperation in cancer research has been a success and 
satisfactory progress continues to be achieved. Since the inception of 
this collaborative program on 14 May 1974, seme 500 scientists from the 
United States and Japan have become involved, either directly or indirectly, 
in this program. Their participation entailed contributions either: 

(1) as active participants in program area meetings and workshops; 

(2) as laboratory exchange scientists in pursuit of joint experimental 
problems; (3) as hosts to visiting individuals or delegations; or 

(4) observers during scientific sessions related to the cancer problem 
areas. The details are reviewed in the article, "US-Japan Cooperative 
Cancer Research Program" by G.R. Newell and H. Sugano, in the JNCI, 
Volume 58, pages 455-456, February 1977. 

The NCI-JSPS Bladder Cancer Program working group assembled in Kyoto, 
Japan in September 1976, for a joint seminar on the "Etiology of Bladder 
Cancer." The state-of-the-art and new concepts of the cause(s) of cancer 
in this organ site were reviewed and discussed. The conferees attenpted 
to develop scientific concepts and clinical strategies for the amelioration 
of the disease, interference with those carcinogenic substances influencing 
its causation, and, ultimately, prevention. Opportunities were explored 
for the mutual developnent of collaborative research projects. The 
approaches for exploration of the etiology of bladder cancers ensued as 
studies of: (1) chemical carcinogenesis enphasizing the possible role of 
tryptophan and products of the bracken fern; (2) environmental, genetic 
and other factors contributory to its epidemiology, for instance, the 
detailed study of urinary cytology in bladder cancer related to an 
occupational environment; and (4) clinical analyses of factors that appear 
to be dominant forces in the etiology of bladder cancer. The seminar, 
interdisciplinary in perspective, enabled the participants to discuss 
individual and/or group views and ideas, both imaginatively and in depth. 

In October 1976, a conference on Comparative Epidemiology was sponsored by 
the NCI-JSPS Analytic Epidemiology Program working group in Tokyo, Japan. 
The objectives established for the conferees were: (1) to review five volumes 
of cancer mortality graphs — based on unpublished data — conparing U.S. whites, 
U.S. blacks and Japanese from 1950-1974, by five year age groups; (2) to 
review recent developments in the etiology of childhood cancer such as 
lyitphoma, Hodgkin's disease, acute and chronic lyiiphocytic leukemia and 



29 



reticulosarcoma; and (3) to discuss the contrasting origins of leukemia, 
bladder cancer and cancer of the cervix. The proceedings ensuing from 
the provocative and innovative discussions were published (iy77) as a 
joint monograph entitled, COMPARATIVE EPIDEMIOLOGY OF CANCER IN THE U.S. 
AND JAPAN — MORTALITY, by the Japan Society for the Promotion of Science. 

"Polycyclic Hydrocarbons" were the topics of a conference convened by the 
NCI-JSPS Chemical Carcinogenesis Program working group in New Orleans, 
Louisiana in January 1977. Forty-five papers were presented by American 
and Japanese participants as well as several scientists from England and 
France who were invited because of their particular expertise. Again, 
the interdisciplinary nature of the participants engendered a wealth of 
information on: (1) the chemistry and metabolism of hydrocarbons including 
their enzymologic degradation, conversion and transformation in vitro; 
macromolecular interaction; and DNA repair; (2) the biologic effects of 
chemical carcinogens particularly as influenced by polycyclic hydrocarbons; 
(3) tobacco carcinogenesis; (4) energy sources and bioenergetics; 
(5) monitoring of environmental factors seemingly involved in the 
epidemiology of lung and other cancers; and (6) the use of animal models 
in the study of lung cancer. The overall product of the meeting was a 
gathering of momentum for enhanced research because of the abundance of 
information on the relationship of polycyclic hydrocarbons to cancer ogenesis. 
The proceedings of the conference are being prepared for publication. 

Beverly Hills, California was the site for a seminar on "Multidisciplinary 
Approaches to Lung Cancer" organized in March 1977 by the NCI-JSPS Lung 
Cancer Program working group. The goal of this scientific exchange was to 
review the current status of treatment for lung cancer in the United States 
and Japan. The stage for intensive study was set by a review of lung cancer 
morphology as a guide to differential therapy. Various therapeutic approaches 
were then discussed including, radiotherapy alone and combined with chemo- 
therapy as well as the use of chemo- immunotherapy, using the BCG cell wall 
skeleton as the immunostimulator. Specific and non-specific immunotherapy 
were given extensive scrunity as clinical therapy modalities. 
Details and results of surgery combined with other modes of 
therapy were reviewed critically. Considerable discussion evolved 
about the clinical studies being pursued in Miami. From the 
discussions it became clear that there is need for a standardization of 
histologic classifications, staging of the disease and systematizing of the 
clinical response criteria. Thus, a future meeting is being planned for 
specific discussions of combined modality therapy for lung cancer as well 
as a review of the status of anticarcinogenesis, especially that apparently 
associated with synthetic chemical analogues of retinoic acid (an intermediary 
metabolic product of the carotenes of Vitamin A) . 

In March, as well, under the auspices of the NCI-JSPS Breast Cancer Program 
working group a meeting was held in Seattle, Washington on "Breast 
Cancer: Diet and Epidemiology." A review took place of the existing 
information relating diet and nutrition to breast cancer. Discussions 
pertained to: (1) the current status of dietary characteristics in American 
and Japanese populations; (2) the distribution of food types, current dietary 



30 



habits and dietary trends in Japan; (3) the relationship between diet, 
nutrition and hormones on the incidence of breast cancer; (4) time 
trends in breast cancer morbidity, mortality and histology; (5) breast 
cancer incidence in Japan in special population groups such as religious 
groups, high risk families and migrants; (6) incidence of breast cancer 
in the United States based on geographic patterns; (7) the influence 
of dietary lipids on breast cancer incidence; and (8) the use of animal 
models for the study of breast cancer. 

Preceding the International Congress of Cytology in Tokyo in April of 1^77, 
a meeting took place to review the cooperative efforts of the working 
groups of the NCI-JSPS Cytology Program . Progress in the development 
of instrumentation for automated cytology was evaluated. Particular 
attention was paid to the problems of rates of error in sample preparation, 
staining of cells and computerization. Explored were the establishment 
and application of new biologic cell markers. Four scientists from the 
Federal Republic of Germany participated in the proceedings because of 
their role in the bilateral program under the Agreement between NCI and 
the Ministry of Science and Technology of the Federal Republic of Germany. 

More than 3U scientists from the United States and Japan participated in 
a "Symposium on Anti-tumor Antibiotics" sponsored by the NCI-JSPS Cancer 
Therapy Program working group in San Francisco in May 1977. A thorough 
review was made of the preclinical testing and clinical utility of a 
number of anticancer antibiotics. Efficacy was discussed of those 
currently in clinical use and consideration was given to those newly 
developed and demonstrating potential as anticancer agents. Attention 
was given to Adriamycin (Italy), aclacinomycin (Japan), actinomycin D 
(USA), bestatin (Japan), bleomycin (Japan), mitomycin C (Japan) and 
neocurzinostatin (Japan) . Reviewed and discussed were the pharmacology, 
toxicity and efficacy of the antibiotics on various tumors such as gastric 
cancer, lyirphomas, testicular tumors and head and neck cancers. Combination 
therapy and combined modalities were discussed. An outgrowth of this 
cooperation is the formation of a new, independent study group comprised 
of members of the Northern California Cancer Program and a Japanese 
clinical group. They are conducting cooperative clinical trials on 
gastric cancer in order to evaluate the efficacy of Adriamycin, ftorafur, 
mitomycin C and BCI^JU (commercially known as Carmustine). 

The "Origin and Function of Oncogenic Sequences in RNA Tumor Viruses" was 
the subject of review by the NCI-JSPS Cancer Virology Program working group 
during its meeting in Pasadena, California. Genetic Expression of various 
types of animal viruses and their relationship to cellular transformation 
were the principal topics of discussion as well as areas of exploration for 
joint research in the future. 

A workshop will take place in Tokyo in September 1977 under the aegis of the 
NCI-JSPS High LET Radiation Therapy Program and the working group for the 
NCI-JSPS Cancer Immunology Program will convene in Osaka, Japan in September 
1977. 



31 



USA-POLISH PEOPLES REPUBLIC AGREEl'ffiNT: 

This year was marked by increasing activity in the exchange of scientific 
personnel. Although most of the American scientists limited their visits 
to Poland from 1 to 2 weeks, several of them were invited by the Institute 
of Oncology to participate in a course on Cancer Chemotherapy and Summer 
Program in Medical Physics. Two scientists spent time at the National 
Research Institute for Mother and Child to observe and discuss the 
treatment of neuroblastoma in Poland. A total of 6 Polish scientists 
spent 3 to 6 months in several leading American cancer centers for 
advanced training and to engage in cooperative research activities in 
the speciality areas of endocrinology, epidemiology, pharmacology, 
radiotherapy, virology and clinical research. 



USA-ARAB REPUBLIC OF EGYPT AGREEMENT: 



This cooperative cancer program, which is sponsored by the National Cancer 
Institute and the Cairo Cancer Institute, Cairo, Egypt, has flourished 
following the election of the Cairo Cancer Institute as a full participating 
member of the Southwest Oncology Group (SWDG), University of Kansas, Kansas 
City, Kansas. Representatives from' the Institute have been invited to 
attend the quarterly meetings of SWX to discuss the progress of cancer 
treatment. Early in ly77, a team of NCI staff members made a survey visit 
to the Cairo Cancer Institute to consult on the collaborative research 
projects on bladder cancer and its treatment. Projects proposed by the 
Egyptians will be forwarded for NIH review for funding under the Special 
Foreign Currency Program. Plans were made to assign one of the visiting 
members, for a period of one year, to the Cairo Institute to collaborate 
on clinical trials on bladder cancer. During the discussion, the group 
met with the Director of the Institute and his associates to screen 
prospective Egyptian candidates to be appointed as Exchange Scientists. 
As a result of the review, it was decided to provide support for a total 
of y scientists for FY iy77 for periods ranging from one week to 12 months. 



NCI-INSERM (REPUBLIC OF FRANCE) CANCER PROGRAM; 

During the one-year period prior to the formal agreement for cancer research, 
there had been considerable exchange of scientists and research sources 
augmented by the earlier NIH Agreement with INSERM (Institut Nationale de la 
Sante et de la Recherche Medicale). 

American and French Viral Oncology delegations met in September Iy76, for 
the purpose of reviewing the viral oncology programs being pursued in both 
countries. It was agreed at this meeting that the Viral Oncology Program 
Area should provide support of the exchange of scientific personnel, 
attendance and participation at scientific meetings and the exchange of 
scientific information and research materials. It was agreed that 
collaboration in several broad areas of research should be supported, 
namely, RNA and DNA tumor viruses and the role of viruses in certain 
human cancers such as leukemia, sarcoma and carcinoma. 

32 



In April 1977, the Chairman and a member of the NCI Viral Oncology Program 
delegation met with the Chairman of the French delegation and members 
of the INSERM office to discuss plans for the next meeting to be held in 
September 1977 in Paris, which will be held in conjunction with a joint 
meeting on "recombinant DNA" studies. 

A joint planning meeting on the Hormone Regulation and Cancer Program 
Area was held in May 1976 to plan the areas of cooperation between 
American and French scientists. It was generally agreed to initiate 
the exchange of scientists as soon as possible. Under the NCI-INSERM 
Cancer Program, there have been 3 American scientists studying in 
French laboratories for periods of 2 weeks to 3 months, during FY 1977 
and one French scientist visited Stanford University for 2 weeks to 
learn new laboratory techniques. It is anticipated that there will be 
an increase in the number of exchange scientists. 

Two planning meetings in the Clinical Trials and Treatment Research Area 
were held during the first year of the program in order to develop 
guidelines for cooperative research and trials as well as for the exchange 
of scientific personnel. Some of the areas in which cooperation has been 
initiated are pharmacology and clinical trials of nitrosourea analogues, 
osteogenic sarcoma study, clinical biochemistry and pharmacology, clinical 
studies of gastrointestinal cancer and phase I and II immunotherapy projects. 



NCI-MINSITRY OF SCIENCE AND TECHNOLOGY (GERMANY) AGREEMENT ; 

This cooperative cancer program, thus far, has been limited only to the 
Automated Cytology Program Area. The first activity was a large "Workshop 
on the Technologies for Automation in Cervical Cancer Screening" held at 
the German Cancer Research Center in Heidelberg with visits by Americans 
to laboratories in Frankfurt, Wetzler and Munich. In January 1977, a team 
of 7 American scientists visited laboratories in Stuttgart and Munich to 
exchange data on conputer programming and software and to discuss and assess 
ongoing research in cytochemistry and conputer analysis. A German biochemist 
has been invited to the NCI as an Exchange Scientist to investigate histones 
as cell markers for cytologic analysis. During the International Congress of 
Cytology, four German scientists were invited to participate in the joint 
US-Japan Cytology Meeting held in April in Hakone, Japan. 

Preliminary discussions have been held to explore the expansion of the 
program to include other cancer research areas. 



33 



THE EXCHANGE OF PERSONNEL UNDER THE AUSPICES OF BILATERAL AGREEMENTS 



A momentum of significance has been established between the NCI and 
international institutions by virtue of the exchange of scientists 
under the six Bilateral Agreements now extant. These exchanges of 
individuals and delegations have engendered close professional 
associations and meaningful person-to-person contact between the 
scientists of the NCI and those of Egypt, France, Germany, Japan, 
Poland and the Soviet Union. 

As shown in Table 2, 36 scientists from the United States participated 
in joint projects in laboratories in the USSR, Japan, Poland and Egypt. 
The projects varied from experimental research to consultation and 
assistance in training. American delegations, on the other hand, 
traveled to three countries to take part in programmatic meetings, 
conferences or syitposia. Two delegations visited the USSR, three 
journeyed to Japan and three exchanged information in France. Conversely, 
45 foreign scientists came to the United States — several for protracted 
visits of up to 4 months — to engage in collaborative research, to learn 
specific technologic procedures, or to exchange data and information on 
researchc projects of mutual interest. The NCI hosted three delegations 
of scientists from the Soviet Union, five fron Japan, and two from France. 
In all, 9U American scientists pursued their scientific interests in 
laboratories and institutions abroad, and 128 foreign visitors were received 
in NCI and other cancer centers in the United States. 

Appropriate at this point are several illustrations of individual pursuit by 
Americans in foreign institutions and by foreigners in scientific and 
clinical centers of the United • States . 

Two American candidates for the Ph.D. degree in anthropology and genetics 
spent 4 months each in the Soviet Institute of Experimental Therapy and 
Pathology pursuing research activities related to testing the hypothesis 
that inbreeding of primates reduces genetic variability which, in turn, 
increases susceptibility to viral infection. 

An American, in INSERM for one month, was able to obtain information on and 
laboratory experience with techniques for prostate superfusion developed 
by INSERM scientists. The exchange in France has enabled the American 
visitor to master many new methodologic details and avoid pitfalls in the 
construction of his own organ culture perfusion chamber. 

Much of utility was accomplished during scientific exchanges by an 
American bladder cancer specialist visiting Japan for two weeks. There 
was exposure to an excellent young American scientist on a day-to-day 
working basis through lectures and informal seminars, and reciprocally, 
he learned a great deal about the Japanese approach to utilize protease 
inhibitors to modify the course of experimental bladder cancer. 

A Soviet geneticist, while a guest of NCI for 4 months, was able to engage in 



35 



research activities on somatic cell hybridization. As such she was able to 
master techniques for the fusion of human tumor and normal cells as well 
as the application of procedures for analysis of the initial karyotype of 
these hybrid cells by differential staining of chromosomes. 

During three weeks of activity in the Frederick Cancer Research Center, a 
visitor fran Japan spent his time learning the technique of Tank-culture 
of mammalian cells, malignant and benign, for harvesting interferon on a 
large scale. 

A scientist from Poland was afforded the opportunity to obtain data from the 
California Tumor Registry and the hospitals of Alameda County, California 
on 489 cases of stomach cancer in that locality. Thus, he has accrued 
sufficient epidemiologic data for the comparative study of stomach cancer 
incidence and mortality in populations of high-risk (Poland), middle-risk 
(Hawaii) and low-risk (Alameda County). 

Another illustration of collaborative laboratory effort is that of a visiting 
German biochemist and his NCI hosts in a joint program for evaluating to 
which extent a quantitative histone stain alone and in combination with a 
DNA stain can be used as a specific marker for premalignant and malignant 
cells of gynecologic material and thus reduce the number of false positives. 
The whole idea was to combine the features of techniques developed in NCI 
and in Germany. 

The survey of new automation devices in hematology and for other clinical 
laboratory procedures was the purpose for a two weeks visit by an Egyptian 
pathologist. Upon return to the Cairo Cancer Institute, he was hopeful of 
applying his findings to proposals for the expansion of the laboratories 
in the CCI. 

From the foregoing, there must be acknowledgement of a very significant 
scientist-to-scientist communication in the pursuit of cancer information, 
both clinical and fundamental. Channels for effective communication and 
productive joint research have been extended by orders of magnitude. Mutual 
regard and respect among scientists of these seven countries has been 
impressive. And, most inportant, such collaboration at the scientist 
level is to the benefit not only of the cancer patients in the countries 
actively engaged in these bilateral efforts, but eventually to patients 
the world over. 



36 



TABLE 2 PERSCWNEL EXCHANGES UNDER BILATERAL AGREEMENTS, FY 1977 



FROM THE USA TO THE USA 

Individuals Delegations Individuals Delegations 



1. USA-USSR: 



Chemotherapy 1 1 (14)^ 

Immunology 1 (7) 

Virology 2 1 (3) 4 

Genetics 1 (8) 1 

Epidemiology 3 

Cancer Control- 
Centers 2 

Cancer Program 

Review 1(12) 

TOTAL 3 2 (11) 10 3 (33) 

NCI-JAPAN: 



Bladder Cancer 2 1 (7) 2 

Breast Cancer 1 3 1(7) 

Carcinogenesis 2 2 1 (10) 

Chemotherapy 2 1 (11) 

Cytology 4 1 (9) 2 

Epidemiology 1 (6) 2 

Immunology 1 ** 3 

Lung Cancer 2 1 (6) 

Metastasis 2 1 

Radiation Therapy 10 ** 1 

Virology _1 1 1 (7) 

TOTAL 23 3 (22) 21 5 (41) 

USA-POLAND: 



Bladder Cancer 1 

Clinical Research 4 1 

Endocrinology 1 

Epidemiology 1 

Immunology 1 

Pharmacology 1 

Radiotherapy 1 1 

Virology __1 1^ 

TOTAL 8 6 



37 



TABLE 2 PERSONNEL EXCEIANGES UNDER BILATERAL AGREEMENTS, FY 1977 (continued) 







FROM THE USA 






TO THE USA 






Individuals 


Delegations 


Individuals 


Delegations 


4. 


USA-EGYPT: 
Bladder Cancer 
Laboratory, 
Clinical 
Medical Oncology 
Nursing in Oncology 
Pathology 
Radiotherapy 


1 
1 






1 
1 
1 
2 
2 










TOTAL 


2 






7 








5. 


NCI-INSERM: 
Clinical Trials 
Hormone Regulation 
Virology 

TOTAL 






1 (6) 
1 (3) 
1 (5) 


1 






1 (4) 
1 (5) 








3 (14) 


1 






2 (9) 


6. 


NCI-GERMANY: 

















Automated Cytology 1 (7) 



NOTES: *(n)= Number of Scientists Coitprising the Delegation 
**= Meetings to be held in Japan in September 1977 



38 



COLLABORATIVE RESEARCH WITH FOREIGN NATIONALS 



The National Cancer Institute, during the fiscal year 1977, has been the 
host of 134 visiting scientists representing 24 nations of the world. 
Young scientists conprised the majority in this group coming to NCI either 
for advanced training or as tenporary NCI staff for collaborative research 
with NCI principals. 

Additionally, 16 invited guest workers were on board by virtue of financial 
support from various sources, other than NCI, such as private research 
foundations or their own governments. Currently, there are 15 Experts from 
foreign countries who have been placed, tenporarily, in senior positions 
in order to pursue independent research or join in that of their NCI 
collaborator . 

Table 3 shows the number of such visitors, their countries of origin and a 
geographic distribution of the iitpact of the NCI Visiting Scientists Program. 

These activities have been most effective in the sharing of scientific 
information and the transfer of technology by virtue of providing these 
foreign scientists with unique opportunities to develop their potential 
for sound research careers or to inprove their mastery of the 
scientific method. The value of scientific interaction of 
such an international scope can be assessed in terms of the return of these 
persons to their home base to pursue dynamic and effective research programs 
in their own environment and gradually to assume positions of scientific 
prominence in their countries and in the world community. 



39 



TABLE 3 SCIENTISTS FROM FOREIGN NATICWS VISITING THE NCI, FY iy77 



Countries of 
Origin 




Visiting 
Scientists 


Guest 
Workers 


Expert 
Appointees 


India 

Italy 

United Kingdom 

Japan 

Israel 

China (Taiwan) 

Canada 




18 
14 
13 
12 
12 
7 
1 


1 
1 

1 
1 


2 
5 

1 


Western Europe 

Eastern Europe 

South America 

Africa 

Asia 

Australia 


(a) 


13 
2 
2 
2 
2 


8 

1 
2 

1 


1 
3 


Alien Residents 


(b) 
TOTAL 


36 


- 


3 




134 


16 


15 



NOTE: (a) - IVo Polish scientists whose visits were not sponsored under the 
Bilateral Agreement, 
(b) - Majority trained in American Institutions and remain in U.S. 
as permanent residents, but not citizens. 



40 



NCI INTERNATIONAL COSITRACTS AND GRANTS 



The National Cancer Institute awarded 76 contracts and 24 grants to 
98 principal scientists conducting basic and applied cancer research in 
77 institutions located in 19 nations of the world. Table 4 shows the 
distribution of contracts and grants awarded by NCI divisions and offices 
in each of the nations, the number of projects supported in a given 
country as well as the total funding in the recipient nation. The NCI 
financial outlay for these research activities has been estimated to 
be ?9, 232, 118 of fiscal year 1977 funds or approximately 1.13% of the 
Cancer Institute budget. 

Each of the projects supported in foreign institutions is applicable 
and contributory to the goals of the NCI research thrusts. A profile 
of the NCI-supported international research and its emphasis is summarized 
in the following scientific disciplines. 

Biochemistry and Immunochemistry 

Carcinogenesis 

Cell Biology 

Chemotherapy 

Drug Metabolism and Activity 

Drug Screening 

Drug Synthesis and Development 

Endocrinology 

Genetics 

Immunology, fundamental 

Immunotherapy 

Virology 

Additionally, support is provided for Cooperative Oncology Groups, the 
European Organization for Research on the Treatment of Cancer as well 
as the I ARC, UICC and WHO. 

Tables 5 through 9 detail the range and spectrum of activities by NCI division 
or office. In the Division of Cancer Biology and Diagnosis emphasis is 
placed on fundamental immunology and immunotherapy. Specifically, research 
activities are related, in general, to the immune response to tumors, tumor 
antigenicity, drug modified antigens, immunostimulators and the study of 
cellular systems that might be established as diagnostic biologic markers 
for given cancer. 

Research being conducted for the Division of Cancer Treatment relates, 

principally, to the characterization of anticancer agents; the search 

for potential anti-cancer agents from natural sources such as microbial; and 

the synthesis, screening and testing of coirpounds developed in foreign 

laboratories. Clinical trials are conducted on specific cancers such 

as tumors of the brain. Support is provided for a WHO regional center 

in Italy which coordinates clinical studies of melanona as well as for the 



41 









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lymphoma treatment center in Uganda. 

Foreign research activities in carcinogenesis, cell biology, epidemiology 
and virology-genetics are of relevance to the Division of Cancer Cause 
and Prevention. Respectively, iirportance is ascribed to enzyme- induced 
chemical carcinogens; N-nitroso compounds and the polycyclic hydrocarbons. 
Information is needed on the preservation of biochemical mutants, 
mammalian transport systems and tissue interacting factors. Morbidity 
surveys, case control studies, seroepidemiology, risk data and cancer 
incidence rates in countries other than the USA are essential. Knowledge 
is required on the induction of genetic aberrations and their possible 
relationship to cancer as well as the role of viruses as suspect or 
potential carcinogens. 

This relationship with international institutions, organizations and their 
scientists certainly has been mutually advantageous because opportunities 
are provided for an extension of our understanding of the causes of cancer, 
its treatment and its control and/or prevention. Certainly, the expertise 
of foreign reseatchers and the results of their investigations are 
contributory to the spectrum of NCI research and its goals to significantly 
reduce the incidence of human cancer. 



SUMMARY 



The foregoing description of the international activities of the National 
Cancer Institute is indicative of the NCI iirpact on the effort against 
cancer by a seeming consortium of nations of the world. Reciprocally, 
those nations collaborating with the NCI in the "war on cancer" are making 
significant contributions to the Congressionally mandated mission of the 
NCI for the peoples of America. Advancing the thesis of international 
cooperation a bit further, the products of this research effort are being 
applied certainly toward the iirprovement of cancer care mechanisms or 
systems in those countries where the socioeconomic environment seems to 
preclude such advances through autonomous research endeavors. By 
continuing, and even expanding, its role in collaborative international 
research, the NCI will understand better the relationshp between cancer 
patients of the world and the differing biologic, econcanic, sociologic 
and technologic conditions that inpinge upon their immediate being. And, 
as each new piece of information is added to the bank of existing knowledge 
related to the cancer disease-complex, milestones in its cure and prevention 
could be achieved at an accelerated pace. This becomes even more pragmatic 
when we consider that a disease is a biologic aberration — abnormal alterations 
in a cell, a molecule, an organ or an entire physiologic system. A disease , 
therefore, can be understood in scientific and objective terms. But, the 
changes in biologic processes that create the disease, cancer, are not fully 
understood. Thus, it is mandatory that the momentum continue in the 
international quest for scientific discoveries related to the origin of 
cancer. Eventually, early detection will be possible, more efficient 
controls and/or cures will be instituted and, ultimately, prevention may 
be possible as occurred in some of the pestilences of mankind of the past. 



49 



NATIONAL CANCER INSTITUTE 

ANNUAL REPORT 

July 1, 1976 to September 30, 1977 

RESEARCH CONTRACTS BRANCH 

General 

Research contracting in FY 1977 is projected to be about 11% higher in total 
dollars than in FY 1976. This confirms a steady increase in dollars each FY, 
beginning with FY 1971. 

The number of contracts also increased at a steady rate beginning with 
FY 1971 through FY 1975, but in FY 1976 the actual number of contracts de- 
clined from FY 1975 by approximately 6%. 



Management of Workload and Manpower 

An analysis of the detailed workload data for NCI shows that four of the five 
Divisions experienced a small increase in dollar volume. Some minor shifting 
of manpower resources was carried out in order to adjust to changing workload 
volumes. The ability of RCB to handle the substantial increase in workload 
since' 1973 with only a token increase in personnel, is attributable to the 
use of multi year contracts utilizing incremental funding and the heavy use 
of overtime. 



Frederick Cancer Research Center 

The Frederick Cancer Research Center (FCRC), located in Frederick, Md . , is 
the only Government-owned-Contractor-operated (GOCO) facility that exists 
within DHEW. The basic contract to operate the Center, initially awarded in 
June 1972, is a cost-plus-award-fee/ fixed fee contract and is one of the lar- 
gest ever awarded by DHEW. Its growth pattern has been constant since its 
inception in 1972, but has stabilized at an annual operational ceiling of 
$25,000,000 beginning with the 1976-1977 contract period. This does not in- 
clude an anticipated $3 million in A&E and construction. Neither does it 
include an Interagency Agreement at an estimated $3 million with the U. S. 
Army landlord for basic support services to FCRC such as electric, heat, 
steam, communication systems, maintenance of roads and ground, etc. 
grounds, etc. 

FCRC continues to serve a dual purpose. That of a resource to NCI, as well 
as a center of cancer research excellence. Primary emphasis of late has been 
on the research oriented aspects. 

During the early part of calendar year 1977, the Director, NIH, in collabora- 
tion with the Directors of NCI, NIAID, NIGMS and other NIH entities, selected 



51 



a three building complex at FCRC as the site for a single national high con- 
tainment (P-4) facility for the conduct of recombinant DNA research. 

Plans are being developed for the alteration, renovation and occupancy of 
this laboratory complex. This new facility should be completed within the 
next two years. In the interim another FCRC building has been modified and 
upgraded to provide a small P-4 containment capability for preliminary risk 
assessment studies. 

The FCRC contract has been recompeted for a five year period beginning 
September 25, 1977. Offerors were required to compete for the management of 
FCRC, and were invited to submit alternative plans to the current research 
program. A vigorous and concerted attempt was made to obtain competitive 
proposals for this new five year venture. At the onset, some 33 organizations 
expressed an interest in this procurement, with 10 firms attending the pre- 
proposal conference and facilities tour. However, only one proposal from the 
incumbent contractor was received. Negotiations are progressing and are 
targeted for completion in late August 1977. 

The total population of FCRC stands at approximately 850 contractor personnel 
and 60 NCI/NIH employees. An estimated 8% of the total current available 
building space has been, or is being, renovated. 



Small Business 

The total amount of National Cancer Institute Small Business contracts in 
FY 1976 was $24,410,061, representing 122 contracts in being (exclusive of 
8(a) contracts). The level for FY 1977 is projected at $25,630,000. This 
reflects wide activity in small business contracting, with the largest 
amounts in contracting for the services of small business companies with 
capabilities in the breeding of animals for experimental purposes. Other 
contracts were in the fields of conference support and biomedical research 
resources, i.e., production of tissue cultures. 

PHS and NIH are now cooperating in a program to expand small business opportu- 
nities at the subcontracting level, on a trial basis, on a negotiated target 
amount concept, and NCI shall follow with interest the results of this study 
to gauge its applicability to its operations. 

EEO Contract Compliance and the Small Business 8(a) Program 

The NCI EEO Contract Compliance Program registered several notable successes 
during FY 1977. The PHS adopted a service wide civil rights program based on 
the NCI prototype. The results of the second annual survey of NCI contractors 
subject to the provision of E.O. 11246 was quite successful. The resulting 
data included the names of several contractors who appear to not be meeting 
the spirit and intent of E.O. 11246. This information was then systematically 
forwarded to the HEW/ OCR regional offices on a quarterly basis. 



52 



The Contract Compliance Office also assisted several compliance agencies in 
dealing with recalcitrant contractors who happen to have contracts with NCI/ 

Under the 8(a) program in FY 1976, five contracts were awarded in the total 
amount of $792,730. So far in FY 1977 the RGB has awarded four 8(a) contracts 
for an amount of $473,203. It is anticipated that two more awards will be 
made before October 1, 1977. The amount of these awards is expected to be 
slightly over $100,000. 

In an effort to increase the role of minority owned institutions in NCI con- 
tracting, the RCB will shortly begin observing its large prime contractors' 
subcontract arrangements with minority owned firms. By this action, it is 
hoped that our large prime contractors will undertake a more active and pro- 
ductive position in this heretofore rather neglected area. 



Contracts Management System 

The usage of the CMS has continued to increase and we continue to try to im- 
prove the system for accuracy and response time. We will continue to 
determine cost effectiveness and try to improve efficiency to make better use 
of our resources. 



53 



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55 



ANNUAL REPORT 
OFFICE OF THE ASSOCIATE DIRECTOR FOR PROGRAM PLANNING AND ANALYSIS (OADPPA) 
NATIONAL CANCER INSTITUTE 
JULY 1, iy76 - SEPTEMBER 3U, 1977 

OFFICE OF THE ASSOCIATE DIRECTOR 

The OADPPA provides leadership, consultation and direct participation in 
program analysis, program planning, and management information systems. 
Organizationally, it is located in the Office of the Director, NCI, to enable 
it to more effectively provide its services to all operating units of the 
NCI and, at the discretion of the Director, to non-Federal organizations 
participating in the National Cancer Program (NCP). Operationally, it 
carries out its responsibilities in close collaboration with NCI operating 
units, and other offices in the Office of the Director. 

The Office consists of two branches: The Program Analysis and Formulation 
Branch (PAFB) and the Systems Planning Branch (SPB) which includes the MIS 
project office. The PAFB is staffed with M.D.'s and Ph.D.'s with broad 
laboratory and clinical research experiences in the major disciplines 
involved in cancer research. The SPB is staffed with professionals with 
extensive experience in general management, planning, operations research, 
systems analysis, and management and technical information systems. Although 
primary and continuing assignments are made to each branch based on 
expertise required, the Office typically operates on a project matrix 
system whereby members of both branches are assigned to specific projects 
to provide the mix of scientific and managerial talents required by much 
of the work performed by the Office. Thus, this annual report describes 
activities and acconplishments in terms of the three major areas of per- 
formance (Planning, Analysis and Formulation, Management Information 
Systems) rather than an accounting by branches. 

ANALYSIS AND FORMULATION 

This Office is engaged in a variety of analytic and formulation activities, 
both scientific and managerial. Position papers, guidelines, and procedures 
are developed for the review and analysis of current programs and the 
inplementation of new programs. Analytic services are provided in response 
to the specified needs of different NCI operating units, and response is made 
to relating to the scientific content of the NCP from both internal and 
external sources. 

I. NATIONAL CANCER PROGRAM SCIENTIFIC ANALYSIS 

During the past year, the principal scientific analysis activity has been 
concerned with a detailed individual analysis of over 5000 research projects 
(contracts and grants) supported by the NCI and their relation to the 
recommendations of the National Cancer Program Plan. 



57 



A. Under contract, the TRW Systems Group has conpleted a computerized 
data base of scientific information concerning the NCP research 
recommendations and FY '75 NCI-supported research grants and 
contracts. Conputer programs have been developed to interrogate 
these data bases to allow analysis of the science content of 
projects and their association with research recommendations of 
the NCPP. 

B. Analysis of FY '75 grant-and contract-supported research activities 
has been completed. A report has been prepared which provides 
detailed information with respect to the distribution of activities 
among the various areas of cancer research and the extent of coverage 
of the National Cancer Program Plan by these projects. 

C. Similar analysis of FY '77 grant-and contract-supported research is 
in progress. 

D. Reports of data on specialized areas of research, e.g., virology, 
immunology, diagnosis, treatment, gastrointestinal cancer, bladder 
cancer are available upon request. 

II. SCIENTIFIC AND MANAGERIAL FORMULATION ACTIVITIES 

A. Correlations were prepared of the scientific recommendations for 
the NCP made by the participants in the first planning sessions 
held at Air lie House, Va. , and the recommendations made at the 
updating conferences held at Tyson's Corner, Va. , in terms of 
the seven objectives of the National Cancer Program Plan (NCPP). 

B. Acting on recommendations of the NCI Executive Committee to improve 
program coordination, the OPPA coordinated a cooperative effort 
with representatives from the Office of the Director and operational 
Divisions to define a set of major NCI programs and develop a 
catalogue describing major efforts contributing to the programs 

and associated staff participants and resources committed to 
activities within the program. During a series of working meetings 
with all participants, lU major programsd were defined and activities 
in each division which contribute directly or indirectly to the goals 
and content of these programs were identified. A catalogue of these 
programs and activities is being developed. The catalogue will serve 
as a program directory and will identify program objectives, resources, 
responsible individuals, and participating activities and organizations. 
It will be kept current through an annual update process. 

C. Work was undertaken to prepare a summary of the scientific recommen - 
dations in the NCPP in the form of abstracts of individual project 
and recommendations related to the seven NCP objectives and to the 
ten NCI Research Programs. A draft report has been reviewed and 

the final summary report is in preparation. 



58 



D. Vv'ork was initiated to prepare an updated National Cancer Program 
Strategic Plan using as input the recomiriendations from the Tyson's 
Corner planning meeting and reflectory changes in the NCP research 
strategy suggested by these recommendations. 

E. A series of conferences to update the NCP scientific recommendations 
was held in ly73. The results of these conferences have been 
documented and work undertaken to assess the inpact of these 
revised recommendations on program content and future plans. 

Work has also been initiated to develop a continuing process for 
reviewing the currency of the scientific recommendations, for 
obtaining revisions and for reviewing the relevance of the NCI 
program to the recommended activities that are feasible in the 
light of today's science. The review concept consists of a series 
of small review meetings structured to be consistent with program 
content. Threee to four meetings on different subjects will be 
held each year allowing for a complete review cycle approximately 
every three years. The revised recommendations will be incorporated 
in the scientific analysis system and reflected in program plans 
and planning reports. 

III. DOCUMENTATION OF FUNDAMENTAL CONTRIBUTIONS OF CATEGORICAL RESEARC H 

Under contract, Dr. Judith Swazey, Boston University, is engaged in a 
survey of contributions of categorical biomedical research to basic 
science knowledge. A first draft of this work, to appear in book form, 
has been coirpleted and reviewed by outside experts in the various 
fields covered. It is anticipated that this work will be conpleted 
by the end of ly77. 

PLANNING 

Since its creation in 1^65, the OADPPA has been primarily responsible for 
the development and application of systems planning techniques to cancer 
research and more recently to cancer control activities; providing direct 
support for National Cancer Program planning, department level planning, 
and individual program planning. The Office also provides general plan- 
ning consultation services to various program areas within the National 
Cancer Institute and other institutions and groups participating in the 
National Cancer Program. In carrying out these responsibilities, staff 
participates as members of planning teams organized to develop individual 
program plans; works directly with program and administrative personnel 
in the development of operational plans; maintains liaison with program 
personnel; provides periodic consultation and direct efforts, as requested 
by program leaders, to revise and update both program and operating plans; 
provides education and training to program staff in the use of systems 
techniques; works closely with the financial management staff during the 
budget preparation cycle to correlate budget preparation with existing plans. 

Specific planning activities engaged in during the past year are 
described in the paragraphs that follow: 



59 



I. NATIONAL CANCER PROGRAM PLANNING EFFORT 

A. Coordinated the preparation of the annual five-year National 
Cancer Plan for the five-year period FY '78 through FY '82 
for sutmission to the President as required by law. 

B. Developed a conputerized tool to projec*-. and display in a 
variety of formats NCI funding levels according to program, 
organization, and traditional budget categories. This 
capability is utilized to arrive at the five-year projections 
for NCI Annual Plans. 

C. Developed the Strategic Planning Data Base, a computerized system 
available via terminals on the NIH Computer System for direct 
access to the informational content of the current National Cancer 
Program Plan scientific recommendations made by representatives 

of the biomedical scientific community at the 1^73 National Cancer 
Program Planning Conferences .(NCPPC Reports). The Strategic Plan 
Data Base provides the capability to retrieve information on the 
scientific content of the NCP recommendations (Tyson's Corner) 
including an audit trail to earlier NCP recommendations (Airlie 
House). Technical Indices to the NCPPC Reports have been prepared. 

D. Staff was also heavily engaged in the development and implementation 
of a program structure, development of the program catalogue, 

the abstracts of scientific recommendations and strategic 
planning efforts. 

II. SUPPORT OF DEPARTMENT LEVEL PLANNING 

As the focal point for the preparation of NCI material required for 
Department level planning, the Office coordinated the NCI/DHEW 
Forward Planning activities and the NCI Evaluation Planning effort: 
during FY '76 the NIH Evaluation Plan; and the processes for preparing 
them annually. A series of planning meetings with NIH and BID planning 
representatives were held during the year. Staff participated with 
the Associate Director in these efforts leading to an inprovea NIH 
program review process. 

III. SUPPORT TO THE OFFICE OF THE DIRECTOR, NCI 

A. Recommendations on topics and issues for review with the new 
NCI Director were prepared, and a briefing book on NCI and OD 
operations was prepared for his use. The briefing book contained 
organizational and operational information relevant to the 
responsibilities of the Director and his staff in NCI operations. 

B. Staff has worked closely with the NCI Financial Management 
Office throughout the year participating in the preparation 

of budget guidance documents, assisting with the implementation 
of program structure in the budget process, with the development 



60 



of narratives for budget documents, congressional hearings 
testimony, and responses to inquiries related to program 
expenditures and priorities. Assistance has also been pro- 
vided in adapting the automated fiscal projection model, 
used in developing five-year projections, to aid in budget 
formulation. 

C. Staff has also provided assistance to the Office of Cancer 
Communications and the Office of International Affairs 

in developing strategies and plans for information services and 
in planning specific projects. 

D. OADPPA recently assumed responsibility as Project Office for 
a contract with the American Association of Cancer Institutes 
(AACI) to develop cooperative action and common practice among 
cancer institutes. This includes working with Project Officer 
Representatives throughout NCI and their AACI counterparts on 
five individual tasks under this contract. 

IV. RESEARCH AND CANCER CONTROL PROGRAM PLANNING 

In the preparation of specific research and control program plans, 
the office provided planning assistance and support to the following 
individual programs in NCI: 

A. Breast Cancer Program - Division of Cancer Biology and Diagnosis 

The Office provides support to the Breast Cancer Task Force on 
an as needed basis. A staff member serves on the task force 
steering committee and participates in program reviews and 
project relevance reviews. 

B. National Prostatic Cancer Project 

For the Prostate Cancer Project, assistance is provided to the 
project office as Roswell Park Memorial Hospital in preparing 
updated program planning charts for use in program relevance 
review and progress monitoring. 

C. National Bladder Cancer Project 

The Bladder Cancer Project is currently engaged in a major program 
progress review after four years of operation. A review of the 
current state of disease management and relevant research in bladder 
cancer has been conpleted and development of a plan for continued 
activities of the Bladder Cancer Project is in progress. The Office 
is providing analytic assistance in developing a description of the 
natural history of the disease to determine risk factors, alternative 
intervention opportunities and relevance criteria and priorities. 
The staff is also providing planning assistance in developing a plan 
for future bladder project activities. 



61 



D. Cancer Centers Program 

Staff participated in the Intra-Institute Conmittee of Centers 
to review the Centers program and clarify issues related to 
future plans for Centers development. The staff also 
participated in the development of the concept for the Cancer 
Centers "profile" analysis. This effort involves collecting 
information on organization, staff, funding patterns, administra- 
tive patterns and the content of scientific programs and demographic 
data from more than 60 individual Centers. When conpleted, these 
profiles will provide valuable data regarding the resources and 
capabilities of individual centers and, collectively, the resources 
and capabilities of the Cancer Centers Program as a national resource. 

E. Division of Cancer Control and Rehabilitation 

Provided assistance to the Division of Cancer Control and Rehabili- 
tation, Community-Based Cancer Control Program in developing planning 
and evaluation concepts and approaches. 

Provided assistance to DCCR in the further development and formula- 
tion of the Cancer Control Objectives and Approaches of the National 
Cancer Plan - based on reccsnmendations obtained at various planning 
conferences during FY '75/76. 

Staff has also provided assistance in the planning and conduct 
of evaluation projects for the Cancer Control Program. One 
staff member was assigned full time to the Division to assist with 
the Division and to establish procedures and criteria for project 
evaluation. During the year an extensive evaluation of the Nursing 
Oncology Training Project was conducted and assistance was provided 
during the evaluation and with the preparation of the Evaluation 
report. Staff has also provided assistance to the Study of 
the Cost of Cancer Control with one member serving as assistant 
project officer on the study contract. 

F. Cancer Treatment Program 

During the past year the Office provided planning and analysis 
support to the Division of Cancer Treatment. This included 
assistance with the preparation of a "Working Document for Cancer 
Treatment" descriptive of the cancer treatment program and planning 
assistance on the Drug Development program. In addition, staff 
provided planning and analysis support to the Division of Cancer 
Treatment on an as needed basis. 

Assistance was also provided to the Ccsnmittee for Radiation Oncology 
Studies (CROS) in the development and preparation of the "Research 
Plan for Radiation Oncology" published as a supplement in Cance r in 
April lb»76. 



62 



Management Information System (MIS) 

The National Cancer Institute's MIS is designed to meet the needs 
of the Office of the Director, NCI, for summary, exception, and trend 
reporting, and the more specific information requirements of the 
operating divisions. The work is performed by the MIS Project Office 
OPPA, in conjunction with the NCI operating divisions. The NCP/MIS 
Catalog of Services, issued in 1975, is presently being updated. 

The development of improved methods for providing information involves: 
maximizing utilization of existing NIH and NCI systems; synthesizing 
information on program, funding and administration to provide an overview 
of NCI activities; and building individual systems that provide immediate 
products and services to NCI staff at all levels as modular units of an 
evolving MIS. 

The coitponents developed to date support the Financial Management Branch, 
Research Contracts Branch, and some of the Divisions via the Divisional 
Information Systems (DIS). The DIS in the Division of Cancer Cause and 
Prevention has been modified to reflect orgasnizational changes with spe- 
cial emphasis being given to the area of Environmental Carcinogenesis 
both in terms of administrative management and in terms of integrating 
program data on compounds under bioassay. 

During the past year, the primary focus of activity has been on support 
of financial and administrative areas; this will continue for at least 
an additional year. Major advances have been made in linking the NCI 
financial system with those of NIK. It is anticipated that this utilization 
of central systems will be most fruitful during the coming year in providing 
detailed budget-oriented reports to the operating divisions and summary 
budget reports to the Office of the Director's staff. 

Staff has continued to work closely with other components of the NIH, and 
coordination with NINCDS has been especially beneficial. Staff is 
assisted by two contractors (TRW Systems Group and METREK Division 
of MITRE). Significant acconplishments of both are reported in the 
contract narrative. 

During the past year, staff devoted considerable time to support of 
various OD Branches and to several divisions. While the specifics 
are too numerous for inclusion here, several significant exanples 
are cited: 

o For the Office of Cancer Communications (OCC), the Project Office 
thoroughly evaluated the OCC Document Reference System. 

o For the Personnel Management Branch, the Project Office, extensively 
evaluated the NCI Personnel Data Subsystem, made a number of inprove- 
ments to the software, markedly reduced the coiiputer costs and 
siirplified production procedures. The Project Office provides full 
technical support for this system. 



63 



o For the Research Contracts Branch, the Project Office reviewed CMS 
documentation, performed a data quality analysis, and recommended 
remedial documentation action. 

o For DCCP, the MIS Project Office provided staff to assist the 
Carcinogenesis Test Program in expediting processing of the 
bioassay data for DCCP test reports. The Bioassay Data System 
has been scrutinized in detail, and modifications recommended to 
iirprove the accuracy and consistency of the data base. 

For all MIS subsystems, the Office assists in maintaining the proper 
interfaces between all subsystems and between MIS subsystems and 
those outside NCI, especially DFM. Much of this activity is facilitated 
through use of the Configuration Management Procedures. Directly 
related to this is the continuing effort to make all capabilities avail- 
able to all potential users which both helps to maintain system compati- 
bility and reduce duplicate efforts. 

PRESENTATICMS AND PUBLICATIONS 

A. The Office has participated in or provided presentations on the 
activities sponsored by this office to a number of groups within 
the NIH during the past year, notably a presentation to the NIH 
Administrative Office on Resources Projections. 

B. The Associate Director chaired a workshop on Research Planning as 
part of a Conference on the Management of Federal Research and 
Development sponsored by the Mitre Corporation and the American 
University in collaboration with the National Institute of Mental 
Health. 

C. 1976 National Cancer Program Annual Plan for FY 1978-82. 

D. Latner, A. E.: Cantarow and Truirper's Clinical Biochemistry , Ed. 7, 
W. B. Saunders Co., 1976. 



64 



CCttilTRACT NARRATIVE 

OFFICE OF THE ASSOCIATE DIRECTOR FOR 

PROGRAM PLANNING AND ANALYSIS, NCI 

FY 1977 



CONTRACTOR ; JRB Associates (Contract #NIH-N01-CO-55426) 

TITLE: Planning and Support Services for the National Cancer Program 

CONTRACTOR'S PROJECT DIRECTOR ; Mr. Frank Wells 

PROJECT OFFICER ; Mrs. Jacqueline B. Parkman 

OBJECTIVE ; Provide the support services necessary to assist NCI in meeting 
the expanded responsibilities established by the National Cancer Act of 1971. 

MAJOR ACCOMPLISHEMENTS ; Provides planning support services for national and 
individual program planning activities. 

Assist in the preparation of briefing and presentation materials. 

Assisted in the preparation of draft documents required to develop the National 
Cancer Program Plan. 

Provided administrative and logistical support for planning conferences and 
meetings. 

SIGN I FICANCE TO THE NATICasiAL CANCER PROGRAM ; The expanded scope and responsi- 
bilities of the National Cancer Program has inposed additional requirements 
for reporting, planning and analyzing alternative courses of action. This 
contract provides assistance in areas which could not be done in NCI. 

PROPOSED COURSE ; This contract expires July 31, 1977. The effort has been 
recompeted and will be continued under a newly negotiated contract. 

DATE CONTRACT INITIATED ; July 17, 1974. 

CURRENT CONTRACT LEVEL; $2,4U0,UUU 



65 



COOTRACT NARRATIVE 

OFFICE OF THE ASSOCIATE DIRECTOR FOR 

PROGRAM PLANNING AND ANALYSIS, NCI 

FY 1977 



CONTRACTOR ; JRB Associates (Contract #NIH-N01-CO-45425) 

TITLE ; Resources Analysis and Planning to Support NCI Annual Planning 
and Budget Formulation. 

CONTRACTOR'S PROJECT DIRECTOR ; Mr. Richard Danzeisen 

PROJECT OFFICER ; Mr. Michael G. Brown 

OBJECTIVE ; Develop and apply resources analysis and planning methodologies 
in support of National Cancer Program (NOP) planning and management. 

MAJOR ACCOMPLISHMENTS ; Update and continue development of a NCP resources 
data base and planning estimating relationships. 

Further development of a fiscal projection crosswalk model and application in 
support of the 1977-81 NCP Annual Plan. 

Further development and adaptation of fiscal projection model to aid in 
formulation of the NCI Budget. 

Application of the fiscal projection model and related resources analyses 
in support of individual program planning activities. 

SIGNIFICANCE TO THE NATIONAL CANCER PROGRAM ; The expanded scope and 
responsibilities of the NCP have imposed a need for a sound analytical 
basis for planning and decision-making. This contract is directed toward 
the development of the necessary analytical methodologies and techniques. 

PROPOSED COURSE ; This effort will be continued into FY 197a. 

DATE CONTRACT INITIATED ; July 1, 1974 ^.^--^^'^ 

CURRENT CONTRACT LEVEL; :?3UU,0UU 



66 



COSITRACT NARRATIVE 

OFFICE OF THE ASSOCIATE DIRECTOR FOR 

PROGRAM PLANNING AND ANALYSIS, NCI 

FY 1977 



CONTRACTOR ; Boston University Medical Center (Contract #NIH-N01-CO-55315) 

TITLE ; A Study of the Contributions of Categorical Research to Basic Science 
Research and Knowledge 

CONTRACTOR'S PROJECT DIRECTOR : Dr. Judith Swazey 

PMXTECT OFFICER ; Dr. Abraham Cantarow 

MAJOR ACCOMPLISHMENTS ; First drafts of several chapters of the projected 
work have been conpleted and reviewed by outside consultants, with suggestions 
for changes, which will be made. First drafts of remaining sections are 
under way and the prospects seem good for production of a satisfactory document 
under the terms of the present contract. 

SIGNIFICANCE TO THE NATIONAL CANCER PROGRAM ; It is anticipated that this 
document will provide information to counter certain statements made in 
opposition to the concentration of effort on the control of a particular 
disease, cancer. It is claimed that this is at the expense of support of 
basic research, upon which progress toward control of disease must ultimately 
depend. 

PROPOSED COURSE ; Continue work on present basis. 

DATE CONTRACT INITIATED ; June 30, 1975. 

CURRENT CONTRACT LEVEL; $4,5UU.U0. Extension to 12/31/77 



67 



CONTRACT NARRATIVE 

OFFICE OF THE ASSOCIATE DIRECTOR FOR 

PROGRAM PLANNING AND ANALYSIS, NCI 

FY 1977 



CONTRACTOR : TRW Systems Group, Inc. (Contract #NIH-N01-CO-55318) 

TITLE: National Cancer Prograin Analysis System 

CONTRACTOR'S PROJECT DIRECTOR : Mr. Don Moen 

PROJECT OFFICER : Dr. Abraham Cantarow 

OBJECTIVE ; To design and develop a methodology for analysis of the National 
Cancer Program Plan (NCPP) and of the NCI supported bionedical research 
activities. To provide specified reports of the analysis, plus an ad hoc 
query capability. 

MAJOR ACCOMPLISHMENTS : The analytical methodology was translated into a 
computer system. The system was programmed to run on the DCRT installation. 
Frcan information provided by PAFB/OPPA, a data base was created for the 
NCPP and for NCI grants and contracts. 

The system was run to provide the specified reports for the NCI staff, and 
a number of ad hoc queries were processed. 

The system design, program and operation were fully documented. 

SIGNIFICANCE TO THE NATICMAL CANCER PROGRAM : The analytical products will 
provide NCI with an objective measure of the coverage of the NCPP by NCI 
funded activities. The Plan and Program activities can then be brought 
into consonance. Specific questions about the NCPP anbd NCI activities 
can be answered from the data base. 

PROPOSED COURSE : To up-date the information content based on recommended 
changes to the NCPP, and on new contracts and grants. To continue to enhance 
the system's analytical capability. 

DATE CONTRACT INITIATED ; July 1975 

CURRENT CONTRACT LEVEL: ^128, 5U0 



68 



COSITRACT NARRATIVE 

OFFICE OF THE ASSOCIATE DIRECTOR FOR 

PROGRAM PLANNING AND ANALYSIS, NCI 

FY iy77 



CaSTTRACTOR ; METREK Division of the MITRE Corporation (Contract #N01-CO-55421) 

TITLE ; Technical Support of the Systems Planning Branch, PPA/NCI/CD and 
the NCP/MIS 

CCMTRACTOR'S PROJECT DIRECTOR ; Mr. Harry Strong 

PROJECT OFFICER ; Mrs. Barbara Murray 

OBJECTIVE ; To furnish technical information systems support services to 
the Office of the Director, NCI, primarily in the area of an improved 
Business Management System for the NCI. 

MAJOR ACCOMPLISHMENTS ; The contract has contributed to overall management 
of the MIS project by developing plans for independent and objective testing 
and audit of systems. METREK has also provided independent review and 
evaluation of technical products such as documentation and manuals. 

SIGNIFICANCE TO THE NATIONAL CANCER PROGRAM ; The National Cancer Act of 
1971 provides for enhanced information systems throughout the Cancer Research 
Community. This contract provides the needed technical evaluation support. 

PROPOSED COURSE ; This contract will operate at a reduced level of effort 
during year two and expire March 31, 1979. 

DATE CC^fTRACT INITIATED ; April 1, 1977 

CURRENT CONTRACT LEVEL; $160,000 



69 



CasITRACT NARRATIVE 

OFFICE OF THE ASSOCIATE DIRECTOR FOR 

PROGRAM PLANNING AND ANALYSIS, NCI 

FY ly77 



CONTRACTOR ; TRW Systems Group, Inc. (Contract #NOl-CO-55420 ) 

TITLE ; Phase II Development of an NCP/NCI Management Information System 

CONTRACTOR'S PROJECT DIRECTOR ; Mr. Peter West 

PROJECT OFFICER ; Mrs. Barbara R. Murray 

OBJECTIVES ; To provide analysis, design, and programming services to the 
NCP/MIS Project Office. To develop subsystems, including all standard 
documentation, and to provide operational and training support, where 
appropriate, to subsystem users. 

MAJOR ACCOMPLISHMENTS ; TRW expanded the NCP/MIS Programming Standards by 
including a section on COBOL. TRW also modified the Operating Budget Sub- 
system to accommodate a changed fiscal year, developed and inplemented a 
multiyear status reporting subsystem, analyzed 42 months of expenditure 
and personnel data to aid in developing forecasting algorithms, and modi- 
fied the financial data report subsystem. In addition TRW evaluated three 
commercially available data element dictionaries, audited the DCT/CTEP 
Protocol Files, evaluated the report generators supported by IDCRT, and 
documented the NCI Personnel Subsystem. Three subcontractors were partic- 
ipants during the present contract period. For the Division of Cancer 
Treatment (DCT), Sigma Data Computing Corporation modified the Contracts 
Management System (CMS)/DCT Interface to accommodate the new fiscal year 
and expanded several CMS reports to provide a finer breakdown on contract 
awards as requested by the DCT Administrative Office. JRB Associates 
designed and inplemented the Scheduling and Tracking System which provides 
a systematic, automated method for administering and managing contracts. 
They also developed a generalized Query Subsystem for the Divisional 
Information Systems. This subsystem was designed primarily for the 
scientific administrative staff and is user-oriented. Search and retrieval 
are performed on any desired canbination of administrative/scientific 
descriptor. Query response time is typically less than five minutes. The 
University of Pennsylvania directed its support to DCCP to the areas of 
upgrading the Carcinogenesis Bioassay Data System and a review and analysis 
of the NCTR data processing system. 

SIGNIFICANCE TO THE NATIONAL CANCER PROGRAM ; The National Cancer Act of ly71 
provides for improved information systems. This contract gives NCI the 
analysis and programming support required to implement its Management 
Information System. 



70 



PROPOSED COURSE ; This contract will expire June 29, 1978. A project 
plan for a support contract at a lower level is being prepared. 

DATE CONTRACT INITIATED : June 30, 1975. 

CURRENT CONTRACT LEVEL; $1,U94,654. 



71 



Office of Cancer Communications 
Office of the Director 
National Cancer Institute 
Program Activities Report, July 1, 1976^-September 30, 1977 



During the year the Office of Cancer Communications continued to expand its 
activities. The Office consists of the immediate office of the Associate 
Director for Cancer Communications, the Program Liaison Branch, and the 
Educational and Technical Reports Branch. The Associate Director is 
Mr. J. Paul Van Nevel . Mrs. Norma Golumbic is also assigned to this office 
as a senior science editor. 

Mr. Robert G. Schonfeld, Chief of the Public Liaison Branch, resigned during 
the year to assume a position with the National Institute of Mental Health. 
Also resigning from the Branch were special assistants Mr. Roland Wussow 
who went to a position with the University of Colorado, and Mrs. Linda 
Sheaffer, who transferred to the Office of the Director, NIH. Mr. Joseph 
Bangiolo was appointed Acting Chief of the Branch after Mr. Schonfeld's 
departure. 

Chief of the Educational and Technical Reports Branch is Mr, William S, Gray, 
Under this entity are the Research and Program Reports Section and the Public 
Inquiries Section. 

Under the terms of the Intergovernmental Personnel Act, Mr. Robert Denniston 
was obtained on loan from the Mayo Clinic and was assigned to the Educational 
Activities Group. He joins two other IPA persons on staff: Ms. Barbara 
Blumberg Turner, assigned to the Office of the Associate Director, and Ms. 
Joan Hartman, in the Research and Program Reports Section. 

During the winter of 1976-77 thru Spring 1977 five other interns served 
periods of six months with the office. Ms, Laura Riesenberg, of Ohio State 
University was assigned as a writer to the Immediate Office of the Associate 
Director; Ms. Donna Schmadel , of Ohio University and Mr. Dale Chaney, of 
Northwestern University were assigned as writers within the Research and 
Program Reports Section; Ms. Michelle Robertson, of the University of Georgia, 
was assigned to the Program and Liaison Branch; and Ms. Martha Vogel , of 
Texas Tech University served in a health education capacity. 

Three information interns were temporarily assigned to the OCC. Mr. Jerome 
Larkin of the University of Oregon was assigned to the Program Liaison Branch; 
Ms. Janice Radak of Ohio University became editor of the NCP Review for 
Communicators; and Mr. J. David Cogdell, was assigned to work on special 
projects. 



73 



The NCP Review for Communicators is a newsletter published by the interns 
for NCP participants. The first issue was produced by the Winter/Spring 
interns. Three issues went to press during the late spring through summer 
intern program. 

Educational Activities 

The Fourth National Cancer Communications Conference, sponsored jointly by 
the National Cancer Institute and the American Cancer Society was held June 
20th and 21st, 1977, in Chicago. The purpose of the meeting was to encourage 
development and coordination of cancer communications programming, to 
motivate participants to support common communications projects, and to 
exchange inforrnation about successful projects undertaken by a variety of 
organizations. 

In addition to representatives from the two sponsoring organizations, 
communications persons from other cancer-related institutions, such as 
comprehensive and specialized cancer centers, voluntary associations, and 
other health agencies with an interest in cancer communications were asked 
to attend. 

The two-day program included plenary sessions and workshops designed to give 
participants an overview of important developments in cancer science, 
communications research, and specific community programs, with an emphasis 
on practical cancer information and educational activities. 

OCC negotiated support services contracts with Thomas Buffington, Associates 
and Porter, Novelli and Associates, Buffington, a minority small business 
firm, aided us in providing minority audiences with appropriate and useful 
information and education about cancer causes, prevention, detection, 
diagnosis, treatment, rehabilitation and available sources of cancer care 
in the community. Their target included heatlh-related groups with 
minority constituents, non-health related groups serving largely minority 
populations, and minority media. 

Services provided by Porter, Novelli and Associates, Inc. supported: NCI 
exhibits, the bioassay program, graphics, the Fourth National Communications 
Conference, the health professionals smoking survey, site pamphlet pretesting, 
the breast cancer education project, the coping with cancer project, the 
Smoking Digest , Cancer Information Service, (CIS), the intermediaries program, 
the media assessment project, an environmental carcinogenesis presentation, 
and the health message testing service. 

The Office of Cancer Communications and the National High Blood Pressure 
Education Program/NHLBI jointly funded and administered the development 
of a health message testing service. This service was designed to help 
producers and sponsors of health public service announcements for television 
assess message potential at early stages, before resources were committed 
for final production and distribution. Prior to the development of this 

74 



service, no standardized method existed to test messages in a pre-production 
stage. A working group composed of persons from academic, health agency, 
and advertising fields evaluated the needs peculiar to such a system and 
decided that certain criteria were essential and that the system must be 
sensitive enough to assess potential effectiveness of alternate message 
executions on levels of attention, recall, personal relevance, believability, 
and diagnostic indicators of message strengths and weaknesses. After much 
evaluation of both the possibilities of developing a new system or 
implementing based upon an already established commercial system, the latter 
course of action was chosen. The system chosen is operated from a controlled 
central location. Random mailings are sent to recruit respondents to view 
a television "program" and selected commercial spots. Respondents are 
interviewed via a television monitor. This already established system was 
modified to suit our needs and proved to be more financially feasible than 
developing a completely new service. 

HEW evaluation funds were awarded to this project to test a number of health 
messages over the period of one year and receive necessary feedback 
to prove the system before it became more widely used. During the period 
of one year benchmark and normative data have been accumulated and will be 
analyzed in order to establish standards for comparing health messages. 
Efforts will be undertaken to further refine and improve the system for 
health message testing. Efforts will be continued to develop the 
capability for indicating behavioral responses to other forms of health 
messages. Promotion of the system and its value will reach institutions, 
organizations and individuals involved in health communications. Eventually, 
it is hoped that the service will test radio and print media messages in 
addition to those for television. At the end of this one year period, the 
service will be reviewed and recommendations will be made for future 
implementation. 

Within NCI, the Office of Cancer Communications serves as the major source 
of information for the public and a substantial source for health 
professionals. The premise underlying all activities of the OCC ts that 
the Institute can best serve its role in communications by reaching out 
to the public and to health professionals on an individual basis through 
intermediary or "access" groups (including the media). This simply means 
that NCI seldom communicates directly with final target audiences, but, 
rather, supports and motivates intermediaries who themselves directly 
address the public, patients and health professionals. This strategic 
positioning has several advantages. The public, patients, and health 
professionals already know and accept such groups as voluntary health 
organizations, labor unions, church groups, health care institutions, and 
the like. Such groups are more able to reach the public, particularly 
their own constituents, more easily and thoroughly than NCI could, In 
addition, NCI resources will be extended by combination with resources 
of the other NCR participants. Given the uncertainities of long-term 
Federal commitment, it is essential that non-governmental resources 
maintain public and professional visibility. And, finally, this role 
provides the NCR with more of a private sector, public-oriented coloration 
than would direct government involvement. 

75 



Criteria for determination of project areas within this effort included 
cancer prevalence, availability of proven intervention methods, 
accessibility of care and other necessary resources, the level of existing 
programs, salience of the problem, cost beneficial ity of the program, the 
level of public awareness, and public knowledge. 

For each project area selected, background materials relating to the state 
of the science, regulation, public and patient attitudes and behavior, 
and existing educational materials and programs were collected through 
literature searches and interviews with experts in the field, Accumulated 
materials were thoroughly reviewed and summarized into a state-rof-^the'rart 
document which served as a base for determining project areas of emphasis, 
as well as serving as a source for health planners, 

Primary target audiences were chosen according to their cancer risk and 
the probability of affecting that risk through intervention programs, 
Secondary target audiences were chosen according to their influence upon 
the primary target group. 

The remainder of the process for determining each intervention was the 
following. Messages were selected to be conveyed to primary and secondary 
targets; the most appropriate routes and methods for each message were 
also determined. Organizations, institutions or other groups having the 
most direct access to or influence upon these targets were identified 
and approached in order to determine if cooperative efforts would be 
feasible and to discuss possible intervention strategies. Program area 
objectives, audiences, messages, and strategies were reformulated, if 
necessary. Work was then begun with one or more groups who were selected 
on the basis of their target audience access, ability to affect these 
persons, and project commitment. This effort would include a joint effort 
between the intermediary and NCI in the testing of materials and programs, 
conducting the program(s) and evaluating the effects of the intervention 
on both quantitative and qualitative bases. Each experience would then 
be documented, modified, packaged, and then presented to other intermediary 
groups for their implementation. 

Project areas addressed in the 1977 calendar year were smoking prevention 
and cessation, psychosocial aspects of breast cancer, and coping with 
cancer. In support of these and future targeted areas, the following 
were also explored: how to best reach minority audiences through the 
media and through intermediary groups, the level of cancer awareness among 
(non-science) media professionals, current media coverage of cancer, CIS 
national publicity and promotion, methods and value of pretesting program 
materials, promotion of the health message testing service for health 
planners, a catalogue of possible intermediary groups, a survey of public 
and professional attitudes about breast cancer, needs for baseline 
information regarding public/patient cancer awareness, attitudes and 
knowledge (other than breast cancer). 



76 



The objective of the smoking information and education effort was to 
reduce the proportion of Americans who smoked cigarettes by encouraging 
cessation among smokers and motivating those who did not smoke not to 
start. Tactics used to carry out this objective were the following: 
Marketing of the new Health Professionals' Smoking Survey to groups 
including the general public, professional journals and societies; 
producing and marketing The Smoking Digest to health planners, other 
potential users, and the news media, and the production of a brochure 
for promoting the Digest ; supporting smoking program efforts of the 
intermediaries and stimulating new ones with groups such as the American 
Academy of Family Physicians, American Medical Association, American 
Pharmacists Association, American Dentists Association, and American Nurses 
Association. 

The information and education about breast cancer effort had as its objective 
the heightening of public awareness and the understanding of overall 
progress against breast cancer in order to: change attitudes and pre- 
dispositions about the disease and increase detection practices, The 
primary target audience was asymptomatic and undiagnosed adult females age 
18 and over. Secondary audiences included woman at above-average risk of 
developing breast cancer, adult males and teenage females. Intermediaries 
approached included organizations with existing health related goals, 
those with no such goals, and the mass media. Example of unions, and 
professional women'^s groups. Specific tactics for health planners included 
developing and marketing an information digest on the disease for use 
by planners at national, regional and local levels; conducting a 
quantitative survey on public knowledge, attitudes, and practices relative 
to breast cancer, which enabled specific tactics and messages to be developed 
for audience segments; producing a leaflet for the public addressing the 
strategies, developing an audiovisual unit addressing the strategies for 
self-use by intermediaries; and assisting intermediaries in the preparation 
of programs and materials to inform their constituents about breast cancer. 
Media tactics included the development of a media guide on breast cancer 
for use by the printed and broadcast media; utilization of existing NIH 
services to disseminate information on progress about breast cancer to 
the media; and the continuation of encouragement of women's magazine 
to cover this area. 

In order to plan positive and substantive programs for cancer patients 
and families, (coping with cancer) it was necessary to explore the psychology 
of the cancer victim and the mv-ehanisms inherent in dealing with cancer. 
This exploration was divided into three tasks: the first was a bibliography 
of the literature on coping, which was divided into four sections: patient, 
family, health professionals, and general information. The second was a 
state of the art paper based upon the above bibliography and targeting 
specifically on the patient and family. The basic focus of this paper was 
on living with cancer and its purpose was two-fold: to provide background 
and up-to-date information for health professionals and program planners 
and to serve as a starting point for the development of concrete strategies 
and tactics. Recommendations for OCC involvement and discrete tactics, 
target audiences, messages and delivery strategies will evolve from the 
completion of this paper and a review of coping-related materials and 
programs currently available. 

77 



Public and Congressional Inquiries 

OCC's contract with Biospherics, Incorporated, for the production of 
responses to public and Congressional inquiries continued during the year. 

Under Congressional Mandate, the National Cancer Institute is responsible 
for disseminating the latest and best information about cancer cause and 
prevention, detection, diagnosis, treatment, and rehabilitation. As part 
of this effort, the Office of Cancer Communications furnishes prompt, 
accurate, and humane responses to inquiries from the public. This task 
encompasses five major areas of activity: (1) custom letters, which are 
individually prepared responses to inquiries from the public; (2) Congressional 
and controlled letters, which are given special attention to provide 
short turn-around time with the contractor; (3) noncustom inquiries, which 
are answered by publications alone (no letter); (4) publications distributed, 
which includes materials mailed in response to noncustom inquiries as well 
as enclosures with custom. Congressional, and controlled letter responses; 
and (5) WATS line telephone calls to NCI's 24-hour-a-day service. The 
table on the following page provides a month-by-month statistical summary 
of these five areas of activity and shows a steady growth in the public's 
interest in obtaining cancer information. 

The volume of inquiries depends heavily upon media exposure of issues 
related to the cancer problem. Fluctuations in the monthly totals in 
the table bear out this correlation. The volume of custom letters in July 
1976 was high in comparison to that of the several following months, July 
represented the last month during which the impact of a March 1976 Parade 
article ("Does Your Doctor Know How to Treat Cancer?") was significant. 
The volume of inquiries had shot up to over 33,000 in April following the 
March article, declined to 3,500 in May, remained stable at about 1,500 
over each of the next 2 months, then fell to pre-April baseline levels. 
During the next 6 months there were many newspaper and magazine articles 
which prompted inquiries to OCC, but none had the impact of the March 1976 
Parade story, which specifically invited readers to contact OCC. Cancer 
articles appearing in Modern Maturity, Better Homes and Gardens, New York 
Daily News, Ladies' Home Journal , and Family Circle prompted no more than 
100 to 200 inquiries each. A January 1977 "60 Minutes" broadcast on 
irradiation-related thyroid cancer had a stimulating effect on the volume 
of vjritten inquiries for several months. Some 200 inquiries on this issue 
were answered with custom letters in March, and about 3,600 copies of the 
pamphlet Irradiatin-Related Thyroid Cancer were distributed. In April the 
demand for information and literature on this problem continued, the result 
of widespread attention in both the professinal and lay press. Another 
contributor to the increase in custom letters in calendar year 1977 was an 
article in Ms. magazine which appeared at about the time of the "60 Minutes" 
broadcast. The Ms. article concerned hazards associated with DBS exposure 
in utero . DES inquiries accounted for ore than a fourth of the custom letters 
in March and about 200 letters during each of the 2 following months. The 
volume of DES inquiries remains high and will probably continue so over 
the next several months. Articles about DES have appeared in both the 
professional literature and popular publications, following a similar pattern 
as the publicity on irradiation-related thyroid cancer. Other recent topics 



78 



that have attracted considerable public interest have included the fire 
retardant TRIS, saccharin, and the question of risk associated with routine 
mammographic screening for breast cancer. (White it is difficult to predict 
the volume of custom letters, if present patterns of publicity continue, 
it is likely that the monthly volume of mail will remain at about its present 
level through September.) 

The most dramatic area of growth over the last year has been in the 
distribution of publications. The monthly volume of requests for Nationl 
Cancer Institute publications has quadrupled, and the volume of items 
distributed has likewise increased fourfold, As with the custom letters, 
the public demand for publications is stimulated by media publicity. Many 
new publications have become available in the last year, and these materials 
have been publicized in both the lay and professional press. Not only have 
single-copy requests from the general public increased, but the demand for 
Institute publications in bulk by various professional health agencies has 
also grown. Some of the new and more popular NCI publications are 
Chemotherapy and You , Feeding the Sick Child , The Leukemia Child , three 
pamphlets on DES, and three pamphlets on thryoid cancer. Among these new 
publications, demand has been highest for Questions and Answers About PES 
Exposure Before Birth , 35,709 copies of which have been distributed since 
November 1976, and Chemotherapy and You , 33,669 copies of which have been 
sent out. Since July 1976, the "best seller" has been Breast Self Exam 
(52,591 copies), followed by Cancer: What to Know, What to Do About It 
(37,006 copies). 

NCI's national toll-free telephone service, which went into operation on 
April 5, 1976, showed marked growth in the number of calls received during 
its first year of service, and the monthly volume now appears to have 
stabilized at about 700 calls. At the present time, 13 States and the 
District of Columbia are served by the local Cancer Information Service 
units. The NCI number itself is not actively promoted anywhere, and most of 
the calls to it are referred by tape recorded messages given to individuals 
contacting local CIS units after hours. Most of these callers are responding 
to local promotion efforts on television and radio, articles in newspapers 
and periodicals, and other types of publicity. Women callers generally 
outnumber men by 2.5 to 1, and about 90 percent of the inquirers are lay 
people. Most of the calls concern individual patient problems and involve 
questions about diagnosis and detection, chemotherapy and other forms of 
treatment, local agencies involved in cancer, risk factors associated with 
environmental contaminants, referral and consultation, and prognosis. The 
average call lasts 5 or 6 minutes, and about half the calls require followtip 
of some kind--publi cations, a letter, or a return call. Telephone aides 
utilize written material in order to respond to particular questions for 
about 80 percent of the callers. 

In contast to the volume of custom letters, publication orders, and telephone 
inquiries, the volume of Congressional and controlled letters remains stable 
from month to month. Half to two-thirds of the letters are referred to the 
Institute by United States Senators and Representatives, while the remainder 
of the letters are referred from the White House, the Secretary of H.E.W., 
or other Government agencies and individuals. Congressional and controlled 

79 



inquiries typically deal with the more controversial aspects of the cancer 
problem. Topics include the Government's cancer-related efforts in funding 
research and the activities, programs, and scope of the National Cancer 
Program. In nearly every month over the last year at least several letters 
have urged the banning of fluoridation of public water supplies or the 
legalization of Laetrile. Other recurrent topics of inquiry have included 
environmental and industrial carcinogens, financial and medical assistance 
for cancer patients, theories and suggestions for cancer prevention and 
treatment, and the incidence and control of malignant disease, 



80 



Fifteen-month cumulative count of letters, publication requests, publications 
distributed, and telephone inquiries, by calendar month. The figures for 
June, July, August, and September 1977 are projected, 



Congress 



July 1976 
August 
September 
October 
November 
December 
January 1977 
February 
March 
Apri 1 
May 
June 
July 
August 
September 
Total 



Custom 


ional 
Controlled 

44 


Non- 
Custom 

861 


Publications 
Distributed 

39,617 


WATS Line 
Calls 


1,542 


266 


818 


33 


955 


32,783 


293 


761 


25 


1,432 


32,301 


359 


980 


29 


1,834 


39,014 


414 


721 


34 


1,102 


34,903 


435 


934 


34 


1,033 


48,529 


457 


730 


32 


2,701 


70,283 


742 


1,456 


43 


2,173 


102,585 


785 


1,329 


38 


3,078 


78,970 


670 


1,622 


40 


2,298 


145,149 


678 


1,503 


35 


3,495 


166,242 


642 


1,500 


40 


3,000 


150,000 


675 


1,500 


40 


3,000 


150,000 


675 


1,500 


40 


3,000 


150,000 


675 


1,500 


40 


3,000 


150,000 


675 


18,396 


547 


32,962 


1,390,376 


8,441 



81 



News Media 

Occ cooperated with other sponsoring organizations in the operation of news 
rooms at major scientific meetings, including the 8th International Symposium 
on Comparative Leukemia Research, Amsterdam, The Netherlands; the National 
Conference on Cancer Research and Clinical Investigation, St. Louis, Missouri; 
the National Conference on the Lymphomas and Leukemias, New York City; the 
"Breast Cancer: A Report to the Profession, 1976" meeting in Washington, 
D.C.; and the annual meetings of the American Society of Clinical Oncology 
and the American Association for Cancer Research, Denver, Colorado. 

OCC staff also assisted science writers and general journalists in covering 
NCI-sponsored conferences, seminars and workshops, including meetings on the 
role of X-ray mammography in breast cancer screening and meetings of the 
Clearinghouse on Environmental Carcinogens, a "Symposium on Environmental 
Carcinogens" at a national meeting of the American Chemical Society, the third 
annual Conference on Modulation of Host Resistance in the Prevention or 
Treatment of Induced Neoplasia, a program meeting of the NCI National Bladder 
Cancer Project, a symposium on cancer therapy at the Baltimore Cancer Research 
Center, and seminars at the National Institutes of Health given by Sir Richard 
Doll, University of Oxford, Oxford, England, and Dr. Cicely Saunders, St. 
Christopher's Hospice, London, England. Articles from these meetings 
appeared in news magazines for scientists and physicians as well as in 
newspapers and magazines for the public. 

The staff issued 18 news releases, announcements and press summaries, and 
responded to approximately 2,800 inquiries from journalists. Additional 
efforts were made to provide the news media, both print and electronic, 
with information on the continuing evaluation of mammography for breast 
cancer screening, thyroid cancer associated with head and neck irradiation, 
the survey of smoking by health professionals, the Cancer Information 
Service, and publication of Atlas of Cancer Mortality Among U,S. Nonwhites ; 
1950-1969 , Genetics of Human Cancer , and "General Criteria for Assessing 
the Evidence for Carcinogenicity of Chemical Substances." 

News media inquiries continued a high level of interest in potential and 
known causes of cancer, including chemicals tested in the NCI carcinogenesis 
bioassay program, saccharin, cyclamate, Tris, smoking, asbestos, estrogen 
drugs, and substances in drinking water or food. Other frequent topics 
were Laetrile and other unproven methods of cancer therapy, new anticancer 
drugs, cancer prevention by retinoids, possible tests for early detection, 
breast cancer therapy, U.S. county cancer mortality data, cancer centers, 
and research funding and progress. OCC staff assisted scientists and 
administrators of NCI and other institutions in the National Cancer Program 
in providing information for the press. Working relationships were 
strengthened with public information staff at other Federal agencies and 
cancer centers. Articles in national magazines and local newspapers 
covered the whole range of cancer research and programs, from cause and 
prevention through diagnosis, treatment and rehabilitation. 



82 



Program Liaison Branch 

The Program Liaison Branch (PLB) is one of the Office of Cancer Communication's 
focal points for coordination within the framework of the National Cancer 
Program (NCP). The Program Liaison Branch helps NCP groups and organizations 
to obtain general information about NCP programs as well as those sponsored 
by other cancer-concerned agencies. Further, PLB provides a central point 
for coordintion of congressional inquiry. Every year, hundreds of patients, 
families, cancer researchers, health workers and others contact their 
Congressional representatives for information about cancer. During FY 1977, 
PLB handled an estimated 700 written and 1000 telephone inquiries from the 
Congress. 

The liaison activity includes contact with numerous divisional organizations 
of NCI. These contacts have meant providing general program information 
to staffers of the five NCI Divisions as well as collecting information 
useful in communications program of OD. 

During FY 1977, the Program Liaison Branch phased out an effort, called an 
Institutional Liaison Program. This program had been effectively replaced 
by the developing presence of institutional liaison by NCI divisions and 
specifically by the maturing of Cancer Centers to conduct effective new 
relations with NCI. 

Program Liaison Branch activities also include the analysis of cancer-related 
legislation and the preparation of appropriate "Legislative Up-Dates" for 
NCI staff. PLB staff routinely scan legislative materials and highlight 
those of particular value to NCI. 

The Program Liaison Branch has also been responsible for the administration 
of NCI's Communication Internship, and for the administration of NCI's 
Spreakers Bureau--a nationwide service to help NCP groups and the public 
obtain speakers on a range of topics. Over 200 topics are available, 

NCI's "Special Communication" is another service that allows NCP information 
to be rapidly, as well as accurately, disseminated. The "Special 
Communication" can be selectively sent up to 3,800 groups and individuals 
based on the specialized nature of the information or more general 
discussions of new programs or research advances. During 1977, PLB reached 
over 32,700 information users in a directly specific way via the mailing 
of 17 "Special Communications." 

Publications and Audiovisuals 

A total of 20 new publications were produced and approximately 6 million 
copies of all NCI publications were distributed. Four million of these 
were distributed for NCI by Supermarket Communications, Inc., in literature 
distribution racks located in 2,400 supermarkets and discount stores 
throughout the U.S. The Consumer Information Service Distribution Center 
in Peublo, Colorado distributed approximately 200,000 copies of NCI 
publications. The balance were distributed in answer to public inquiries, 
by Cancer Information Services, State health departments, professional 
and voluntary organizations, and with exhibits. 

83 



The NCI prepared an exhibit to be part of the Bicentennial Exposition on 
Science and Technology held at the Kennedy Space Center, Fla., from May 30, 
1976 to Labor Day, 1976. Over 600,000 tourists visited the Exposition. 
Following local showings, the NCI exhibit will become a part of the Kansas 
City Museum. 

Another NCI exhibit was included among the Bicentennial exhibits displayed 
in the lobby of the HEW South Portal building from Jan. 1976 to June 1977. 
More than 75,000 persons visited this exhibit. 

Other NCI exhibits were shown at 17 professional meetings, 

Numerous national and local radio and television programs interviewed NCI 
staff during the year. The topics covered the same broad range reflected 
in inquiries from the written press. 

Slides were produced on the National Cancer Program for use by the NCI 
professional staff. A 30-second public spot announcement was prepared to 
call attention to the availability of publications from NCI and, where 
appropriate, from Cancer Information Services. The 77 TV stations airing 
the spot covered an estimated 24 million households, 

Bookings for the NCI films, "Progress Against Cancer" and "Research to 
Prevent Cancer" continue to increase. There were approximately 20,000 
bookings with an audience of 20 million and 500 TV showings with an 
estimated audience of 10 million. 

Computerized Information System 

OCC has established a Cancer Information Clearinghouse with the purpose of 
developing a timely information link among organizations producing and 
using public and patient educational materials. These materials will be 
collected from government agencies; cancer centers; voluntary and lay 
organizations; educational, labor, and industrial organizations; and 
professional associations. 

The materials acquired will provide a broad spectrum of subject areas 
related to public and patient education, including materials for health 
professionals concerned with educating patients and patient families, 
Among broad categories will be: detection, diagnosis, incidence, prevention, 
rehabilitation, risk factors, screening, treatment, and psychosocial factors, 

The clearinghouse will utilize other data bases and information resources 
(e.g., CANCERLINE, MEDLINE, Clearinghouse for Mental Health Information 
Smithsonian Science Information Exchange, OCC Document Reference System, 
etc.). Since the Clearinghouse will function primarily as an information 
link, it will not act as a warehouse for documents, but will make available 
bibliographic information, and will direct inquirers to the appropriate 
source. 



84 



other Activities 

1) Opening Statement , FY 1978 Appropriations Hearings, February 1977. 

2) Program Descriptions and Program Accomplishments for PHS Act Extension 
Hearings before the Senate Health Subcommittee on Tuesday, February 
22, 1977 and before the House Health Subcommittee on February 23, 1977, 
Acting Assistant Secretary for Health Dr. Dickson testifying. 

National Cancer Program, National Cancer Institute, Accomplishments of 
Benefit to People Since 1971. Revised 1976. 

Cancer Control in the Community . Chapter prepared for Dr. Diane Fink 
for PROGRESS IN CLINICAL CANCER: Vol. VII, Irving M. Ariel, M,D., 
Editor, 1977. March 1977. 

5) Cancer Care Today , published in CONTINUING EDUCATION FOR THE FAMILY 
PHYSICIAN, March 1977, pp. 96-105. 

6) What You Can Do to Protect Yourself Against Cancer , ASSOCIATION OF 
OPERATING ROOM NURSES JOURNAL, April 1977, Vol. 25, No. 5., pp. 909-924, 

7) The First Five Years of the National Cancer Program , for U.S. MEDICINE, 
January 1977. 

Foreword (Guy R. Newell, M.D.), 40th Anniversary Issue, JOURNAL OF 
THE NATIONAL CANCER INSTITUTE, August 1977. 

Statement of Guy R. Newell, M.D. on the National Cancer Program before 
the Intergovernmental Relations and Human Resources Subcommittee of 
the House Committee on Government Operations, June 15, 1977 (L.H. 
Fountain, Chairman). 

10) National Cancer Program, Report of the Director, 1977, Report on the 
progress, activities and accomplishments of the National Cancer Program 
during 1976. 

11) Statement by Guy R. Newell, M.D. on Scientific Evidence on Saccharin 
as a Cause of Human Cancer before the Subcommittee on Environment 
and Health, Committee on Interstate and Foreign Commerce, House of 
Representatives, June 27, 1977 (Paul H. Rogers, Chairman). 

12) Environmental Carcinogenesis and the National Cancer Program. Manuscript 
in preparation for SCIENCE. 

13) Statement of Guy R. Newell, M.D. on Laetrile before the Senate Health 
and Scientific Research Subcommittee of the Committee or Human Resources. 



85 



OCC staff prepared several articles to provide information on selected 
cancer topics to specific audiences. Articles on anticancer drugs for 
pharmacists were published in Pharmacy Times ("What You Should Know About 
Adjuvant Chemotherapy With Anticancer Drugs") and Hospital Formulary 
("Drug Therapy for Solid Tumors"). "Cancer And The Environment: A Look 
at Nationwide Patterns," was published in The Science Teacher for high 
school science teachers. Information for older people on detection and 
treatment of large bowel cancer was provided in "Major Gains in the Fight 
Against Colorectal Cancer," in Modern Maturity magazine. 

Several short articles on cancer research findings of significance for 
practicing physicians were prepared for inclusion in the "From the NIH" 
sections of issues of the Journal of the American Medical Association . 

OCC cooperated with the Division of Cancer Cause and Prevention in I 
disseminating information on findings of tests of individual chemicals for 
cancer-causing activity in animals. Information was distributed to Federal 
regulatory agencies, workers, industry, environmentalists, the press, 
and the general public. 

OCC cooperated with the Division of Cancer Control and Rehabilitation 
in informing health professionals and the general public about detection, 
diagnosis and management of medical problems associated with exposure to 
diethylstilbestrol (DBS) before birth, and with irradiation of the head 
and neck area. Information for physicians on both topics was published 
in a number of national and state medical journals and made widely available 
in booklet form. Information for the public, encouraging prompt examination 
by a physician for anyone suspecting exposure to DES in utero or head and 
neck irradiation, was disseminated through the mass media, units of the 
American Cancer Society, cancer center information services, clinics and 
doctor's offices, education programs of other health organizations, and 
supermarket bulleting boards. 

OCC assisted Chemistry magazine in preparing and publishing a series of 
articles on cancer research, including cancer cell biology, immunology, 
carcinogenesis and drug therapy. Chemistry is a monthly publication of 
the American Chemical Society for high school chemistry students and teachers, 

Speech material was prepared on six occasions for the Vice President, 
members of Congress and the Acting Director, NCI, to be used on the occasions 
of dedications of new cancer centers. 



86 



SAMPLE COPY 



RESEARCH PROJECTS 

OF 




JANUARY 1976 



This booklet contains descriptions of current research projects from several organizational 
units at the Memorial Sloan-Kettering Cancer Center. This type of publication can be prepared 
by any cancer research organization from computer printouts provided as a service of the 
International Cancer Research Data Bank (ICRDB) Program of the National Cencer Institute. 
See the Preface for additional details. 



87 



PREFACE 

One of the major activities of the INTERNATIONAL CANCER RESEARCH DATA BANK (ICRDB) 
PROGRAM is the collection, analysis, and dissemination of descriptions of current 
research projects (including summaries of clinical therapy protocols), from cancer 
research organizations throughout the world. Input from major cancer research centers 
in the U.S. is clearly a very important source of valuable project descriptions. 

To carry out this activity the ICRDB Program, through a special agreement with the 
Smithsonian Science Information Exchange (SSIE), has established a special center, 
the Current Cancer Research Project Analysis Center (CCRESPAC) , which handles all 
processing and disseminating activities of the ongoing research project summaries. 

This publication was prepared by CCRESPAC from a collection of research summaries 
provided by Memorial Sloan-Ketter i ng Cancer Center. It is considered a sample and 
does not represent a complete compilation of all cancer research projects in progress 
at Sloan-Kettering. 

Appendix I indicates the form in Which camera ready copy would be available to any 
institution wishing to prepare a similar publication of their own projects. A pub- 
lication of this type would be useful for in-house distribution in order to keep 
investigators updated on the research projects being performed at their own insti- 
tutions. 

Appendix II shows a printed copy of similar projects which can be prepared through 
the use of a 1 inotron process and specially formatted computer tapes. This method 
provides a higher quality publication. If an institution is interested in this for- 
mat they should request more details by contacting either of the offices listed below. 

Other Products and Services of CCRESPAC 

Any institution (and its staff) which participates in supplying research summaries to 
SSIE directly or through the CCRESPAC activity (some institutions have routinely sup- 
plied input to SSIE for many years) is eligible to receive various products and ser- 
vices of CCRESPAC including: 

- Special Listings which contain their project summaries along with 
those of other investigators working in the field covered by the 
Listing. 

- CANCERGRAMS designed to keep scientists aware of new articled and 
projects in their immediate subject areas. 

- Custom search services from SSIE; requests will be honored by tele- 
phone or letter for the identification of ongoing studies in any 
given area of cancer research. This service is available at the 
present time. 

In addition to the above mentioned printout of all project summaries received from 
the institution, an institutional representative can also request, through CCRESPAC, 
administrative information searches which may include the combination of subject 
matter interest with such other interests as geographic location of various types of 
research, etc. that might be useful for program planning. 

For further information of any of the above products or services contact either of 
the offices 1 isted: 

CCRESPAC ICRDB 



Dr. Donald A. Elliott Dr. John H. Schneider 

Smithsonian Science Information Exchange Room 128 Blair Building 

Room 300, 1730 M Street, N.W. National Cancer Institute 

Washington, D.C. 20036 Bethesda, Maryland 2001/( 

Telephone: (202) 3&]-k2\] Telephone: (301) '♦27-7150 



TABLE OF CONTENTS 



Abstract 
Numbers 



Laboratory of Animal Virology 1-11 

Laboratory of Cellular and Biochemical Genetics 12-18 

Laboratory of Drug Resistance and Cytoregul at ion 19-25 

Laboratory of Experimental Tumor Therapy 26-33 

Laboratory of Immunobiology 3^~^7 

Laboratory of Lipids and Lipid Complexes ^18-52 

Department of Medicine 53-62 

Laboratory of Ul trastructural Research 63-69 

Laboratory of Veterinary Oncology 70-75 

Example of computer generated printout available from CCRESPAC Appendix I 

Example of a linotron composed page Appendix II 



89 



LABORATORY OF ANIMAL VIROLOGY 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

410E.68THST. 

NEW YORK, NEW YORK 10021 



OBJECTIVE: TO idantifr '"il characterize the 
particles coDtaioing reovirus replicase and 
transcriptase. 

kPPROtCH: Both the >iid-trpe Tims and ts 
■utants oC reoTirns aill be used for infection at 30 
degrees and at 37 degrees. He expect that structures 
»jothesiiin9 double-stranded UN* will iccmulate in 
cells infected at 37 degrees with our autant viruses. 
•• will extract the subviral particles fro. various 
cytoplasiic fractions and separate thea into their 
different size classes by sediientation through 
sacrose or glycerol density gradients. He will 
concentrate our efforts to identify structures aaong 
the particles synthesizing double-stranded BNA's which 
contain only the single-stranded BNK templates. By 
varying ionic conditions, pH, or by use of Bild 
detergents, we will attempt to identity whether the 
single-stranded RKS's of these particles arc in any 
way linked to fori an CNA lolecule greater than 2as. 

PBOGBESS: le have analyzed the particles froi 
Infected cells which sedlaent froa 200S to 250S, froi 
2S0S to 309S, and froa UOOS to 600S for their BHA 
content and for active replicase and transcriptase. 
Our results suggest that the presuaed precursor to the 
particle synthesizing double-stranded 8KX is a 
particle which sediients froa about 2005 to 2503. 
These particles do not synthesize in vitro any 
double-stranded SUA, but they do contain in vivo 
synthesized virus-specific RNA. He presuae that these 
are the particles which contain the single-stranded 
Bat teaplates for double-stranded BNA synthesis, and 
that these particles do not have active replicase. 
These particles have a density in cesiua chloride of 
1.34 g/il, which is different froa that of virus or 
viral cores. Particles greater than 250S do synthesize 
double-stranded BHA. In addition, these particles have 
an actiwe transcriptase. They support synthesis of 
single-stranded BNA's using as taaplates the nascent 
double-stranded RKA's, even though all the double- 
stranded BNA synthesis within a particular particle has 
not been coapleted. 



OBJECTIVE: TO identify and characterize the 
Sealiki Forest virus (SFV) RHA replicase (s) , its 
teaplates, and its products. 

APPROACH: Initial steps in purification of the 
sr» enzyae(s) have focused on the use of detergents, 
chelating agents, ul trasonication, and lipase 
treataent, followed by subseguent density gradient 
centrif ugation to separate the treated aaterial froa 
Infected cells into coaponents of different size and 
density. For our proposed worn, we will need a puce 
preparation of cBHA (RNA coaplea^ntar y to viral SNA). 
This will be used as template for the SFV 
BHA-synthesizing er.zyae during its various steps of 
purification, if necessary, as ligand bound to 
Sephatose to achieve purification of te»plate-f ree SFV 
enzyee, and for an analysis of the b> and J" terninil 
nucleotide seguences of the cENA. 

PROGRESS: we find that 75 to 9rj of the SFV 
BHA-synthesizing enzyae with its associated tenplate 
Is found in a large particle fraction obtained froa 
eitracts of infected BHK cells, along with nuclei and 
cytoplasBic debris. The in vitro-synthesized products 
of the SFV enzyae are the replicative foras (ar's) and 
teplicative interaediates (SI'sl, and single-stranded 
BNA's sediaenting at U2S, 265, and 225. Sequential 
treataent of the large particle fraction with li 
sarkosyl and C.05B EOTA removes lysosoaes, the 
contents of the nuclei, and poly ribosoaes, without 
loss of any SFV PNA-synt hesizlng enzyie which remains 
in the large particle fraction. In the 
characterization of SFV cRNA, we have found that 
agarose chrowatography coapletely separates the 
double-stranded BF's or FI's from single-stranded 
viral BNA's. By displacement froa the »F's and El's 
of the strands of the same polarity as viral BNA, we 
have shown that the CBNA strand contains a poly (U) 
seguence. No poly (U) seguence has been detected in 
strands of the same polarity as viral RNA. 

3. C ONTROL or PROTEIN SINTHESIS BT 
TEBPEBATOBE-SENSITIVE HUTANIS OF REOVIROS 
Ikegaai, N. 



proteins iihlch occurs in the infected cells at the 
non-perilssive teaperature, 37 degrees, with 
teaperature-sensitive (ts) mutants of reovlrus. 

APPROACH: The ts mutants of human reovirus type 
3 Isolated in this laboratory are no longer virulent 
to the susceptible animals, as growth of these mutants 
Is restricted at 37 degrees. »e have shown that 
restriction of replication of these mutants lies at 
the level of translation. 

To elucidate any mechanism which controls 
synthesis of viral proteins, we are looking at two 
areas: (1) possible defects in viral messenger RNA 
(bRNA), (2) possible defects in initiation, 
elongation during protein synthesis or release of 
newly synthesized proteins. In the first area, the 
question whether unaethylated viral mRNA's are 
synthesized in cells infected at 37 degrees with 
mutant viruses, so that binding of viral aRNA to 
ribosomes may be defective, will be studied. In the 
second area, studies are being performed in the in 
vitro protein-synthesizing system to identify the 
step(s) during protein synthesis that responds to 
factors present in the postribosomal supernatant, or 
factors extracted by salt from ribosomes such that 
translation of viral mRNA's is controlled by the 
presence or absence of such factors. 

PROGRESS: The results from mixing experiments 
using an in vitro protein-synthesizing system which is 
reconstituted with postribosomal supernatant (5150) 
and the pellet (P-150) obtained froa postmitochondriai 
supernatant froa infected cells, showed that S150 froa 
autant-infected cells at 37 degrees is inhibitory to 
synthesis of viral peptides of both wild type and 
autant during in vitro translation of endogenous viral 
mBSA present in the P-150 fractions, whereas, S150 
from wild-type virus-infected cells is not. 



OBJECTIVE: To characterize influenza viral 
messenger RNA. 

APPROACH: RNA complementary to virion BNA or 
cBNA is expected to be the viral messenger BNA (mBNA) . 
Viral cBSA is being purified froa the cytoplasm of 
infected cells, employing oligo dl-cellulose 
chromatography, which selects cBNA by virtue of its 
poly A segments, and sepharose «B chromatography, 
which separates single-stranded cRNA from 
double-stranded forms. Annealing experiments are 
being carried out to determine the purity of the cRNA 

information in the viral genome. The ability of the 
viral CRNA to direct the synthesis of virus-specific 
proteins in wheat germ cell-free extracts is being 
tested. The viral cRNA will be separated into its 
individual segments by gel electrophoresis, and it 
will be determined which segment codes tor which 
virus-specific protein. Using methionine labeled in 

whether, as with other mBSA's, the 5' terminus of cBNA 
consists of a 7-methyl guanosine "cap" structure. 

PPOGBESS: The purification procedure yields a 
preparation of cBSA free of any detectable virion BNA. 
Annealing experiments indicate that the purified CBNA 
contains at least 8U-90% of the genetic information in 
the viral genome. In wheat germ cell-free extracts, 
the purified cBNA directs the synthesis of four 
proteins which co-migrate during gel electrophoresis 
with the four major nonqlycosylated virus-specific 
proteins. Three of these proteins have been 
identified after specific immunoprecipitation, and one 

methionine-con taining tryptic peptides as the 
corresponding authentic virus-specific protein. 



OBJECTIVE: To determine the site(s) of influenza 
viral BNA transcription and replication in the 
infected cell, with the goal of ascertaining whether 
the host nuclear function (s) regui.-ed for viral 
replication is involved in virus-specific RNA 
synthesis. 

APPROACH: - In one approach, we are taking 
advantage of the fact that influenza viral 
coBplementary PNA (cBNA) contains poly A, and that in 
infected, cord ycepin- treated cells, viral cSNA is 
essentially the only poly A-containiny BHA which 
continues to be synthesized. The cRNA in replicative 
Internediates (El's), the in terx 9d rates involved in 
viral BNA replication and in transcri pti ve 
intermediates (TI's), the intermediates involved in 
viral FNA transcription, might be expected to contain 
poly A. For the cRNA in TI's to contain poly A, it is 
necessary that poly A be added soon after the cRNA is 
synthesized and before it is released from the virion 
RNA (vRNA) teaplate. The site(s| in the cell in which 



90 



BI<E or TI's are found identifies the site(s| of Tiral 
BIO replication or transcription, rcspectiiely. 
toother approach involves the use of hybridization 
techniques to detect the sites of accjaulatior of vRIIA 
•Dd CRNA. Hybridization experiaents using 
radiolabeled vRHk have already identified the 
cytoplasa as the site of cSNA accuaulation. For the 
deteriination of the site of vRNt accuaulation, DHt 
coapleaentary to vRNA (cDNA) has been synthesized in 
vitro using AdV reverse transcriptase as enzyae and 
the end products of DHase digestion of calf thymus D»A 
as priaer. Cells infected by teaperature-sensitive 
(ts) lutants are being analyzed for blocks in viral 
BNt transcription and/or replication using these 
procedures. 

PBOGBESS: Putative TI'S, sedlaenting 22 to 38S, 
have been Identified in the cytoplasa: none »ere 
identified in the nucleus. lith Che cDHA as probe, 
vBRA has been detected in both the nucleus and 

foand to possess defect (s) in viral RBA transcription, 
and Butants in tvo other coapleaentation groups appear 
to possess defect (s) in viral BNA replication. 



6. CHlBlCTEBIZATIQg Of TBE tH2IHBS IHVOLVED I» 
IBPLPtllZA VIRAL BMA TBABSCBIPTIOII AMD BEPLICATIOB 

Itrug, B. n. , Plotch, s. j. 

OBJECTIVE: To characterize the enzyaes involved 
in. the transcription and replication of the influenza 
viral genoae. 

iPPBOACH: Initially, the enzyae activities 
associated with the purified virion are being 
characterized. Three enzyae activities are being 
studied: BNA-dependent BHA synthesis (transcriptase): 
the addition of poly A to the 3* terainus of the nevly 
synthesized RNA: and the addition of a Gppp... "cap" 
to the 5* end of the BHA and subseguent aethylation of 
this terainal G and the base at the 3> end of this 
"cap." Once the activities associated with purified 
virus arc fully characterized, the transcriptase 
coaplci froa the infected cell viU be purified, and 
Its capabilities Bill be compared to those of the 
vlrion-associated transcriptase coaplei. Also, the 
•niy»e(s) synthesizing virion BSA (viral replicasel 
•ill be purified and characterized. 

PBOGRESS: Dinucleoside aonophosphates stiaulate 
the rate of in vitro BHA synthesis catalyzed by the 
virion-associated transcriptase, vith ApG and GpG 
being aost effective. This is consistent with ApG and 
GpG serving as initiators at, or near, the 5* end of 
the nevly synthesized BNA. In the presence of ApG or 
GpG, the B«A synthesized is siailar, or identical, in 
size to that of the virion BNA, and up to 50 percent 
of the BHA chains contain poly A. In contrast, in the 
absence of ApG or GpG, the synthesized BNA is saall 
and contains little poly A. 



OBJECTIVE: To provide strict biocheaical 
parameters for the identification of RNA-dependent DBA 
polymerase froa leukocytes obtained from patients with 
various forms of acute leukemia, and to purify the 
enzyme in those cases where its presence may be 
established. 

APPROACH: Leukocytes are obtained from patients 
»ith acute leukemia by the process of leukophoresis. 
The cells are fractionated a variety of ways, vith the 
cytoplasmic material saved as the most likely fraction 
to contain reverse transcriptase activity, vhich is 
enriched by the use of such procedures as isopycnic 
density ultracentrif ugation. Solubilized fractions are 
chroaatographed on polycytidylat "^-agarose, an affinity 
■atrii vhich >e have shown to be extremely efficient 
tor the purification of oncornaviral reverse 
transcriptases. DNA polymerase activity recovered 
from the affinity column vill be tested for synthetic 
template-primer utilization patterns similar to those 
exhibited by type-C RKA tumor virus DMA polymerases. 
Por the term "reverse transcriptase" to be applied to 
any DHA polymerase thus obtained, it must be shown to 
copy heteropolymeric regions to naturally-occurring 
BHA molecules. 

PROGRESS: Preliminary studies indicate that the 
above approach is useful for the purification of a DNA 
polymerase activity with patterns of synthetic 
template-primer utilization similar Co oncornaviral 
reverse transcriptase. Sufficient enzyae has not yet 
been isolated to permit the testing of natural BNA as 
a teaplate. 



OBJECTIVE: To purify, characterize, and compa 
the biocheaical properties of aouse mammary tumor 
virus (nilTV) and nason-Plizer monkey tumor virus 



(HP-nV) to determine the sleilarities and differences 
between two type-B particle reverse transcriptases. 
To determine whether certain properties of the type-B 
viral polymerases are unigue compared to those of 
type-C oncornaviral reverse transcriptases and 
cellular R-ONA polymerases. 

APPROACH: Purification protocols for the ONA 
polymerases from nnTI and np-nv will be established, 
combining the techniques of ion-exchange 
chromatography and affinity chromatography on 
polycytidylate-agarose, a procedure we have found to 
be effective for the high-yield rapid purification of 
C-type oncornaviral reverse transcriptases. The 
spectrum of synthetic and natural teaplate-prioet 
utilization will be determined for each enzyae, along 
vith the conditions optimal for the copying of each 
template. The synthesis of DNA complementary to 70S 
RNA and mRNA will be especially closely studied, to 
determine whether cellular or viral factors arc 
required for efficient heteropolymeric DNA synthesis. 
Nuclease activities associated with the purified 
polymerases will be assayed for. Biochemical and 
biophysical parameters such as subunit structure and 
antigenic relatedness will also be examined. 

PROGRESS: The nP-nV DHA polymerase has been 
purified to homogeneity and the NNTV polymerase to 
near-homogeneity. Preliminary studies indicate that 
qualitative similarities exist between the two 

teaplate-prlaer utilization may differ. 



OBJECTIVE: To purify Bauscher Leukemia virus to 
hoBoqeneity and to fully characterize the enzyme's 
properties regarding optimal conditions for DNA 
synthesis and the biochemical parameters affecting 
enzyee-template-primer binding. 

APPBOACH: The enzyme will be purified to 
near-hoBogeneity using affinity chromatography on 
polycytidylate-agarose, a procedure which we have 
developed. Purification to complete homogeneity will 
be accomplished through the use of additional 
techniques such as ion-exchange chromatography or 
velocity gradient centrif ugation . Associated nuclease 
activities will be. examined, and polymerase binding to 

catalysis, to determine accual binding conscants and 
those factors affecting such binling, will be examined 
using insolubilized template-primers. If sufficient 
enzyme quantities are available, monospecific antisera 
against the BLV polymerase will be prepared and used 
for the development of a sensitive tadioiaune assay 
for the enzyme. 

PBOGBESS: BLV DHA polymerase has been purified 
to near-homogeneity by affinity chromatography on 
polycytidylate-agarose. T^aplace-specific 
requirements for optiaal rates oE DNA synthesis 
regarding mono- and divalent cations used m the 
reaction have been found. BNase H activity was found 
to be associated with the purified polymerase. A 
preliminary report of these findings has appeared 
(AACB neeting Abstract, 1975), orthopbosphace was 
found to inhibit DNA synthesis by the purified BLV 

this inhibition are under way. 



OBJECTIVE: TO purify and characterize the ONA 
polymerases froa aammalian type-C oncornaviruses and 

toward understanding the possible species-soeci f Ic 
characteristics of the individual enzymes. 

APPROACH: Purification procedures for the 
various DNA polyaerases using affinity chromatography 
on polycytidylace-agarose, a tecnnigue which we have 
found to be excellent for one-step, high-yield 
purification of reverse transcriptase. If necessary, 
additional purification procedures such as 
ion-exchange chromatography will also be used. The 
spectrum of synthetic and natural template- primer 
utilization will be determined for each enzyae, along 
with those conditions which prove optimal for the 
copying of each teaplate. The mechanism of DNA 
synthesis complementary to 70S genomic BNA will be 
especially closely studied, in order to determine 
whether cellular or viral factors, in addition to the 
polymerases, are required for efficient synthesis, in 
order to better understand the m vivo functioning of 
the polymerases. Nuclease activities associaced wich 
the purified polyaerases will also be examined. 

PBOGBESS: The DNA polyaerases from Bauscher 
murine leukemia virus, BBTC virus, Histar rat virus, 
simian sarcoma virus, and feline leukemic virus have 
been purified using affinity cbrooatography , and their 
biochemical properties are being compared. 
Differences in the spectrum of teaplate utilization 



91 



have beeo noted that appear to be dependent upon the 
host specificity of the viruses (autioe vs. priaate o 
leline). Prelialnary studies have also revealed 
differences in the aaount of nuclease activity found 
associated vith the polynerases. 



11. peTgLOPami of a BADioinaonoisstT ro» TBnamiL 

DBOIIBIBQllllCl.gOIIDIL T8AHSPBBASE 
nodak, n. J., narcus, S. 1. 

OBJECTIVE: To prepare antisera aqainst purified 
teralnal deoiynucleotidyl transferase and to use it 
for the developaent of a radioiiaunoassay for the 
quantitation of the enzyne in huaan leukocyte 
fractions. 

APPCOACR: Teriinal deoiynucleotidyl transferase 
is being purified froa calf thymus on a lar^je scale. 
The standard techniques of DEAE cellulose, 
phosphoccliulose, Sephadei a-100 chroaatoqraphic and 
velocity gradient centrif ugation are eaployed for the 
purification of enzyie. For conparlson, »e shall 
purify the enzyie froa huaan thymus (obtained as 
autopsy speciaens) and coapare in detail the 
biochealcal properties and structural relatedness of 
the t»o enzyaes. This enzyie is unique to the thyaus 
9land of all aaiialian species and all eiaained have 
siailar aolecular weights. The enzyie froi various 
species is eipectcd to be quite siailar structurally. 

Antibodies to purified enzyie will be raised 
after lodifying the enzyie protein in order to develop 
the radioiiaunoassays for the detection of the enzyie 
In huian leuKeiic lyjaphocytes. 

PBOGBESS: A preliminary work-up on the isolation 
of teriinal deoiynucleotidyl transferase from calf 
thymus has just begun. Prior to this, the enzyaes 
froi huian ALL cells have been partially purified and 
characterized, using phosphocellulose and glycerol 
gradient centrif ugation to establish conditions for 
the expression of optiaal activity. 



PBOGBESS: A prelialnary analysis of Chinese 
haister plasia aeibranes froi actinoaycin D-sensitive 
DC-JF cells and drug-resistant, nontumotigenic 
derivatives revealed differences in glycopeptides, as 
analyzed by polyacrylaiide SDS gel electrophoresis and 
gel filtration chromatography. In general, lalignant 
cells were found to synthesize glycopeptides of a 
higher molecular weight than do their noniallgnant 



1». DECBEASED BALIGIIAIICI OF DBOG-BESIST«»T CELL 

UBIAMTS 

Peterson, B. H., Biedler, J. L. 

OBJECTIVE: To study the lechanisi of resistance 
to actinoiycin and other cancer chemotherapeutlc 
agents of cells growing in culture. 

APPBOACH; Various biocheaical properties of 

chemotherapeutlc agents are assessed in order to 
elucidate mechanisms of drug resistance. Drug uptake 
assays are performed and transport rates are measured 
with radioactive drugs. Effects of drugs are measured 
on the rates of protein, DKA and BNA synthesis. 
Agents which aid in the potentiation of drug uptake 
are tested. 

PBOGBESS: Further evidence was obtained 
indicating resistance to actinomyicin D in Chinese 
hamster cells is due to reduced permeaoility to drug. 
DC-3F, actinomycin D-sensitive cells, took up 50 times 
more tritiated antibiotic than the highly resistant 
DC-3F/ADS subline. Accumulation of actinoaycin D was 
shown to be temperature-dependent in both cell lines, 
m addition, highly resistant cells which are cross- 
resistant to puroaycin were shown to have reduced 
capacity to take up labeled puroaycin. 

15. CELLDLAB BECHAmSriS OF AHTIFOLATE BESISTAHCE 
Biedler, J. I., Belera, P. w. 



LABORATORY OF CELLULAR AND 
BIOCHEMICAL GENETICS 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

145 BOSTON POST ROAD 

RYE, NEW YORK 10580 



12. DECBEASED BALIGIIAIICT OF DBaC-BESISIAIIT CELL 

TABIABTS 

Biedler, J. t. , Peterson, P. H. , Hachsman, J. T. 

OBJECTIVE: To investigate possible mechani 
account for reduced tumorigenicity of cells with 
acquired resistance to actinomycin D and other c 
chemotherapeutlc agents. 

APPROACH: De 
drug resistant sub 
syngeneic aouse tu 
be continued. Agents used are actinomycin D, 
vincristine, daunoaycin, and ethidium bromide. 
Parameters to be studied include tumorigenici t 
rphology, saturation density, and fibrinolyt 



ment and cha 

of Chinese 
ells grown i 



ell cult 



vld 



drug-r 



ivity. Since w 
that resi 



to these agents and the 
:ogenic potential of the 
nt cells are mediated by the cell 
meibrane, we plan also to deteriine whether there a 
antigenic differences between tuiorigenjc, 
drug-sensitive cells and the less tuiorigenic, 

PROGRESS: Dose-response assays indicate that 
resistance to any one of the four agents is 
accompanied by cross resistance to all of the other 
and that degree of reduced tumorigenicity is genera 
proportional to degree of increased resistance. 
Initial studies have been reported (J. L. Biedler, 
Riehm, R. H. F. Peterson, and D. A. Spengler, J. Na 
Cancer Inst,, in press, 1975). 



13. PECBEAStP BALIGIIHICT OF DBOG-BESISTAIIT CELL 

TABIAHTS 

Peterson, B. »., Biedler, J. L. 



OBJECTIVE: To eiamin 
alterations of drug varian 
accompanying resistance to 
malignant progenitors. 

APPROACH: plasia lea 

Biochemical analysis of aa 
with the cell surface is d 
on the regulation of ptote 
glycollpids in the maligna 



reductase. 

APPBOACH: Betaphase cells are prepared for 
karyotype analysis by trypsin-Giemsa or quinacrine 
hydrochloride staining methods. chromosome banding 
analysis reveals the presence of long, homojeneoasly 
staining regions (HSR) in drug-resistant cells with 
high dihydroEolate reductase activity. Resistant 
sublines maintained in cell culture are also examined 
by radioautography with tritiated thymidine in order 
to determine patterns of DNA replication. other 
staining methods are used and other approaches taken 
in order to elucidate the functional significance of 
the anomalous regions as related to excessive 
production of dihydrof olate reductase, wnich may 
comprise as much as 2» of the total cell protein. 

Bibliographic references: J. L. Biedler, A. n. 
Albrccht and B. A. spengler. Genetics 77:su-s5, 197U 



OBJECTIVE: To characterize various cell surface 
membrane components (protein, glycoprotein, glycolipid 
and glycosphingolipid) for correlation with 
differentiated traits, and to assess their regulation 
during t.ie process of differentiation as compared to 
that of cells of nonneuronal origin. 

APPROACH: Plasma membranes are isolated from 
monolayer cultures of huean neuroblastoma cells grown 

differential cent rif ugdt ion. Biochemical analysis is 
performed in order to correlate regulation of 

differentiation. 

PBOGBESS: Preliminary analysis of glycopeptides 
by SDS pOiyaccylamide gel electrophoresis of two 
adrenergic cell lines showed a remarkable degree of 
similarity. 



17. SELECTIVE PROG BESPOMSE OF BDaA» HEDBOBLASTOIIA 

CELLS 

Biedler, J. L. , Peterson, B. H. , Freedman, L. s. 

OBJECTIVE: To develop and utilize a cell cultur 

that may he specifically effective against" 



neurotransmitter biosynthesis in malignant neuronal 
cells. 

APPBOACH: Three human neuroblastoma lines and 
clones derived from them are being characterized in 
respect to in vitro growth properties (population 
doubling time, saturation density, etc.) and to 



92 



•ctifltj le»_.j ot several 

Beurotransiitter-synthesizinq enzy»es: tyrosine 
hydroiylase, dopaBiDe-Beta-ljydroiylase, and choline 
•cetyltransferase. Dose-iespoose data are obtained in 
a 6-day growth assay based on cell counts ot 
drug-treated and control (no drug) cultures, 
leuroblastoaa cell lines are coipared to each other 
•nd to scleral different huian fibroblast strains of 
Borial tissue origin. Cbeaical agents tested so far 
Include vincristine, 6-brdroxydopaaine, and aethotrezate. 



OBJECTIVE: To dateraine the prevalence and the 
significance of a specific cbroaosoae abboraality. 
tclsoay ot cbroaosoae 15, in leuHeaogenesis in the HB 
aoase strain. 

IPPSOtCH: netaphase cells froa thyaoaas of AKR 
alee are prepared for karyotype analysis with the use 
of trypsin-Gieisa cbroaosoae banding aethods. 
Karyotypes are prepared froa photographic enlargeaents 
of aetapbase cells and arranged according to a 
standardized systea for nus ausculus. other 
bigb-leukea.'a strains such as CSJ/J, carrying aurine 
leukeaia virus of the AKR type, are also being 
eiaained. Atteipts are being aadc to correlate 
cbroaosoae constitution «ith serologically 
deaonstrable thyaocyte antigens, e.g., TL, Thy-1, 
ty-1, and Ly-2, in a collaborative investigation. 

PBOGBESS: In an initial study, 7 out of the 11 
th;aoaas eiaained vere predoainantly trisoaic for 
cbroaosoae IS. 

Bibliographic references: B. A. Spengler, and L, 
J. Old, Proc, »at. Acad. sci. 72:1515-1517, 19751. 



LABORATORY OF DRUG RESISTANCE 
AND CYTOREGULATION 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

410 E.68TH STREET 

NEWYORK. NEW YORK 10021 



19. rOI.ATE-DEPE»DENT IIETABOLISa III TflE lALKEB 
256-CABCIIIOSABCOnA AtD IK THE TISSDE OF H0B8AL AIID 
lOgOB-BEABIilG BATS 
Albrecbt, A. n. , Hutchison, D. J. 

OBJECTIVE: To produce inforaation concerning 
enzyaes ot tetrahydrof olate coenzyae foraaticn and of 
aaino acid biosynthesis in noraal and neoplastic tlssu. 

APPROACH: TKis project is an integral part of a, 
prograa dealing with the enzyae therapy of neoplasia' 
based on the depletion of tetrahydrof olate coenzyaes 
in tuaor cells. of interest are the comparative 
levels of enzyaes indicated above in tissues of 
anlaals fed standard laboratory chow and several 
deficient diets. 



OBJECTIVE: To evaluate bacterial enzyaes ahich 
transtora folates and anti-folates for their activity 
to Inhibit tuaor growth and/or to improve the 
therapeutic index of aethotrexate. 

APPBOACH: The Kalker 256-carcinosarcoaa in the 
cat Is the experiaental tuoor systea for testing the 
anti-neoplastic effectiveness of purified enzyaes. 

The evaluation of anti-folate enzyaes as agents 
In laproving the therapeutic index of antifolates is 
carried out vith the 11210 leukeaia in BDFl aice. 



21. THE STDDI OF TBE tIBOS-CELL BELATIQISBIPS III L1210 

ICLII-ABP L1210 TGL1I-/ACTIII0IITCIH D 

Hutchison, D, J., Calvelli, T., Gallo, J. II., Oehacven, 

OBJECTIVE: To deteraine the biocheaical, 
oltrastructural, and iaaunological characteristics ot 
the viruses released by an L1210 actinoaycin 
D-resistant line and its parent line. 

APPROACH: Virus froa both cell lines is 
harvested by the ceo trif ugation of culture aedia. 
BesQspended concentrate is applied to sucrose density 
gradients, spun at high speed, and virus bands at 1.16 
g/cc to 1,20 q/cc are collected. Proteins are 
analyzed on 5DS-polyacry laaide gels. Proteins are 
analyzed either by staining with Cooaassie Blue, or, 
when radiolabelled with tritiua or C^<* aaino acids, by 
llguld scintillation counting. virus pellets ate 
eiaained by thin section and negative staining 
electron aicroscopy. 

Iaaunological analysis is carried out by 



leaunof laocescence techniques on whole cell 
preparations and by iaaunodif fusion with antibody 
directed against specific, known viral proteins 
(C-type and B-type) . 

Biological characterization of the viruses Is 
carried out by injection of virus concentrate into 
BOrl (C57BL I DBA/2), DBA/2 neonates, and nude aice 

PBOGBESS: Both cell lines exhibit particles o 
Intercisternal-A, intracytoplasaic-A, C-type and 
B-type aorphology. soae of these particles have be 
found to be aore coaaon to the resistant line. 
Purified virus froa both lines has been shown to fu 
i-c cells. The drug-resistant line seeas to have 1 
tuaocigenicity and to exhibit iaaunogenic potential 



Hutchison, D. J., Gallo, J. B. 

OBJECTIVE: To deteraine the cross-resistance and 
collateral sensitivity of two actinoaycin D and two 
1-Beta-D-arabinof uranosylcytosina (ara-C) -resistant 
11210 tissue culture lines to other therapeutic drugs. 

APPBOACH: Actinoaycin D and ara-c-resistant lines 
are treated with varying concentrations of certain 
known active anti-cancer aqents. starting with a known 
inoculua, the cultures are grown (or 6 days, after 
which their ID-50 is deterained. 

PBOGBESS: Cross-resistance to vincristine, 
adrlaaycin and daunoaycin has been observed in one 
actinoaycin D-resistant line. Possible collateral 
sensitivity to 1, 3-Bis (2-chlorethyl) - 1-nitrosourea has 
been observed in an actinoaycin D-resistant line. 

23. OETEBBIBATIOB OF BIOLOGICAL iCTITIIIES OF 

flBImDUE IIOCLEOSIDES 

Hehta, B. B. , Fox, J. J., Hutchison, D. J. 

OBJECTIVE: To provide rapid test of biological 
activity of newly synthesized pyriaidine nucleosides. 

APPROACH: Two streptococcal strains, an 
actlnobolin-resistant Streptococcus faecalis ATCC 
8083, and a strain of streptococcus faeciua var. 
durans resistant to aethotrexate and 6-aercaptopurine, 
were found to be collaterally sensitive to 
1-Beta-D-arabinof uranosylcytosine (ara-C) and a few 
other pyriaidine nucleosides. The sensitivity to the 
other pyriaidine nucleosides corresponded with the 
sensitivities obtained in tissue culture systeas. The 
aicrobiological assay systea will be developed using 

for the testing of the biological activities of the 
newly synthesized pyriaidine nucleosides. 

PROGRESS: The sensitivities of the two 
streptococcal strains to certain pyriaidine 
nucleosides such as ara-C, 2- -f 1 joro-ara-C, 
2'chlorocytidine, 5-azacytidine, etc., corresponded 
with the activities ot these coapounds tested against 
culture systeas. 

2«. DEVELOPIIEBT OF HICBOBIAL ADD CELL COLTOBE ASSAY 
SISTMS FOB THE A1I7ICAIICBB AGBHTS 
Hehta, B. a., HutchisoQ, D. J. 

OBJECTIVE: Develop new aicrobial or cell culture 

cheaotherapeutic agents and also for new agents with 
potential anticancer activities. Also develop assay 
systeas for drugs used in coabinations, including 
those used with antibiotics. 

APPBOACH: Soae of the anticancer agents show 
antiaicrobial activities, and can best be assayed using 
aicrobiological assay techniques siailar to one used 
in antibiotic assays. By developing several resistant 
autants, resistant to drugs used in coabinations, but 
sensitive to one drug, the autants aay be used for the 
deteraination of the drug to which they are sensitive, 
in the presence of the drugs to which they ate 
resistant. 

PBOGBESS: Deteraination of citrovocua factor in 
the presence of relatively high aaounts of 
aethotrexate has been achieved by use of a strain of 
Pediococcus cerevisiae resistant to aethotrexate. 
Slailarly, using a strain of streptococcus faeciua 
var. durans resistant to aethotrexate and 
6-Bcrceptopurine, but highly sensitive to 1-8eta-D- 
atabinofuranosylcytoslne (ara-C), deteraination of 
ara-C can be achieved in the presence of aethotrexate, 
6-aercaptopurine and 6-tbioguanine, the drugs coaaonly 






a-C. 



25. DISTBIBOTIOII OF ABTICABCEB AGEMTS I» TISSOES ABO 
BOOT F LU IDS OF AMIHALS POLLOMIMG PIFFEBEBT BODES OF 
ADHImSTBATIOH ' 

nehta, B. n. , nerker, P. C, Berlinger, H. T. , 
Hutchison, D. J, 



93 



vith potential anticancer activity, using aonkeys and 
cats as aniaal aodels. 

APPFOACH: SaaplQS of blood and cerebrospinal 
fluid (CSP) are obtained following administration o£ 
drugs such as aethotrexate. The drug levels in the 
saaples are then assayed by using licroblological 
assay technigues. 

PROGRESS: (1) In follovlng the kinetics of 
absorption of aethotrexate froa the ventricle-luabar 
space of aonkeys (collaboration vith Dr. P. nerker, 
Arthur D. Little Company, Cambridge, nassachusetts) , 
distribution in the intrathecal space vas siailar to 
that observed in huaans following Oaaaya Reservoir 
adiinistcation. Tvo aonkeys vere studied. Tvo 
different eiperiaents were carried out on each aonkey. 
(2) Following an Intravenous dose of aethotreiate (1 
g/a2) , eguivalent anounts of aethotrexate were found 
in CSF and perllyaph fluids. The serua aethotrexate 
levels followed the conventional distribution route. 
High dose of aethotrexate probably overcoaes the 
blood-csr barrier. A further confirmation to this 
finding is needed. (Dr. N.T. Berlinger) . 



LABORATORY OF EXPERIMENTAL 
TUMOR THERAPY 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

145 BOSTON POST ROAD 

RYE, NEW YORK 10580 



26. COBTROl. or ACQOIReP DBDG BESISIAHCe BI TABIOOS 

TRgATBEIIT SCHEDULES 

Schaid, r. A., Hutchison, D. J., Stock, C. C. , Old, L.J. 

OBJECTIVE: To attempt by leans of various 
treataent schedules: a) to prevent the eaergence of 
drug resistance and b) to revert drug resistance. 

APPROACH: The prevention of emergence of 
resistance is studied in L1210 leukemia and in 
syngeneic solid tumor Ridgway osteogenic sarcoma, by 

generatiqns, and b) in Ridgway osteogenic sarcoaa by 
development of resistance in 1 generation by means of 
treatment-induced tumor regression and regrowth 
cycles. Clinically used antimetabolites and alkylating 
agents are employed both singly and in various 
combination treatment schedules. The treated sublines 
are tested for cross-resistance and collateral 
sensitivity, and the combination-treated lines also 
against each of the individual combination drugs 
itself. In the reversal experiments, resistant 
sublines of 11210 and of Ridgway osteogenic sarcoaa 
will be treated with appropriate drug combinations and 
treatment schedules. 

PfiOGBESS: Development of resistance to a 
combination of 6 antimetabolites in L1210 leukemia 
showed that in simultaneous treataent it took 31 
generations to reach partial resistance, 5 generations 
tn the (1-6) seguentlal and only 3 generations in the 
(6-1) seguentlal schedule. 



27. TESTIBG or ERZIHES FOB IBEIB EPFECTS 0» TOHOB 

GRO»TH ARD CELL BEHBRAHES 

Schaid, F. A., Roberts, J., Old, L. J., Stock, C. C. 

OBJECTIVE: TO determine the toxic and antitumor 
effects of enzymes on transplanted and spontaneous 

APPROACH: A spectrum of leukemias and of 

are used. Standard transplantation and treatment 
technigues are employed. Single enzymes, especially 
amino acid degrading enzymes, are tested. 
Combinations of enzymes with either standard 
chemotherapeutic agents (alkylating agents, 
antimetabolites) iamunostimulators, other enzymes, or 
deficient diets are evaluated. The rate of 
developaent of drug resistance and collateral 
sensitivity is studied in enzyme-sensitive tumors by 
the use of successive treatment generations. The in 
vitro effect of the enzymes on the membranes of tumor 
cells Is studied. 

PROGRESS: Several glutaminases exhibited 
antitumor activity, especially against ascitic tumors. 



OBJECTIVE: To detect new antineoplastic drugs 
and to find improved usefulness of known agents 
through various treatment schedules. 

APPROACH: Sew compounds synthesized within the 
Institute and materials obtained froa outside sources 
are tested against one or more of the following 



tumors: melanoma B16, Ehrllch ascites tumor, 
carcinoma E0771, necca lymphosarcoma, Ridgway 
osteogenic sarcoma. Sarcoma 160, Taper liver tumor, 
sarcoma 12111, Walker rat carcinosarcoma 256, and the 
leukemias L121C, LS178T, and C1»93. Transplantation 
technigues and treatment schedules have been 
described. 



29. ILTEBATIOll OF IHnmOGEBICIII AIID GBOIITH 

CHABACTERISTICS OF TOBOB CELLS 

Schmid, F. A., Stock, C. C, Old, L. J., Hutchison, D, 



OBJECTIVE: To Investigate alkylating and 
alkylating-type agents for their capacity to alter the 
inmunogenlclty and cell kinetics of tumor cells. 

APPROACH: Alkylating and alkylating-type agents 
are investigated for their capacity to alter the 
immunogenicity and growth characteristics of L1210 
leukemia and iamunosensitive Ridgway osteogenic 
sarcoaa. 

The technigues for inducing cell changes are: a) 
In vivo treatment of successive transfer generations; 

b) short in vivo treatment with supralethal doses. 
Inoculation Into untreated mice, and repetition of 
this cycle with stepwise increases of the drug. 

The parameters for detecting and measuring the 
cell changes are: a) increase in survival tine of the 
treated passages: b) range of transplantability; and 

c) collateral sensitivity to other chemotherapeutic 
agents. 

PSOGBESS: Resistant sublines of L1210 and LS178T 
leukemias showed collateral sensitivity to other 
agents and changes in cell kinetics. Also, three 
trlazenes altered growth characteristics of L1210 
leukemia. 



OBJECTIVE: In collaboration with Dr. G. B. 
Brown, to design, carry out and interpret biological 
assays for carcinogenicity of purine N-oxides for the 
determination of structure-activity relationships. 

APPROACH; Biological assays for carcinogenicity 
are integrated with metabolic and chenical studies 
(Dr. Brown) in an attempt to correlate oncogenicity 
with a chenical reactivity, either via a substitution 
reaction involving an ionic mechanism, or with a 
reactivity via a radical mechanism. Several purine 
S-oiides, analogs of nucleic acid bases present in al 
cells, are highly oncogenic in rats. These 
derivatives are thus possible endogenous initiators o 
spontaneous neoplasms. 

PROGRESS: Guanine 3-oxide, 3-hydroiyianthine an 
adenine l-oxide induce fibrosarcomas and fibronas whe 
administered subcutaneously in cats; the former two 
also induce liver tumors. The results with various 
methyl derivatives, and with altered ring systems, ar 
correlating the chemical information on the mechanism 
of the "3-acyloxypurine-8-substitutlon reaction" with 
its probable operation in vivo in the carcinogenesis 
process. The appearance of small nodules in the 
subcutaneous site of administration requires careful 
interpretation of carcinogenicity. Microscopically, 
these are collagenous in structure, but somewhat 
larger masses contain fibroblasts and resemble 
fibroaas. 



OBJECTIVE: Both human and animal cancers contain 
antigens absent in normal tissues. Cell-mediated and 
buaoral immune mechanisms in tumor-bearing hosts have 
the potential, but are generally unsuccessful, for 
eradicating the antigenic tumor. However, tumor 
regressions, but rarely cures, are obtainable by 
chemotherapeutic means. Both goals may be attained by 
rational selection of drugs based on in vivo-in vitro 
correlations among drug, tumor and host immune 
mechanisms. 

APPROACH: Recently, "cures" were induced in 
plasmacytoma tumor-bearing isogeneic BALB/c mice with 
various drugs, singly and in combination. The most 
effective chemotherapy not only yielded the highest 
proportion of "cures", but also rendered them 
comparatively more resistant to tumor challenge. 
Apparently, drug activity and host imsunity acted 
conjointly. Our goal is a rational selection of drugs 
which will Initiate tumor regression activity leading 
to tumor immunity. To achieve this, we will define the 
mechanisms of drug-initiated regression and immunity 
by examining "cured" nice for lymphocyte-mediated, 
antibody-dependent, cell-mediated, and 
complement-dependent cytotoxicity. The differential 
Influences of the various drugs on these parameters 
will also be determined in serial samples during and 



94 



aftst drug tceat»ent. Specificity, ■agnitude and 
duration of iaiuntty nil! be assassed by challenging 
"cures" with, respectively, other tumors, tuBor doses 
and at different tines after "cure." uhether other 
tu»or-host systcis respond similarly will be 
deteriined. 



OBJECTIVE: The change froa single to coabination 
drug therapy of aetastatic breast cancer in woaen 
resulted in reaission rates of 50« or better. 
However, only a liaited nuaber of useful compounds and 
effective drug cocibinations are available for 
additional therapy for treataent failures, partial 
responders and patients with recurrences. Egually 
important is the identification of hormones and/or 
their metabolites, removed by endocrine organ 
ablation, which worsen the disease status and which 
■ay be antagonistic to the effects of drug therapy. 
Our aim is to design and assay combination 
chemotherapies eaphasizing greater use of hormonal and 
antihormonal coipounds together with cytotoxic drugs. 

«PPPOSCH: Compounds will be tested for 
tumor-regressing activity against the DMBA-induced rat 
■ammary adenocarcinoma. These will include 
antiestrogens, prolactin inhibitors, androgens, and 
estrogens to cover additional metabolic sites of 
attack not considered in present combinations, as well 
as unigue, potentially useful drugs disclosed by our 
assays. Active compounds will be integrated into a 
baseline combination of cytotoxic drugs to increase 
tumor remissions and duration of remissions. In 
addition, over 30 androgen, estrogen, and corticoid 
steroid metabolites and hormones are availabe to 
determine, in operated and nonoperated rats, what 
compound (s) favorable to tumor growth is removed in 
surgical ablation of endocrine organs. combining the 

for therapy with the identification of endogenous 
compounds supporting tumor growth should eventuate in 
greater means of control of breast cancer. The 
objectives can be attained more guicfcly in the 
DHBA-induced rat nansary adenocarcinoma model, and 
with drug regimens ethically and practically not 
possible to investigate in clinical practice. 

33. TESTIHC or CUEHI CA L AHD BI01.QCICH. HATESHLS FOB 

iaiioiionoDiii.tTOBi acthiii 

Teller, n. N. , StocK, C. C, Old, L, J., nountain, I. 

B. 

OBJECTIVE: Our aim is to test materials of known 
chemical composition and crude biologicals for 
immunomodulatory activity, for use in cancer therapy. 

APPROACH: Two systems are used to disclose 
agents with the ability to increase (or decrease) 
immune reactivity. These are a) clearance of colloidal 
carbon from the blood (phagocytic index K) of CD-I 
•ice. Involving macrophages mainly in liver and spleen, 
and b) survival of C57BL/6 mile tail-skin grafts on 
isogeneic females, involving the weak H-l antigenic 
difference. Graft rejection is believed to involve 
T-cells. 

PR0G8ESS: With respect to phagocytic Index, mean 
increases of K greater than or equal to O.OHl (control 
K equals 0.C17) were achieved by 2/15 chemical 
compounds tested, poly I:C and an Indologuinolin 
analog. The latter also induced earlier re-)ection of 
skin grafts; mean survival times (ST50) were 23.5-29 
days, compared with the control ST50 of UC.5 days. of 
8 crude substances tested, the phagocytic indices (K) 
for 7 were greater than O.CUl. These were zymosan, 
polysaccharide PS-K, endotoxin. Bacillus calmette- 
Suerln, Corynebacteilun parvum, lentinan and 
carboxypachymaran. None of the u crude biologicals 
tested affected rate of skin-graft rejection. 



LABORATORY OF IMMUNOBIOLOGY 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

410 E.68TH ST. 

NEW YORK, NEW YORK 10021 



OBJECTIVE: To define the Immunological 
aberrations in sympathetic ophthalmitis and idl 
uveitis, and to establish immunogenetlc relatio 

APPROACH: I. Eiperljental subjects: Patie 
have had sympathetic ophth?.;::iti3 and uveitis. 



source: The Hew Tork Hospital, The Edward S. Harkness 
Eye Institute, Harlem Hospital, nanhattan Eye, Eat and 
Throat Hospital. Amount equals 50 cc. of venous 
blood. II. nethods: 1. Blast transformation: UO cc. 
of blood will be used to provide lymphocytes for blast 
transformation studies, a. nitogan stimulation (PHA, 
PUB, con A). b. Antigenic stimulation (urea, retina, 
lens, chlamydia, tuberculin (PPD) , mumps, Candida, 
herpes simplex mixed bacterial, Z. Coll, Staph. 
aureus). 2. Immunoelectrophoresis. 3. T- and B-cell 
determinations (rosette formation and direct membrane 
Immunofluorescence) . u. Immunogenetics: 10 cc. of 
blood will be used for HLA and BIC typing. 5. 
Controls: Persons who have had Injury to one eye, but 
did not develop sympathetic ophthalmitis, will go 
through Steps 1-u. 



35. IIIB0»O6I0l0gI AHD IHBDIOCEIBTICS Of CHHE 

d istehpeb viBns 

Bushkin, s. c. Good, B. A., Lopez, C, , o'Peilly, B. 

OBJECTIVE: Due to the similarities between the 
human CHS manifestations of multiple sclerosis (nsi 
and the canine CHS disorders of canine distemper virus 
(CDV) and the viral agents which cause them, as well as 
the new-found similarity between the human and canine 
immunogenetlc systems, we believe that the dog Is an 
excellent model of a comparative Investigation of the 
expression of the cell-mediated Immune responses of 
dogs with the systemic expression of CDV, and dogs 
with the encephalltic expression of CDV. In addition, 
an investigation of the possible association between 
susceptibility to CDV-lnduced encephalitis and the 
immunogenetlc constitution of the host Is also 
necessary. 

APPBOACH: Specific deficits of cell-mediated 
immunity will be sought using the lymphoblast 
transformation assay (LBT) and the indirect 
leukocyte-migration inhibition assay (LHIf) . These 
tests will include stimulation with non-specific 
mitogens (PHA and conA) , as well as with purified CDV 
antigen. T-cell populations will be quantltated with 
the EAC-rosette assay. The canine histocompatibility 
system (DIA) of each dog In the study will be 
determined in a collaborative investigation with Dr. 
J.w. Templeton (Baylor ned. College, Houston, Texas). 

PROGRESS: We have prepared and purified a highly 
titred CDV antigen which stimulates lymphoblast 
transformation, and production of LUIF. We have 
modified and optimized the EAC-rosette, LBT and Lllir 
assays for the canine system. our recent work has 
Indicated specified deficits of virus 
antigen-specific, cell-mediated Immunity to herpes 
sicplcx virus, detectable with the assays described. 

36. I50LATI0H AHD CBEHICAL CBABACTEBIZAIIOH Of A BOBtll 
LTHPHOCYTS PC BECEPTOB 

Cunnlnghaarundl, c, , Dupont, B. , Good, B. A, 

OBJECTIVE: To isolate from human lymphocytes the 
surface protein (s) which binds the Fc fragment of 
human IgG. 

APPBOACH: Human IgG attaches to lymphocyte 
surfaces to a distinct antigen known as the Fc 
receptor. The chemical nature of this protein is 
unknown, although It Is apparently a trypsln-resistant 
glycoprotein, the Integrity of wnlch Is dependent upon 
disulfide bonds. Using lactoperoxldase lodlnation of 
human lymphocytes and an Immune conplexing procedure. 

It is composed of several polypeptide chains, one of 
60,000 and one of 90,000 daltons, which are both 
covalently and non-con valent 1 y Joined into larger 
molecular structures. Isolated Fc from pooled human 
IgG and an IgGI myeloma protein were found to bind to 
this structure. Since T-cell lines molt 3 and molt u 
(obtained from Dr. J. nlnowada) were found to have no 
comparable surface proteins. It appears that this 
protein is derived from B-cells. 

37. DETECTI01 OF BEASLES AHTIBODIES III CEBEBBOSPHAL 
PLDID AHD SEBUB BI B ADIOI B U O NOASSAI 
Cunnlnghaarundl, C, Dupont, B., Posner, J., Good, B. 



OBJECTIVE: To demonstrate the antigenic 
determinants of the measles virus for which BS 
patients have antibodies, to classify antibodies in 
serum and CSF as IgG and/or IgB. 

APPROACH: Evidence that different structural 
components of th" measles virus may act as antigens 
has been demonstrated by the serologic methods of 
hemagglutinin inhibition, hemolysis inhibition, and 
nucleocapslde complement fixation. Using 
radloiodinated measles viral antigens, an immune 
precipitation assa/ has been designed which is capable 
of discriminating the measles viral structural 
component to which serum or CSF antibody is directed, 
and of differentiating IgG and Ign antibody 
reactivity. This technique has been applied to the 



95 



Btadr of aeasles antibodies la CSP and sees of 
patients with ■ultiple sclerosis (flS) and other 
neurologic diseases. It is found that both groups of 
patients have indi^idudl ceactivity to aeasles 
proteins^ present in CSF and secua, while 3 noraal CSP 
saiples vere not found to ha?e such antibodies. It 
appeacs that oligoclonal iaaunoglobulins in CSP of ns 
patients aay be detected by this aetbod, and that one 
patient with ns «as found to hare CSP antiaeasles 
antibodies. 



38. BTIDEBCE PQH TIBOSIIIE PgPTIDB HOnOLOGIES IH THE 
HH KMTIGBB SISTEH 

Cunninghaarundl, C. , Sve jgaard, A. , Dupont, B. , Good, 
5. A. 

OBJECTIVE: To cheaically analyze HLA antigens 
for protein sequence hoaologies. 

APPPOACH: The tetraaeric HLA antigens are 
coBposed of two heavier chains which carry the 
allo-antigenic deterainants, aod two lighter chains 
identified as Beta 2-aicrogiobalin. Although 25- 3C 
different antisera ace required to define the Tarying 
HLA specificities, it appears that these ar.tigens nay 
be closely related to each other and to the 
iaauDoglobulins. Through the use of a new 
electrophDtetic technique which is able to 
siaultaneously coapare the tyrosine peptides produced 
froB radioiodinated cell surface proteins, this report 
qi»es evidence that HLA antigens of the three 
chroBosoaal loci aay have sisilar aaino acid 
sequences. Since the retention of homologous tyrosine 
residues is a feature of ianunoglobulin structure, 
this aay indicate that siailacly conservative 
evolutionary aechanisas have been operative in the HLA 
allelic proteins or that iaaunoglobulins and HLA 
antigens aay indeed have a coaaon evoXutionary origin. 



39. BOB-SPECIPIC BESISTAHCE TO I8PECTI0B AMD 
IBTOIICATIOM 

Good« R. A. 4 

OBJECTIVE: To study in the developaental 
perspective the aechanisas of non-specific resistance 
to infection and intoiication. 

APPPOACH: Analysis in both ontogenetic and 
phylogenetic perspective of the developoent of 
capacity for organized i nf lasaation , phagocytosis and 
digestion by polyaorphonucleic neutrophils, leukocytes 
and heterophils; phagocytosis and digestion by 
eosinophils and »acrophages. Natural etoeriBents 
involving disturbances in these functions in both Ban 
and eiperieental anirals are analyzed. Analysis of 
the developaent of capacity to datoxify such toiic 
proteins as bacterical endotoxins, venoas and 
naturally occurring toxins. 

40. OaAMTITATIOH OP CELLOLAS IHHONE BESPOHSB BT PLOe 
CTTOPLDOBinETBl 

Good, P. A.. Braunstein, J. D., Aelaaed, n. B. 

OBJECTIVE: To develop standard quantitative test 
of cellular iiaune response. 

APPROACH: I. Dev;>lop fluorescent histocheaical 
■ethods of quantitating attributes of three different 
categories of iaautiologlcall y responsive cells: a. 
lyaphocyte, b, aonocyte aacrophage, c. neutrophil - 
granulocyte, II. Study variation in cell 
subpopulations or saturation in response to 
iaaunologic stiauli. 

PROGRESS: Lymphocyte transforaation has been 
quantitated using acridine orange staining and flow 
cytcfluoriaetry. The aethod has been described and 
applied to Bitogcn stiaulation, antigen stiaulation 
and HLC. 



•1- PBIHABT AHD SECOHDART IBaOIODEPICIEHCT DISEASES IH 

HAH 

Good, R. A., Dupont, B. , Siegal, P., Saithwick, E. 

OBJECTIVE: Analysis of patients with priaary and 
secondary i»Bunodcf iciency diseases. 

APPROACH; Extensive and intensive studies of 
priaary iaaunodef iciencies, the association of 
aalignancy and ioaunodef iciencies observed in 
lyaphoreticular aalignancies, lyaphoprolifecative 
disorders, ayeloaa and dissen inated cancer, studies of 
the iBBunodef iciencies associated with infection, 
exploration of the iaaanologic consequences of bone 
Barrow transplantation, and cellular engin-jering 
including: 1. bone aarrow transplantation and thyous 
transplantation to correct inborn errors of aetabolisa 
In the inaunity systea; 2. iaaunobiologic analysis of 
the patient after reconstruct ion of the heaatopoietlc 
systea in idiopathic and iatrogenic aregenerative 

transplantation to extend therapeutic approaches to 
disseainated cancer and leukeaia; U. coabination of 
ceLIulac engineering uith cbeaotherapy and 



iBBQnotherapy. The iaaunodef iciency diseases will be 
dissected in teras of the state of lyaphoid cellular 
differentiation and potentiality of their stea cells 
to be differentiated to T-lynphocytes by thyaic 
preparation. Analysis of capacity of the aarrow cells 
to be differentiated to T and B lyaphocytes by crude 
thyaic extracts and purified ubiquitous B-inducing 
polypeptides. Developaent of specific antisera to 
objectively define different populations of huaan 
lyaphocytes, with such antisera being used in analysis 
of ontogeny, involution and pathology of lyaphoid 
apparatus. study of a factor released froa culture 
B-lyaphocytes and stiaulated f-lyaphocy tes used for 
detecting early stages of T-cell antigens. 
Developaent of automatic set hods for quantifying 
lyaphocytes of different classes and lyaphocyte 
responses. Investigation of the nature and 
distribution in ontogeny involution and pathology of 
lyaphoid tissues after various therapeutic 
aanipulations of a population of huaan lyBphocytes 
bearing both B- and T-cell Barkers. 



12, PHTLOGBJETIC COHPABISOH OP AMTIBODIES, 
AMTIBODT-LIKE PBOTEIBS ADD AGGLOTITMS IW LOBEH 
VERTEBRATES AMD IHVEBTEBBATES 
Good, B. A,, Pinstad, C. L., Finstad, J. 

OBJECTIVE: To exaaine and coapare in a 
phylogenetic perspective the "antibody-like" proteins 
found in the sera of two prinitive cyclostoaes, 
Petroayzon narinus (laaprey) and nyxine glutinosa 
(hagfish) with invertebrate agglutinins. 

APPROACH: The structure of these aolecules will 

reactive substances as well as vertebrate and 
invertebrate cell agglutinins, in an attenpt to 
understand the biological function of these aolecules 
within the species froa which they were derived and to 
appreciate the biochemical aechanisas involved in such 
■iaaune" responses. Invertebrates do not have 
classical immunoglobulins: the natural cell 
agglutinins in the heaolyaph or coeloaic fluid appear 
to function in a protective capacity for the aniaal 
and do not require prior stiaulation with an antigen 
for the presence of biological activity. The 
-antibody-like" aacroaolecules froa cyclostoaes will 
be isolated, characterized and coapared with other 
cell agglutinating substances as to aamo acid 
cooposition and sequence analyses, secondary 
conf oraation, tertiary and quartgrnary subunit 
structural interactions as well as to aolecular 
weight, electrophoretic aobility and divalent cation 



03. PATBOGEHESIS OP fS AMD AqTOIHHDME PISOBDEBS AMD 

IBHUMODEPICIEWCT 

Good, R. A. , Cunninghaarundl, C. , Dupont, 6. , Po^ner, 

OBJECTIVE: To analyze the association of 
iaaunodef iciency and autoiaaune disease, particularly 
as this relationship applies to central nervous systei 



Gille 
disteaper 
nship of 



ularly in liqh 



ro.pared. 
particul 
:o the di 


Th( 
arly 


■bilit] 
.body ( 


f I 


■egioi 
iple.. 



• ». THE STOPT or DE»eLOPIIEIIT A»D DiyrBBEllTIlTIO» 0? 

POSTTBIBIC CELLS 

Incefy, G. s. , Good, 8. «. 

OBJECTIVE: In Titro studies oC hu.an T-cell 
differentiation under the influence of »arious thy.ic 
extracts (huaan or bo»lne thy.osinl and purified 
peptides (thysopoietin and Ubiquitin). 

»PPI10«CH: Only noraal subjects »ith no recent 
history ot infections are selected for volunteers. 
Each subject has the procedure described to hia prior 

questioned about hypersensitivity to local anesthesia, 
narrow aspirations are conducted in the Outpatient 
Dept. under local anesthesia. Five to 6 aspirations 
(each 0.5 - 0.6 al( of a total of not aore than 10 al. 
of aarro. are usually obtained froa the posterior 
iliac crest. Barrow cells are separated froa 
erythrocytes first on Eicoll-Hypaque density gradient 
and further fractionated into 5 fractions of BSl (or 
ficoll) discontinuous density qradient by 
centrifuqation or by velocity sediaentation at unit 
gravity. Appearance of T- or B-cell aarkers is 
studied after short incubation in the presence of 
thy.lc factors (bovine or huaan thyaosin rS| , 



96 



tbr«apoi«tln or ablquitin. For recoqnitlon of r-CBll 
cbaCACteristics, two aethods of assay are used: 1) a 
■Icrotoiicity test m the presence of specific 
anti-buian T-cell sera prepared against surface 
cODStituents of I-lyiphocy tes and coapleaent, 2) 
foraatioB of spontaneous E-rosette .itl. sheep red 
blood cells (SBBC). For recognition of B-cell aarkecs, 
tbe folloninq aarkers are studied: receptor for 
coapleaent (EAC-rosettes» » receptor for aouse 
trithrocytes (B-rosette) and surface Iq by 
iiaunofluorescence. 

PROGBESS: Partially purified huaan or bovine 
tbjaosln (fractions 3 or 5» , or purified polypeptide 
Itbyaus poietin or ubiquitin) , have the ability to 
iDiIuce in »itro certain populations of huaan aarron 
c«lls, to differentiate into cells bearing 
characteristics of T-lyaphocytes as detected by the 
two techniques described above, as well as a B-cell 
■arker as recognized by the n-rosette after a 2-hour 
i&cubation. Osinq this approach to study 
aifferentlation of precursor cells into T or B 
Irapbocytes, 20 healthy volunteers and 8 patients with 
vacious foras of priaary iaaunodeficiency have been 
■tadied so far. Appearance of T-cell aarkers could be 
induced on narrow cells of all subjects studied except 
on those froa 3 infants with severe coabined 
iaiunodeflciency (SCID) before bone transplantation. 
m addition in narrow cells froa healthy volunteers a 
saall population of cells could be induced to eipress 
tbe receptor for aouse erythrocytes but no coaplenent 
receptor (or Ig) induction was observed on these cells 



«5. iDIIH »- kgP T-CtLt DirrtBElTHTIOl Bt HOIIH 

tunic BOBBOIES 

Incefy, G. S. , Good, B, 1. 

OBJECTHE: To purify, characterize and study the 
BOde of action of huaan thyaic factors (horaones) used 
in vitro as inducers of huaan T- and B-cell 
differentiation. 

IPPBOkCH: Huaan thyaic factors are prepared froa 
biopsy speciaeos reaoved froa children undergoing 
cardiac surgery in the course of access to the 
operative site, or froa huaan thyauses and spleen 
obtained froa infants at autopsy, within a few hoars 
following sudden death. The tissue speciaens are 
frozen and stored in Bevco Preezer before being 
processed. The factors are purified according to the 
procedure of k.L. Goldstein (Hooper, J. A. et al., knn. 
».I. »cad. Sci. 2U9, 125, 1975) and purified eitracts 
equivalent to his calf thyjosin fractions 3 and 5 have 
been isolated. They both have the ability to induce 

Isolated by BSl (or Ficoll) density gradient 

gravity, to differentiate into cells bearing 
T-lyaphocyte characteristics. These aarkers of 
induction include; a) antigens which are reactive in 
a aicrocytozic analysis in tbe presence of coapleaent 
with specific antisera prepared against surface 
constituents of T-lyaphocytes and b( receptors for 
sbeep erythrocytes able to fora spontaneous 
5-rosettes. Surface aarkers of aature B cells have 
also been studlel; they are: receptor for coapleaent 
(E»C-rosette| and receptor for aouse erythrocytes 
(Jl-tosette) . 

PBOGBESS: Bone narrow froa 20 healthy volunteers 
and froa 8 patients with various foras of priaary 
iaaunodef iciency diseases hate been studied so far. 
■ben their narrow cells were incubated 2, » or 16 
boats in the presence of huaan tbyaosin F3 or F5, 
appearance of T-cell aarkers could be induced in vitro 
on cells of all subjects studied, eicept on those froa 
3 infants with severe coabined iamunodeticiency 
(SCID(. However, after bone narrow reconst it ut ion , 
•arrow cells froa these infants could also be induced 
to bear these Barkers. It was also deaonstrated that 
appearance of these T-cell aarkers required RNA and 
protein synthesis. In a aore recent study, only 

precursor cells as a aarkar of B-cell differentiation 
by thyaopoiet in. 



• e, EFFECTS OF P B OTEIl IHLHOTBITIOil OB TBE ImniE 
1 E5P0IISE OF CnlllEA PIGS 
Kraaer, T. B. 



pigs. 

IPPBOkCH: Ueanllng Bale Hartley strain guinea 
pigs are placed on a designated low protein diet at 
days of age and aaintained on this die* for 7 to 1C 
•weeks. Following four weeks of dietary tegiien the 
anlaals are iaounized with bovine gaaaa globulin 
(BGG). Three to five weeks post i=aunizatlon the 
huaoral and cell-aediated iaaune responsi venc-ss of 
these aniaals to BGG is evaluated. 

proCBESS: loung guinea pigs aaintained on thr 
levels of low protein diet for the duration noted 



above display reduced aicro-passive heaagqlutinatlon 
antibody titers to BGG, along with reduced skin test 

aniaals retain the ability to produce the lyaphokine 
nlF which is aeasurable both in the direct and 
indirect nlF assay systeas. Peritoneal eiudate cells 
(PEC) froa non-sensitiied aniaals on a siailar 
nutrition regiaen as above are capable of being 
inhibited in aigration by BIF froa hiqh-protein- 
noarished aniaals to the saae degree as PEC froa 
noraal, DOarished noo-sensitized guinea pigs. 



»7. TBE BOLE OF SDPPBISSOt CELLS II BOBAl PEBIPHEBAL 

BLOOD 

Shou, L. , Good, B. A., Schwartz, S. 



or lyaphocytes in 
igate suppressor 
y iaaune deficient 



OBJECTIVE: 1. Study th 
functions of con A-induced s 
noraal peripheral blood. 2. 
lyaphocytes in priaary and s 
patients. 

APPROACH: Peripheral blood lyaphocytes of nori 
and iaaune deficient patients are separated by 
Ficoll-Hypaque gradient centrif ugation. Suppressor 
lyaphocytes of noraal individuals are induced by 
incubation for 2 days in the presence of Con A. Ihi 
cells are treated with aitoaycin C and then aiied w, 
responding lyaphocytes. Isolated patients' lyaphocy 

responder lyaphocytes and noraal stiaulator cells 
treated with aitoaycin c. The cell aiktures are 
cultured for 5 days in huaidified 5» C02 ataosphere 
H3-thjaidine is added for the last 16 hours of 

isotope-labelled thyaidine is aeasured in a liquid 
scintillation counter. 

stiaulators instead of noraal, aitoaycin C-treated 
stiaulator lyaphocytes to exaaine the response of 
noraal lyaphocytes to aitogens and specific antigen 
in the presence of suppressor cells. 

The suppressor activity of patients* lyaphocyt 
which are capable of Inhibiting noraal lyaphocytes 
response to aitogens and specific antigens is 



E 


>B0 


GBESS: 


Our i 


!rel 


.iai 


nari 


f dal 


ta show 


are supp 


ressor 


cells 


in 


nor 


aal 


con 


A-actit 


lyaphc 


)cy 


tes, wl 


lich ai 


:e caoa 


ble 


of suppres: 


respor 




of noi 


r.al 1, 


fapf 


locy 


tes 


to • 


illogen. 


aiied 


ly 


aphocyi 


te cull 


Lur« 


■s a 


nd 1 


to a: 


Ltogen ; 



LABORATORY OF LIPIDS AND LIPID 
COMPLEXES 

SLOAN-KETTERING INSTITUTE FOB 

CANCER RESEARCH 

145 BOSTON POST ROAD 

RYE, NEW YORK 10580 



us. DE?ELOPnEHT OF A SIHPLE, PBECISE BETHOD TO 
SEPABATE A MD OUAMTITATE SEROB HIGH DEHSITI 
LIPO-PBOTEIHS, (8012 ABD HDL3) 
Barclay, B., Stock, c. c. 

OBJECTIVE: To devise a relatively siapler 
procedure than analytical ultracentrif ugation to 
separate and quantitate both hDL2 and HDL3 of blood 

APPBOACH: There are soae indications that tbe 
levels of certain high-density lipoproteins, 
specifically HDL2, jiay be related to cancer, therefor 

accurate values for these in huaan serua is being 
sought. Polyacrylaaide gel electrophoresis has been 
used to separate successfully the serua HDL2 froa 
B0L3. The two bands containing the lipoproteins are 

acid are used to identity then. The sera are treated 
concurrently with the density gradient separation, 
using sequential increases in KBr, in the preparative 
ultracentrlfuge (Deckaan - Spi nco Bodel L) to separate 
HDl,2 (D is greater than 1.0635 and less than 1.125 q 
per al) and HDL3 (D is greater than 1.125 and less 
than 1.210 y per al) in KBr solutions. The exact 
quantities of HDL2 and HDI.3 are calculated after 
sedlaentation velocity (flotation) in the analytical 
ultracentrifuge (Beckaan-Spinco Bodel E) . 

PROGRESS: These two HDL's appear to separate 
well on polyacrylaaide gel under specific conditions. 
The principal ongoing problem is to treat the bands- 
(disc) containing t^e HDL in ways that will yield a 
■easure of their quantities which will correlate 
significantly with data froa the analytical 
ultracentrifuge. 



97 



tbliopoietln or Ubiquicln. Por recognition ot I-cell 
characteristics, t.o aathods of assay arc used: 1) a 
■Icrotoilcity test in the presence of specific 
antl-huian T-cell sera prepared against surface 
constituents of T-ly«phocytes and coaplcaent, 2) 
fornation of spontaneous E-rosette with sheep red 
blood cells (SRBC). Por recognition of B-cell narkers, 
the following larkecs are studied: receptor foe 
coapleient (EAC-rosettes) , receptor for louse 
erythrocytes (n-rosette) and surface Ig by 
iaiuootluorescence. 

PB0GB2SS; Partially purified huaan or bovine 
thyaosin (fractions 3 or 5) , or purified polypeptide 
(thyaus poietin or ubiquitini , have the ability to 
Induce In vitro certain populations of huaan aarro« 
cells, to differentiate into cells bearing 
characteristics of T-lyaphocytes as detected by the 
t»o techniques described above, as well as a B-cell 
Barker as recognized by the B-rosette after a 2-hour 
incubation. Using this approach to study 
differentiation of precursor cells into T or B 
lyaphocytes, 20 healthy volunteers and 8 patients «lth 
various foras of priaary iaaunodef iciency have been 
studied so fat. Appearance of T-cell aarkers could be 
Induced on aarrov cells of all subjects studied eicept 
on those froa 3 infants with severe coabined 
iaaunodeficiency (SCIDI before bone transplantation. 
In addition in aarrov cells froa healthy volunteers a 
saall population of cells could be induced to eipress 
the receptor for aouse erythrocytes but no coapleaent 
receptor (or Ig) Induction Mas observed on these cells. 



«5. HIH>» »- HIID T-C81.L DIff tBElII ATIOl BI Bn»H 

THtBIC Hoaaoiits 

Incefy, G. s. , Good, R. A. 

OBJECTIVE: To purify, characterise and study the 
iode of action of huaan thyaic factors (horaones) used 
in vitro as inducers of huaan T- and B-cell 
differentiation. 

APPROACH: Huaan thyaic factors are prepared froa 
biopsy speciaecs reaoved froa children undergoing 
cardiac surgery in the course of access to the 
operative site, ot froa huaan thyauses and spleen 
ob'nlned froa Infants at autopsy, vlthin a fe» hours 
follovlng sudden death. The tissue speciaens are 
frozen and stored In Revco Preezer before being 
processed. The factors are purified according to the 
procedure of A.L. Goldstein (Hooper, J. A. et al., Ann, 
H.I. Acad. 5cl. 2U9, 125, 1975) and purified eitracts 
equivalent to his calf thyaosin fractions 3 and 5 have 
been isolated. They both have the ability to induce 
certain populations of huaan bone aarcov cells. 
Isolated bj BSA (ot Picoll) density gradient 
ccntrlfugatlon or by velocity sediaentation at unit 
gravity, to differentiate into cells bearing 
T-lyaphocyte characteristics. These aarkers of 
Induction Include; a| antigens vhich are reactive in 
a aicrocytoiic analysis in the presence of coapleaent 
with specific antlsera prepared against surface 
constituents of T-ly»phocy tes and b) receptors for 
sheep erythrocytes able to fora spontaneous 
!-rosettes. Surface aarkers of aature B cells have 
also been studied; they are: receptor for coapleaent 
(EAC-rosette) and receptor for aouse erythrocytes 
(a-rosette) . 

PROGRESS: Bone aarrow froa 20 healthy volunteers 
and froa 8 patients with various foras of priaary 
iaaunodeficiency diseases have been studied so far. 
«hen their aarrow cells were Incubated 2, u or 16 
hours In the presence of huaan thyaosin F3 or P5, 
appearance of T-cell aarkers could be Induced In vitro 
on cells of all subjects studied, eicept on those froa 
3 Infants vith severe coabined iaaunodeficiency 
(SCID). However, after bona aarrow reconstitut ion, 
narrow cells froa these infants could also be induced 
to bear these aarkers. It was also deaonstrated that 
appearance of these T-cell Barkers required RNA and 
protein synthesis. In a aore recent study, only 
receptor for aouse rosettes could be induced 



ells 
by thyaopoietln. 



of fl-cell differentiatlo 



*6. rPPECTS OP PBOTEH BALBOtalTIOB OH THE IBBOIE 
BESPOMSE OP COIHEA PIGS 
Kraaer, T. R. 

OBJECTIVE: To study the effects of dietary 
protein insufficiency on the laaune systea of guine 

pigs. 

APPROACH: Ueanllng aale Hartley strain guinea 
pigs are placed on a designated low protein diet at 
days of age and aaintained on this diet for 7 to 10 
weeks. Following four weeks of dietary reglaen the 
anlaals are iaaunized with bovine gaaaa globulin 
(BGG). Three to five weeks post iaaunizatlon the 
huaoral and cell-nediated laaune responsiveness of 
these anlaals to BOG is evaluated. 

PPOGRESS: young guinea pigs aaintained on thrae 
levels of low protein diet for the duration noted 



21 



above display reduced aicro-passive heaagglutlnatlon 
antibody titers to BGG, along vith reduced skin test 
activity to the saae antigen. However, these saae 
anlaals retain th- ability to produce the lyaphokine 
KIP which Is aeasurable both in the direct and 
indirect BIT assay systeas. Peritoneal ekudate cells 
(PEC) froa non-sensitized anlaals on a siailar 
nutrition reglaen as above are capable of being 
Inhibited In aigration by BIF froa hign-protein- 
nourished anlaals to the saae degree as PEC froa 
noraal, nourished non-sensitized guinea pigs. 



«7. TBB BOLE OP SOPPBESSOB CELLS 11 HOHAI PEBIPBEBAl. 

BLOOD 

Shou, L., Good, B. A., Schwartz, S. 

OBJECTIVE: 1. Study the nature and iaaunologic 
functions of Con A-induced suppressor lyaphocytes in 
noraal peripheral blood. 2. Investigate suppressor 
lyaphocytes in priaary and secondary laaune deficient 
patients. 

APPROACH; Peripheral blood lyaphocytes of noraa 
and laaune deficient patients are separated by 
Plcoll-Hypaque gradient centrif ugation. suppressor 
lyaphocytes of noraal individuals are induced by 
Incubation for 2 days in the presence of Con A. The 
cells are treated with aitoaycin C and then aiied wit 
responding lyaphocytes. Isolated patients' lyaphocyte 
are treated with aitoaycin C, then aixed with noraal 
responder lyaphocytes and noraal stiaulator cells 
treated with aitoaycin C. The cell aixtures are 
cultured for 5 days in huaidificd 5J C02 ataosphete. 
H3-thyaidine is added for the last 16 hours of 
Incubation, then harvested. The incorporation of 
isotope-labelled thyaidine is aeasured in a liguid 

Bitogens and specific antigens are used as 
stiaulators instead of noraal, iaitoaycin c-treated 
stiaulator lyaphocytes to eiaaine the response of 
noraal lyaphocytes to aitogens and specific antigens 
in the presence of suppressor cells. 

The suppressor activity of patients" lyaphocytes 
which ate capable of inhibiting noraal lyaphocytes ir 
response to aitogens and specific antigens is 
ezaalned. 

PROGRESS: Our prellalnary data show that there 
are suppressor cells in noraal Con A-activated 
lyaphocytes, which are capable of suppressing the 
response of noraal lyaphocytes to allogeneic cells it 
aixed lyaphocyte cultures and to aitogen stiaulation: 



LABORATORY OF LIPIDS AND LIPID 
COMPLEXES 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

145 BOSTON POST ROAD 

RYE. NEW YORK 10580 



118. DEVELOPHEIIT OP A SIHPLE, PRECISE BETHOD TO 
SEPAR ATE AHD OUAHTITATE SEROB HIGH DES5ITI 
LIPO-PBOTEIBS, [HDL2 AMD aDL3) 



OBJECTIVE: TO de 
procedure than analyti 
separate and guantitat 

APPROACH: There 
levels of certain high 
specifically HDL2, aiy 
a less expensive and s 
accurate values for th 
sought. polyacrylaaid 
used to separate succe 
HDL3. The two bands c 
discretely obvious whe 



L3 of blood 
ns chat the 



using 
ultrac 
HD12 (D Is 



.fuge (Beckaan-Spinco flodel L) to 
greater than 1.0635 and less thai 
ater than 1. 125 ai 



d le 



and HDLl (D Is greate 
than 1.210 g per al) in KBr solutions, 
quantities of HDL2 and HDL3 are calculat 
sediaentation velocity (flotation) in th 
ultracentrifuge (Beckaan-Spinco .lodel E) 

PROGRESS: These two HDL's appear to Sep 
well on polyacr ylaaide gel under specific con 
The principal ongoing problea is to treat the 
(disc) containing the HOI in ways that will y 
•easure of their quantities which will correlate 
significantly with data froa the analytical 
ultracentrifuge. 



analytic 



id 



98 



• 9. BIOCHEmOL STUDIES Of PUSIH BEIIBBtllES fBOB EIT 
tITEB »IID BEPtTOmS 

Barcldy, n. , DnisCrian, A. 

OBJECTIVE: TO deteraine ind quantitate certsin 
of the cheiical (and biocliemical) coiponents of plassa 

• eibtmes froi iior«al cat liter and relate these 
levels and relationships to the sane paraneters in 
plasaa Beabranes froa hepatoaas. 

APPSOACH: Plasia aeabranes are isolated in 
acceptable purity and yields froo both noraal rat 
liver and froa the norris hepatoaa 5123tc. 4 systeaati 
analjsis of the saline-soluble (eitrinsic) and 
Insoluble (intrinsic) proteins included assays for 
Barker enzyae (s) activities: anino acid compositions; 
analytical ultrac antrif uqe (Eeckaan-Spinco .lodel E| 

and identification of protein subunits by 
polyacry laaide gel vith SDS; heiose and lipid 
coapositions by gas chroaatography. The intrinsic 
fraction is coaposed of a number of subcoapleies 
containing substantial aaounts o£ lipids (especially 
free cholesterol) , carbohydrates and proteins. These 
are separated routinely by a density gradient system 
devised here, and studied as described. 

PROGRESS: A number of the physicochemlcal and 
biochemical characteristics of the membrane 
lipoprotein complexes of the intrinsic portion of the 
plasma membrane are no» Icnown. These are relatively 
less polar than the saline-soluble eitrinsic protein 
■hlcb has no measured enzyae activities, less lipid 
and acre carbohydrate associated vith it. A number of 
the documented features of the plasma membranes from 
normal liver are aberrant in plasma membranes from 
hepatomas, not only quantitatively, but qualitatively. 



OBJECTIVES: a) To elucidate the chemical 
composition of proteln-ilpid complexes of a 
proteolipid type, tentatively called neoproteollplds 
isolated from malignant tumors; b) To determine the 
degree of specificity of association of these 
complexes vith malignant growth; c) To investigate t 
appearance (or raised level) of these complexes In 
blood sera In order to serve as a potential diagnost 
cancer test and/or as a test of the efficacy of the 
aedlcal treatment of cancer. 

APPFOACH/PSOGRESS: From the lover phase of Pol 
partitions of lipid extracts from tuaors, protein-li 
complexes, neoproteollplds |NPL), have been Isolated 
systems of silicic acid chromatography columns. The 
ate two types of NPL: neoproteolipid- tf (NPL-i*) , 
originally Isolated froa ualkec carcinosarcoma 256 
(U2S6I , and neoproteolipid-S (NPL-S) , originally 
isolated froa sarcoma lac. Around 20 different 
transplanted, chemically-induced and spontaneous tum 
(including human tumors) were tested, and all of the 
contained either NPL-M or KPL-S (Prog. Blochea. 
Pharaacol. 10:112, 1975). Both neoproteollplds are 
coaplexes of glycosphlnqoli pids with other lipids 
(phospholipids, cholesterol) and proteins (or 
polypeptides). NPL-w contains neutral 
glycosphingolipids (which contain fucose) , whereas 
1IPI.-S contains slaloglycosphingollplds as has been 
deteralned by gas-llguid chromatography. Blood sera 
of normal rats do not contain NPL-a, whereas the ser 
of 11256-bearing rats do contain around 16 micrograms 
»PL-»/100 mg lipid. Blood sera from norris hepatoma 
5123-bearlng rats contain 5-7 times more NPL-3 than 
sera from normal rats. The presence of UPL (without 
identification of Its type) was demonstrated also in 



ental appr 



Details of the , 

Cancer Lipids: 

«ood| pp. 225-2143, AOCS, 197J. 

51, GLTC05PHING0L IP ID COHPOSITIOH OP PLAS H A HEHBRAWES 
raOH HORHAL BAT LIVER CELLS AND HEPAT0I1A C ELLS 
Sfclpski, V. P., Dnistrian, A. n. , Barclay, .1. 

OBJECTIVE: To demonstrate that plasma membranes 
(PB) of solid tumors have a different 
glycosphlngollpld profile as compared with plasma 
membranes of noraal tissue. 

APPBOACB: Plasma membranes were Isolated froa 
normal' rat liver (Pn-NL) and norris hepatoma 5123tc 
(Pn-MH) by discontinuous sucrose gradient 
centrlfugation. The purity of preparations was 

microscopy. Gangliosides were separated by several 
syst«>s of thin-layer chromatography (TLC); spots on 



togc 



spray, quant 
acid was det 



ill 
ely eluted, and the 



mull 



reagent (Blochea. Biophys. Ses. 
Seutral glycosphingol I pids were separated from c 
lipids by sialic acid-magnesium silicate column 
chromatography and preparative silica gel TLC, 
followed by separation of the different classes 



neutral glycosphlngollplds on analytical TLC plates 
and a quantitative determination made by densitometry. 

PB0GBE5S: A 10-fold increase of llpld-bound 
sialic acid was observed in norris hepatoma cells as 
compared with those from normal liver. This increase 
of llpld-bound sialic acid In hepatoma cells is due to 
a substantial Increase in the amounts of monoslalo- 
and dlsialogangliosldes. There is an average 2.5-fold 
increase of gangliosides in PB-NL and PB-BH as 
compared with their content in the corresponding whole 
cells. PB-BH contains 5 times more hematosldes, 8 
times more monoslalogangllosldes and 22 times more 
dlsialogangliosldes than PB-NL. Tr islalogangliosides 
In PB-BH were not detected, but they are present In 
PB-RL. There are increases also in the levels of 
neutral glycosphinqoliplds In hepatoaa cells and PB-BH 
as coapared with those in noraal liver cells and 
Pn-8L, respectively. 

52. POSSIBLE BELATIOHSalP BETBEEH FOBBATIOH Of 
BETtSTASES 1»D GLICOSPBIBGOLI PIDS IB SOBE TOBOBS 
SlilpsJcl, V, P., Gltteraan, C. 0., stock, c. C. 

OBJECTIVE: To elucidate whether there Is any 
;hip between glycosphlngollpld patterns of 



allqnant tuao__ _ 

APPROACH: Apparently 
ay de 



app 



aetastases of malignant tumors, 
degree of cell adhesion In the p 
glycosphlnogllpids play a role In cell adhe 

different glycosphlngollpld patterns in the 
ines (cell surface glycosphinqoliplds) 



■eral 
if them 



Bo 



s by the application of antimetastatic dr 

may also alter the glycosphingolipid pattern of th 
tuaors. This hypothesis was tested on two tuaors, 
I (Huaan Sarcoma-I) and HEP-3 (Human Epit hell oaa- 3 
Both these tumors are cultured on chick embryo sac 
Ondec experimental conditions HS-1 djes not 
metastasize, whereas UEP-3 extensively metastasize 

PROGRESS: Ganglloside spectra of these tumor 
were Investigated. It was found that HEP-3 contain 
approximately 1/3 of the amount of llpld-bound sia 
add as that found In HS-1. These differences In 
content of llpld-bound sialic acid are due to a 
smaller content of monoslalogangllosldes and 
dlsialogangliosldes in lipid extracts froa HEP-3. 
Treatment of HEP-3 with a drug (a qulnazollnol 

substantially Increases the amount of llpld-bound 
sialic add In HEP-3 due to increases in the conte 
of hematosldes, monoslalogangllosldes and 
dlsialogangliosldes. These experiments so far wer 
performed on whole cells; however, results apparen 
have a bearing on the plasma membrane, because 
gangliosides are predominantly concentrated In thi 
structure of the cell. 



DEPARTMENT OF MEDICINE 

MEMORIAL HOSPITAL FOR CANCER 

AND ALLIED DISEASES 

444 E. 68TH ST. 

NEW YORK, NEW YORK 10021 



OBJECTIVE: To localize abscesses in septic 
patients and study the experimental conditions which 
may influence detectablllty of the lesions. 

APPROACH: Gallium 67 citrate purchased from New 
England Nuclear (IHD 8377) or Bedl-Physlcs (IND 8371) 
will be calibrated in our laboratory and dispensed 
under sterile conditions for use in our patients. 

Gallium scans will be performed in patients with 
septicemia when localized abscesses ace suspected. 
The aaiiaua dose will be O.OUS aCl/kg, adalnlstered 
intravenously. Scans will be pecforaed fcom US to 72 

no infants not suspected of having malignant disease 
will be Included. Whenevec possible, we will attempt 

results and follow the patients sequentially following 
specific therapy. 



50 . mitbogeb-13 ahhowiuh chlqbide fob toho b 

locali;atio» 

Benua, R. s.. Fuller, Teh, Leeper 

OBJECTIVE: To evaluate the effectiveness of 
nltrogen-13 labeled ammonium chloclde solution In the 
localization of malignant tuaocs In man, especially in 



99 



coiparlson to Gamui-67 citrate md Ill-In chloride 
oc blaoBycln. By applying quantitative scaaninq and 
coBputer analysis, the relative counting rates of 
tuiors and organs Mill be coapaced aaong the 
radiopharaaceuticals in relation to til" of inlection 
and aaonq various histologic types and priaary sites. 
«PPBO«CH: Kitcogen-13 labeled a»»oniu« chloride 
solution »ill be obtained froi the SKI cyclotron in 
sterile, pyroqen-free fors. Patients with 
histologically proven aalignant tuaots at sole tise 

•ill receive 10 aci of the radiophar.aceutical 
Intravenously, and laaqing vill be carried out at once 
on digital scanners or caaeras of the Biophysics 
Laboratory. Scans vill be perforaed during the first 
2 hours after injection. Blood levels and 
concentrations in biopsied tissues vill be aeasuced in 
selected patients. Hospitalized and out-patients vill 
be studied, especially those vho have had Ga67 citrate 
stadies coapleted on the aorning of the day of aaaonia 
injection, since the energy of the nitrogen- 13 is 
sufficiently high that other nuclides Kith a lover 
energy such as Ga67 vill not interfere. 



OBJECTIVE: TO define the clinical usefulness of 
67-galliua in detecting cancers and folloving their 
progress. Collaboration with the Cooperative Group to 
Study Localization and Radiopharaaceuticals and OaK 
Bidge Ussociated universities vill include receipt of 
Ga67 for use in the study of lung cancer and staging 
of Hodgkin's disease by their protocol. 

»PPEO»CH: 67-Galliu» chloride coipleies with 
sodiua citrate will be supplied by CGSR or purchased 
fros comercial suppliers. Patients with untreated 
Hodgkin's disease (biopsy proven), untreated lung 
cancer (suspected and to be operated upon or biopsied) 
will be selected for the furnished 67-Galliui. He 
■111 study other patients with histologically proven 
evidence of aalignancy at soae tiae with clinical 
evidence of soae active tuior, and without prior 
therapy except radiation or surgery at a site different 
froa the one of current interest. 

The aaxiaua dose will be U5 aicrocuries/kg. 
Scans will be f.-rforaed at »8 to 72 hours after 
cleansing enetn:. no pregnant women or infants will 
be studied (d.-! ;rric patients with aalignant disease 
• 111 be incl'^ .: they can cooperate). whenever 
possible we « : . ■ -.oapt to obtain surgical or biopsy 
confiraation -s and guantitate tissue levels 
after scans. 



56. SCIBTIGBlf 
CII-BILtmi!! 

eenua, R. s, , fl 



for 



g>GI»G A»D IV TITO DISTBIBOTIOH Of 
, Helson, Stavchansky 



dyn 



the tissue distribution and evaluating the 
of C11-DPH In brain lesions. 

APPROACH: Experiaents vill involve intravenous 
adulnistration of 8-12 ici (0.11 aci/kg to 0.17 «ci/kg 
body weight) of the radlopharaaceutlcal to selected 
neuroblastoma and brain tuaor patients. Scans will be 
perforaed during the first two hours after 
adainlstratlon with dynaaic and static iaages of the 



and 
rlbut 



till 



Bio 



ill 



15, 20, 25, 30, 00, 50, 60, 90, a 
a, 6, S, 12, 211, and US hours pes 
children, ages 6 to 12, at the di 
Helson, 2.5 al. of blood aay be i 
tiaes; C, 2 and u ai.iutes (during 
10, 20, 30, UO, 8C, and 16C alnut 
and 72 hours after infusion, a to 
of blood. 

PSOGRESS: Several ■ 



; the fo 


llowii 


™g 


.on; 2.5 


, 5, 


10, 


120 linu 


tes; i 


ant 


ifuslon. 


For 




itlon of 


Dr. 




1 at the 


foll^ 


ow: 


iusion). 


2.5, 


b, 



of the brain 



57. HDIOISOTOPE BEHOGBAIIS DSIKG 1123 LABELED 
ORTHO-IODOHIPPUIIATE (HIPPOBATE) 
Benua, R. S. , Powell, Grando, Pitesa 

OBJECTIVE: To perfora routine radioisotope 
renograas using 1123 labeled Hippurate prepared at 
neaorial Hospital. It is planned to adainlster an 
activity of 2 aCi which will Increase the counting 
rate by a factor of less than two coapared with the 
present procedure. If It were iaportant to reduce the 
radiation dose In order to perfora repeated studies, 
the adainlstered activity could be reduced while still 

APPROACH: Instead of using a coaaerclal 
preparation of 1131 labeled Hippurate for routine 



radioisotope renograas, the 1123 labeled Hippurate 
will be used. This aaterial will be prepared at 
neaorial Hospital in the Radioactive Isotope Service 
of the Departaent of Itedlcal Physics. A aodiflcatlon 
of the procedure outlined by short, et al. will be used. 

Patients will be those who are referred to the 
nuclear Hedlcine Service for routine radioisotope 
renograas. 

The renograas will be perforaed on the gaaaa 
caeera of the Huclear nediclne Service. Data will be 
stored on aagnetic tape In a digital fora. Data 
Processing, which includes area integration and 
plotting of tlae-actlvlty histograas, will be done on 
the Biophysics I.B.a. 1800 Coaputer. 

58. lOHIC 11111311 TO LABEL TBABSFEaHIB TOB BLOOD POOL 
SCAHHIHG 

Benua, S. S. , Powell, Laughlin, Teh 

OBJECTIVE: To provide an isotope with a short 
halt-life which can be used as a blood label for 
differentiating Intravascular froa eitravascular 
fluid. 

APPROACH: Indiua Chloride is eluated froa a 
sterile pyrogen-free Sn113-In113a generator in the 
Central Isotope Laboratory vith elutlng fluid supplied 
by the aanufacturer. New England Nuclear. Although New 
England Nuclear has no IND or NDA for this product, we 

probleas for two years. other users are nui^erous and 

cannot be aade because of the 1.7 hour half-life. If 
a reaction occurs ve will cease use of the aaterial 
until the source Is identified. The generator eluate 
in acid solution binds directly to transferrin of the 
patient's blood in vivo. It will be used to detect 
pericardial effusions atd similar types of blood pool 
localization. 

PROGRESS: Because of the infrequent use of this 
procedure and the high cost of the generator, this 
prograa is being discontinued for the present tiae, 

59. ETALOATIOH OP TC9gil-TH-HEDP «ITB ADDED SODIOll 
ASCOBBATE 

Benua, R. S., Yeh, Leeper 



OBJECTIVE: 


Ti 


with 991 


.Tc dlst 


:anni 


stabilized wit) 


1 C. 


APPROACH: 


Pa 


indicatf 


=d bone 


seal 


labeled 


HEDP conta: 


sodlua i 


iscorbal 


:e. 


Proctor 


and Gamble 


17-U511 i 


ipplies 


to 


Scans w: 


ill be evali 


evidenci 


1 of fr< 


■e p. 


saliva. 






Coded case 


1 re| 


Proctor 


and Gai 


ible 



0.6 



(HEDP) 



ed fo 



ng le 



Lcally 
given 15 acl of <)9aTC 
than 9. 1 mg per dose of 
terlal will be furnished by 

a kit under their IND 16853 (HDA 
ir HEDP vlthout ascorbate added), 
ed for guallty of laaqe and 
echnetate in the stoaach and 



OBJECTIVE: To evaluate the usefulness of 
cyclotron-produced P18 sodlua fluoride for the 
detection of bone lesions. 

APPROACH: Sodlua fluoride (P18) produced in the 
Sloan-Ketterlng Cyclotron will be used under IND 15373 
to detect bone lesions of patients with beniqn and 
aalignant disease. Patients without proven aalignancy 
will receive 2.0 «Cl proportionally with body weights 
below 70 kg. 

Iniectlon will be Intravenous, and scans 
perforaed 2 hours after injection (1.5 - u hours). No 
pregnant woaen will be scanned, and children with jo 
cancer who are below 18 years of age will be excluded 



1. Ill TITBO STHDIKS OP THE HBTABOLISB Or ABA-C A»D 

HO III HUHAH leohebia 

ajager, R. L., Chou, A., Philips, C. , Krels 

OBJECTITE: Detecalnatlon of quantitative 
Ifferences in the aetabolisa of 

-Bcta-D-arabinof uranosylcytosine (ara-C) In huaan 
eukeaic and normal hematopoietic cells, and the 
nfluence of the pyLiaidine deaminase Inhibitor, 
otrahjdrouridlne (THU) , on ara-C aetabolisa. 

APPROACH: The net synthesis of ara-CTP, the 
ctlve aetabolite of ara-C, by leukemic and noraal 
ells and their subpopulatlons vas studied In vitro I 
he presence of trltiated ara-C. Aq1i8 and Ag5Cx8 
oluan as well as high pressure liquid chroaa t ogr apy 
ith peraarase or pcllloner SAX anionic exchanger wer 
aployed 1 



nucle 



a-C. 



offe 



tlula 



100 



PBOGBSSS: tra-CTP foriatlon (ng/106 cells/US 
■ in) in blood saiples ace la the Collouliiq order: 
AHHoL greater than km greater than AnoL greater than 
CBL greater than ALL greater than CLL greater than 
norial. This Conation aas increased by THU in AflL, 
innoL, Anol, and Cn:. but not in ALL, CLL or noriai 
blood. Cells that hare negligible capability to 
incorporate 3H-TdB into DSA aay still have significant 
capability to synthesize ara-CTP. 

Ira-CTP Conation in bone narroii aspirates are in 
the following order: AHL greater than cnL greater than 
AnoL greater than AnnoL, ALL, CLL. This foraation was 
increased by TKU in AHL. ARoL, AlnoL and CAL but not 
in ALL and CLL. 

Sole of these preliiinacy results bare been 
reported (Proc. Ai. Assoc. Cancer Bes. 16, 79, 1975). 



62. IBtLTSIS OF BEGULATOBI CO»TBOL OF CELL 

PBOLIFERATIOM IH HOBHAL. PBgBALlGWAHT AMD HALIGBAWT 
COLOBIC TISSUES IB FABILIAL POLIPOSIS 

Lipkin, «., Augenlicht, L. , Deschner, E. , Kopelowich, 



OBJECTITE: To develop indices of neoplastic 
transf orsation defining the stages of preneoplasia in 
cells of a huian population at high risk of colon 
cancer. 

APPBOACH: Patients are stuiied who have 

due to inherited adenoaatosis of the colon and cectua 

bariuo eneaa, in selected instances colonoscopy, and, 
in addition, radiological eiaaination of bone 

neoplasas. Biopsies of colonic lucosa are reaoved and 
incubated with tritiated thyaldine to detect abnoraal 
location in colonic crypts of cells synthesizing DBA, 
and for evidence of atypia and aalignancy. washing of 
colonic aucosa containing surface epithelial cells 
also ate analyzed for thyaidine incorporated, enzyaes, 
atypical cytology and carcino-eabr yonic antigens. 
Speciaens of colonic aucosa are iaplanted under the 
kidney capsule of iaiunodef icient nude aice and growth 
characteristics of speciaens studied. 

In addition, skin biopsies are taken froa the 
upper an of the patients, cutaneous cells cultured, 

various aedia and under the influence of growth 
factors. Blood speciaens are taken for analysis of 
cell-aediated and huaoral iaaunologic paraaaters. The 
ability of viral and cheaical agents to induce 
ttansforaatlon of the patients' cells is studied. 

PP0GE5SS: Intestinal and cutaneous cells begin 
to develop characteristics of neoplastic 
transforiation while still appearing norpal on 
conventional lorphological eiaiinations. Individuals 
arc being classified on the basis of abnoraal early 
cellular phenotypic changes that ewolve during the 
stages of transf oraation of intestinal and cutaneous 
cells. These include the devalopaent of an increased 
ability of cells to proliferate and then to accunulate 
In Intestinal aucosa, decreased nutritional 
tcgulreaent for growth of cutaneous cells. Induction 
of transfonation by viral and chealcal agents, 
nuclear protein nodif ications and associated changes 
In ianunologlc paraaeters developing during early and 
advanced transfonation. Faailies with genetic 
susceptibility increasing their risk of colon cancer 
are being studied in a screening prograo in which 
these Banifestations of early disease are identified. 



LABORATORY OF ULTRASTRUCTURAL 
RESEARCH 

SLOAN-KETTERING INSTITUTE FOR 

CANCER RESEARCH 

410 E.68TH ST. 

NEW YORK, NEW YORK 10021 

63. BETHODS FOB SCABBIBG BLECTBOI H1CB0SCOPE CITOLOCT 



Deharven, E., Bystricky, 



Laapen, N. 



OBJECTIVE: To detenine what additional 
infonation on the fine structure of cell surface can 
be obtained by recently developej techniques oC high 

APPBOACH: Coaiiace various aodes of cell saapllng 
(silver neabianes vs. polylysine fllas). Co.pare 
various .nodes of conductive coating (gold evaporation 
vs. gold- sput terlng vs. evaporation in oil-free 
vacuu.). Co.pare i. aging of cell surface with 
conventional scanning electron aicroscopy, field 
eaisslon scanning electron aicroscopy, and 



PBOGBESS; The labile natara of surface 
structures is being clearly recognized. The 

aicroscope has aade it possible to identify viruses 
budding on cell surfaces. The advantages of critical 
point drying have been well established. 



OBJECTIVE: Characterization froa a biological, 
ultrastructural and blochealcal viewpoint of the viru 
particles released by L1210 cells aade resistant to 
actlnoaycin-D. 

APPBOACH: To apply techniques of transalssioD 
electron aicroscopy and blochealcal analysis to the 
study of virus derived froa the supernatant of 
cultured L121C cells chronically aalntained under the 
influence of actinooycin-D (1 aicrogra«/al( , and 
correlate the results with the tusorigenicity of the 
drug-resistant cells. 

PBOGBESS: The t uaor igeniclty of the 
drug-resistant cells is low but their iaounogenic 
potential in BDFl (OflA/2 i C57BLI alee is intact. In 

treataent of the cell line with actinoaycin-D results 
In a sodden decrease In viral expression. 



65. TBJBSBISSIOB ELECTBQB BICBOSCOPT OF B»l TOBOB 



en, E., EV 



on, D. P., Bystricky, ». 



OBJECTIVE: Apply techniques of high resolution 

characterization of RHA tuaor viruses, and apply 
techniques of critical point drying to these saae 
viruses with the purpose of developing better aethods 
of direct counting under the electron aicroscope. 

APPROACK: A aethodology of transaisslon electro 
aicroscopy which routinely gives 3 angstroa units 

bright field and dark field aodes of illuaination, 
will be applied to SUA tuaor viruses prepared by 

critical point dried BHA tuaor viruses (Friend 
leukeaia viruses and Fauscher leufceaia viruses 
produced in vitro) are being counted visually or by 



type 



utoa 



al cha 



alyz 



e-drying. Our prelinlnary res 
ate that aethods based on also 
rbon fllas is grossly Inadequa 



66. IDEHTIFICATIOB OF CELL SOBFACE AHTIGEBS WITH 

BABBEBS BECOGBIZED OHDBB TBE SCAMHIBG ELECTBOM 

aiCBOSCOPE 

Deharven, E. , Paaaerllng, U., Laapen, M. 



recognized 



OBJECTIVE: TO apply specific 
interpretation of cell surface stri 
by scanning electron aicroscopy. 

APPBOACH: Apply the technique of hybrid antibody 
(developed by one of us, U. Haaaerlmg) to the 
identification and possible aapping oE cell surface 

PROCBESS: Specific identification of various 
■urine antigens on the surface of lyaphocytes has been 
achieved with Inv as a aarker recognizable under the 
scanning electron aicroscope. 

Biblographic references: Haanerling et al., J. 
E«p. Bed.. Hl:i18, 1975. 



67. SCABBIBG ELECTBOB BICB05C0PI ABD TEABSBISSIOB 



OBJECTIVE: Characterize surface aorphology of 
huaan leukocytes with special eaphasis on lyaphocytes 
collected froa noraal and leukealc individuals. 

APPROACH: Apply iaproved preparatory procedures 
for the saapllng of concentrated leucocytes to the 
study of these cells under the scanninq electron 
aicroscope. The cells will be dricj by the critical 
point drying aethod. Aliquot saaples will be prepare 



opy 



ntrolled. Surfa 



ercnce of the 
upon concentrated 

their saapllng tor 
ng progressiv-ly be 



101 



scanning electron ml 
observations aade or 
conditions, ulth the light aicroscope equipped Kith 
Koaacskl optics. Kuaan lyaphocytes, purifiei by the 
rlcoll-Hypaquc technique and collected on silver 
aeabcanes, ace coapaced <ith cells collected on 
polyljsine (lias accocdinq to the technique recently 
described by nazia. 



(S. TBHSBISSIOI EI.ECTBOH HICBOSCOPI OF TIBtL »nCl.EIC 

BCID 

Eienson, D, p., Debarven, B. 

OBJECTIVE: Contribute by electron aiccoscopy to 
the structural characterization of the SNA aurine 
lenkeala viruses and soae o£ their replicative foras. 

kPPBOACH: Focus attention on optiaua 
preservation of intact virions (friend leukeaia 
viruses and Bauschet leukeala viruses) prior to RH» 
eitraction. Apply aodified Kleinschaidt techniques to 
the electron aicroscope study of Bm aolecules in 
various conditions of denaturation. Take advantaqe of 
cecent developaents in this laboratory in dark field 
electron alcroscopy to study unstained and 
unshadov-casted aacroaolecules. 

PBOGBESS: Histograas of length distributions 
have already clearly indicated a significant 
difference betveen SHA isolated froa Friend virus 
gtovn in tissue culture as coapared to Friend virus 
isolated froa leukeaic mice. The problea of DBA 
contaalnation of aany BHA saaples is being critically 
studied. 



OBJECTIVE: Study, by scanning electron 
alcroscopy, the interactions between nacrophages and 
lyaphocytes of 6CG sensitized rabbits. 

IPPSOACH: Lung rabbit aacrophages collected froa 
BCG sensitized aniaals vill be incubated in vitro, 
under various eiperiaental conditions aiaed at 
reaching a better understanding of the conditions 
leading to the focaation of giant cells. 

PBOGBESS: Giant cell foraation in this 
ezperiaental systea is being reproducibly observed and 
characterized both under scanning electron microscopy 



»S, (c) cobra venoa factor (cvr) inactivated serua, 
(d) ahole blood, (e| fresh plasaa, and (f| leukeaic 
serua. The BC are infused tvice veekly for 2 veeks 
or until a aarked anti-leukeatc effect is seen. 

PBOGBESS: When adainlsterei to cats, noraal c 
secUB, heat and CVr inactivated US, fresh plasaa an 
■bole feline blood have a narked antl-leukeaic effe 

antl-leukeaic activity. To date, only noraal ahole 
canine blood and fresh plasaa have been adainistere 
to dogs with ISA and both have been shown to be 
effective in causing a regression of the disease, 
are now atteapting to deteraine the antl-leukeaic 
factors In cat and dog blood. 



72. SBBOEPIDEBIOLOGICAI. STUDIES Of FBLIBE lIOBEgH 
VIBOS IFEtVI IH PET CATS 

Hardy, u. D., Old, L. J., ncClelland, A. J., Zuckecaan, 
E. E. 

OBJECTIVE: To prevent the infectious spread of 
FeLV in the natural environaent. 

APPROACH: Pet cats living in their natural 
environaent (i.e. households or catteries) are tested 
for FeLV by the indirect iaaunof luorescent antibody 
(IFA) test pecforaed on peripheral leukocytes. All 
infected cats are reanved (or isolated) and any 
reaaining uninfected cats cetested after a period of 3 
aonths. If all the cats which are negative in the 
first test reaain negative in the second test, the 
household is considered to be virus free. 

PBOGBESS: Using this test and reaoval prograa, 
the spread of FelV has been successfully prevented in 
the natural environaent. Ve have now iapleaented FeLV 
control studies in 16 households. In 51 households, 
the owners reaoved or isolated their FeLV-inf ected 
healthy cat (s) iaocdiately after testing, while in 25 
households the infected healthy cat(s) were left with 
uninfected healthy cats. In the 51 households where 
the infected cats were reaoved, a total of 3u7 healthy 
cats were initially tested for FeLV, of which 190 were 
infected and 6S7 were uninfected. Of these 657 
uninfected cats, only 3 (0.U6 percent) subsequently 
becaae infected. In the 25 households where the FeLV- 
infected cats were not reaoved or isolated, u13 cats 
were Initially tested, of which 129 were FeLV Infected 
while 261 were uninfected. of these 2eu uninfected 
cats, 55 (19.3 percent) subsequently becaae infected 
and 7 have developed lyaphosarcoaa (LSA). These 
teenlts show that it is possible to prevent the spread 
of FeLV, and the diseases it causes, by relatively 
slaple procedures. 



LABORATORY OF VETERINARY 
ONCOLOGY 

MEMORIAL SLOANKETTERING 

CANCER CENTER 

1275 YORK AVE. 

NEW YORK, NEW YORK 10021 



ith and without 



OBJECTIVE: TO invest! 
coaposition and quality of 
coapleies In FeLV infected 
lyaphosarcoaa. 

APPBOACH: Infectious virus-antibody coaplex 
are detected by the technique developed by Botkin 
This technique consists of incubating the 
FeLT-antibody coapleies with anti-iaaunoqlobulins 
The antl-iaaunoglobulins attach to the antibody 
coaponent of the coapleres, resulting in 
neutralization of infectivlty. J virus which is 
associated with anti 
neutralized by anti- 
Infected cats is collected and reacted with either 
noraal rabbit serua or rabbit antl-fellne 
laaunoglobulin. The reaction aiitures are then added 
to separate feline tissue culture cells. After 3 
weeks the 2 cultures will be assayed for FeLV 
Infection by the fixed cell laaunofluorescent antibody 
test. 

PBOGBESS: Infectious circulating laaune 
(FeLV-neutraliiation antibody) coapleies have been 
found in all 8 healthy vireaic cats tested to date. 



OBJECTIVE: To deteraine the aecbanlsa of 
seruB-aedlated leukeaic cell destruction. 

APPBOACH: Cats and dogs with naturally occurring 
LSA are treated with the following blood constituents 
(BC|: (a) noraal serua (HS) , (b) heated inactivated 



73. PDBLIC BEALTH ASPECTS OF rgtllt lEOKEglB TIBBS 
IPELV) 
Hardy, ■. D. , old, L. J., BcClelland, A. J., Zucker 

E. e. 

e whether FeLV Is a haz 



OBJECTIVE: To dete 
to haaan health. 

APPBOACH: Huaans 1 
are tested for the prese 
m addition, serua froa 
neutralizing antibodies 
past eiposure to the vir 

PBOGBESS: SO far, 
and neoplastic huaan tis 
have been tested for the 
As yet, no FeLV antigen 
including those living o 
cats. One hundred and fo 

tested for neutralizing antibody to FeLV, including 
soae with cancer who had been exposed to FeLV. 
neutralizing antibody has been found. whil 



ving with FeLV-inf ected 
ce of FeLV by the IFA te 
hese people is tested fo 
o FeLV to deteraine thei 

of nor 



ny huB 



150 


speclae: 


and 


505 1 


huaal 


senc 


f> of 


PeLl 


been 


foul 


nd li 


leopl 


e ha' 


ve a: 


body 


to 


FeLV, 



ed 



and the possibility that iaaunosv 
fetuses and newborn Infants are i 
infection has to be investigated. 



eds to be do 



ppr 



7U. PBTELOPHEBT OF A FBLIBE LEOKEHIA VIBOS (FELV) 

VACCIBB 

Hardy, w. D. , Old, L. J., BcClelland, A. J., Zuckeraan, 

E. E. 

OBJECTIVE: To develop a safe and effective Fol» 
vaccine for veterinary use. 

APPBOACH: Three possible types of FeLV vaccine 
are being studied; (1) a vaccine coaposed of live FeLV 
attenuated by long-tera passage In tissue culture; (2) 
a killed FeLV vaccine; and (3) a vaccine coaposed of 
only the outer envelope antigen of the virus. 

PBOGBESS: Nine cats have been laaunized with 
live attenuated FeLV and have developed high 
neutralizing antibody titers (1:2C to 1:6U0). Three to 
6 weeks after laaunization, u of these cats becoae 
vireaic and were thus a potential source of infection 
for susceptible cats. This problea would be overcoae 
with a killed FeLV vaccine. To date, u cats have been 
laaunized with killed FeLV, but only one cat developed 
neutralizing antibody and then only at a low titer 



102 



(1:20). Dabblt 



s hsTe produced neuttalllinq 
»lth ?8LV gp 70 <]lycoprateln. 
thus appears to b<» feasible. 



75. IDElTinOTOl OF ftLUe LEOKEBU HIOS (fCLt) 
SElOTIPtS II rtLItt DISEtStS 

Batd7, a. D., Old, I. J., ncclelland, k. J., Zuckeraa 
E. E. 

OBJECTITE: To detecaibe nhethec diffecent reLf 
••cotypes causes diffecent diseases, 

IPPBOACH: Three diffecent PeL« secotypes ace 
kBoao <A, B, and C) . It Is possible that these 
diffecent serotypes cause diffecent diseases by 
•ffectib? diffecent cell types. This labocatocy is 
atteipting to pcoduce specific antiseca to identify 
the reLf secotypes. These antiseca aill be .tilized 



in the fiied-cell flu 
in ordec to deteraine 
disease association o 

PtOSRESS: Peiv 
96 cats (56 healthy c 



type 



cotypes have been isolated fcoa 
s, 38 »ith Tall diseases and 2 
d identified by Dc. 0. Jaccett 
Qslng the •ical irtecfecence tests. There ace not yet 
enough cats in this study to allow us to dcaw any fica 
conclusions as to the association of specific FeLV 
secotypes aitb specific FeLV diseases. Thece ace, 
hovevec, pceliainacy indications that FeLT secotype A 
is the pcedoBinant secotype in healthy infected cats. 
To date, FeL? secotype », eithec alone oc in 
coebination with othec secotypes, has been isolated 
ftOB evecy pet cat tested. Thece has only been 
liaitcd success in pcoducing specific antiseca to each 
FeLV secotype because of difficulties in growing the 
puce serotypes in tissue cultuce. 



103 



APPENDIX I 

LXBOHATORI OF ANIHAL VIROLOGY 

SLOAM-KETTERING INSTITOTE FOR CANCER RESEARCH 

aiO E. 68TH ST. 

NEH YORK, HEH YORK 10021 



1. REPLICATION OF REOVIRUS 
Gomatos, P. J. 

OBJECTIVE: To identify and characterize the 
particles containing reovirus replicase and 
transcriptase. 

APPROACH: Both the wild-type virus and ts 
mutants of reovirus will be used for infection at 30 
degrees and at 37 degrees. We expect that structures 
synthesizing double-stranded RNA will accumulate in 
cells infected at 37 degrees with our mutant viruses. 
He will extract the subviral particles from various 
cytoplasmic fractions and separate them into their 
different size classes by sedimentation through 
sucrose or glycerol density gradients. We will 
concentrate our efforts to identify structures among 
the particles synthesizing double-stranded RNA's which 
contain only the single-stranded RNA templates. By 
varying ionic conditions, pH, or by use of mild 
detergents, we will attempt to identify whether the 
single-stranded RNA's of these particles are in any 
way linked to form an RNA molecule greater than 2US. 

PROGRESS: He have analyzed the particles from 
infected cells which sediment from 2003 to 250S, from 
250S to 3C0S, and from UCOS to 60CS for their RNA 
content and for active replicase and transcriptase. 
Our results suggest that the presumed precursor to the 
particle synthesizing doubla-stranded RNA is a 
particle which sediments from about 20CS to 2503. 
These particles do not synthesize in vitro any 
double-stranded RNA, but they do contain in vivo 
synthesized virus-specific RNA. We presume that these 
are the particles which contain the single-stranded 
RNA templates for double-stranded RNA synthesis, and 
that these particles do not have active replicase. 
These particles have a density in cesium chloride of 
1.34 g/ml, which is different from that of virus or 
viral cores. Particles greater than 2503 do synthesize 
double-stranded RNA. In addition, these particles have 
an active transcriptase. They support synthesis of 
single-stranded RNA's using as templates the nascent 
double-stranded RNA's, even though all the double- 
stranded RNA synthesis within a particular particle has 
not been completed. 



2. REPLICATION OF SEHLIKI FOREST VIRDS 
Gomatos, P. J., Sawicki, D. L. 

OBJECTIVE: To identify and characterize the 
Semliki Forest virus (SFV) RNA replicase (s) , its 
templates, and its products. 

104 



APPENDIX II 



Laboratory of Lipids and Lipid Complexes 



AS, Development of a simple, precise method to 
separate and quantitate serum high density 
lipo-protelns, (HDLZ and HDL3) 

Barclay, M.. Stock. C. C. 

OBJECTIVE: To devise a relatively simpler 
procedure than analytical ultracentrifugation to 
separate and quantitate both HDL2 and HDL3 of 
blood serum. 

APPROACH: There are some indications that the 
levels of certain high-density lipoproteins, specif- 
ically HDL2, may be related to cancer, therefore a 
less expensive and simpler procedure to obtain 
accurate values for these in human serum is being 
sought. Polyacrylamide gel electrophoresis has 
been used to separate successfully the serum HDL2 
from HDL3. The two bands containing the 
lipoproteins are discretely obvious when either a 
dye or trichloracetic acid are used to identify' them. 
The sera are treated concurrently with the density 
gradient separation, using sequential increases in 
KBr, in the preparative ultracentrifuge (Beckman- 
Spinco Model L) to separate HDL2 (D is greater 
than 1.0635 and less than 1.125 g per ml) and 
HDL3 (D is greater than 1.125 and less than 1.210 
g per ml) in KBr solutions. The exact quantities of 
HDL2 and HDL3 are calculated after sedimenta- 
tion velocity (flotation) in the analytical ultra- 
centrifuge (Beckman-Spinco Model E). 

PROGRESS: These two HDL's appear to separate 
well on polyacrylamide gel under specific condi- 
tions. The principal ongoing problem is to treat the 
bands (disc) containing the HDL in ways that will 
yield a measure of their quantities which will 
correlate significantly with data from the analytical 
ultracentrifuge. 



49. Biochemical studies of plasma membranes 
from rat liver and hepatomas 

Barclay, M., Dnistrian, A. 

OBJECTIVE: To determine and quantitate certain 
of the chemical (and biochemical) components of 
plasma membranes from normal rat liver and 
relate these levels and relationships to the same 
parameters in plasma membranes from hepa- 
tomas. 

APPROACH: Plasma membranes are isolated in 
acceptable purity and yields from both normal rat 
liver and. from the Morris hepatoma 5123tc. A 
systematic analysis of the saline-soluble (extrinsic) 
and insoluble (intrinsic) proteins included assays 
for marker enzyme(s) activities; amino acid 



compositions; analytical ultracentrifuge (Beckman- 
Spinco Model E) studies to prove their lipoprotein 
nature; separation and identification of protein 
subunits by polyacrylamide gel with SDS; hexose 
and lipid compositions by gas chromatography. 
The intrinsic fraction is composed of a number of 
subcomplexes containing substantial amounts of 
lipids (especially free cholesterol), carbohydrates 
and proteins. These are separated routinely by a 
density gradient system devised here, and studied 
as described. 

PROGRESS: A number of the physicochemical 
and biochemical characteristics of the membrane 
lipoprotein complexes of the intrinsic portion of the 
plasma membrane are now known. These are 
relatively less polar than the saline-soluble extrinsic 
protein which has no measured enzyme activities. 
less lipid and more carbohydrate associated with it. 
A number of the documented features of the 
plasma membranes from normal liver are aberrant 
in plasma membranes from hepatomas, not only 
quantitatively, but qualitatively. 



SO. Neoproteolipids associated with malignant 
tumors 

Skipski. V. P.. Barclay. M.. Stock. C. C. 

OBJECTIVES: a) To elucidate the chemical 
composition of protein-lipid complexes of a proteo- 
lipid type, tentatively called neoproteolipids, 
isolated from malignant tumors; b) To determine 
the degree of specificity of association of these 
complexes with malignant growth; c) To investigate 
the appearance (or raised level) of these complexes 
in blood sera in order to serve as a potential 
diagnostic cancer test and/or as a test of the 
efficacy of the medical treatment of cancer. 

APPROACH/PROGRESS: From the lower phase 
of Folch-partitions of lipid extracts from tumorf. 
protein-lipid complexes, neoproteolipids (NPL), 
have been isolated on systems of silicic acid 
chromatography columns. There are two types of 
NPL: neoproteolipid-W (NPL-W), originally iso- 
lated from Walker carcinosarcoma 256 (W256), 
and neoproteolipid-S (NPL-S), originally isolated 
from Sarcoma 180. Around 20 different trans- 
planted, chemically-induced and spontaneous 
tumors (including human tumors) were tested, and 
all of them contained either NPL-W or NPL-S 
(Prog. Biochem. Pharmacol. 10:112, 1975). Both 
neoproteolipids are complexes of glycosphingo- 
lipids with other lipids (phospholipids, cholesterol) 
and proteins (or polypeptides). NPL-W contains 
neutral glycosphingolipids (which contain fucose). 



105 




ICf^OB 



CANCERGRAM 



ONCOFETAL 
PROTEINS 



NCI/ICRDB/CBOl 77/03 



JUNE 17, 1977 



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In this issue: 



STRUCTURE/IDENTIFICATION/ 

CHARACTERIZATION 1-4 

ASSAY PROCEDURES 5-8 

CYTOCHEMISTRY/ 

HISTOCHEMISTRY 9-12 

SYNTHESIS 13-15 

CLINICAL/DIAGNOSIS 16-32 

OTHER RELATED STUDIES 33-35 



STRUCTURE/IDEN- 
TIFICATION/CHARACTERIZATION 



CARCINOEMBRYONIC ANTIGEN-LIKE SUBSTANCES OF 
HUMAN BILE: ISOLATION AND PARTIAL CHARACTERIZA- 
TION. 

Svenberg T 

Departments uf Clinical Chemistry and Surgery, Daiideryd Hospital. 

Danderyd, S»cden 
Inl J Cancer; l7(5):588-596 1976 

Three species of carcinoembryonic antigen (CE.'\)-!ike 
niacromolcculc'i. called the biliary glycoprotein 1. II and III 
(BGP I, II and III) were idenuried in human bile. BGP 1 was 
found in normal gall-bladder bile and hepatic bile but not in 
bile subjected lo inflanlmation ( while bile ). It was im- 
munologi--5i!ly related to CEA and NGP (Ihe normal CE.\- 



like glycoprotein . Synonyms: NCA, CCEA-2, etc.). BGP I dif- 
fered immunologically from CEA in that it lacked the tumor- 
associated determinants of CEA. It was different from NGP 
(and CE.A) in thai it contained BGP I specific determinants as 
revealed by anti-BGP I antibodies. In bile from gallbladders 
with obstructed outlet and subjected to cholecystitis, a non- 
malignant inflammatory process, BGP I was replaced by BGP 
II and BGP III. Immunologically and physicochemically. BGP 
II and BGP III appeared to be closely'similar to NGP and 
CEA, respectively. (Author Abstract) 



IMMUNOLOGICAL CROSS-REACTIVITY OF ANTIBODIES 
TO A SYNTHETIC LNDECAPEPTIDE ANALOGOUS TO THE 
AMINO TERMINAL SEGMENT OF CARCINOEMBRYONIC 
ANTIGEN, WITH THE INTACT PROTEIN AND WITH HU.MAN 
SERA. 

Amon R, Buslin M, Calef E. Chaitchik S, Haimovich J, Novik N, 
Sela M 

Department of Chemical Immunology, The Weizmann Institute of 
Science, Reho^ot, Israel 

Proc Natl Acad Sci USA; 73(6):2123-2127 1976 

A peptide corresponding to the 1 1 amino acid residues of 
the NH2-terminal portion in the sequence of car- 
cinoembryonic antigen (CEA) has been synthesized by the 
solid phase technique. The synthetic CEA(l-ll) peptide was 
attached by means of a water-soluble carbodiimide reagent to 
multichain poly(DL-alanine) as well as lo bovine serum 
albumin. Both macromolecular conjugates provoked in rabbit 
;inti-CEA(l-l 1) peptide antibodies. The specificity of this im- 
munological system and the crossreactivity between the pep- 
tide and inlact CCA were investigated by two methods-passive 
hemagglutination and modified bacteriophage inactivation. 
Hemagglutination experiments showed that not only ami- 



U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 
Public Health Service a National Institutes of Health ■ National Cancer Institute 



107 



CEA(1-1 1) sera, but also anti-CEA sera, agglutinated CEA(I- 
ll)-coaled sheep erythrocytes, and both these reactions were 
inhibited with CEA(l-ll) peptide. In experiments with the 
chemically modified bacteriophage technique CEA(l-ll)- 
coated phage was efficiently inactivated with antisera against 
the CEA( 1-11) conjugates, and the inactivation reaction could 
be totally inhibited with the free peptide. The semipure CEA, 
but not the pure protein, could also inhibit the phage inactiva- 
tion, even though less efficiently. On the basis of the above 
results, sera of some cancer patients were tested for their 
capacity to inhibit the inactivation of CEA(I-1 l)-coated phage 
by means of anti-CEA(l-l 1) antiserum. The results indicate 
that sera from a large proportion of patients with adenocar- 
cinomas of the digestive tract, pancreas, and breast are capable 
of inhibiting the above inactivation, whereas most normal sera 
do not inhibit. (Author Abstract) 



METHYLATION ANALYSIS OF THE CARBOHYDRATE POR- 
TION OF CARCINOEMBRYONIC ANTIGEN. 

Coligan JE, Pritchard DG, Schnute WC, Todd CW 

Department of Immunology, City of Hope National Medical Center, 

Duarte, Calirornia 91010 
Cancer Res; 36t6):1915-1917 1976 

The carbohydrate structural units of carcinoembryonic 
antigen samples isolated from four different tumors were 
quantitated using gas chromatography-mass spectrometery 
after methylation and subsequent conversion to their alditol 
acetates. Different carcinoembryonic antigen preparations 
showed some quantitative but no qualitative differences in the 
structural units present. The results indicate that a large por- 
tion of the fucose residues in the glycoprotein was linked to N- 
acetylglucosamine and that most of the branching mannose 
residues were probably linked to three N-acetylglucosamine 
residues. (Author Abstract) 



CARCINOEMBRYONIC ANTIGEN IN CEREBROSPINAL 
FLUID. (MEETING ABSTRACT) 

Snitzer LS, Mckinnev EC 

University of Miami, Miami, Fl 33152 

Proc Am Soc Clin Oncol; 17:249 1976 

This study was undertaken to determine whether 
carcinoembryonic antigen (CEA) is present in the 
cerebrospinal fiuid (CSF) of patients with neoplastic disease. 
CSF samples from 64 patients with suspected central nervous 
system (CNS) disorders were tested for CEA using the Hansen 
(Roche) assay. Patients were then grouped according to the 
presence or absence of neoplastic disease in the CNS or 
elsewhere in the body. Fifty patients had no demonstrable 
malignancy. Of these, 35 patients had no detectable CEA in 
their CSF, while 15 had CSF-CEA titers ranging from 0.5 to 
1.3 ng/ml. Six patients had some form of active malignancy 
outside of the CNS without demonstrable CNS metastases. 
None of these patients was found to have detectable CSF- 
CEA. Plasma-CF-.^ in these 6 cancer patients ranged from 3.1 
to 1480 ng/ml. Two patients with primary gliomas had no 
detectable CSF-CEA, but one patient with a 
craniopharyngioma had a CSF-CEA level of 2.2 ng/ml. Five 
patients had some form of carcinoma with microscopically 
verified CNS metastases. The range of CSF-CEA in 4 of these 
patients was 3.2 to 445 ng/ml. 1 he liter was 1.8 ng/ml in the 
fifth patient. These results indicate the CEA can be present in 
the CSF of patients with carcinoma metastatic to the CNS. 
Further investigation will be necessary to confirm the observa- 
tion that CSF-CEA is usually undetectable or present in very 
low titer in patients without CNS tumors. (Author Abstract) 



ASSAY PROCEDURES 



DETERMINAIION OK CARCINOEMBRYONIC ANTIGEN 
(CEA) IN PATIENTS WITH TUMORS OF THE LARGE 



INTESTINE. EXPERIENCE WITH A NEW RADIOIMMUNOS- 
SAV. 

Lamerz R, Ruider H 

I. Med. Klinik der Universitat, Ziemssensir 1, D-8000 Munchen 2, 

W. Germany 
Munch Med Wochenschr; ll8(12):37I-376 1976 

Specimens from 93 patients with histologically confirmed 
tumors of the large bowel (53 single, 40 sequential deter- 
minations) were investigated by a new carcinoembryonic an- 
tigen (CEA) radioimmunoassay (double antibody method, 
direct serum determination). Of the single and preoperative se- 
quential determinations, 37% to 40% were normal (below 2.5 
nanog/ml), 33% were intermediately elevated (2.6-15 
nanog/ml) and 26% to 28% were highly pathologically 
elevated (over 15 nanog/ml). Following surgery, patients with 
local or regionally confined tumor showed significantly more 
normal or normalizing CEA levels within I to 6 wk (17/27). 
whereas patients with overt metastases developed more 
pathological or increasingly pathological levels (8/11). (26 
refs) 



A DIRECT RADIOIMMUNOASSAY FOR CAR- 
CINOEMBRYONIC ANTIGEN IN PLAS.MA. (MEETING 
ABSTRACT) 

Coates JE 

WW Cross Cancer Institute, Edmonlon, Alberta T6g 1Z2 

Proc Am Assoc Cancer Res; 17:154 1976 

Evidence that the tumour-associated antigenic site of 
carcinoembryonic antigen (CEA) may be located on the pro- 
tein backbone has important implications with regards to the 
radioimmunoassay (RIA) of this substance in the plasma of 
cancer patients. The commercially-available RI.A (CEA- 
Roche) is indirect, utilizing the solubiluy of CE.A in perchloric 
acid (PCA) to isolate the antigen from interfering plasma pro- 
teins. Conceivably, some malignant tissues produce the pro- 
tein moiety of CEA without subsequent aliachmenl of suf- 
ficient oligosaccharide side chains to confer PCA solubility. 
The apparent CEA concentration in the plasma of patients 
with such neoplasms would thus be falsely low by the indirect 
assay. An assay without PCA extraction has been developed 
which uses a two-step dilution to overcome interference by 
plasma proteins. Good agreement with the indirect assay has 
been observed for 151 samples. However, serial plasma sam- 
ples from two patients with metastatic colonic carcinoma 
which showed normal CEA titres in the indirect RIA were 
significantly elevated in the direct assay, .^ssay of plasma sam- 
ples directly may decrease the incidence of false-negative 
results. (Author Abstract) 



MODIFICATIONS AND EVALUATION OF DOUBLE AN- 
TIBODY RADIOIMMUNOASSAY OF HUMAN CAR- 
ClNOEMBR^OMC ANTIGEN. 

Das S, Das BR, Terry WD 

Advanced Testing and Development Laboratories, Litton Bionctics, 

Inc, Kensington, Maryland 20795 
Cancer Res; 36(6):1954-I961 1976 

Double antibody radioimmunoassay of carcinoembryonic 
antigen (C~EA), a cancer-associated antigen of the human 
digestive system, was subjected to certain modifications and 
critically evaluated. Modifications pertained to: la) the 
production of a high tiler goat anti-CEA antiserum that was 
rendered highly specific by solid phase immunoubsorplion 
with cyanogen bromide-activated Sepharose conjugates of 
normal plasma, liver, and colon perchloric acid-soluble 
glycoprotein antigens; (b) the introduction of suitable allcra- 
Cions in the experimental conditions of radioiodinalion 
procedure to minimize and to prevent breakdown of the an- 
tigen, thus prolonging the storage of the labeled antigen; (c) 
the extended incubation period of CEA-anii-CEA immune 
reaction; and (d) the use of sodium acetate buffer, pH 6.1 
Furthermore, the use of an automatic pipetling station for ac- 
curate and rapid reagent dispensation and statistical analysis 



108 



of the radioimmunoassay data on a modern computer to en- 
sure strict quality control of the assay provided some defmite 
improvement over the existing assay. (Author Abstract) 



CLINICAL EVALUATION OF CARCINOEMBRYONIC AN- 
TIGEN ASSAY IN VARIOUS DISEASES. 

Imaeda T, Scnda K, Kato T, Asada S, Matsuura S, Vamawaki V, 

Kunieda T, Do! II 
Dcpt. Radiology, Faculty Medicine, Gifu Univ., Japan 
Nippon Acta Radiol: J6(ia):9IO-92l 1976 

Carcinoembryonic antigen (CEA) was examined in various 
diseases by radioimmunossay. By fixing the upper limit of nor- 
mal CEA value to 2.5 nanog/ml. highly positive CEA values 
were found mainly in carcinomas of the digestive organs such 
as gall bladder, colon, rectum, and stomach, and in metastatic 
liver carcinoma, pancreatic carcmoma, and lung carcinoma. 
Positive values were observed in adenocarcinoma except m 
epidermoid carcinoma of the lung. The most elevated level was 
seen in a 69-yr-old woman with adenocarcinoma of the rectum 
and liver metastasis. Examination of the relationship of CEA 
values with well differentiated and poorly differentiated 
adenocarcinomas of the stomach and large intestine revealed 
no significant correlation between the degree of differentiation 
and CEA value. However, when patients with carcinoma of 
the stomach, large intestine, and pancreas, with and without 
liver metastasis, were compared, elevated CEA values and 
positive results were found in those with liver metastasis. It is 
conceivable that CEA levels are highly related to the extent of 
carcinoma infiltration. Comparison of patients with car- 
cinomas of the stomach and large intestine with liver 
metastasis, showing multiple or single defect on liver scin- 
tigrams, indicated that elevated CEA values and positive 
results were significant In those with multiple defects. This fact 
suggests that the CEA value is also highly related with the size 
or vol of carcinoma mass. Through assaying both CEA and 
alpha-fetoprotein (radioimmunoassay method) in the serum of 
a patient with liver carcinoma, either hepatoma or metastatic 
liver carcinoma from digestive organs was differentially 
diagnosed. In patients with CEA values below 8 nanog/ml and 
alpha-fetoprotein values above 20 nanog/ml, 98% of the cases 
were hepatoma while only 2% were metastatic liver carcinoma. 
On the other hand, all cases showing CEA values above 10 
nanog/ml and alpha-fetoprotein values above I0'*3 
nanog/ml were metastatic liver carcinoma from the stomach. 
Successful surgery results in a rapid negative CEA value. The 
half-life of CEA is under 7 days, similar to the half-life of 3.1 
to 5.1 days for alpha-fetoprotein Since the CEA positivity is 
low in early carcinoma, the CEA assay does not seem adequate 
for the detection of early carcinoma. The most elevated CEA 
value (4.6 nanog/ml) of 138 benign diseases was seen in a 59- 
yr-old man with active chronic hepatitis. The CEA value for 
all cases of benign diseases was below 5 nanog/ml. The limit of 
CEA value to differentiate malignant and benign cases is as- 
sumed to be 5 nanog/ml. (33 refs) 



CYTOCHEMISTRY/HISTOCHEMISTRY 



IMMUNOFLUORF.SCE\T DEMONSTRATION OF ALPHA- 
FETOPROTEIN AND OTHER PLASMA PROTEINS IN YOLK 
SAC TUMOR. 

Shirai T, Itoh T, Voshiki T, Noro T. Tomino Y, Hayasaka T 
Dcparlmcnl of Pa(holo|!y, Sapporo City General Hospital, Kila-I, 

Nishi-9, Sapporo, Japan 060. 
Cancer; 3«(I):I661-I667 1976 

All seven pure yolk sac tumors of gonadal and extragonadal 
origin tested showed a bright positive lluoresccnce for alpha- 
fetoprotein in the tumor tissue. A positive reaction was seen in 
both the tumor cells and the hyaline globules. In all cases. 



however, the positive fluorescence was distributed in some 
focal areas of the tumor tissue. Certain tumor cells showed a 
strong granular intracytoplasmic fluorescence, whereas others 
showed a weak or a negative Huorescence. The fiuorescence- 
positive tumor cells were located mainly in the areas rich in 
fluorescence-positive hyaline globules. Besides alpha- 
fetoprotein, certain plasma proteins-albumin, alpha-l- 
antitrypsin, and transferrin-were also demonstrated in all five 
yolk sac tumors tested. The pattern of the distribution of 
positive fluorescence was basically similar to that of alpha- 
fetoprotein. Other plasma proteins-orosomucoid, hap- 
toglobin, Gc-globulin. alpha-2 macroglobulin, hemopexin, 
and ceruloplasmin-were present in certain tumors, and were 
distributed mainly in a limited number of hyaline globules. 
Both IgG and IgA were present in two tumors of ovarian 
origin. The immunoglobulins were for the most part present in 
extracellular hyaline globules, suggesting that these are taken 
up from the circulation. Test for fibrinogen, beta-lipoprotein, 
IgM, IgE, bela-lC/beta-lA and beta-IE globulins were 
negative or questionable. In a hepatoblastoma, tests for alpha- 
fetoprotein were positive, but those for other plasma proteins 
were negative. Fine granular fiuorescence was seen in each 
hepatocellular tumor cell. .Mesenchymal elements were virtual- 
ly unstained. (Author Abstract) 

10 

PRIMARY INTRACRANIAL YOLK SAC TUMOR IM- 
MUNOFLUORESCENT DEMONSTRATION OF ALPHA- 
FETOPROTEIN SYNTHESIS. 

Yoshiki T, Itoh T, Shirai T, Noro T, Tomino Y, Hamajima I, 

Takeda T 
The Department of Pathology, Sapporo Municipal General Hospital, 

Kita-I, Nishi-9, Chuoku, Sapporo, Japan, 060 
Cancer: 37(5):23-43-2348 1976 

An autopsy case of a 20-year old male with primary 
intracranial yolk sac tumor (endodermal sinus tumor) is 
reported. Whereas the biopsy specimen obtained from the 
pineal region showed diffuse proliferation of atypical tumor 
cells, the metastatic subdural tumor removed from lumbar 
spinal region had the characteristic histologic appearance of 
yolk sac tumor. The histologic diagnosis was intracranial yolk 
sac tumor originating in the pineal gland. The elevated amount 
of alpha-fetoprotein in the cerebrospinal fiuid and in the 
serum further supported the diagnosis. At autopsy, only 
metastatic tumor was present in the posterior fossa. The im- 
munofiuorescence study demonstrated the presence of intra- 
and extracellular alpha-fetoprotein globules in the tumor tis- 
sue. The intra- and extracellular distribution of alpha- 
fetoprotein, in general, appeared to coincide with that of the 
PAS-positive hyaline globules in the tumor. (Author Abstract) 



BRIEF COMMUNICATION: IMMUNOFLUORESCENT 
LOCALIZATION OF ALPHA-I-FETOPROTEIN IN YOLK SAC 
CARCINO.MAS OF THE RAT. 

Delacourl MC, Sobis H, Vandeputle M 

Rega Institute, University of Leuven, Leuven, Belgium 

J Natl Cancer Inst: 57(6 1:1375-1377 1976 

Alpha- 1 -fetoprotein (AFP) was demonstrated by the 
immunofluorescent antibody staining technique in I primary 
and 3 transplantable yolk sac carcinomas of rats. AFP was 
observed only in structures with a characteristic endodermal 
appearance. This protein was not detected in embryonal car- 
cinoma cells. (Author Abstract) 

12 

INTRACELLULAR DISTRIBUTION OF ALPHA- 
FETOPROTEIN AND ALBUMIN MESSENGER RNAS IN 
DEVELOPING MOUSE LIVER. 

lio T, Tamaoki T 

Showa College of Pharmaceutical Sciences, Tsurumaki, Setagaya- 

Ku, Tokyo, Japan. 
Can J Biochem;-54(5):408-4I2 1976 



109 



Intracellular distribution of active mRNAs for alpha- 
fetoprotein (alphaFP) and albumin in fetal and adult mouse 
liver was studied. Livers were fractionated into nucleus and 
cytoplasm. The latter was further fractionated by sucrose 
density-gradient centrifugation into four subfractions: the top 
fraction containing soluble components, the 1.0 M sucrose 
layer containing primarily SOS ribosomes, the 1.5 M sucrose 
layer containing light polysomes, and the pellets containing 
heavy polysomes. RNA was extracted from each fraction and 
its ability to direct the synthesis of alphaFP and albumin was 
determined in a mouse sarcoma 180 cell-free system. Distribu- 
tion of alphaFP and albumin mRNAs in fetal mouse liver was 
similar: 2% in the nucleus, 98?c in the cytoplasm, of which 
more than 90% was found in the polysome fractions. The 
results suggest that alphaFP and albumin mRNAs, once 
formed, are quickly and efficiently utilized for protein syn- 
thesis. The major proportion of albumin mRNA m adult 
mouse liver was also found to be associated with polysomes. 
However, the amount of translatable alphaFP mRNA was low 
in all subcellular fractions examined, suggesting that transcrip- 
tion or processing of alphaFP mRNA is defective in adult 
mouse liver. (Author Abstract) 



SYNTHESIS 



PROMPT ELEVATION OF RAT SERUM ALPHA- 
FETOPROTEIN BY ACUTE LIVER INJURY FOLLOWING A 
SINGLE INJECTION OF ETHIONINE. 
Watanabe A, MiyazakI M, Taketa K 

Department of Internal Medicine; and Division of Pathology, Cancer 
Inslilute, Okayama University Medical School, Okayama 700, 
Japan 
Inl J Cancer; 17(4):5l8-524 1976 

The mechanism of increased alpha-fetoprotein (AFP) 
production following a single injection of ethionine was in- 
vestigated by using rats aged 5 weeks at the lime of killing. 
Marked elevations of serum AFP concentrations occurred 
within 4 days in both male and female rats after admmistration 
of DL-elhionine or L-ethionine, although the increased levels 
of serum AFP and liver triglyceride in the adults were less 
marked in the male than in the female. No apparent necrosis 
of liver cells was observed in ethionine-treated rats. Frequent 
administrations of adenosine triphosphate after a single dose 
of ethionine prevented the increases in liver triglyceride and 
serum AFP levels. The increased concentrations of serum 
AFP, reaching a maximum level within 4 days, occurred 
before a slight increase in incorporation of **3H-thymidine 
into liver DNA. The serum AFi^ from ethionine-treated rats 
was immunologically and electrophoretically indistinguishable 
from that of fetal, carbon telrachloride-treated or hepaloma- 
bearing rats. These observations suggest that the increased 
production of AFP in ethionine-treated rats is closely as- 
sociated with hepatic injury and is not the consequence of liver 
cell regeneration. (Author Abstract) 

14 

ESTABLISHMENT OF A HUMAN CEA-PRODUCING COLON 
CARCINOMA LINE AND ITS RESPONSE TO ANTITUMOR 
AGENTS. (MEETING ABSTRACT) 

Vang LY, Dretvipko B, Ronisdahl MM 

M. D. Anderson Hospital and Tumor Institute, Houston, Texas 

7702S 
Proc Am Assoc Cancer Res; 17:37 1976 

A line (LoVo cells) derived from human colon carcinoma 
tissue has been propagated for over two years. Cells grow in 
monolayers, display acinar structures, and form colonies with 
a plating efficiency of 40%. Kinetic parameters of exponential- 
ly growing LoVo cells are; doubling lime, 37 hr; generation 
time, 30 hr; and growth fraction, 90%. CEA synthesis is ac- 



complished primarily by cells in stationary phase of growth 
while exponentially growing cells produce negligible quan- 
tities. Release of CEA is independent of phase of growth. 
LoVo cells exposed to increasing doses of ionizing radiation 
show a threshold-type survival curve with Dq and Do values 
similar to those of other human lines. Recovery from sublethal 
damage was demonstrated in fractionated exposure experi- 
ments. Survival curves for LoVo cells treated with increasing 
concentrations of adriamycin show a continuous exponential 
decrease. Survival of hydroxyurea treated cells decreases ex- 
ponentially to a plateau of 45%. Ftorafur and 5 fluorouracil 
show similar threshold type survival curves but ftorafur ap- 
pears significantly more effective. Our data indicate that LoVo 
cells constitute an excellent in vitro model to investigate 
mechanisms of CEA synthesis and to define lethal effects of 
drugs potentially useful in the treatment of colon carcinoma. 
(Author Abstract) 

IS 

A NEW ONCOFETAL ANTIGEN ASSOCIATED WITH 
GASTROINTESTINAL CANCER. (MEETING ABSTRACT) 

Goldenberg DM, Pant KD, Dahlman H 

Depl. Path., Univ. of Kentucky Med. Ctr., Lexington, Ky. 40506 

Proc Am Assoc Cancer Res; 17:155 1976 

The GW-39 human colonic carcinoma continuously 
xenografted to unconditioned, adult golden hamsters has been 
reported to synthesize carcinoembryonic antigen, CEA and an 
organ-associated antigen, CSA. A water extract of GW-39 has 
now yielded an antigen which is distinct from these others, and 
which has immunoreactivity, based upon antibodies prepared 
in hamsters to this extract, with carcinomas of the stomach 
and colon, but not to other neoplastic or normal tissues tested. 
In addition to being present, as demonstrated by immunodif- 
fusion, in gastric and colonic tumors obtained as surgical or 
autopsy specimens, this antigen is also contained in colonic 
cancer cells propagated in vitro and in fetal colon, thus in- 
dicating that it is an oncofetal product. Preliminary im- 
munofluorescence suggests thai it is predominantly a 
cytoplasmic component. This Gl oncofetal antigen also differs 
from CEA and CAS because it is very labile in phenol or 
perchloric acid solutions, as well, as to exposure to boiling 
water for 5 minutes. Preliminary gel filtration indicates that 
this antigen is predominantlv a protein with a molecular size 
range of about 100,000 to 300,000. (Author Abstract) 



CLINICAL/DIAGNOSIS 



16 

CARCINOEMBRYONIC ANTIGEN (CEA) IN OVARIAN 
CANCER; FACTORS INFLUENCING ITS INCIDENCE AND 
CHANGES WHK H OCCUR IN RESPONSE TO CYTOTOXIC 
DRUGS. 

Khoo SK, Mackay EV 

Univ. Queensland, Dcpt. Obstetrics Gynaecology, Royal Brisbane 
Hosp., Brisbane, 4U29, Queensland, Australia 

Br J Obslet Gynaecol; 83( 10);753-759 I<*76 

The serum levels of carcinoembryonic antigen (CE.A) in 109 
women with ovarian cancer were investigated. Histology, 
degree of differentiation, and clinical stage infiuenced the in- 
cidence of positive CEA. Although CE.^ was significantly 
raised in patients with a variety of tumors, the highest in- 
cidence (77%) occurred in patients with serous cystadenocar- 
cinonia. Nearly all (94%) of the poorly differentiated tumors 
were associated with a positive CE.A result. Serial CEA levels 
provided a useful guide to management during cyioH'.Mt 
chemotherapy; rapidly falling levels indicated a I'aviirahie 
tumor response which was .'cllected clinically. However, only 
Iwo-ihirds of tumors were associated with deicciable CE.\ 
levels in serum, day-to-day variations of individual scrum 
levels occurred, and CEA levels tended to fall paradoxically 



110 



during terminal illness. The long term followup by serial CEA 
levels of two patients is presented. The significance of per- 
sistently low levels in the apparent absence of disease was un- 
certain. (19 refs) 

17 

CARCINOEMBRYONIC ANTIGEN (CEA) LEVELS IN 
METASTATIC BREAST CANCER: QL'ANTITATIVE 
CORRELATION WITH PATTERN OF METASTASES. 
(MEETING ABSTRACT) 

Henderson IC, Lokich J, Mayer R. Skarin A, Zamchctk N 
Sidney Farber Cancer Center, Boston, M.A 
Proc Am Assoc Cancer Res; 17:202 1976 

Plasma CEA levels were determined in 172 patients (pts) 
with metastatic breast cancer. 43%(74/l72) had a CEA greater 
than 5 ng/ml, 65/74 with an elevated CEA had either liver 
metastases, an abnormal chest x-ray, or both. Although the 
percentage of pts with pulmonary metastases and an elevated 
CEA was high, a similar number had a CEA greater than S 
ng/ml. In addition, at least 8/41 pts with lung involvement 
and an elevated CEA also had liver metastases and just one 
was unequivocally free of hepatic involvement. In contrast, 
only 4 pts with liver metastases had a CEA less than 5 ng/ml. 
8/24 pts with hepatic disease and a CEA greater than 5 ng/ml 
had no evidence of bone or lung metastases. When serial CEAs 
were obtained in the course of the disease, changes in CEA 
levels were closely correlated with both clinical response to 
therapy and progression of disease, particularly in the liver. 
We conclude that a rising CEA in a breast cancer pt warrants a 
thorough evaluation for evidence of liver involvement. 
(Author Abstract) 

18 

CARCINOEMBRYONIC ANTIGEN-AN ADJUNCT TO 
CLINICAL FOLI.OW-LP OF PATIENTS WITH COLORECTAL 
CANCER. (MEETING ABSTRACT) 

Rao B, Wanebo H, Pinsky C, Steams ,M, Oellgen H, Schwarti M 
Memorial Sloan-Keiterjng Cancer Center, N.Y., N.Y. 10021 
Proc Am Assoc Cancer Res; 17:170 1976 

In order to determine if serial measurements of 
carcinoembryonlc antigen (CEA) are useful in the follow-up of 
patients with colorectal cancer. 147 patients had CEA 
measured by Hoffman LaRoche using The Hansen Zirconyl 
Phosphate gel method. CEA levels greater than or equal to 
Sng/ml were considered elevated. At the time of surgery, CEA 
was elevated in 2/28 (7%) patients with Dukes A, 7/36 (19%) 
patients with Dukes B and 24/45 (53%) patients with Dukes C 
lesions, and 0/38 (0%) patients with benign colon lesions. Post 
operative CEA elevation returned to normal in all these 
patients In a select group of 28 patients with Dukes C who 
had serial determination from 3-24 months, 16 maintained 
normal levels (2 recurred), 12 patients developed elevated 
levels and 9 recurred. Preoperative CEA levels greater than 
lOng/ml were associated with high recurrence rates. 11/12 
patients with Dukes C lesions, who had CEA greater than 
lOng/ml. developed recurrence within 18 months. In contrast, 
only 1 1/33 similar staged patients with initial CEA values less 
than l(Jng/ml developed recurrence (P less than.OS). In 34 
patients who developed recurrence or presented with advanced 
colon cancer 75% had elevated CEA levels. CEA elevations 
were most frequent in patients with liver metastases, and were 
less common in patients with local recurrence. Sequential CEA 
determinations are useful in clinical follow-up of patients who 
have been treated for colorectal cancer and appear most help- 
ful in detecting subclinical liver metastases. (Author Abstract) 

19 

CEA MONITORING OF PALLIATIVE TREATMENT FOR 
COLORECTAL CARCINOMA. 

Herrera MA. Chu TM, Holyokc ED, Millelman A 

Department of Lahoralory \ledicine and Surgery, New York State 

Department of Health, Rosnell Park Memorial Institute, BufTalo, 

New York 14263 
Ann Surg; l8S(I):I>-30 1977 



Palliative treatment was applied to 131 cases of unresectable 
or palliatively resected colorectal carcinoma being monitored 
with serial CEA determinations. There were 84 Instances of 
disease progression with 67 (80%) of them showing an increase 
in CEA above pretreatment levels or maintaining high levels, 
and 17 (20%) showing a fall when compared to pretreatment 
values or maintaining low initial values. There was a clear-cut 
regression of the disease in only 9 instances. In all 9, the CEA 
clearly dropped or maintained low values throughout the 
period of regression. No patient in regression had a rise or 
maintained an elevated CEA level. These changes in CEA 
followed closely the clinical response of our patient to the use 
of a particular agent, although for the Nitrosourea compounds 
there may be a tendency to lower the CEA regardless of the 
patient's tumor response to the drug. This could be due to the 
fact that the Nitrosoureas produce a diffuse block of cellular 
activity, both at the nucleus and cytoplasm; while other com- 
pounds act as alkylating agents or by inhibition of enzymes in- 
volved in the metabolism of nucleic acids (ie, 5-FU inhibiting 
thymidylate synthetase). In general, longer survival was found 
in those patients w ho had initially lower levels of CEA as com- 
pared to those with high initial levels. The patients with a 
favorable CEA response to the treatment (falling CEA or 
maintained low value), even in many who did not show a 
clinical response had a longer survival than the group with ris- 
ing or stable high levels. The main value in CEA monitoring of 
patients resides in its correlation with the amount of disease 
present and then its ability to detect progression of tumor mass 
which is not clinically measurable. (Author Abstract) 

20 

PROGNOSTIC SIGNIFICANCE OF PERIPHERAL 
LYMPHOCYTE COUNTS AND CARCINOEMBRYONIC AN- 
TIGENS IN COLORECTAL CARCINOMA. 

Kim US, Papalestas AE, Aufses AH 

Department of Surgery, Mount Sinai School of Medicine, Fifth 

Arenue and lOOth Street, New York, N> 10029 
J Surg Oncol; 8(3):257-262 1976 

An association between pretreatment lymphocyte counts 
and 5-year prognosis was noted in colorectal cancer. Among 
188 patients with 5-year follow-up significant difference in sur- 
vival rates in relation to lymphocyte counts was noted: 61% 
for patients with counts greater than 2,000/cmm. 30% for 
those with counts less than 1,000/cmm, and 58% for the in- 
termediate group. Similar differences were also noted within 
groups with Dukes' B and C lesions and in elderly patients. 
Highly significant differences were noted in women. Those 
with Dukes' B and C lesions with counts greater than 
2,000/cmm had an 81% survival rate, compared to 50% for 
those with lower counts X*'2 "6.81 p less than 0.01. Women 
had significantly higher lymphocyte counts and higher survival 
rates than men. An inverse correlation was noted between 
pretreatment lymphocytes and simultaneously determined car- 
cinoembryonlc antigens. These observations indicate that 
lymphocyte counts may be of prognostic value in colorectal 
cancer when used in association with carcinoembryonlc an- 
tigens. (Author Abstract) 

21 

BIOLOGICAL MARKERS: POLYAMINES AND CEA IN 
COLORECTAL CARCINOMA AND BONE MARROW 
POLYAMINES IN LEUKEMIA. (MEETING ABSTRACT) 
Nishioka K, RonudanI MM, Fritsche HA, Hart JS 
The University of Texas System Cancer Center, Houston, Tx. 77025 
Proc Am Assoc Cancer Res; 17:193 1976 

Polyamines may regulate cell growth. Patients with cancer 
often have high excretory levels. Polyamine analysis (Clin 
Chim Acta. 57:155. 1974) of sera from control subjects were: 
(nmole/ml) putrescine (PU) 0-0.28, mean 0.166, spermidine 
(SP) 0.17-0.33, 0.233, spermine (SPN) 0-0.06, 0.026, 
cadaverine (CD) not detected. Twenty-five preoperative 
patients with colorectal carcinoma showed: PU 0-0.57, 0.25; 
SP 0.18-0.79, 0.37; SPN 0-0.32, 0.07. CD was delected in 4 
patients with metastasis. Smokers and non-malignant tumors 
had no polyamine elevation. Normal serum CEA levels (Todd 



111 



and/or modified Roche(R)) were 2.8-10.2 ng/ml (R), mean 
4.88, while patient values were 11-1540 (Todd) and 2.7-533 
(R). In all 13/25 (52%) had high CEA and 15/25 (60%) had 
high polyamines. Combined, 18/25 (72%) were positive. A 
good correlation between polyamine levels and clinical course 
was found. Control bone marrow (BMS) from patients with 
no BM invasion were: (means) PU 0.21, SP 2. 1 2 and SPN 1.43. 
Untreated leukemia patients showed: PU 0-29.5, SP 0-10.23 
and SPN 0.25-18.11. Patients undergoing chemotherapy had 
values as high as: PU 95.2, SP 27.7 and SPN 23.3. Patients in 
remission had low values. The e studies suggest the potential 
of polyamines as a marker for both solid tumors and leukemia. 
(Author Abstract) 



22 

HUMAN CHORIONIC GONADOTROPHINS (HCG) IN 
NONTROPHOBLASTIC NEOPLASMS-ASSESSMENT OF AB- 
NORMALITIES OF HCG AND CEA IN BRONCHOGENIC AND 
DIGESTIVE NEOPLASMS. 
Gailani S, Chu TM, Nussbaum A, Ostrandcr M, Christoff N 
Roswell Park Memorial Institute, Buffalo, New York. Department 

of Medicine. 
Cancer; 38(4):1684-1686 1976 

Evaluation of plasma HCG measurement in the diagnosis of 
nontrophoblastic neoplasms and assessment of the value of 
concomitant measurement of plasma HCG and CEA in 
patients with bronchogenic carcinoma and neoplasms of the 
digestive tract were undertaken. Only one of 70 normal control 
subjects had positive plasma HCG (3.5 ng/ml). whereas 54 of 
320 patients with nontrophoblastic neoplasms had measurable 
plasma HCG (1.9 to 160 ng/ml). Forty of these patients had 
less than 5.1 ng/ml, 10 had 5.1 to 10 ng/ml, and only three had 
high levels of 96, 1 10, and 160 ng/ml. Elevated plasma CE.A 
levels of 3.6 to 140 ng/ml were found in 38 of the 70 patients 
with bronchogenic carcinoma and 30 of the 72 patients with 
neoplasms of the digestive tract in this series. Concomitant 
positive HCG was found in only six of the 68 patients who had 
elevated CEA levels, and positive HCG was found in eight of 
74 patients who had normal plasma CE.A. The low frequency 
and the modest elevation of plasma HCG, despite frequent ad- 
vanced disease, indicate plasma HCG has limited value as a 
biologic marker for diagnosis and assessment of non- 
trophoblastic neoplasms. (Author Abstract) 



23 

CEA AS A PROGNOSTIC MONITOR IN THE LUNG CANCER 
PATIENT WHO HAS BEEN SURGICALLY RESECTED FOR 
CURE. (MEETING ABSTRACT) 

Vincent RG, Chu TM, Ferecn TB, Oslrander M 
Roswell Park Memorial Institute, Buffalo, N.V. 14263 
Proc Am Assoc Cancer Res; 17:157 1976 

The purpose of this study is to determine if surgical ablation 
of a lung tumor is followed by a marked reduction in CEA 
levels and if subsequent progression of disease can be an- 
ticipated by increasing levels of CEA. Seventy-five patients 
with lung cancer who underwent surgical resection for cure 
have now been followed for 3 to 48 months. The median CEA 
value for all surgical candidates at the time of their initial ex- 
amination was 4.0 ng/ml. Additional CEA determinations 
were taken in the immediate postoperative period and monthly 
theteaftcr. The median CE.^ values for samples taken 60 and 
90 days after operation dropped to 2.0 and 1.3 ng/ml, respec- 
tively. Ill those patients where surgery had not cured the 
patient of lung cancer, the concentration of CEA began to in- 
crease at about the sixth postoperative month and portended 
the demise of the patient. While the CEA increased at least 4.5 
ng/ml among the patients who were c\entual surgical failures, 
those patients who were surgical cures were characterized by 
CEA levels which did not exceed 2.5 ng/ml in the 
postoperative period. (Author Abstract) 



CEA LEVELS IN HEAD AND NECK CANCER. 

Silverman NA, Alexander JC, Chretien PB 
Surgery Branch, NCI, Bethesda, Maryland 20014 
Cancer; 37(5):2204-221 1 1976 

Serum carcinoembryonic antigen (CEA) levels were 
determined for 439 patients with squamous carcinoma of the 
head and neck region, 154 healthy smokers, and 122 non- 
smokers. Among nonsmokers 95S''o of the CEA levels did not 
exceed 5 ng/ml, but among smokers this discriminatory level 
was 7 ng/ml. Among tumor-bearing patients 36% of the CEA 
levels exceeded 5 ng/ml but only 17% exceeded 7 ng/ml. Both 
the incidence and magnitude of CEA elevations correlated 
with clinical stage of tumor; however, excluding patients with 
clinically apparent advanced malignancies, the incidence and 
magnitude of elevations were similar among tumor-bearing 
patients, tumor-free treated patients, and smokers. Although 
not predictive of ultimate survival, elevated preoperative CEA 
levels declined to the range of normals after resection. Similar- 
ly, during palliative irradiation for incurable tumors, CEA 
levels declined with regression of tumor. Irradiation did not 
nonspecifically elevate CEA levels. The data indicate that in 
patients with head and neck squamous carcinomas CEA level 
is not likely to contribute to a determination of prognosis after 
therapy, however, serial determinations may have adjunctive 
value in monitoring tumor response. (Author Abstract) 



CARCINOEMBRYONIC ANTIGEN IN CHILDREN WITH 
NEUROBLASTOMA. 

Helson L, Ghavimi F, Wu CJ, Fleisher M, Schwartz MK 
Memorial Sloan-Kettering Cancer Center, New York, N.Y. 10021. 
J Natl Cancer Inst; 57(3):725-726 1976 

Plasma carcinoembryonic antigen (CEA) was assayed with a 
radioimmune procedure in 27 healthy control children. The 
upper limit of plasma CEA (mean-2 SD) was derived from 
healthy controls and was 3.35 ng/ml. This value was compared 
with those obtained from 15 children with active 
neuroblastoma, 7 with active embryonal rhabdomyosarcoma, 
16 with treated neuroblastoma and without evidence of dis- 
ease, 14 disease-free patients with em.bryonal rhabdomyosar- 
coma, and 17 patients still on therapy. The neuroblastoma and 
embryonal rhabdomyosarcoma patients with active disease 
had higher CEA values than did the successfully treated 
neuroblastoma and embryonal rhabdomyosarcoma patients. 
CEA plasma values greater than 3.35 ng/ml were found in 35% 
and 24% of patients with neuroblastoma and embryonal rhab- 
domyosarcoma, respectively. (Author Abstract) 



CLINICAL ASPECTS OF HEPATOCELLULAR CARCINOMA 
IN MAN. 

Desai UN 

Oept. Medicine, Univ. Nalal, Durban, Republic South Africa 

S Afr J Med; 50(41 ):I61 1-1613 1976 

The clinical and biochemical findings of hepatocellular 
carcinoma in 207 inhabitants of Natal and Transkei are 
presented. The patients comprised 1 78 men and 29 women; the 
youngest patient was a lO-yr-old boy and the eldest was an 87- 
vr-old man. The av age was 42 yr and 7 mo. Hepatomegaly 
was present in 97% of the patients and the liver w:is usually 
tender and hard. A.sciles occurred in 48%. An analysis of the 
laboratory data revealed that 28/30 biopsy proven cases had 
elevated alpha-fetoprotein levels. Hepatitis B antigen was 
found in 41% of the patients. Only one patient had a partial 
hepatcctoiny and she was alive 10 mo later. The av survival of 
untreated patients was 75.9 days. (7 refs) 



112 



SERUM ALPHA-FETOPROTEIN IN VIRAL HEPATITIS AND 
ITS COMPLICATIONS. 

Esposito R, Pollavini G, de LaJla F 

Istituto di Malatiie Infettive dell'ljniversita di Milano, Via Livigno 

3, 20158 Milano, Italy 
Boll Isl Sieroier Milan; 55(l):59-64 1975 

Alpha-fetoprotein levels were measured by 
radioimmunoassay in 40 patients with acute viral hepatitis, 5 
patients with chronic persistent hepatitis, 15 with chronic 
aggressive hepatitis and 5 patients in hepatic coma from fulmi- 
nant viral hepatitis. Serum concentrations were increased in 
55% of the pa;:ents with acute viral hepatitis and in about 33% 
of the patients with chronic aggressive hepatitis. The levels 
were markedl) raised in patients in a coma resulting from 
fulminant viral hepatitis who survived. The failure to find 
significant e!e\ations of alpha-fetoprotein in the patients with 
viral hepatitis cannot be completely explained since the 
mechanism b> which its synthesis is induced is not fully 
known. The high alpha-fetoprotein values may refiect liver cell 
regeneration after necrosis of a critical mass of hepatic tissue. 
(15 refs) 



Moore MR, Vogel CL, Walton KN, Counts P, Waldmann TA 
Department of Medicine, Division of Hematology and Oncology, 

Emory Univ. School of Medicine, Atlanta, Ga. 30J22 
Proc Am Soc Clin Oncol; 17:239 1976 

Serial determinations of hCG and AFP were carried out in 
50 patients. In 24 patients marker levels were determined prior 
to orchiectomy. While all 5 patients with germinal tumors had 
abnormal marker studies pre-orchiectomy, AFP and hCG 
were not elevated pre-operatively m 3 patients with non- 
germinal tumors (although I patient had a minimally elevated 
hCG on follow up) or 16 patients with benign disease of testi- 
cle. In 26 patients hCG and AFP levels were obtained after 
orchiectomy for malignant germinal tumors, 10 had active dis- 
ease and 16 were free of clinical evidence of disease. 6/10 
patients with active disease had abnormal marker studies (4 
false negatives). All 16 patients with no evidence of disease had 
normal hCG and AFP values (0 false positives). Seventy-three 
percent ( 1 1 / 1 5) of patients with active germ cell maliaiiancies 
of the testis had elevated hCG or AFP. Only 3% (1/35) of 
patients with no active germ cell malignancy had elevated hCG 
or AFP. Serial determinations will be presented and correlated 
with clinical status. The above findings suggest that hCG and 
AFP are sensitive and specific tests for the diagnosis and 
evaluation of patients with testicular cancer. (Author 
Abstract) 



STAGING OF PROSTATIC CANCER EMPLOYING BONE 
SCINTIGRAPHY AND RADIOIMMUNOASSAY. (MEETING 
ABSTRACT) 

Opier SR, Shea LP 

Unitersity of California, San Francisco, CA. 94110 

Proc Am Assoc Cancer Res; 17:218 1976 

Patients wi'.h prostatic biopsies positive for cancer were 
studied for evidence of metastatic disease employing Gamma 
camera bone scans and carcinoembryonic antigen (CEA) 
radioimmunoassay. The accuracy of clinical staging of 
prostatic cancer can be improved by employing these 
modalities. Technetium-99m bone scan is more sensitive than 
conventional bone surveys. Since the nuclide is taken up by ac- 
tively metabolizing bone, it is nonspecific and may require 
biopsy. The scan is positive considerably earlier than the 
roentgenogram and can indicate lesions available for 
histological co.nfirmation of dissemination. CEA is a tumor- 
associated antigen and elevated levels in patients with positive 
prostate biopsies and/or bone scans appear to indicate dis- 
seminated tuir.or. In preliminary studies employing bone scin- 
tigraphy and CE/\ antigen levels, it has been possible to stage 
more accurately the disease prior to performing definitive 
therapy and a:d in the selection of the most rational form of in- 
dividual treatment. (Author Abstract) 



PROGNOSTIC VALUE OF ALPHA-FETOPROTEIN RADIOIM- 
MUNOASSAY IN SURGICALLY TREATED PATIENTS WITH 
EMBRYONAL CELL CARCINOMA OF THE TESTIS. 

Bourgeaux C, Martel N, Sizaret P. Guerrin J 

Laboratoire d'immunologie, Faculte de Medecine Boulevard Jeanne 

d'Arc, F 21 033 Dijon Ccdex, France. 
Cancer; 38;4i: 1658-1660 1976 

Alpha-fetoprotein was assayed radioimmunologically in 51 
samples of sera from 26 patients who had been operated on for 
embryonal cell carcinoma of the testis. The test was found to 
have good prognostic value. Elevated levels were seen fre- 
quently in patients with metastase or who developed 
metastases. The kinetic study of alplia-fetoprotein allows us to 
monitor treatment efficiency, as well as to study cancer evolu- 
tion. (Author .Abstract) 

30 

THE USE OF HI MAN CHORIONIC GONADOTROPIN (HCG) 
AND ALPHA-FETOPROTEIN (AFP) IN EVALUATION OF 
TESTICULAR TUMORS. (MEETING ABSTRACT ) 



CARCINOEMBRYONIC ANTIGEN AND SKIN TEST REAC- 
TIVITY IN TUMOR RADIOTHERAPY. 

Vider M, Kashmiri R, Moses B, Earlywine D, Meeker WR, Utley 

JF, Maruyama Y 
Department of Radiation Medicine, University of Kentucky, A.B. 

Chandler Medical Center, Lexington, Ky. 40506 
Radiology; 119(3):677-^81 1976 

Serial carcinoembryonic antigen (CEA) levels were obtained 
from 122 cancer patients. In a random selection, the levels in 
67 of these patients were compared with clinical response to 
radiotherapy. Skin tests were also performed for histoplasmin, 
tuberculin and mumps. CEA levels, skin-delayed hypersen- 
sitivity reaction (DHR) and clinical tumor response were 
evaluated and correlated. Clinical response of tumors to 
radiotherapy was more often seen in patients with positive skin 
tests, but no correlation was observed between skin test reac- 
tivity and CEA response curves. (Author Abstract) 



32 

CLINICAL USEFULNESS OF CEA ASSAY. 

Luporini G, Manglarotii F, Fraschini P, Labianca R, Tassi GC, de 

Barbieri A 
Inst. IV Medical Clinic of Univ., Milan, Italy 
Boll 1st Seroter Milan; 55(2):151-163 1976 

To evaluate the correlation between carcinoembryonic 
antigen (CEA) serum levels, pathological stage and 
histological type of tumor, and to define the usefulness of CEA 
in monitoring the patients with gastroenteric neoplasms, 177 
patients were tested for CEA. Sixty-two of these patients had 
gastric heteroplasia and 115 had large bowel carcinoma; 83 
patients had pre-surgical CEA tests. CEA positivity (serum 
levels b nanog/ml) was higher in colonic than in gastric 
neoplasms, in adenocarcinomas than in undifferentiated 
forms, and was dependent on the pathologic stage. One 
hundred eight patients were tested for CEA several times: a 
correlation between CEA variations and clinical evolution was 
observed. This investigation indicates the importance of 
monitoring patients with gastrointestinal neoplasms by the 
CEA test, before and after surgery. It can also be used to 
evaluate the usefulness of surgery and, when necessary, 
chemotherapy and, eventually, to adopt more suitable 
chemotherapeutic modalities. (20 refs) 



113 



OTHER RELATED STUDIES 



ALPHA-FETOPROTEIN: THE MAJOR HIGH-AFFINITY 
ESTROGEN BINDER IN RAT UTERINE CYTOSOLS. 

Uriel J, Bouillon D, Aussel C, Dupiers M 

Inslitul de Recherches Scienliflques sur le Cancer, Boite Postale No 
8, 94800 Villejuif, France 

Proc Natl Acad Sci USA; 73(5):1452-I456 1976 

Evidence is presented that alpha-fetoprotein (AFP), a serum 
globulin, accounts mainly, if not entirely, for the high estrogen 
binding properties of uterine cytosols from immature rats. By 
the use of specific immunoadsorbents to AFP and by com- 
petitive assays with unlabeled steroids and pure AFP, it has 
been demonstrated that in hypotonic cytosols AFP is present 
partly as free protein with a sedimentation coefficient of about 
4-5 S and partly in association with some intracellular con- 
stiluent(s) to form an 8S estrogen-binding entity. The AFP/8S 
transformation results in a loss of antigenic reactivity to an- 
tibodies aeainst AFP and a significant change in binding 
specificity. This change in binding specificity is manifested by 
an increase in binding affinity for estradiol, estriol, 
diethylstilbeslrol,and nafoxidine (a nonsteroidal anti- 
estrogen), and by a concomitant decrease in estrone binding. 
Both the ar.tigenic and binding properties of native AFP are 
recovered after dissociation of the 8S complex in 0.4 M KCl. 
An AFP-mediated mechanism of early intracellular events as- 
sociated »iih estrogen entry in target cells is suggested and dis- 
cussed with regard to current views on steroid action. (Author 
Abstract) 

34 

EFFECT OF A-FETOPROTEIN AND OTHER SERUM FACTORS 
DERIVED FROM HEPATOMA-BEARING RATS ON THE MIX- 
ED LYMPHOCYTE RESPONSE. 

Parmely MJ, Thompson JS 

Dcpt. Cell Biology, Univ. Texas Health Science Center, Dallas, TX 

75235 
J Immunol: I15(S,pl2):I83Z-l837 1976 

The effect of alpha-fetoprotein (AFP) and other serum 
factors from Morris hepatoma 7777 rats was investigated by 
using mixed lymphocyte cultures as in vitro correlates of 
lymphocNie reactivity to transplantation antigens. Serum 
alpha-globjlin fractions isolated by physicochemical techni- 
ques from normal adult Buffalo rats suppressed lymphocyte 
f)roliferaiion in vitro. The factors responsible for mixed 
ymphocyie culture suppression appeared to be strain specific 
since they were not demonstrable in the same fractions from 



normal LBN rat serum. Similar fractionation of the serum 
from Buffalo rats bearing the Morris hepatoma 7777 obtained 
from two different sources also yielded suppressive protein 
fractions that differed both chemically and functionally. Both 
variants of this hepatoma produced high serum concentrations 
of AFP, providing an opportunity to study the possible im- 
munoregulalory role of their fetal-associated globulins. Frac- 
tions rich in AFP that lacked other serum alpha-globulins 
were obtained by gel filtration chromatography and were 
devoid of any in vitro immunosuppressive activity. When AFP 
that was further purified by immunoabsorption was added to 
mixed lymphocyte cultures, no effect was observed at doses 
below 400 microg/ml. The mixed lymphocyte culture response 
was augmented with higher doses, similar to albumin purified 
by the same methods. Antigenic differences between the AFP 
molecules may be responsible for their immunosuppressive ac- 
tivity and explain the discrepancies. (28 refs) 



35 

FURTHER CHARACTERIZATION OF I.MMUNOSPECIFIC 
DNA-PROTEIN COMPLEXES. (MEETING ABSTRACT) 

Chiu J, Fujitani H, Hnilica LS 

Dept. of Bioctiemislry, Vanderbilt University, Nashville, Tennessee 
37232 

Proc Am .Assoc Cancer Res; 17:188 1976 

It was shown that tissue specific antibodies can be elicited 
against complexes of DNA and chromosomal nonhistone pro- 
teins (NP-DNA). During neoplasia the immunospecificity of 
chromosomal nonhistone protein-DNA complexes changed to 
a new type, common to many malignant tumors. Administra- 
tion of dietary hepatocarcinogen (N,N-dimethyl-p-(m- 
tolylazo) aniline) to Fisher rats produced an early change (2-3 
weeks) in the immunospecificity of the NP-DNA complex. 
When chromatin isolated from livers of fetal. 3-week old and 
adult rats was assayed in the presence of Novikoff hepatoma 
NP-DNA antiserum, the fetal liver chromatin fixed the com- 
plement significantly, resembling chromatin from hepatomas. 
The chromatins from 3-week old and adult rat livers were not 
reactive. Chromatin prepared from rat livers 6, 12, 24, and 48 
hours after partial hepatectomy were assayed for complement 
fixation in the presence of Novikoff hepatoma NP-DNA an- 
tiserum. Immunoreactive NP-DNA complexes similar to those 
found in malignant cells were observed only in the 24 and 48 hr 
samples. Thus, the behavior of the inimunospecific NP-DNA 
complexes resembles that of the various carcinoembryonic an- 
tigens. Fractionation of Navikoff hepatoma chromatin 
localized the immunologically tissue specific NP-DNA com- 
plexes in the transcriptionally active fraction. (Author 
Abstract) 



114 



AUTHOR INDEX WITH CITATION NUMBERS 



de Barbieri A 32 

de Lalla F 27 

Alexander JC 24 

Arnon R 2 

Asada S 8 

Aufses AH 20 

Aussel C 33 

Bouillon D 33 

Bourgeaux C 29 

Bustin M 2 

Calef E 2 

Chaitchik S 2 

Chlu J 35 

Chretien PB 24 

Chrisloff N 22 

Chu TM 23 

Chu TM 22 

Chu TM 19 

Coates JE 6 

Coligan JE 3 

Counts P 30 

Dahlman H 15 

Das BR 7 

Das S 7 

Delacourt MC 11 

Desai HN 26 

Doi H 8 

Drewinko B 14 

Dupiers M 33 

Early wine D 31 

Esposito R .' . 27 

Fergen TB 23 

Fleisher M 25 

Fraschini P 32 

Frilsche HA 21 

FujitanI H 35 

Gailani S 22 

Ghavimi F 25 

Goldenberg DM 15 

Guerrin J 29 

Haimovich J 2 

Hamajima 1 10 

Hart JS 21 

Hayasaka T 9 

Helson L 25 



Henderson IC 17 

Herrera MA 19 

Hnllica LS 35 

Holyoke ED 19 

lio T 12 

Imaeda T 8 

Itoh T 9 

Itoh T 10 

Kashmiri R 31 

Kato T 8 

Khoo SK 16 

Kim US 20 

Kunieda T 8 

Labianca R 32 

Lamerz R 5 

Lokich J 17 

Luporini G 32 

Mackay EV 16 

Mangiarotti F 32 

Marlel N 29 

Maruyama Y 31 

Matsuura S 8 

Mayer R 17 

Mckinney EC 4 

Meeker WR 31 

Mittelman A 19 

Miyazaki M 13 

Moore MR 30 

Moses B 31 

Nishioka K 21 

Noro T 10 

Noro T 9 

Novik N 2 

Nussbaum A 22 

Oettgen H 18 

Opier SR 28 

Ostrander M 22 

Ostrander M 23 

Pant KD 15 

Papatestas AE 20 

Parmely MJ 34 

Pinsky C 18 

PoUavini G .27 

Pritchard DG .3 

Rao B 18 



Romsdahl MM 14 

RomsdanI MM 21 

Ruider H 5 

Schnute WC 3 

Schwartz M 18 

Schwartz MK 25 

Sela M 2 

Senda K 8 

Shea LP 28 

Shirai T 10 

Shirai T 9 

Silverman N A 24 

Sizaret P 29 

Skarin A 17 

Snitzer LS 4 

Sobis H 11 

Stearns M 18 

Svenberg T I 

Takeda T 10 

Taketa K 13 

Tamaoki T 12 

Tassi GC 32 

Terry WD 7 

Thompson JS 34 

Todd CW 3 

Tomino Y 9 

Tomino Y 10 

Uriel J 33 

Utiey JF 31 

Vandeputte M 11 

Vider M 31 

Vincent RG 23 

Vogel CL 30 

Waldmann TA 30 

Walton KN 30 

Wanebo H 18 

Watanabe A 13 

Wu CJ 25 

Yamawaki Y 8 

Yang LY 14 

Yoshiki T 10 

Yoshiki T 9 

Zamcheck N 17 



115 



-k£^Cx 





INFORMATION SHEET 



DATABANK 



As one of its directives, the National Cancer Act of 1971 stated 
that the Director of the National Cancer Institute (NCI) shall "establish 
an international cancer research data bank to collect, catalog, store, and 
disseminate insofar as feasible the results of cancer research undertaken 
in any country for the use of any person involved in cancer research in 
any country." In response to this mandate, the NCI established the 
International Cancer Research Data Bank (ICRDB) Program, which provides 
the following types of products and services to cancer researchers and 
research clinicians: 

A. CANCERLINE — A computer-based information retrieval system containing 
several data bases for immediate retrieval of abstracts derived from 
published cancer research results (CANCERLIT), descriptions of ongoing 
cancer research projects (CANCERPROJ) , and summaries of clinical protocols 
(CLINPROT). 

B. Cancer Information Dissemination and Analysis Centers (CIDACs) — These 
operate m three broad areas of cancer research stressing the active 
dissemination of cancer research information to scientists and acting 
as reference and referral centers for investigators. 

C. CANCERGRAMS — Current awareness publications produced approximately 
monthly by CIDACs which contain abstracts of recently published articles 
in narrow subject areas. 

D. Current Cancer Research Project Analysis Center (CCRESPAC) — This Center 
collects and processes descriptions of ongoing research projects for 
CANCERPROJ and for compilation into SPECIAL LISTINGS. It is operated 

for the ICRDB Program by the Smithsonian Science Information Exchange 
(SSIE). 

E. SPECIAL LISTINGS -- Publications produced by CCRESPAC which contain 
descriptions of ongoing cancer research projects in narrow subject areas. 



International Sc ient ist-to-Sc ient ist Communication 



A two-part project 



which provides awards of individual grants for research visits of scientists 
between countries, and provides basic support for international workshops 
in cancer research. 

Clearinghouse for Ongoing Work in Cancer Epidemiology — This Clearinghouse 
supported by ICRDB and operated by lARC in Lyon, provides lists of epidemiology 
researchers and resources and responds to technical questions in this subject 
area. 



'A service of the International Cancer Research Data Bank (ICRDB) 

National Cancer Institute 

Room 128, Blair Building, Bethesda, Md. 20014 



116 



NCI/iCRDB/SL-76/40 



PB-265 085 




/ 

.researchL. 




SPECIAL LISTING 



mmm zhiizm research 



on 



CUr^lCAL ASPECTS of 



mmR ummmuKmrn 



mm, 



April 8, 1977 



U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service • National Institutes of Health • 

National Cancer Institute 



A SERVICE OF THE 
INTERNATIONAL CANCER RESEARCH DATA BANK (ICRDEJ) 



117 



Dear Cancer Researcher; 

This Specfal Listing of Current Cancer Research Projects is a service of the INTER- 
NATIONAL CANCER RESEARCH DATA BANK (ICRDB) PROGRAM of the National Cancer Institute. Each 
Listing contains descriptions of ongoing projects in selected cancer research areas. The 
purpose of this Listing is to facilitate and promote the exchange of information between 
cancer scientists by keeping them aware of ongoing projects related to their research in 
other laboratories throughout the world. 

If you would like to receive other ICRDB publications and learn about other ICRDB 
Information services, please notify us and send your comments and suggestions regarding 
this Listing to: 

ICRDB Program Office, Room 128 Blair Building 

National Cancer Institute, Bethesda, Maryland 2001't, U.S.A. 

Material published in the Listing is derived from current cancer research project 
descriptions supplied by cancer investigators and cancer research organizations in many 
countries. 

These Listings are prepared for the ICRDB Program by the Current Cancer Research 
Project Analysis Center (CCRESPAC) which is operated for the ICRDB Program by the Smith- 
sonian Science Information Exchange (SSIE). Procedures for improving the acquisition of 
project descriptions and the preparation of these Special Listings are still evolving, 
in order to make these publications more current and more complete. In this Listing and 
until we begin the next full cycle in 1977. there may be some older 1975 projects which 
appear in order to include as much as possible of the 2 year data base. The next cycle 
will emphasize more recent projects. 

Since each Listing focuses on a specific subject area, some project descriptions that 
deal with several different topics have been edited or abridged to delete portions not 
relevant to a given section in the Listings. In these cases, the phrase "(Text Abridged)" 
appears at the end of the project description. Minor editorial changes, including the 
addition of short phrases to the original titles, have also been made in some cases. Oc- 
casionally the* original title has been modified (as shown by parentheses around the title) 
to more clearly show how the project is related to a section in the Listing. When the 
whole project or parts of a project deal with different related topics, the project de- 
scription (or part of it) may appear in more than one relevant section of the Listing. 

Automatic distribution of these Listings is limited, at present, to scientists whose 

project descr i pt ion (s) appear in a given Listing. If you would like to provide a more 

complete and current description of your research project, forms for this purpose 

(as well as additional information about data input or special searches) are available 
from: 

CCRESPAC, c/o SSIE, Suite 300 

1730 M Street, N.W., Washington, D.C. 20036, U.S.A. 

Additional copies of this Listing can be ordered from: 

United States Department of Commerce, National Technical Information Service 
5285 Port Royal Road, Springfield, Virginia 22161, U.S.A. 

Descriptions of these projects as well as more than 13,000 other current cancer- 
related projects can be retrieved via on-line computer terminals at more than 500 locations 
in the U.S. and other countries. Any organization linked to the HEDLARS/MEDL i NE System at 
the National Librsrv of Medicine has access to this on-line file of research project sum- 
maries called "CANCERPROJ." 

Each researcher is urged to circulate this listing to co-workers and others 

WHO are ENGAGED IN PROJECTS RELATED TO THE AREA COVERED BY THIS PUBLICATION. 

118 



RESEARCH AREAS 



ABSTRACT 
NUMBER 



I. CLINICAL STUDIES OF LEUKEMIA 1-203 

A. Diagnosis of Leukemia 1-15 

B. Prognostic Studies in Leukemia 16*55 

1. Cytokinetics in Leukemia Prognosis 16-25 

2. Cytogenetics in Leukemia Prognosis 26-3'* 

3. Immunoprognosis of Leukemia 35-'i1 

k. Development of Multivariate Analysis Techniques for kZ-kJ 
Management of Leukemia Patients 

5. Other Studies in Leukemia Prognosis '♦S-SS 

C. Therapy of Leukemia in Children 56-102 

1. Chemoimmunotherapy of Childhood Leukemia 56-65 

2. Chemo- and Rad iotherapeut ic CNS Prophylaxis in 66-75 
Treatment of Childhood Leukemia 

3. Other Chemotherapy and Radiotherapy for Childhood Leukemia 76-102 

D. Therapy of Leukemias in Adults (or Unspecified Age Groups) 103-189 

1. Leukemia Treatment Regimens Containing Immunotherapy 103-12A 
or Splenectomy 

2. Chemotherapy and/or Radiotherapy for Leukemia 125-159 

3. Other Therapy of Leukemia I6O-I89 

E. Complications and Side Effects of Leukemia and Leukemia Therapy 190-203 
I. CLINICAL STUDIES OF LYMPHOMAS 204-320 

A. Diagnosis of Lymphomas 20*1-211 

B. Prognostic Studies of Lymphomas 212-235 

1. Staging and Prognosis of Hodgkin's Lymphoma 212-221 

2. Prognostic Studies of Non-Hodgkin' s Lymphoma 222-230 

3. Other Prognostic Studies of Lymphoprol iferat i ve Disorders 231-235 

C. Therapy of Hodgkin's Disease 236-274 

1. Combined or Sequential Radiotherapy and Chemotherapy for 236-251 
Hodgkin's Lymphoma 

2. Single Modality Chemotherapy for Hodgkin's Lymphoma 252-267 

3. Other Therapy for Hodgkin's Lymphoma 268-274 



119 



ABSTRACT 
NUMBER 



D. Therapy of Non-Hodgkin' s Lymphoma (or Unspecified Lymphomas 

1. Multimodal Therapy for Non-Hodgkin' s Lymphoma 

2. Chemotherapy for Non-Hodgkin's Lymphoma 

3. Other Chemotherapy for Malignant Lymphoma 

h. Other Therapy for Malignant Lymphoma 

III. SUPPORTIVE THERAPY OF PATIENTS WITH LEUKEMIAS, LYMPHOMAS AND 
OTHER LYMPHOPROLIFERATIVE DISORDERS 

A. Marrow Transplant 

B. Platelet- and Plasmapheresis 

C. Leukapheresis 

D. Treatment and Prevention of Infections in Immunosuppressed 
Patients 

IV. COOPERATIVE GROUP STUDIES 

A. Members of the Acute Leukemia Group B 

B. Other Cooperative and Comprehensive Studies 
THERAPY AND OTHER CLINICAL ASPECTS OF MYELOMAS 



V. 
VI. 



THERAPY AND OTHER CLINICAL ASPECTS OF MYCOSIS FUNGOIDES 



275-320 
275-288 
289-301 
302-314 
315-320 
321-382 

321-3'«0 
3^1-352 
353-367 
368-382 

383-'«2'» 
383-A06 
407-'t2ii 
A25-Ai»5 



INVESTIGATOR INDEX 



(These project descriptions and others related to cancer research can be 
retrieved from the ICRDB Program's computer file, CANCERPROJ. See inside 
front cover for details). 



120 



I. CLINICAL STUDIES OF LEUKEMIA 



A. DIAGNOSIS OF LEUKEMIA 



1, BIOCHEMICAL CHAtiGES IN SURFACE GLYCOPROTEIN AS 
A POSSIBLE TOOL IN DIFFERENTIAL DIAGNOSIS OF 
LEDKEniA AND L YHPHOPROLIFEP ATI V£ DISORDERS 
Vanbeek, H. P., Smets, L. A., Immelot, P., 
Seth€rlands Cancer Institute, Cytology, 106-108 
Sarphatistraat, Amsterdam, Netherlands 

OBJECTIVE: To study biocheaiical changes in 
surface glycoprotein of human tumor cells and to 
investigate the value of the assay as an aid xn 
diff erentiaj. diagnosis ana prognosis. 

APPROACH: Human tumor cells are labeled in 
prlnary tissue culture with radioactive fucose and 
the labeled glycoproteins are isolated from the 
cell surface and studied by gel filtration. 
Differences with controls have teen observed in 
the eluticn profiles of many experimental tumor 
systems and in human leuKemia. 

It will be investigated whether similar 
differences can be observed in solid tumors. 
Horeover, details of the elution profiles and the 
effects of enzymic modification will be correlated 
with clinical diagnosis. 

BurJcitt lymphoma cells and Epstein-Earr virus 
infected normal cells are similarly studied to 
investigate the oncogenic potential of this virus 
in humans. 

PROGPESS: Human leuKemia can be discrimin- 
ated from non-malignant lymphoprolif erative 
diseases by differences in the elution behavior of 
surface glycoprotein. In addition, chronic 
nyeloid leukemia glycoproteins respond differently 
to enzyme treatment and can therefore be discrimi- 
nated from related malignancies. 



2. SURFACE ANTIGENS OF THE HUMAN LEDKEHIA CELL - 
STUDIES UTILIZING RABbIT ANTI5EHA TO LYMPHOBLASTIC 
lEOKEHIA CELLS 

Greaves, n. F. , Hogg, N. , Janossy, G. , Imperial 
Cancer Research Fund, Tumor Immunology Unit, 
Lincolns Inn Fields, Hc2a 3px, London, England, 
United Kingdom 

He have continued to analyze the specificity 
of rabbit antisera to acute lymphoblastic leukemia 
(ALL) cells. These sera are the first to be 
described vnich clearly identify individual 
leukemic cells. Their diagnostic value is now 
fairly well established. To date, over 300 human 
leukeoias have been tested. These include samples 
from patients entering a national MRC chemotherapy 
trial and a prospective survey of individual 
patients, "at St Bartholomew's Hospital. The 
antiserum identifies over 90* of patients with 
non-T, non-B ALL, the major group of non-myeloid 
acute leukemias. In addition, two other leukemia 
types bind the serum; a proportion of acute 
undifferentiated leukemias and the majority of 
chronic myeloid blast crises in a "lymphoid" blast 
crisis. 

He are continuing to study individual 
patients through treatment, A considerable number 
of patients considered to be in heraatoloyical 
remission do have some leukemic ceils as defined 
by anti-ALL serum. The prognostic significance of 
these findings remains to be established, 

determine the cheEDiical nature of tne antigen (sj 
detected by anti-ALL sera. The ALL antigen is 
Pronase-sensitive and can oe "co-capped" on the 
cell surface by lentil lectir.. It has no demonst- 
rable cross- reactivity with a variety of oncornav- 
iruses including tluLV, ReLV, SSV and HuLV-231, the 
virus isolated from an AML patient by Gallagher G 
Gallo and passaged by Dr. N, Ttich. 



3. inHUHO AND CYTOCHEHICAL STUDIES OF LEPKEHIC 

CELLS - SURFACE BARKERS IN NEOPLASTIC LYHPHOID 

CELLS 

Koyama, R., Urushizaki, I., Sapporo Medical 

College, Cancer Researco Institute, Medicine, S. 

1, H. 17, Chuoku, Sapporo, Hokkaido, Japan, C60 

Modern iBmunology reveals that lymphocytes of 
■an and oaamals consist of two distinct T- and B- 
cell populations. He have studied the surface 
markers of lymphocytes to evaluate clonal nature 
of lymphocytes in various lymphoid malignancies. 
Analyses of cell membrane properties have been 
shown to be used as a new basis for classifying 
lymphoid neoplasms. 

On the other hand, we have studied various 
enzymes, peroxidase, acid phosphatase, beta- 
glucuroQidase, arylsulpr.atase, lactic dehydrog- 
enase, esterase and catalase, in human leukemic 
cells by cytochemical method, polyacrilamide gel 
electrophoresis and isoelectric-f ocussmg method. 
Results from these investigations indicate that 
clinical application of tnese methoas is useful to 
estimate cell specificity of enzymes and matura- 
tion in human leukemic cells. 



Click, A. D., U.S. Veterans Administration, 
Hospital, Pathology, 1310 2ath Ave, S,, Nashville, 
Tennessee, 37203, U.S,A. 

A systematic study of the ultrastructural and 
cytochemical features of acute, non-iymphoid 
leukemia has consistently revealed that the 
majority of cases can be classified with reason- 
able accuracy. The major proliferating cell in 
the great majority of cases (greater than 70%) is 
monocytic. These results have also demonstrated 
differences in the morphologic appearance of 
reactive monocytes from those in leukeir.ia. 
Huramidase levels in urine and serum appear to 
correlate with monocytic cases. 

Employing similar technigues, a number of 
cases of what has been called "histiocytic 
lymphoma" have been found to be actually composed 
of transformed iymphocyzas, not cells of the 
mononuclear phagocyte system. Similar stuaies on 
Hodghin's disease indicate that this disease is 
also of lymphoid origin. Tumors of "true histioc- 
ytes" appear to be rare. 

Future studies include correlation of 
clinical features and response to therapy with the 
various cell types involved in leukemia and 
lymphomas. 

Additional ongoing studies involve the use of 
ultrastructural and cytochemical techniques in the 
evaluation of certain non- hematopoietic neoplasms. 
with the result of improving the diagnostic 
capabilities of the VA laboratory. 



Gendel, B. R., Batn, D. H. , U.S. Veterans Adminis- 
tration, Hospital, 1030 Jefferson Ave., Memphis, 
Tennessee, 38115, U.S.A. 

The discovery of the Philadelphia (Phi) 
chromosome and its relationship to chronic 
granulocytic leukemia has stimulated interest in 
the cytogenetics of other malignant diseases. A 
study is being made of patients admitted to the 
hospital with leukemia or preleukemia to identify 
cytogenetic anomalies. Approximately 35 patients 
have been studied using conventional and new 
banding techniques for accurate identification of 
both structural and numerical changes. A method 
for chromosome despiralization has also been 
developed to permit better resolution of highly 
contracted chromosomes, especially bone marrow 
chromosomes. 

Investigators have made reference to blurred 
chromatin in abnormal cells of leukemic and 
preleukeBic patients which disappears during 
remission but reappears in relapse. Techniques 
for transmission and scanning electron microscopy 



121 



: the 


nature 


■elatioi 


iship 


oscoi 


^1 


IS 



hav« been developed in ocder to reso 
of this "blurring" and understand it 
to the leukeaic process. Electron n 
also being used to study the ul trastructure o 
■Dnoraal chroBOSoaes observed in routine ligh 
■icroscope examinations. Electron nicroscopy 
"noreal" cells froi patients with uyeloprolif 
rative diseases nay also reveal ultrastcuctur 
changes which heretofore have gone undetected 
Experiaents are now in progress to deternine 
applicability o£ electron Bicroscopy to the 
clinical study of cytogenetics in ayeloprolif 
rative disorders. 



(. DUGIIOSIS or HUllAII LEUKEBItS UTItlZIBG IBBgHOf- 
IDOBESCEIII METHODS 

Huaphreys, B. E. , Univ. ot Massachusetts, School 
of Hcdicine, Pharmacol, 119 Belmont St., Uorcester, 
Bassachusetts, OieOU, U.S.«. 

OBJECTIVES: Isolate and characterize human 
lymphocyte surface molecules bearing antigenic 
determinants. Develop rabbit antisera to these 
antigens. Develop cytotoxic and immunof luorescent 
assays with antisera and radioimmunoassays with 
purified antigens to examine normal and malignant 
cells. Establish specificity, sensitivity, and 
reliability of assays. 



7. BOllPHOlOglCHHlYSIS 0? >CniE LEPKEHU 
Hart, J., Srewinko, B., Freireich, B., Haynie, 
t,, Bniv. of Texas, B.D. Anderson Hosp. £ Inst. 
Developmental Therapeutics, P.O. Sox 2C036, 
HouEton, Texas, 7702S, U.S.A. 

OBJECTIVE: To develop a rapid and reprod- 
ucible method for quantitating the number of 
nttcl«ated cells in the marrow cavity employing 
single and selected instances of multiple site 
aspirations in patients with acute leukemia. 

PROCEDURE: 1) TO correlate the magnitude 
the leukemic cell irfiltrate both at the local 
site of aspiration and at multiple sites with 
other pre-therapy variables including age, 
oagnitude of the blast count in the blood, 
diagnosis, cytogenic and cytokinetic factor. 

PBOGBESS: The pro;Ject is developing impro 
■ethods for quantitating total numbers of blast 
cells in the narrow cavity. Sather than evalua 
lion of leukemic cell infiltrate from smears 
alone, the value of clot sections, direct cell 
counts and tibial aspirates are also being 
studied. 



8. GBAMniOCYTE AMD HaCBOPHAGE PEOLIFERAIION IK 
LEDICEHIA - STODIES OF REGUtATOK SUBSTANCES 
Betcalf, D., Baiter 6 Eliza Hall Institute, 
Belbcurne, Victoria, Australia, 3050 

OBJECTIVES: Chemically purify the regulat 
CSP to improve present procedures for large sea 
production of this regulator, and to determine 
■ode of action on target normal and neoplastic 
granulocytic and macrophage cells. Explore 
further the mechanisms by which antigens stimul 
granulopoiesis and macrophage formation via CSF 
production. Characterize the leukemic colony- 
forming cell in humans using in vitro culture 
techniques, to develop methods for separating 
normal from leukemic colony-forming cells, and 
determine abnormalities in regulation of granul 
Oiesis and monocyte formation in preleukeoic an 
leukemic patients as an aid to diagnosis and 
■anageaent of these diseases. 



S. Ill VITRO STUDIES 07 PRELEnHEHIC AMD LEUKOPENIC 

gPBAN DISOBDEBS 

Schrier, S. L., Stanford University, School of 

Hedicine, Medicine, Palo Alto, California, 9«305, 

U.S.A. 

In vitro paraeeters of granulopoiesis were 
evaluated in patients with myeloproliferative 
disorders in order to determine factors involved 
Id the evolution of these disorders. Decrements 



of marrow granulocytic colony forming capacity 
(CEC) , a high proportion of light density colony 
forming cells, and increases of urinary output of 
colony stimulating factor (CSF) occurred preceding 
or concomitant with transformation of these 
disorders into aggressive stages. These findings 
indicate that progressive abnormalities of both 
marrow clonal growth and levels of humoral 
regulatory substances develop during evolution of 
these diseases. 



10. COMPUTER-ASSISTED CLASSIFICATION OF ACUTE 
LEOKEalA 

I. F., Neurath, P. W., Brenner, J. F., 
England Medical Ctr. Hosp. 
son Ave., Boston, Massach- 



Nechele 

Tufts University, New 
Pediatrics, 136 Harri 
usetts, 02111, U.S.A. 



The primary objective of this project is to 
establish objective and quantitative morphological 
parameters for the subdivision of classical 
varieties of acute leukemia. Computer-oriented 
image processing techniques, developed at this 
institution for chromosome analysis and, more 
recently, for an automatic white blood cell 
scanner and analyzer will be adapted for the 
analysis of leukemic cells. Slides from i40 
children with acute lymphoblastic leukemia will be 
scanned, the images of 100 leukemic cells from 
each recorded, and the digitized images analyzed 
using cell size, color and texture parameters 
developed for leukocyte analysis and identific- 
ation. The resulting quantitative morphological 
data will be analyzed for significant correlation 
with clinical data including clinical response to 
specific therapy, overall survival and cure 
expectancy. Once developed, these techniques can 
be extended to the field of acute myelotiastic 
leukemia where clinical results are relatively 
poor and where many different combinations of 
therapy exist. The overall goal is to develop 
objective criteria which may help to identify 
those patients who will (or will not) respond to a 
given mode of therapy. 



11. MYELOGENOUS LEUKEMIA-ASSOCIATED ANTIGENS - 

PRODUCTION AND ANALYSIS OF BABBIT ANII-CHL 

ANIISEBUn 

Bust, C. J., Lozzio, C. B., Lozzio, 3. B., Whitson, 

M. E., Univ. of Tennessee, Scncol of Lineral Arts, 

Microbiology, W. Cumberland Ave. S . W . , Knoxville, 

Tennessee, 37916, U.S.A. 

He have developed and characterized a unique 
cell-line (K-562) originally derived from a 
patient with chronic myelogenous leukemia (CKL) . 
This CMl cell line has the Philadelpnia (Phi) 
chromosome and is free of Epstein-Barr virus 
genome, herpes-like virus and mycoplasma and does 
not have T or B cell markers. Sucn a cell line, 
which also can yield sublines with two and three 
Phi chromosomes, not only provides a controlled 
and reliable source of CML cells free of some 
common oncogenic viruses, but can also be examined 
for relative synthesis of specific antigen with 
respect to the karyotype. 

These CBl cells when injected into rabbits 
cause the production of specific antibody which 
demonstrates complement-dependent cytotoxicity for 
CML cells. In preliminary experiments,' the 
cytotoxicity for C.IL cells is not removed if the 
serum is absorbed with either leukocytes or 

CML cells does effectively remove the cytotoxic 
activity. Furthermore, the immune serum is not 
cytotoxic for normal human leukocytes. other aata 
indicate that the antiserum is cytotoxic for 
leukocytes trom patients with CBL obtained prior 
to treatment or during relapse. 

The purpose of 'his project is: 1) to 
evaluate the specificity of the antiseium and its 
use as a diagnostic and/or prognostic aid; 2) to 
isolate and characterize the CHL specific ant- 
igen (s) ; 3) to characterize the antibody during 
the immune response at selected intervals and 
assess the cytotoxicity on cells from normal and 
human patients suffering from leuxemias, lymphomas 



122 



and several other hematologic and oon-beaatologic 
diseases. 

BEFEBENCSS: Uhitson, H. E. , Lozzio, C. B., 
Lozzlo, B. B., Uust, C. J., Sonoda, T., and Avery, 
B. Cytotoxicity of antisera to a myelogenous 
leuJcemic ceil line with the Philadelphia chrom- 
osome. J. Nat. Cancer Inst. <1976). Collins, J. 
L., Nust, C. J., Lozzio, B. B., and Lozzio, C. B. 
Isolation and characterization of human leukemia 
cell line K-562. Fed, Proc. (1976). 



12. DBIWABY EXCRETION PATTERNS IN LEDKEHIA 
Beid, J. C. U.S. Dept. or Hlth. Ed. e Wel., Natl. 
Cancer Institute, Cancer Physiology Section, 
Bethesda, Raryland, 200ia, U.S.A. 

Drinary excretion patterns in leukemia are 
investigated in an effort to devise a diagnostic 
procedure. 



13. CHBQH050ME ANALISES IK THE DIAGNOSIS OF 

PBELEDKEHIA 

Pierre, P. v., Univ. of Minnesota, School of 

Medicine, 200 1st St. S.H., Rochester, Hinnesota, 

55901, U.S.A. 

The study is a prospective study of bone 
marrow chromosome changes in preleukemia. Ue are 
studying patients with refractory cytopenias and 
nondiagnostic bone marrow aspirates by direct bone 
marrow chrotDosome studies. All suspected pre- 
leukenic patients are followed by serial clinical, 
laboratory, and cytogenetic studies. Data 
collected on these patients is entered into a 
computer to be correlated with the course of the 
patient. The type and incidence of chromosome 
abnormalities will be determined in the preleuk- 
emic patients and the presence .of such abnorma- 
lities related to the development of acute 
leukemia. The computer will be used to determine 
wnether any clinical, laboratory or cytogenetic 
data have potential value as predictors of 
progression froa preleukemia to leukemia. Con- 
secutive patients with suspected preleukemia will 
be studied until 100 patients with chromosome 
abnormalities are collected; 273 patients with 
suspected preleukemia have been studied by 
chromosome analyses, 146 patients with overt acute 
leukemia and 151 "normal" subjects have been 
studied to date. The normal subjects provide data 
on normal variations in the normal human marrow 
karyotype, and are used as a basis for deciding 
normalcy or abnormality in the study patients. 



in. PBOSPECTIVE EVALUATION OF SUSPECTED PRg- 

leOKEHIA 

Cabanillas, F,, Univ. of Puerto Rico, School of 

Medicine, F.O. Box 5067, San Juan, Puerto Rico, 

00936 

This is part of a broader project. A summary 
of this subproject is not available. 



15. COLONY STUDIES IN REFRACTORY CYTOPENIAS 
Testa, N. G., Dexter, T. M., Paterson Laboratories, 
550 Hilnslow Rd., n20 9bx, Manchester, England, 
United Kingdom 

OBJECTIVE: To characterize the behaviour of 
progenitor cells in the haemopoietic tissue in 
syndromes which may preceae the development of 
acute granulocytic leukaemia. 

APPROACH: Bffne marrow samples from patients 
with idiopatic neutropenia, thrombocytopenia or 
anaemia are assayed in vitro by measuring their 
capacity to produce granulocytic and erythroid 
colonies, 

PROGRESS: Granulocytic colonies were absent 
or greatly diminished in 18 of 2^4 patients. These 
patients also tended to have low numbers of cells 
able to form erythroid colonies. This defect in 
colony forasation (which occurs also in acute 
leukaemias) was found in the absence of clinical 
or morphological evidence of leukaemic change and 
vas maintained unaltered for several months. 



B. PROGNOSTIC STUDIES IN LEUKEMIA 



1. CYTOKINETICS IN LEUKEMIA PROGNOSIS 



16. BONE-HARROW CELL KINETICS AND RESPONSE TO 
CHEMOTHERAPY IN CHILDHOOD LEUKEMIA 

Siets, L. A., Netherlands Cancer Institute, Cancer 
Hospital, Exper Chemotherapy & Radiotherapy, 
iDtODi van Leeuwenhoek, Ziekenbuis Plesmanlaan 121« 
Amsterdam, Netherlands 

OBJECTIVE: Applying pulse-cy tophotcmetry to 
bone-marrow aspirates of leukemic patients for 
early detection of the occurrence of response of 
the individual patient to chemotherapy, 

APPROACH: DNA per cell distributions were 
recorded by automated cytof luorcmetry (pulse- 
cytophotoaetry) in bone-marrow aspirates or lymph 
node biopsies of leukemia and lympaosarcona 
patients subjected to chemotherapy. In most 
cases, early perturbations in DNA per cell 
histographs were observed, characteristically 
reflecting the known node of action of the drugs. 
These changes in general preceded the clinical 
observation oi drug response. 

PROGRESS: In a series of 15 patients 10 
patients showed a positive correlation between 
early cytophotometric changes and clinical effects 
of chemotherapy, 3 patients were negative for both 
pulse-cytophotometric and clinical reactions, 1 
was probably false -negative in the pulse-cytophot- 
ometric assay, and 1 false-positive. The validity 
of the assay for early detection of drug resist- 
ance in acute leukemia and related diseases is 
suggested by these results. 



17, BONE-BARRQg KINETICS AND RESPONSE TO CHEM - 
OTHERAPY IN LEUKEMIA PATIENTS 
Saets, L. A,, Netherlands Cancer Institute, 
Experimental Cytology, 1C6-108 Sarphatistraat, 
Amsterdam, Netherlands 

OBJECTIVE: To detect early changes in the 
proliferation of bone-marrow ceils of leukemia 
patients to monitor the effects of chemotherapy 
and to predict drug-resistance. 

APPROACH: Bone-marrow aspirates are obtained 
from leukemia patients before and auring chemothe- 
rapy. The DNA per cell distributions of the cell 
populations are recorded by automated flow-through 
cytophotometry. The clinical responses to therapy 
ace compared with (a) the proliferative activity 
at the start of therapy and with (o) the drug- 
induced alterations in the DNA per cell distr- 
ibutions after 2a hours. 

Model studies in animals and in tissue 
cultures are performed to improve the interpre- 
tation of the measurements, 

PROGRESS: Alterations in the DNA profiles 
were observed within 2a hours after the start of 
therapy and could be correlated with the known 
■ode of action of the drugs used. 

A positive correlation between early cytopho- 
tometric changes and clinical responses to therapy 
was observed in 17 patients. 6 patients who did 
not respond to therapy were also nagative for 
early changes in bone-marrow proliferation and one 
patient was false-positive for the cytophotometric 
assay. The assay may be of clinical value for the 
early detection of drug-resistance in patients 
tflth acute leukemia. 



18, (CELL PROLIFERATION KINETICS IN ADULT ACUTE 
LEDKEHIA IN RELATION TO CLINICAL RESPONSE) 
Robert, F. , Omura, G. , Gams, A., Univ.* of Alabam 
School of Medicine, Medicine, 1919 7th Ave. S., 
Birmingham, Alabama, 35233, U.S.A. 



OBJECTIVE: To determine the tritiated 
thymidine labelling index in adult acute leukemia, 
pce-treatment and after the first course of 
current drug regimens to: a. Attempt to confirm 
and extend the observations of Hart, et. al., that 



123 



A nigh labeling index correlates with subsequent 
achievement of renission. b. Observe the degree 
of suppression of DNA synthesis post-treatment and 
ascertain xhether this also correlates »ith 
clinical response. 

»PPROACH: standard autoradiography and DBA 
deteraination using liquid scintillation counter 
and diphenylanine reaction of Burton techniques 
are used to determine tne labelling indei and DNA 
synthesis in patients with acute lauKeeia. Ihis 
analysis is made at different time intervals. 



19. lEDKOCtlE THYBIDINE OPTAKE IN nOWITOBIllG 
gESPOMSE TO IBEAIBENT OF CBBOmc LEUKEBIA 
Hoayeri, H., Sokal, J. E. , Pauly, J. L., Gomez, 
G., Eos»ell Park Memorial Inst., Medicine, 666 Elm 
St., Buffalo, Nev York, 14203, U.S.A. 

«e Kill measure in vitro thymidine uptake by 
circulating leukocytes periodically during the 
course of chronic myelocytic leukemia and chronic 
lymphocytic leukemia. Frequent serial determ- 
inations vill be obtained when therapy is inst- 
ituted or changed. In vitro effects of antile- 
ukemic drugs vill also be determined. Results 
•ill be correlated Kith clinical and hematologic 
data to determine whether leukocyte thymidine 
uptake can serve as a sensitive index of quality 
of disease control and predict response or 
resistance to chemotherapy in advance of other 
parameters. In vitro effects of an ti-leukemic 
agents on circulating leukemic cells will be 
correlated with clinical responses to those 
agents. 



20. A SIDDI OF lEDKOKIKETICS WITH DFP32 IM 
BOMIIOgmG TREATMENT OF ACUTE lEUKEfllA 
Bauer, A. M., Murphy, s., Hayes, A., Strauss, B., 
Dow, L., Thompson, E., St. Jude Ch . Ses. Hosp., 
Hematology, 332 N. Lauderdale St., Box 318, 
Bemphis, Tennessee, 38101, U.S.A. 

Studies of cell kinetics in patients with 
acute leukemia are being done. In order to 
determine the proliferative activity of the cell 
population, blood and bone marrow saoiples are 
obtained. The mitotic indices are measured and 
the number of cells in DNA synthesis determined 
autoradiographically from the labeling index with 
tritiated thymidine. Currently studies are being 
done to determine the effect of chemotherapeutic 
agents singly and in combination on the proli- 
ferative activity of the leukemic cells. These 
results will be used in the design of chemotherap- 
eutic regimens for acute leukemia. 

Studies are also being done in patients with 
abnormal but non-malignant myelopoiesis in order 
to learn more concerning variations of normal 
proliferation and maturation patterns. In vitro 
and in vivo studies will be designed in order to 
obtain information concerning the growth regula- 
tory mechanisms for leuxemic and non-leukemic 
marrow cells. 

Infections are a ma:|or problem for leukemic 
patients. Therefore studies of cellular and 
humoral defense mechanisms in these and other 
patients having an apparent increased predispo- 
sition to infection will be done. 

REFERENCES: Murphy, S.B., Borella, 1., Sen, 
I., and Bauer, A.M.: Lack of correlation of 
lymphoblast cell size with presence of T-cell 
markers or with outcome in childhood acute 
lymphoblastic leukemia. Brit, J. Haematol. 31: 95, 
1975. Bauer, A.M.,: Cell kinetics and practical 
consequences for therapy of acute leukemia. Hew 
Eng. J. Bed. 293: 389, 1975. 



21. lEUKOCYTE TURNOVER H MONITORING TSEtlBEIIT OF 
ACUTE LEUKEMIA AND LEUKOPENIAS 
Brubaker, L. H., Univ. or Missouri, School of 
Bedicine, Medicine, M228 Medical Sciences, 
Columbia, Missouri, 65201, U.S.A. 



Our overall goal is to develop methods to 
study the turnover of neutrophils in patients with 
acute leukemia and other malignancies to detect 



pathophysiologic abnormalities which may cause 
neutropenia. As a major prior accomplishment, we 
have developed a test involving the exposure of a 
patient's own heparinized blood to the cellophane 
of a hemodialysis coil followed by reinfusion of 
this blood to produce a transient neutrophilia. 
Ihis coil test is doubly useful. The magnitude of 
the neutrophilia is proportional to the marrow 
neutrophil reserves as defined by the tcature 
neutrophil cellularity of a marrow specimen. The 
fall-off of the neutrophil count from the peak 
back to baseline is the sane as the DFP32-measured 
neutrophil survival. Short neutrophil survival 
may be detected as readily by the coil test as by 
the much more complex DFP32 test. »e are propo- 
sing simplification of the coil test by putting 
the cellophane into a blood bag. Currently we are 
testing various models of the preliminary bags in 
dogs. «e are also gathering information regarding 
how much cellophane is needed, how long exposure 
to cellophane is needed, how much olood is needed 
as a minimum, and what is the biocaemical basis 
for these changes. This seems to involve acti- 
vation of the alternate complement pathway. 

We will compare the coil and/or bag test 
along with other tests for marrow neutrophil 
reserves with a new, more precise method for 
quantitating the total marrow mature neutrophils 
in order to find out which of the simple tests is 
most reliable. He will test patients on chem- 
otherapy to see if the coil test can predict more 
reliably tnan the white blood count future marrow 
toxicity by drugs. In the same patients we will 
test for antineutrophil antibodies using DFP 
labeled neutrophils from patients with paroxysmal 
nocturnal hemoglobinuria, a test which we deve- 
loped. He will also test the same patients* bone 
marrows with the soft-agar colony growth technique 
for correlations with the studies of peripheral 
turnover of neutrophils. Ultimately, we hope to 
demostrate whether cancer patients can actually 
survive longer due to the use of tnese tests. 
Studies are being designed to test this. 

BEFESENCES: 1. Carmel, E., Coltman C.A., 
Jr., and Brubaker, L.H: Serum Vitamin b-12 Binding 
Proteins in Various Neutropenic States. Proc. Soc. 
Exp. Biol. Med., lUB: 1217, 1975. 



22. CITOKIMETICS EVALUATION IN TREATMENT OF 

LEDKEBIA 

Hart, J., Freireich, E., Hester, E. M., Ho, D., 

Univ. of Texas, M.D. Anderson Hosp. 5 Inst., 

Developmental Therapeutics, P.O. Box 20036, 

Houston, Texas, 77025, U.S.A. 

OBJECTIVE: To study the kinetic behavior of 
the leukemic cells obtained from the marrow and 
blood of patients with acute leukemia. 

APPROACH: 1) To correlate the kinetic data 
with other patient variables, response to therapy, 
duration of response and survival. 2) To define 
through serial measurements of the labeling index 
X, marrow morphology and peripheral blood, the 
generation time of leukemic cells for patients 
with myeloblastic and lymphoblastic disease. 

PROGRESS: The data indicate that there is a 
positive correlation between the growth fraction 
(labeling index) of the leukemic cells and 
response to chemotherapy. The foregoing data have 
already formed the basis of several new clinical 
chemotherapeutic trials. 



23. GRANDLOCTTE AND MACROPHAGE PROLIFERATIOII IN 
LEUKEMIA AND RELATED NEOPLASMS - STUDIES UIILIZIUS 
AGAR CELL CULTUEE TECHNIQUES 
Betcalf, D., Walter G Eliza Hall Institute, 
Belbourne, Victoria, Australia, 3050 

This part of a broader project includes 
evaluation of the agar cell culture techniq'Je as a 
tool for (1) diagnosis of human leukemia and 
preleukemic disorders, (2) evaluation of tumor 
cell responsiveness to chemotherapy, (3) evalua- 
ting leukemic and normal cells in ceil separation 
procedures, and (4) study of leukemic cell 
kinetics with cell cycle killing agents. We will 
correlate these studies to the clinical course of 



124 



leukemic patients and with the colony stimulating 
factor levels in their urine and cell cultures, 
utilizing an established protocol. (Text Abri- 
dged. ) 



2«. THE IHHIBITIOII OB BEGULATIOM OP THE CELL CYCLE 
OF HOBHAL UnPHOCYTES - PROGiiOSTIC SIGNIFICAN CE 
auBphrey, G. B., Oleinick, s. a., Lankford, J. A., 
O.S. Veterans Administration, Hospital, 921 N.E. 
13th St., Oklahoma City, Oklahoma, 7310it, U.S.A. 

OBJECTIVE AND METHOD OF APPBOACH: The 
overall objective of this research is to determine 
the prognostic significance and mechanism of 
action of leukemic serum inhibitor (s) of normal 
blastogenic transformation. The method of 
approach at this time includes the isolation, 
purification and characterization of the inhi- 
bitor (s) so that a specific quantitative assay can 
be developed. The mechanism of action is being 
investigated by expansion of the blastogenic assay 
system to include immune stimulants, other than 
phytohemagglutinin (PHA) and pokeweed mitogen 
(PUB), which are thought to differ in mechanisms 
and the lymphocyte subpopulations which they 
activate. 

BESULTS TO DATE: Leukemic sera significantly 
inhibit the blastogenic transformation of normal 
allogeneic lymphocytes stimulated with PHA and 
P»H. This effect is dependent upon the clinical 
status and absolute leukocyte count of the 
patient, and the mitogen used. Inhibitory activity 
diminishes during remission and appears to be 
associated with a heat-stable macromolecule of 
greater than 100,000 molecular weight which is 
possibly glycoprotein in nature. 

PLANS FOB FUTUBE BESEABCH: Plans include 
confirmation of preliminary results on characteri- 
zation of the inhibitor (s) using gel sieving and 
ion exchange column chromatography. Also, US 
diagnosis-remission sera pairs from patients with 
acute leukemia have been collected for batch 
analysis of inhibitory activity using various 
■itogens and inactivated allogeneic lymphocytes as 
stimulants. Data from these studies will be 
analyzed for correlation with clinical response 
and prognostic lactors such as initial leukocyte 
count and histocytochemical reactions. 

REFESENCES: Humphrey, G.B., Lankford, J., 
and Nitschke, B. : The influence of diagnostic and 
remission leukemic sera on lymphocyte transfo- 
rmation. Biomedicine 23: 121, 1975. Humphrey, 
G.B., Peterson, L.B., uhalen, «., Parker, D.E., 
Lankford, J., Krivit, w., Nesoit, M.E.: Lymphocyte 
transformation in leukemic serum. Cancer 35:13"tl- 
1345, (lay, 1975. 



25. DECISION-AIDING METHODOLOGY FOB LEOKEHIA 
CHEBCTHEBAPY 

Aroesty, 0., Lincoln, I., Borrison, P., Gazley, 
C, Gross, J. F. , Lundguist, C. , Juncosa, B., 
Beier, G., Kagiwada, H., Bigelow, J., Shapiro, N., 
Carter, G., Band Corporation, physical Sciences, 
1700 Bain St., Santa nonica, California, 9CU06, 
O.S. A. 

He are exploring the feasibility of a 
computer based quantitative decision-aiding 
methodology to assist physicians during the 
chemotherapy of leukemia. Our methods use 
Batheoat ical models, computer simulations, and 
data analysis to formalize existing relevant data 
on the biology of the disease, the physiology of 
the bone marrow, and" the action of the drugs. Our 
system, when completed, could be used to identify 
critical decision points in therapy, to quantify 
the risk and benefit to the patient of medical 
alternatives, and to provide the optimum treatment 
plan to coordinate clinical practice and the major 
cancer centers. Our system is modular: the first 
module is the leukemia/therapy simulator where 
cell kinetics, pharmacokinetics, the patient's 
data on blood counts and prior therapy, and marrow 
mechanics are all used to predict the response of 
the patient to anti-tumor drugs and schedules. 
Other modules, to be developed later, deal with 
the prediction of complications, the effects of 



organ toxicity, the activity status of the 
patient, and the development of optimal scheduling 
strategies. 



2. CYTOGENETICS IN LEUKEMIA PROGNOSIS 



26. CHBOHOSOME STDDIES, ChABACTEBISIICS AND 

PROGNOSTIC SIGNIFICANCE IN HUBAN LEOKEBIA AND 

PBELEUKEBIC CONDITIONS 

Hitelman, F., Brandt, L. , Levan, G., Univ. of Lund, 

Univ. Hospital, clinical Genetics, s-221 85, Lund, 

Sweden 

OBJECTIVE: To characterize in detail the 
chromosomal status of human leukemia with modern 
banding techniyues in order to: 1. determine 
•hether leukemic cells with an apparently normal 
karyotype have structural aberrations overlooked 
by staining techniques; 2. determine whether the 
karyotypic aberrations are nonrandom; 3. 
determine unether the chromosomal picture can be 
used as a prognostic parameter in acute leukemia. 

APPROACH: The chromosomes are studied in 
direct bone marrow preparations by means of a 
trypsin-Giemsa banding technique, in all patients 
presenting witn acute myeloid leukemia and 
pceleukemic conditions. 

PBOGBESS: The bone marrow chromosomes have 
been studied in detail in 30 patients with acute 
myeloid leukemia. The results support the 
conclusion that leukemic cells may have a comp- 
letely normal chromosome banding pattern. 
However, when chromosome changes occur, these are 
clearly nonrandom. 



27. KABYOTYPIC STUDIES IN PATIENTS gITH ACUTE 
HYELOID LEUKAEBIA IN ASSOCIATION UITH IBHUNOTHE- 
BAPY AND CHEBOTKERAPY 

Huldal, S., Paterson Laboratories, 550 Uilmslow 
Bd., B20 9bx, Banchester, England, United Kingdom 

OBJECTIVE: To assess the fundamental and 
clinical significance of chromosome changes in 
leukaemic cells. 

APPBOACH: Constitutional karyotypes (lympho- 
cytes or skin) , karyotypic changes in leukaemic 
cells and changes during the course of disease 
(serial samples) are investigated by means of 
banding techniques (C-, G-, B- and Q-banding) . 

PROGRESS: In about half the cases chromosome 
changes are recognised. These form a number of 
groups where the changes are identical. 



28. VALUE OF PEEBATURE CHROBOSOBE CONDENSATIOK 
STDDIES IN PREDICTING RESPONSE OF HOHAW TUMORS TO 
CANCER DRUGS 



Bao, P. N., Gottlieb, J. A., Hittelman, U. N. , 
Univ. of Texas, M.D. Anderson Hosp. 6 Inst., 
Developmental Therapeutics, P.O. Box 20036, 
Houston, Texas, 77025, U.S.A. 

OBJECTIVE: To develop an in vitro predictive 
system to evaluate the response of human tumors to 
a broad spectrum of chemotherapeutic agents before 
a patient is scheduled to a particular therapeutic 
regimen by making use of the phenomenon of 
premature cnromosome condensation (PCC) . 

APPROACH: The approach is based on the fact 
that most of the cancer chemotherapeutic agents 
not only cause cell death but also induce chr- 
omosomal aberrations. The PCC method makes it 
possible to visualize chromosome damage in 
interphase cells or those cells that will not be 
able to enter mitosis because of the lethal 
effects of the treatment. Cells from human tumors 
treated in vivo or in vitro with a given drug will 
be fused with mitotic HeLa cells and the PCC of 
the tumor cells will be scored for aberrations. 
The data on chromosome aberrations and the 
clinical regression of the tumor will be compared 
to find any correlations. 

PROGRESS: Initial studies with tissue 
cultures have been published. Studies with 
leukemic patients, tumor cells are in progress. 



12S 



29. RBLATIOH BETUEEN INITUt CHBOHOSOBE FIIIDINGS 
IND PBOGSOSIS III ACUTE LEUKEMUS Of ADULTS 
Hossfeia, D. K. , Univ. Clinic for Internal Med., 
55 Huf elandstrasse, Essen, Federal Republic of 
Geraany, <i3 

OBJECTIVE: To confirm or reject findings by 
Dr. Sandberg*s group in Burtalo who did find a 
correlation between the bone narrovf chromosome 
constitution and prognosis. 

APPROACH: Chromosome preparations - folio- 
King standard technigues - are done prior to 
initiation of treatment. All patients with acute 
leukemia, except the lymphoblastic variety. Kill 
be given the same modality of treatment. 

30. CYIOGEMETIC STUDIES OH PATIENTS BITH A VABIST? 
OF MYELOPBOLIFERATIVE DISEASES INCLUDING LEUKEMIA 
Horse, K. G., Robinson, A., Humbert, J. S., Hutter, 
J. J., Univ. of Colorado, School of Medicine, 
Biophysics Genetics, •J^iCO E. 9th Ave., Denver, 
Colorado, 80220, U.S.A. 

OBJECTIVE: Use cytogenetic analysis to 
resolve problems such as definition of remission 
in patients with leukemia, early diagnosis of 
relapse, differential diagnosis of the various 
types of acute leukemias, and when to initiate or 
vithhold therapy of the preleukemic patient and 
the patient with a leukemoid reaction. 

APPROACH: Ne applied recent cytogenetic 
technigues of chromosome banding to a study of 
unselected leukemic patients either new (untre- 
ated) , in relapse, or in remission. Cultures of 
bone marrow, and PHA-stimulated and unstimulated 
peripheral blood from preleukemic patients, 
leukemic patients, patients with nonleukemic 
diseases, and apparently nealthy individuals were 
karyotyped, and mitotic index was determined. We 
explored substituting unstimulated peripheral 
blood for bone marrow as a source of leukemic 
clones and also tried to perfect banding en 
malignant cells which respond poorly to present 
technigues. 

PEOGBESS: Since most of our leukemic 
patients had acute lymphatic leukemia, aberrations 
were marked by hy perdipioidy. Multiple trisomies 
were the most common aberrations; oreaks, frag- 
ments, deletions, translocations, and rearrang- 
ements were infreguent. Two ALL patients showed 
aberrations when in relapse but normal metaphases 
when in remission. Aberrations found in the 
leukemics were not found in controls. Metaphases 
were ouch more numerous in the peripheral blood of 
acute leukemics than in the blood of either normal 
persons or patients with nonleukemic diseases. 

This type of cytogenetic study may have 
Barked value, particularly when a patient has 
demonstrable chromosomal aberrations, since 
detection of the abnormal, presumably leukemic, 
cell line early in remission can be used to 
diagnose the onset of relapse well in advance of 
clinical signs.- Similarly, a change from multiple 
aberrations to normal karyotype in the transition 
from relapse to remission could indicate the 
effectiveness of treatment. 



31, lEUKOCtTE REGULATORY MECHANISMS - INCLUDING 
PROGNOSTIC SIGHIFICANCE OF MARBOU CHROMOSOME 
STUDIES IN PRELEUKEMIC STATES 

Nowell, P. C, Univ. of Pennsylvania, School of 
Medicine, Pathology, 36th t Hamilton Ualk, 
Philadelphia, Pennsylvania, 1910U, U.S.A. 

Within the general framework ot studies on 
the control of leukocyte proliferation and 
differentiation, specific investigations will 
attempt to: a) Further clarify the life history of 
immunocompetent lymphocytes in the rat, and their 

b) Extend preliminary studies on subpopulat ions of 
B and T lymphocytes in normal and leukemic human 
blcod; c) further delineate the prognostic value 
of marrow chromosome studies in human "preleuk- 
emia." For the tat studies (a) in vivo labelling 
with tritiated thymidine will be combined with 
autoradiographic and cytogenetic studies on mixed 



lynphocyte cultures to test a proposed model for 
the life history of rat cells responsive to major 
histocompatibility antigens and their relationship 
to aging and neoplasia. For the studies of human 
B cells and T cells (b) the techniques will 
include kinetics in culture, cytogenetics, rosette 
formation, and immunofluorescence. Initially, 
attempts will be made to characterize the neop- 
lastic clone in typical chronic lymphocytic 
leukemia. For human "preleukemia" (c) marrow 
chromosome findings will be correlated with tne 
subsequent clinical course to determine the 
prognostic significance of marrow chromosome 
abnormalities in "preleukemic" states. 



32. BYElOgONOCYTIC LEUKEMIA - DOCOMENTATION OF 
CLINICAL AND LABOBATOBY PASAMEIEBS 
Pierre, R. v., Univ. or Minnesota, Scnool of 
Medicine, Medicine, 200 1st St. S.W., Rochester, 
Minnesota, 55901, U.S.A. 

OBJECTIVE: To document the clinical, 
hematologic, biochemical and cytogenetic findings 
in myelomonocytic leukemia. 

APPEOACH: Patients with untreated myelomono- 
cytic leukemia are studied serially tnroughout the 
course of their disease. Various clinical and 
laboratory parameters are recorded m a computer 
format for later correlation of disease features. 
Cytogenetic studies are performed on initial bone 
marrow studies, and correlation of the presence or 
type of cytogenetic abnormalities with tne course, 
response to therapy, and clinical features of the 
disease will be carried out. A parallel study of 
similar design is being carried out of the 
preleukemic phase of the disorder. 

PROGRESS: 1«2 subjects had been entered on 
study by January 1975. Cytogenetic studies have 
been completed in all and data entered into 
computer storage. Serial observations and 
followup of all patients ha^ been maintained. 137 
of the subjects have died to date. Protocols are 
being constructed for analysis of the stored data. 



33. CYTOGENETIC AND ULIRASIBUCTUBE ANALYSIS OF 
ACUTE LEUKEMIA - COBRELATIONS WITH CLINICAL C0U5SE 
Hart, J., freireich, S., Ahearn, s. J., Trujillo, 
J. H., Univ. of Texas, S.D. Anderson Hosp. 6 Inst., 
Developmental Therapeutics, P.O. Box 2C036, 
Houston, Texas, 77025, U.S.A. 



OBJECTIVE: To correlate cytogenetic abnorma- 
lities found in patients with chronic and acute 
myelogenous leukemia with many clinical variables 
such as number of marrow blasts, response to 
chemotherapy, survival, etc. 

PROCEDURE: 1) To investigate the occurrence 
of cytogenetic aberrations during long-term 
chemotherapy and the effect of these abnormal 
clones on subseguent response to chemotherapy. 2) 
To identify the frequency with which certain 
abnormal cell lines occur and their correlation 
with other pre-therapy variables. 3) To correlate 
the abnormal nuclear bleb formation with tne 
cytogenetic abnormalities and define their role in 
response to chemotherapy. 

PROGRESS: Bone carrow and peripheral blood 
has been re-evaluated prior to eacn renissicn 
induction course of therapy to complete remission. 
During remission maintenance cherotherapy , the 
bone marrow has been cy togenet ical ly re-evaluated 
prior to every 2nd or 3rd remission maintenance 
course. 



314 . ( CYTOGENETIC STUDIES AND PEOGNOSIS IN CHILD- 
HOOD LEUKEMIA) 

Benedict, w. F. , Univ. of southern California, 
Childrens Hosp. of Los Angeles, Pediatrics, «650 
Sunset Blvd., Los Angeles, California, 90051, 
U.S.A. 

We shall study chromosomal changes in 
children with various types of leukemia to see 
whether or not cytogenetic findings prior to 
treatment can be a prognostic ir.dicator of a 
patient response to treatment. We also hope to be 



126 



able to diagnose recurrent disease before other 
■ore conventional techniques are able to do so. 



3. IMMUN0PR0GN0SI5 OF LEUKEMIA 



35. IWHDNE-RESPONSE GEHES IN PATIENTS WITH ACPTE 
HTELOGEMOUS LEUKEfllA - EVALUATING HL-A AND HLC 
AHTIGENS FOR PROGNOSIS 



Oliver, R. T. , Williams, A., Lawler, S., Imperial 
Cancer Research Funa, Medical oncology Unit, 
Lincolns Inn Fields, Hc2a 3px, London, England, 
Onited Kingdom 

HL-Jl antigen fre-juency in 100 controls and 
100 patients with acute myelogenous leukemia has 
revealed no overall difference in antigen freq- 
uency, suggesting that there is no relation 
between HL-A antigens and susceptibility to 
induction of AML, 

However, when the HL-A antigen frequencies of 
the long-term survivors are compared with those 
who died early, it becomes clear that certain HL-A 
groups are associated with a better prognosis. We 
are currently investigating the basis of this 
association by looking at the levels of complement 
factors, serum lysozymes, and anti-HL-A antibody 
response in these patients, as well as studying 
the MLC antigens which are thought to be even more 
closely associated with immune response genes than 
HL-A antigens. An understanding of the mechanisms 
involved will enable a more rational approach to 
iamunotherapy in these patients. 



36. ANTIBODIES TO AUTOLOGODS LEOKEHIC CELLS - CELL 
SDRFACE HEMBRANE ANTIGENS AND SURFACE IHHUNOG- 
LOBPLIBS AS PROGNOSTIC INDICATORS 

Catley, P. F., Balkwill, F. R. , Lea, S. , Imperial 
Cancer Research Fund, Medical Oncology Unit, 
Lincolns Inn Fields, Wc2a 3px, London, England, 
Dnited Kingdom 

Three assays: leukemic cell migration, 
leukenic cell cytostasis, and immunof luorescent 
techniques, have provided evidence for antibodies 
in nany patients with prolonged remissions. As 
soDe of these patients also have antibodies at the 
tine of diagnosis, our current studies are 
directed towards under stanaing escape mechanisms 
by which the cells avoid immunological control. 

Two approaches are *6ing used to exaciine this 
question. First, the nature of the iomanoglobu- 
lin, which can be demonstrated on the membranes of 
cells from some patients with acute myelogenous 
leukemia, is under study. Patients whose leukemic 
cells have immunoglobulin attached to the leukemi- 
C-cell membrane have a better survival than those 
who do not, and there appears to be a relation 
between the presence of immunoglobulin attached to 
the membrane and the capacity of cells to dem- 
onstrate macrophage differentiation in culture, 
suggesting that immunoglobulin may be bound to Fc 
receptors of these cells. Limited pepsin diges- 
tion is being used in an attempt to separate Fc 
from Fab portions of the immunoglobulin molecule 
to determine the site of attachment. 

Secondly, we are investigating cell-surface 
■eabrane antigen shedding and re-synthesis. 
Preliminary indirect immunofluorescence studies of 
shedding and pinocyt.osis of memnrane-bound 
antibodies indicate marked differences between 
acute and chronic leukemic cells, and there is a 
suggestion that patients whose cells demonstrate 
rapid antigen sheddj-ng and pinocytosis have a 
worse prognosis than those who do not. 



37, SDRFACE-HARKEH STUDIES IN PATIEMTS BITH 
■OB-HODGKIN'S DISEASE - B £ T CELL SURFACE 
BARKERS, SURFACE IHHUNOGLOBULI N5 AND PROGNOSIS 
Catley, F., Lister, T. A., whitehouse, J. M., 
Imperial Cancer Research Fund, Hedical Oncology 
Onit, Lincolns Inn Fields, Hc2a Jpx, London, 
England, United Kingdom 

iBBunofluorescence positivity with anti-huaan 
gammaglobulin and E-rosetting capacity have been 
used as markers for T and B lymphocytes. These 
tests have been used to study: (1) Normal 
peripheral blood of patients with non-Hodgkin 's 
lymphoma. Nineteen patients have been studied: 
in six there is a definite increased proportion of 
B cells, and m all of these the histology has 
been suggestive of a tumor of B-cell origin; all 
have bone-marrow involvement. (2) Chronic 
lymphocytic leukemia. In almost all cases there 
has been a very marked increase in the proportion 
of lymphocytes having membrane-bound immunoglo- 
bulin. There have been no cases to date of 
"T-cell" chronic lymphocytic leukemia, (3) Acute 
non-myelcgenous leukemia (acute lympnoblast ic 
leukemia and acute undifferentiated leukemia) . 
Twenty-three patients have been studied. Three 
were positive using the E-rosette technique, and 
one by immunofluorescence for surface immunogl- 
obulin (the latter was a Burkitt-like leukemia). 
(4) Lymph node suspensions. Eight nodes from 
lymphoma patients have been studied. One from a 
patient with acute lymphoblastic leukemia showed 
no markers; four from patients with diffuse, 
poorly differentiated lymphoma were studied. 
Monoclonal IgM Lambda was demonstrated in the 
surface or the cells in three cases, and Ign Kappa 
was shown in the fourth; two were studied from 
patients with nodular poorly differentiated 
lymphocytic lymphoma. Monoclonal IgH Kappa was 
demonstrated in the lymphocytic surface of both; 
one Hodgkin's disease lymph node was studied, and 
70% of the cells were E rosette positive. 

Leukemia specific antigen studies. Antisera 
to acute lymphoblastic leukemia raised m rabbits 
are being used; (1) as possible diagnostic aids; 
(2) as markers for detecting early relapse in the 
bone marrow. 



38. IBBDMOCOHPETEHT CELLS IS ACPTE LYHPHOCTTIC 

LEUKEMIA - B AND T CELL SURFACE MARKERS IN 

PROGNOSIS 

Borella, L. D. , Green, A. A., Sen, L. , Marphy, 1. 

J., St. Jude Ch. Res. Hosp., Lab of Virolcgy & 

Immunology, Box 318, 332 N. Lauderdale St., 

Memphis, Tennessee, 38101, U.S.A. 

The main objectives of this research are: 1. 
To determine if the differences in response to 
therapy of children with ALL lie m the origin of 
the leukemic blasts (thymocytes vs bone marrow 
stem cells) and to correlate ceil origin with 
prognosis. Bone marrow and peripheral blooJ cells 
from children with untreated ALL will be 5:f!l:.ed 
to establish if a correlation exists betwe: :' ~ and 
B cell-surface markers, presence of DNA teiai.ial 
transferase in leukemic lyraphoblasts, kinetics of 
colony formation by granulocyte precursors, 
clinical features and response to therapy. 2. To 
determine m children with ALL "in remission" the 
selective effects of four different antileuke- 
mia-drug combinations upon lymphocyte subpopul- 
ations and to establish whether a correlation 
exists between immunocompetence, as measured by 
"in vivo" and "in vitro" assays, ana the clinical 
course of the disease. 



39, ANTISERA TO HUMAN LEUKEMIA-ASSOCIATED ANTIGEHS 

- CHARACTERIZATION AND PROGNOSTIC VALUE 

Baker, M. A., Toronto Western Hospital, Medicine, 

399 Bathurst St., Zone 2b, Toronto, Ontario, 

Canada 



OBJECTIVE: He have attempted to identify and 
characterize antigens associated with huaan 
leukemic blast cells. 

APPROACH: Firstly, we have examined the 
huBoral and cellular response of patients with 



127 



leukeaia to autologous and allogeneic blast cells. 
Patients with acute leuXemia may manifest delayed 
hypersensitivity to autologous leukemic cells 
indicating a response to LAA but the response was 
unpredictable and did not correlate with stage of 
disease or prognosis. Patients receiving iomunot- 
berapy with allogeneic leukemic cells produced 
hoDoral antibody directed against LAA, and 
production of antibody correlated with stage of 
disease. 

Secondly, heteroantisera were prepared in 
■ice to human leukemic blast cells and examined 
for specificity against panels of leukemic and 
Don-leukemic cells. LAA were found to be asso- 
ciated with both myeloblasts and lymphoblasts. 

Thirdly, leukemic cell membranes have been 
radio-labelled and solubilized. Soluble products 
have been coprecipita ted with antibody raised in 
patients receiving immunotherapy. 

PBOGIi£SS: These antisera are being used to 
screen bone marrow samples or patients in remis- 
sion for early evidence of relapse. Chromatogra- 
phic technigues have allowed preliminary molecular 
sizing of radioactive membrane derivatives. 



110. (IREATBEm SELECTION AMD PEOGilOSIS, DSIBG 
LEOKEMIA-ASSOCIATED ANTIGEHS OF PE5IPHEBAL BLOOD 



AND BONE MAHaOW CELLS) 
Biller, D. S., Metzgar, R. 
Duke University, School of 
3711, Durham, North Caroli 

The objective of this 
treatment of leukemia. Ser 
eral blood and bone marrow 
associated antigens (LAAs) 
primate and rabbit anti-hu 
be performed. Our intenti 
between leukemic and non-1 
clones during chemotherapy 
Bia. Comparison will be a 
morphological ana serologi 
Particular attention will 
and subseguent sensitiviti 
noii-leukemic clones to che 
relative growth rates dun 
recovery. 

Serial determinations 
bone marrow leukemia-assoc 
obtained from over 200 pat 
acute leukemia. Their cli 
findings have been abstrac 
entered into a computer, s 
patterns indicating sensit 
chemctherapeutic agents, o 
Hill be made. The signifi 
immunoglobulins of varying 
IgG and Ig«) will be asses 



S., nohanakumar, T. 
nedicine, Bedicine, 
la, 27706, U.S.A. 

program is to impro 
Lai studies of perip 
cells for leukemia- 



on IS to distinguish 
eukemic bone marrow 

of adult acute leuke- 
ade between classical 

be paid to the initial 
es of leukemic and 
motherapy and their 
ng post-chemotherapy 

of peripheral blood and 
lated antigens have been 
ients having chronic and 
nical and laboratory 
ted and are being 
earch for antigenic 
ivity to specific 
r favorable prognosis, 
cance of surface bound 
types (IgA, IgD, IgE, 
^ed. 



m. milUSOLOGIC TEST FOB TEBHINAL DEOXi WDCLEOTIDIL 
TRANSFERASE AND ITS PBOGNOSIIC USEFULNESS IN 
LEUKEHIA 

Srivastava, B. I., Chan, J. Y., Siddigui, F. A., 
Roswell Park nemorial Inst., Experimental Therape- 
utics, 666 Elm St., Buffalo, New York, 114203, 
U.S.A. 

OBJECTIVES: 1) To determine whether terminal 
deoiynucleotidyl transferase is of actual clinical 
value in the diagnosis, treatment and prognos- 
tication of patients with acute lymphoblastic 
leukemia; 2) To prepare antibodies against 
terminal deoxynucleotidyl transferase from human 
cells so that these antibodies could be used to 
develop an immunof luorescent test for this enzyme 
which may pi'ove useful for the detection of 
leukemic lymphoblasts. 



12. DECISION-HAKING FOR PATIENTS MITH ACUTE 
LEUKEMIA USING BULTIVARIATE ANALYSIS TECHNIgOE S 
Gehan, E. A., Univ. of Texas, Cancer Center, M D 
Anderson Hosp Tumor Inst, P.O. Box 20036, Houston, 
Texas, 77025, U.S.A. 

The major objective is to develop a metho- 
dology of decision-making for patients with acute 
leukemia. The aim is to utilize all relevant 
clinical and laboratory data during the time 
course of the disease to predict therapeutic and 
toxic results of various schedules and doses of 
treatment. Eegimens of treatment will be sugge- 
sted to the physicians cased upon continuing 
analyses of data from a given patient and frcm 
patients receiving the same treatment. 

A working system has been developed for the 
collection, storage, retrieval and analysis of 
clinical and laboratory data frcm patients wirh 
acute leukemia. The system will be modified to 
utilize the computer more efficiently and to 
permit input of data from multiple sources, such 
as from a medical record analyst, a research 
nurse, the laboratory of clinical pathology, 
laboratories doing special studies (infection 
studies, immunology studies) and other sources. 

The continuing analyses will include: 
characterizations of the time course of disease 
for individual patients; analyses and summaries of 
data on a regular basis for a group of patients on 
one regimen of treatment; and long-term studies to 
determine characteristics of patients related to 
prognosis for patients with acute leukemia. 

The entire system will be designed for use in 
multiple hospitals and clinics so that comparable 
studies and analyses can be performed. 

•We plan to develop new methodology for the 
analysis of data from patients with acute leukemia 
based on technigues of multivariate analysis. 



m. ANALYSIS OF LABORATORY PABAilETERS IN NORHAL 
AND DISEASED INPIVIDUAL5 - MULII CI HENS lOK AL 
PLATELET PROFILES IN THBOBBOCYTOPENIA & LEUKEBIA 
Johnston, D. A., Zimmerman, S. 0., Drewinko, B. , 
Univ. of Texas, n.D. Anderson Hosp. i, Inst., 
Biomatbematics, P.O. Box 20036, Houston, Texas, 
77025, U.S.A. 

OBJECTIVE: To increase the utilization of 
multivariate technigues in the analysis of 
laboratory and clinical test measurements. 

APPEOACH: A variety of standard and new 
multivariate test procedures are being developed 
and applied to a wide range of clinical and 
research situations as they arise and as standard 
univariate technigues prove inadequate or possibly 
incomplete. These procedures have been applied to 
the use of multi-dimensional platelet profiles in 
the detection of early thrombocytopenia in acute 
leukemia patients. (Text Abridged.) 



im. DECISION-AIDING nETHODOLOGY FOR LEUKEMIA 
CHEBOTBERAPY 

Aroesty, J., Lincoln, T., norrison. P., Gazley, 
C, Gross, J. F., Lundquist, c, Juncosa, .1., 
Beier, G., Kagiwada, ".., Bigelow, J., Shapiro, N., 
Carter, G., Band Corporation, Physical Sciences, 
1700 Main St., Santa Bonica, California, 90106, 
U.S.A. 

He are exploring the feasibility of a 
computer based quantitative decision aiding 
methodology to assist physicians during the 
chemotherapy of leukemia. Our methods use 
mathematical models, computer simulations, and 
data analysis to formalize existing relevant data 
on the biology of the disease, the physiology of 
the bone marrow, and the action of the drugs. Our 
system, when completed, could be used to identity 
critical decision points in therapy, to quantify 
the risk and benefit to the patient of medical 
alternatives, and to provide the optimum treatment 



128 



plan to cooidioate clinical practice and the aajor 
cancer centers. Our systea is aodalar: the first 
■odule is the leutceaia/therapy simulator vhere 
cell kinetics, pharaacoxinetics, the patient's 
data on blood counts and prior therapy, and aarron 
•echanics are all used to predict the response of 
the patient to anti-tuoor drugs and schedules. 
Other nodules, to be developed later, deal with 
the prediction of conplications, the effects of 
organ toxicity, the activity status of the 
patient, and the developaent of optiaal scheduling 
strategies. 



«5. 1E0KEHIA/THER>PI SIHOLATOR AHD TOIICITT 

BODIFIER AS AN AID TO TREATHEHT SELECTION AND 

aOMITORING 

iroesty, J., Rand Corporation, Physical Sciences, 

1700 Hain St., Santa Bonica, California, 90U06, 

O.S.A. 

Re are exploring the feasibility of a 
coaputer based quantitative decision-aiding 
methodology to assist pnysicians during the 
cbeaotherapy of leulcemia. Our methods use 
■athenatical models, computer simulations, and 
data analysis to formalize existing relevant data 
on the biology of the disease, the physiology of 
the bone marrow, and the action of the drugs. Our 
systea, when completed, could be used to identify 
critical decision points in therapy, to quantify 
the risk and benefit to the patient of medical 
alternatives, and to provide the optimum treatment 
plan to coordinate clinical practice and the major 
cancer centers. Our system is modular: the first 
■odule is the leukemia/therapy simulator where 
cell kinetics, pharmacoKinetics, the patient's 
data on blood counts and prior therapy, and narrow 
■echanics are all used to predict the response of 
the patient to anti-tumor drugs and schedules. 
Other Bodules, to b€ developed later, deal with 
the prediction of complications, the effects of 
organ toxicity, the activity status of the 
patient, and the development of optinal scheduling 
strategies. 



46. PROGNOSTIC INDICATORS OF LONG-TEBH SDPVIVAt 
BITH CHILDHOOD LEUKEMIA, EPIDEHIOLOGICAL STUDIES 
AMD CONTROLLED CLINICAL TRIAL OF CHEflOTHERAPY 



Colebatch, J. 
Tauro, G. P., 
Hematology, Pa 



ille 



al. 



OBJECTIVE: To id 
with long-tern su 
•ore reliable and 
stopped. 

APPROACH: Of 300 ch 
leuJteiia diagnosed in 1960 
for 5 years, 60 for ** year 
logical, clinical, cytolog 
other data are recorded fo 
long-term with short-term 
long-term survivors who h 
those who have. 

Children who have ne 
and who are imnuno-compet 
are then investigated cyto 
biopsies, seruD copper, e 
suggesting persistent leu 
findings then enter a ran 
trial of maintenance chem 
Their subsequent progress 
ously. 

PROGRESS: Of tW 31 
hawe survived so far for 1 
for 8-9 years. In those w 
only 1/14 studied has show 
on aultiple biopsies. 12 
the random-controlled tria 
follow-up period of 40 aon 



Royal Childrens Hosp, 



fy features associated 
o make prognostication 
s when therapy should be 

Idren with acute 

71, 31 have survived 
s or Bore. Epidemio- 
ical, immunological and 
r the comparison of 
survivors and of 
ve never relapsed with 

er relapsed for M years 
nt when off chemotherapy 
logically with multiple 
c, for any evidence 
emia. Those with nornal 
oaly controlled clinical 
therapy, or no therapy, 
is monitored neticul- 

five-year survivors, 5 
0-15 years and another 6 
ho had never relapsed 
n evidence of leukemia 
patients have entered 
1, and in a nedian 
ths 2 have relapsed. 



«7. ClASSiriCATIOB AHD PROGWOSIS Of CHILDREB JITH 
iCOTE LTHPHOCTTIC LEUKEMIA ACCORDING TO CLINICAL 
AMD LABORATORI FINDINGS 

Deveber, L. L., uar Henorial Childrens Hosp., 
Pediatrics, 391 South St., K6b 1b8, London, 
Ontario, Canada 



OBJECTITE: To identify cases of T-cell 
leukenia who do not have the clinical picture of 
lynphona-leukemia cases, but who have a poor 
prognosis and require more intensive therapy tha 
other cases of acute lymphocytic leukenia. 

APPROACH: Acute lymphocytic leukenia 
patients will be classified on the basis of: 1. 
T-narkers on their blast cells; 2. high white 
blood cell count at diagnosis (above 20,000 
BBC/cu.nm); 3. clinical features (as compar 
lynphona-leukenia) ; U. in vitro sensitivity of 
blasts to antineoplastic drugs at diagnosis and 
relapse. 

These findings will be correlated with their 
prognosis. 



ith 



6. OTHER STUDIES IN LEUKEMIA PROGNOSIS 



U8. IN TITRO STODIES OF NORMAL AWD LEOKEHIC 
HAEH0P0IE5IS - POSSIBLE PROGNOSTIC VALUE 



Hale 



Australia 



Sydney Hospital, Sydney, New South 



il hun 



bone 



ill 



nedi 



and/or 
mi-solid 
o study 



agar 



marrow 



OBJECTIVE: 

rise to colonies of granu 
cytic cells when cultured 
um. The ain of this proje 
frequency of these cells in th 
with acute leukemia in relapse and in remission as 
■ell as factors controlling their proliferation 
and differentiation, if any. 

APPROACH: Bone narrow samples fron adult 
patients with acute leukemia are being studied at 
the tine of presentation and during maintained 
reaission. Cultures in semi-solid agar are 
established using feeder layers of nornal human 
blood leucocytes or monocytes. 

PROGRESS: Harrow sanples fron a significant 
proportion of acute leukemic patients at the tine 
of first presentation failed to grow in culture, 
while in the remainder an abnormal growth pattern 
with large numbers of cell clusters and nelatively 
few colonies is seen. The complete remission rate 
in patients who failed to show any growth is 
significantly greater than in those where growth 
occurs. During sustained complete renission nost 
patients show the sporadic occurrence of leukemic 
growth pattern in culture, despite the persistence 
of noraal peripheral blood counts and morphol- 
ogically nornal marrow sanples. 



49. 



BONE HARROW COLONY FORMING UNITS IN PATIENTS 
ilTH ACUTE LYMPHATIC LEUKEMIA ON BCG AND CHEM- 
OTHEBAPY OR ON CHEMOTHERAPY OBLY 

Royal Childrens Hosp. 
ington Rd., Melbotjrne, 



Haters, K. D. , Ekert, 
Res. Fdn, Hematology, 
Victoria, Australia, 



3052 



OBJECTIVE: To compare the number of colony 
forming units in bone narrow of patients with 
acute leukemia in remission, in those patients 
given innunotherapy with BCG, with those treated 
siailarly and not given BCG. 

APPROACH: once remission is achieved, 
intermittent maintenance chemotherapy will be 
begun with a six week cycle of chemotherapy 
followed by two weeks of no therapy. Patients 
will be randomized to receive or not receive BCG 
in the middle of the 2 week period of no therapy. 

The agar culture technigue of Pike and 
Robinson will be used. Bone aarrow will be 
obtained at the end or the six week period of 
chemotherapy, on the day of BCG adainistration (in 
both groups) and on the day cheaotherapy is due to 
resuae^ Conparison will be aade between the 
auaber of colonies produced in both groups. The 
study is an atteapt to assess the effect of BCG in 
COaaltted granulocyte-progenitor stem cells in a 



129 



group of patients vbo otherwise receive Identical 
treatBcnt. 



50. GRANULOPOIESIS IH HfcLIGHAWT *HD BENIGM HOBAl 

DISEASES - RELATIONSHIP TO PROGNOSIS AND CLINICAL 

BESPONSE 

Greenberg, P. L. , Schrier, S., Elias, L., HarHor, 

J., Stanforti University, School of Hedicine, 

Medicine, Palo Alto, California, 94305, U.S. A, 



Utilizing in vitro culture techniques, «e 
propose to study huoao granulopoietic contcol 
■echanisms with the najor focus directed toward an 
understanding of the changes which occur in 
■alignant diseases of tne granulopoietic systea. 
In specific terms, we plan to test an hypothesis 
regarding oulticlonal populations in acute 
leukeoia marrow, and study leukemic clones 
directly for understanding their proliferative 
characteristics, responsiveness to huncral 
Etiaulatory and inhibitory substances, sensitivity 
to drug therapy, impact on adjacent noraol 
granulocytic clones, and for detecting saall 
nuabers of residual leuKemic precursor cells. 

The recent development of techniques pera- 
Itting the proliferation of granulocytic clones 
froa human granulocyte progenitor cells in agar 
and liquid culture, and methods for effectively 
separating these disparate cell populations by 
their density distribution ' patterns, allows these 
studies, and studies evaluating serum colony 
Etiaulating factor (CSF) levels to be performed. 
Clinical correlates will be provided by basing our 
studies on patient populations being managed 
according to prospective protocols. To date the 
results suggest that clinical benefits may be 
derived from our studies by anticipating leukeaic 
relapse or evolution, and for devising chemothera- 
peutic regimens with diminished potential for 
neutropenic toxicity. Our studies should enable 
us to evaluate critical factors involved in, and 
perhaps regulating, the transition from relatively 
benign to frankly malignant disease states. 
Parallel studies will be performed in the nonaali- 
gnant disorders of granulopoiesis for purposes of 
coaparison and understanding pathogenetic mech- 
anisms underlying these disorders. 



HOBAS MYELOID 



51. HARROW CULTDBE STUDIES 

LEUKEHIA 

Boore, M. A'# Sloan Ketteri 

Hematopoietic Development, 4 1 

lork. New York, 10021, UiS.A. 

The project has two major objectives. The 
first is the application of a nuaber of standard 
investigations to a large number of cases of 
leukemia and other myeloproliferative disorders in 
both the untreated phase and during the course of 
'therapy. This screening protocol is designed to 
provide detailed information available for patient 
diagnosis and to assess responsiveness to therapy. 
The second major objective evolves from the 
screening program and is aimed at the investiga- 
tion of (1) the nature of the cellular and 
regulatory lesions in leukemia and other hemop- 
oietic disorders; (2) the interaction between 
normal and leuKemic populations during the 
development and treatment of leukeaia. 



52. IN VITRO STUDIES OF DRUG-RESISTANT LEUKEHIA * 
CELLULAR RESISTANCE TO RADIO-LABELLED CHEHOTHERAp"- 
EOIIC DRUGS 

Kundu, D., Oliver, P. T., Saith, B. J., Imperial 
Cancer Research Fund, Medical oncology Unit, 
Llncolns Inn Fields, Uc2a 3px, London, England, 
United Kingdom 

In about 70% of patients with acute myelo- 
genous leukemia, chemotherapy eventually fails to 
control the disease process, indicating secondary 
drug resistance. In only about 531 of patients is 
primary drug resistance apparent: that is disease 
resistant to chemotherapy from the outset, A 
technique has been developed to assess the effect 
of Increasing concentrations of drugs on the 



growth of leukemic cells in vitro as measured by 
thyaldine incorporation after four days* culture. 

Two types of secondary resistance can be 
deaonstrated: true resistance, i.e. leukemic 
cells are initially sensitive to the drug both in 
vitro and in vivo, but after relapse a five- 
tenfold increase in the quality of drug is 
necessary to cause 50» suppression of thymidine 
incorporation. The second type is of pseudo- 
resistance, in that m vitro and in vivo, cells 
after relapse are as responsive as those at the 
time of diagnosis. However, in vivo, the leukeaic 
population grows so rapidly that the disease 
recurs in the interval before further chemotherapy 
can be given. Efforts have been concentrated in 
studying acquired secondary resistance. It has 
been possible to show in vitro that these cells 
are cross-resistant to all drugs which have ceen 
tested, including some which the patient has not 
received. Preliminary studies in vitro sdow that 
it is possible to overcome resistance by binding 
the drug to DNA as this complex is actively 
pinocytosed. He will investigate the molecular 
basis of resistance using radio-laoelled drugs. 



TIVITY AND ADHESIVENESS WITH THERAPEUTIC FESPCNSE 
Thomson, A. E., Oconnor, T. H. , Wetherley tnein , G., 
laperial Cancer Research Fund, Cytochemistry, 
Lincolns Inn Fields, Mc2a 3px, London, England, 
United Kingdom 



Ongoing studies in patients with CLL on 
lyaphocyte sub-populations characterized D-f 
colchicine ultrasensitivity, unaided death, 
abnormal adhesiveness end other parameters, have 
continued. About 170 studies have been made in 60 
patients. Sufficient time has now elapsed to 
perait analysis of the cell-population data in 
terms of clinical and hematological features, with 
particular reference to known duration of disease- 
requirements for and response to treatment and 
patient life span. This analysis is in progress. 

Techniques for cell studies on simultaneous 
saaples from bone marrow, spleen and lymph r.oje 
have been developed. Although the group of i1 
patients so far studied is still too small for 
definitive conclusions, the findings suggest that 
while in classical CLL consistent and typical 
abnormalities are found in all sites (such as tne 
bone marrow lymphocytes being always mostly 
colchicine ultrasensitive like the blood lymp- 
hocytes) there are notable variations in other LPO 
patients. (Text Abridged. Use investigator index 
to locate a complete description of this project.) 



54. HETEROGENEITY OF LYMPHOCYTE RADIOSENSITIVITT 
IH VITRO IN LYHPHOPROLIFERATIVE DISORDERS (LPD) 
Vaughansmith, S. , Thomson, A. E. , iJetherieyaein, 
G., Imperial Cancer Research Fund, Cytochemistry, 
Lincolns Inn Fields, Mc2a 3px, London, England, 
United Kingdom 



Evidence to date suggests that the 
vity in vitro to the killing action of X 
the B lyaphocyte sub-population circulat 
health is constant for aifferent donors 
tested) and greater than the variable se 
displayed by the coexisting T lymphocyte 
population in different donors. 

The colchicine-ultrasensitive lymph 
(CUL) that predominate in patients with 
lyaphocytic leukemia (CLL) , and which mi 
classed as B cells using immunological c 
surface markers alone, have proved more 
in radios.9nsitivity than B ceils and the 
radiosensitivity varies widely between d 
patients (20 tested). 

Identification of lymphocyte sub-po 
on the basis of radiosensitivity may hav 
tical, diagnostic, and predictive value 
lyaphoprolif erative diseases. (Text Abr 
Use investigator index to locate a compl 
description of this project.) 



. ir.g m 

: SUb- 


locytas 

.ght oe 
:ell- 
variaole 

litferent 


ipulation; 
'6 prac- 



130 



55. gyALOATIOB OP CHEMOTHERAPT IM HALIGMfcHCIBS- 
'IHPLOEHCE OF LEDKEHIC SEBUH 

Busphrey, G. B., Univ. of Oklahona, School of 
Bedicine, Pediatrics, 800 N.E. 13th St., OJtlahoaa 
City, OJtlahooa, 7310H, U.S.A. 

This is part of a broader project, A suBiarj 
of this subproject is not available. 

C. THERAPY OF LEUKEMIA IN CHILDREN 



1. CHEMOIMMUNOTHERAPY OF CHILDHOOD LEUKEMIA 



Baters, K. D., EXert, H., aoyal Childrens Hosp. 
Res. Fdn, Heoatology, Flemington Rd., Helbourne^ 
Victoria, Australia, 3052 

HISTOLOGIC TYPE; Acute myeloblastic leuk- 
aeaia, acute nyeloBonocytic leukaenia, acute 
■onocytic leukaeiaia: All patients aged O-Hiy with 
above types of leuk.aeaia, refractory to standard 
cheaotherapy. 

TREATMENT HODAIITIES: S-azacytidine HSC- 
102816; BCG, prepared by ComnonMealth Serum 
Laboratories, Helbourne, Australia, with a 
bacterial content of VSog/aapouie and a viable 
bacterial count of 6-20 x 10 to the 6th power/mg 
seii-dry weight. Allogeneic blast cells, prepared 
fron adult patients with AHL, irradiated and 
stored in liguid nitrogen, giving 3 x 10 to the 
8th power cells per dose, 

PROTOCOL OUTLINE: 5-azacy tidine and imnunot- 
herapy will be given to patients refractory to 
standard cheaotherapeutic agents. Pre-treataent 
investigations will include complete blood count 
and platelet count, bone oarrow exanination, liver 
function tests, BON and urinalysis, 5-azacytidine 
will be given in a dose of 100aig/a2 IV push every 
12 hours for a total of 10 doses. The course will 
be repeated every three weeks. Three courses will 
be given and if progressive disease occurs, 
subject will be removed from study. If remission 
occurs (documented by bone marrow) two further 
courses of 5-azacytidine will be given. Treatment 
will then be continued with immunotherapy alone. 
The blast cells will be injected intraderoally (3 
X 10 the eth power cells) and 0.25d1 of BCG given 
by Heaf gun in four separate areas around the 
cells, Imounotherapy will be given every two 
veeks, until relapse occurs. When relapse occurs 
reinduction with 5-azacytidine will be attempted 
in the above manner. 

PRESENT STATUS: 3 patients entered thus far. 
Expect to enter 4-5 patients per year. Trial is 
still open. 



57. CLIHICAL PROTOCOL (PHASE II) OF REHISSIOH 
IHDOCTION IN CHILDHOOD ACUTE HYELOBLASIIC LEOKA- 
EHIA (AHL) 

Ekert, H., Waters, K. D., Royal Childrens Hosp. 
Bes, Fdn, Heoatology, Flemington Rd., Helbourne, 
Victoria, Australia, 3052 

HISTOLOGIC TYPE AND CLINICAL STAGE: All 
children with morphologic and cytocheaical 
evidence of AML. 

TREATMENT MODALITIES >ND AGENTS: CytOSine 
arabinoside lOog/Kg is infused over 24 hours. 
This is followed immediately by daunorubicin 
HSaq/ni2 and 2a hours later by adriamycin U5mg/a2. 
A second course is repeated in 2 weeks. Bone 
■arrow aspiration is used to test remission. All 
patients continue with cytosine arabinoside and 
6-Tbioguanine for 3 courses at 5 day intervals 
followed by 5 days of oral cyclophosphamide and 2 
further injections of adriamycin U5ng/m2. 
Beaission is maintained with cytosine and 6- 
Thloguanine and intermittent BCG (Heaf Gun 
inoculation) and allogenic AHL cells injected 
intradoraally, 

PROTOCOL: Hot controlled or randomized. 



PfiESEBT STATUS: Six entered, complete 
sslon 3, partial remission 1, progressive 
ase 2. Study open. 



58. ( CaEBO-IHBaHOTBERAPY FOB AHL OB AMBL - CCSG 

211) 

Hartmann, J. R., Chard, R. L. , Bleyer, 8. A., 

Bernstein, I. D. , Childrens Orthopedic Hospital, 

Hematology, 4800 Sand Point Hay N. £. , Seattle, 

flasbington, 96105, U.S.A. 

This is for previously untreated patients 
with AHl or AHHL, This program involves treatment 
with cytosine arabinoside, 5-azacytidine, pred- 
nisone and vincristine. naintenance with the same 
agents on a monthly basis and, on a random basis, 
half of the patients will receive immunostimulant 
therapy consisting of BCG and leukemia cells. 
This study is now being approved by the Clinical 
Investigaton Branch of the National Cancer 
Institute. He have placed six patients on this 
study on a pilot basis. At this institution we 
receive approximately six patients with acute 
■onocytic, acute monomyelogenous leukemia per 
annum and have averaged approximately twelve 
patients entered on previous studies over a two 
year period. tfe anticipate that the new study 
will take about two years to finish once it is 
started, which is anticipated to be in April, 
1975. 



59. COHTROLLED CLIHICAL TRIAL (PBASE III) OP 
CHEHO-IBHUNOTHERAPY IH CHILDHOOD ACUTE LYMPHOCYTIC 
LEUKEMIA (ALL) 

Ekert, H., Jose, D. G., Tauro, G. P., Australian 
Cancer Society, Hematology, Flemington Rd., 
Parkville, Victoria, Australia, 3052 

OBJECTIVES: 1) Compare duration of first 
complete remission maintained with intermittent 
chemotherapy and BCG compared with intermittent 
chemotherapy only. 2) Determine the effects of 
these regimens on iamunologic function and 
infective complications. 

HISTOLOGICAL TYPE AND CLINICAL STAGE: 
Children with Borphologic and cytochemical 
diagnosis of ALL are stratified on the basis of 
age, organomegaly and total white cell count into 
good prognosis (HCC 5-10,000), average prognosis 
(HCC 10-30,000) and intensive therapy (WCC 30,000) 
groups, 

TREATMENT MODALITY AHD PSOTOCOL OUTLINE: 
Good and average prognosis induced with vincris- 
tine and prednisolone, but cytosine and aspara- 
ginase are added in average prognosis groups. 
Intensive therapy group induced with cytosine, 
cyclophosphamide and asparaginase. All children 
given prophylactic skull irradiation (2«00r) and U 
injections of intrathecal aethotrexate. Remission 
is confirmed by bone aarrow aspiration. All 
patients are then randomized into either group A - 
6 weeks of chemotherapy consisting of 6mP daily, 
weekly aethotrexate and sonthly vincristine 
followed by 2 weeks of no treatment; or group B 
-some chemotherapy but one week after its cessa- 
tion 0.25ml of BCG is inoculated with a heaf gun. 
(BCG Coamonwealth Serum Laboratory Pasteur strain, 
protein content ?5a9/Bl viable organisms 6-20 x 10 
to the 6th power/ag) , 

PRESENT STATUS: Twenty five patients 
entered. Study open. 15C patients anticipated. 



60. CHEBO-IHHUHOTHBBAPY (BCG) CONTROLLED TRIAL IH 
ACUTE LYMPHOCYTIC LEUKEMIA OF CHILDhOOD 
Bice, H. S., Leahy, H. A., Toogocd, I. P. , 
Adelaide Childrens Hospital, 72 King villiam Rd.« 
North Adelaide, South Austral,, Australia, 5006 

OBJECTIVE: 1. To investigate whether 
interaittent cheaotherapy, combined with immunoth- 
erapy, prolongs the duration of the first complete 
remission, compared with intermittent cheaotherapy 
alone, 2. To investigate whether intermittent 
cheaotherapy, combined with immunotherapy, results 
in longer survival, than from intermittent 
cheaotherapy alone. 3. Xo dstecaine the effects 



131 



of these reginens on inounological. function and on 
the incidence of infective and other complicati- 
ons. 

APPBOftCH: A cooperative study (Australian 
Cancer Society Childhood Leukenia Study Group) 
using a standard protocol, chairman of Study 
Group -Dr. H. Ekert, Boyal Children's Hospital, 
Parkville, Victoria. 3052. 



Bauger, D. C. , Auckland Hospital, Pediatrics, Pa 
Bd., Auckland, Nev Zealand, 

OBJECTIVES: 1) compare duration of first 
complete remission maintained with intermittent 
chemotherapy and BCG compared with intermittent 
chemotherapy only. 2) Determine the effects of 
these regimens on immunologic function and 
infective complications. 

HISTOLOGICAL TYPE AND CLINICAL STAGE: 
Children with morphologic and cytochemical 
diagnosis of ALL are stratified on the basis of 
age, organomegaly and total white cell count int 
good prognosis {wee 5-10,000), average prognosis 
(«CC 10-30,000) and intensive therapy (WCC 30,00 
groups. 

IBEAIHENT HODALIII AND PBOIOCOL OUTLINE: 
Good and average prognosis induced with vincris- 
tine and prednisolone hut cytosine and asparagi- 
nase are added in average prognosis groups. 
Intensive therapy group induced with cytosine, 
cyclosphamide and asparaginase. All children 
given prophylactic skull irradiation (2,'JOOr) in 
Injections of intrathecal methotrexate. Remissi 
is confirmed by bone marrow aspiration. All 
patients are then randomized into either group A 
6 weeks of chemotherapy consisting of 6nP daily, 
weekly methotrexate and monthly vincristine 
followed by 2 weeks of no treatment; or group B 
-some chemotherapy, but one week after its 
cessation 0.25 ml of BCG is inoculated wirh a he 
gun. (BCG Commonwealth Serum Laboratory Pasteur 
strain, protein content 75 mg/ml viable organism 
6-20 I 10 to the 6th powet/mg) . 

PRESENT STATUS: Twenty five patients 
entered. Study open. 150 patients anticipated. 



Hartmann, J. P., chard, R. L., Bleyer, U. A., 
Bernstein, I. D. , Childrens Orthopedic Hospital, 
Hematology, 1600 Sand Point Way N.E., Seattle, 
Hashington, 96105, U.S.A. 

This study was approved in April, 1970, and 
closed in October, 1971. Forty-two patients were 
entered into this study from this institution; 
four patients remain on study. There will be no 
new patient entries. 



Hartmann, J. E. , Chard, E. L., Bleyer, u. A., 
Bernstein, I. D. , Childrens Orthopedic Hospital, 
Hematology, 1800 Sand Point Hay N.E., Seattle, 
Washington, 98105, U.S.A. 

This program was for previously treated 
patients who had had two or more relapses, the 
only criteria being that they be under eighteen 
years of age and not have received L-asparaginas 
prior. The 6-np was used as an immunosuppressiv 
agent and not an induction agent for remission. 
After the patient achieved remission, they were 
then maintained on oral Velban which was done in 
conjunction with Lilly Laboratories to ascertain 
wnether or not oral Velban was effective. At a 
dose of 100 mg/m2, it did appear to have an effe 
on maintaining remission; but a dose lower than 
this had no effect. The study was approved in 
January of 1971 and has not yet been closed. 
Fifty-four patients have been entered on this 
study from this institution. It is anticipated 
that eight to ten would be entered per year. 



65. TRANSFER FACTOR IN IBERAPI OF LEOKEHIA. Iniiu: 
DEFICIENCY DISEASES 

Lampkin, B. C, Oniv. of Cincinnaiii, Childrens 
Hosp. Bed. ctr.. Pediatrics, Elland f. Bethesda 
Aves., Cincinnati, Ohio, US229, U.S.A. 



Thi 



of 



62. THE USE OF C-PARYUH AS ADJUNCT THERAPY IN 
CASES OF CHILDHOOD ACUTE LYMPHOBLASTIC LIUKEHIA 
KITH ONE RELAPSE 

Deveber, L. L., War nemorial Childrens Hosp., 
Pediatrics, 391 South St., N6b 1b8, London, 
Ontario, Canada 

OBJECTIVE: To see if the addition of C. 
parvum to the therapy of children who have had one 
relapse of leukemia will increase their remission 
time and/or survival. Also, to assess side 
effects of c. parvum. 

APPROACH: Patients with acute lymphoblastic 
leukemia who have been in remission and then 
suffered their first relapse will have standard 
reinduction routine until they obtain an HI 
marrow. At this point, they will be started on 
regular injections of C. parvum as well as the 
usual chemotherapy maintenance. The patients will 
be studied carefully for side effects and also 
their remission and survival times will be 
carefully noted and compared to previous cases who 
have received identical chemotherapy and maint- 
enance but who have all died. 

PPOGEESS: Since this is not a controlled 
study, we will have to wait three to five years to 
see if the survival or median remission time in 
the group treated with C. parvum is significantly 
different from those not treated previously. 



66 . COBPABIS OS OF TBO DOSAGES OF CRANIAL lEBAD- 
lATION IN THE PROPHYLAXIS OF CNS INFILTRATION IN 
CHILDHOOD ACUTE LEUKEBIA 

Colebatch, J. H., Lay, H. N., Ekert, H., Binty, 
C. J., Royal Childrens Hosp., Hematology, Park- 
ville, Victoria, Australia, 3052 



mine whether the overal 
benefits and toxicity, 
ower dosage than Z'AOd 
on for the prophylaxis 



OBJECTIVE: To d 
effects, in prophylac 
are satisfactory with 
rads of cranial irrad 
CNS leukemia. 

APPROACH: Earlier reports from St. Jude 
Children's Research Hospital claimed that for th 
prevention of CNS leukemia, cranial irradiation 
dosages of 500, 1000, and 1000-1500 rads were 
inadequate, but a Minnesota group reported 
acceptable results in a small series given 1250 
rads. 

In this study, previously untreated childre 
with acute lymphocytic leukemia (ALL) are induce 
with vincristine and prednisolone. CNS prophylax 
begins in the fifth week for those in complete 
remission -intrathecal methotrexate twice weexlj 
for five doses, and concurrent cranial irradiat- 
ion. Patients are randomly allocated to Group ■ 
receiving 2100 rads, or Group F, receiving loOO 

Antileukemic maintenance chemotherapy is contir.' 
throughout the period of observation, which wll- 
be extended to three years. Pundoscopy is part 
routine assessment at each follow-up visit. 
Lumbar puncture is repeated after five months, ;- 
thereafter as indicated on clinical grounds. 



132 



PROGRESS: Forty patients have entered this 
controlled, randomized trial, and the ininimuo 
follo«-up period is now 18 months. In addition, 
another 22 patients woo were not eligible for this 
study are being treated similarly and observed. 
Wo significant difference in the developnent of 
CNS leukeoia in the two groups is apparent as yet. 



67. "CIT" THERAPY OF HENIHGEAL LEUKEMIA VIX 
SOBCUTAHEOUS RESERVOIR 

Bleyer, W. A., Poplack, D. G,, Ommaya, A. K., 
Ziegler, J. L., Childrens Orthopedic Hospital, 
aeaatology, ueoo Sand Point Way N. 2. , Seattle, 
HashingtoQ, 96105, U.S.A. 

OBJECTIVE: The primary purpose of this 
protocol is to compare conventional bi-weekly 
intrathecal methotrexate therapy with repeated 
injections via an Omniaya F.eservoir to maintain a 
■iniaal cytocidal methotrexate concentration for 3 
days alternated with one week resting period. A 
secondary objective is to compare intrathecal 
■ethotrexate given via an Ommaya Reservoir versus 
via a lumbar puncture. 

APPROACH: Patients with overt meningeal 
leukemia are implanted with an Ommaya Reservoir 
and then randomized to receive single injections 
of Bethotrexate twice weekly or repeated inject- 
ions every six hours for three days every other 
veek. Following remission induction, the same 
courses given during induction are repeated for 
six weeks and then every 6-8 weeks thereafter. 
Patients on the single injection therapy receive 
12»g/in jection and those on the "concentration x 
time" therapy receive Img per injection. 

PROGRESS: Thus far, seven patients have been 
entered onto each limb and all except one have 
achieved remission. Patients receiving "CxT" 
therapy required one-third to one-fourth of the 
■ethotrexate to achieve remission. Remission 
durations have thus far not been significantly 
different than the two groups. When the two 
groups are combined and compared with the previous 
protocol (same schedule of methotrexate given by 
lumbar puncture) and evaluated at the same point 
during follow-up, there have been four relapses of 
15 patients treated by lumbar puncture and no 
relapses of fourteen patients treated via the 
OBiaya Reservoir. Overall toxicity has been 
conparable in the groups. 



68. PHARHAC0KIHETIC5 OF INTRATHECAL HETHOTREXATE 
FOB TREAIHEHT OF ACUTE LEUKEMIA 

Hartmann, J. R. , Bleyer, W, A., Fred Hutchinson 
Cancer Res. Ct, Pediatric oncology Grp, 1102 
Columbia St., Seattle, Washington, 98104, U.S.A. 

OBJECTIVE: To characterize the pharmaco- 
kinetics of intrathecal methotrexate therapy and 
the factors responsible for interpatient variat- 
ion. 

APPROACH; Methotrexate disappearance 
profiles in cerebrospinal fluid and plasma are 
being obtained in patients treated with intrath- 
ecal methotrexate for acute leukemia. Body 
surface area, sex, age, bead circumference, 
cerebrospinal fluid, protein concentrations, 
presence of malignant cells in the cerebrospinal 
fluid, and dates of central nervous system 
radiotherapy are being recorded and will be 
assessed as variables m the disappearance 
kinetics. ^ 

PROGRESS: Twenty-two patients have thus far 
been evaluated during the current funding period. 
The half-disappearance time of methotrexate in the 
cerebrospinal fluid ranged from 2-5 hours during 
the day after intrathecal injection of 12mg/M2 and 
from 12-18 hours thereafter, resulting in mean 
(plus or minus SD) and type folate levels at 1.3 
(plus or minus 0.9) x 10 to the minus 5th power 
and 3.4 (plus or minus O.U) x 10 to the minus 8th 
power molar at 12 and 72 hours respectively, 
Plasaa methotrexate concentrations peaked at 6-12 
hours after the intrathecal administration, 
reaching 10 to the minus 7th power molar in most 
patients, and declining at a hall time of 12-2U 
hours thereafter. Comparison with the plasma 



concentrations after intravenous injections of the 
sane dose revealed persistence of methotrexate 
concentrations of greater than 10 to the minus 8th 
power molar for periods of 2-3 times longer with 
intrathecal injections than with intravenous 
injections. 



69. PHARMACOKINETICS OF INTRATHECAL HETHOTREXATE 
Bleyer, W. A., Chilarens orthopedic Hospital, 
Hematology, 4800 Sand Point Hay N-E., Seattle, 
Washington, 981C5, U.S.A. 



See preceding project for a complete 



rip- 



70. (THERAPY OF ACOTE LEUKEHIA AND PROPHTfLAIIS OF 
CHS LEUKEMIA WITH HETHOTREXATE IN CHILDREN) 
Heyn, R. M., Holland, R. , Tubargen, D. G,, Univ. 
of Michigan, Sciiool of Medicine, Pediatrics & 
Communicable Dis, 1335 E. Catherine St., Ann Arbor, 
Michigan, 48104, U.S.A. 

For acute lymphocytic leukemia, the current 
new patient study is designed to investigate 
front-end immunologic parameters such as immunogl- 
obulins, skin-testmg, HLh typing and immunologic 

outcome. The treatment program will involve a 
more intensive induction and intensification 
program for half of the cnildrsn woo have initial 
WBC»s over 20,000, and/or mediastinal masses. The 
other half of these children will be treated in 

than 20,000 initially and no mediastinal masses. 
All children will receive CNS prophylaxis with 
cranial irradiation and IT methotrexate. 

Children with acute granulocytic leukemia are 
receiving induction therapy with 5 drugs and 
maintenance therapy with monthly cycles of 4 
drugs. Immunotherapy with BCG and leukemic cells 
is being given in 3 doses during toe first 3 
months of chemotherapy to half the children. (Text 
Abridged.) 



71. ( COBBIMATION CHEMOTHERAPY WITH PROPHYLACTIC 
CKS TREATHEST IN ACUTE LEUKEMIA) 
Hartmann, J. R., Chard, a. L., Eleyer, W. A., 
Bernstein, I. D. , Childrens Orthopedic Hospital, 
Hematology, 4800 Sand Point Way N,3., Seattle, 
Washington, 98105, U.S.A. 



CCG 142 - The protocol is still in develop- 
ment for patients who relapse in the bone marrow 
from CCSG 101 or 143 which involves prophylactic 
central nervous system treatment - three drug 
induction and maintenance with 6-MP, methotrexate 
and monthly pulses of prednisone and vincristine. 
It involves reinduction with L-asparaginase, 
prednisone, vincristine, cytosine arabinoside and 
Cytoxan, The patients have a rerandomized central 
nervous system therapy for patients who have not 
developed central nervous system disease; they 
will either receive retreatment to the cranial 
spinal axis or no treatment; for patients who have 
developed central nervous system occurrence during 
the previous study, they will be retreated. To 
date, this institution has entered four patients 
on this program. Since there are seventy-six 
patients entered on 101 and 143, that would at 
this time bring the possible eligible patients for 
this program to 76; however, since it is predicted 
that approximately 50% of patients on 101 and 143 
will have long term disease-free remissions, this 
will apparently give us approximately thirty-two 
patients eligible for this study within the next 
four years. 



133 



72. COHBIWAIION THEBAPI OF CHILCHOOD LEOKEIIIi. 
IMCLUDIIIG COMPtRISOM Of TWO BEGIHEMS FOR COHTROL 
OF CMS LEUKEHH 

Aur, R. J., Verzosa. N., Hustu, 0., Hood, A., 
Slsone, J., Hauei, A. n., St. Jude Ch. Res. Uosp., 
Box 318, 332 H. Lauderdale St., Heiphis, Tennessee, 
38101, O.S.A. 

This research in the treatment of children 
with acute lyophocytic leukemia has the following 
objectives: 1) To determine in a controlled 
■anner the relative efficacy and tonicity of two 
therapeutic reginens given early in remission for 
prophylaiis of central nervous system leukemia; 2) 
To deteriine the efficacy and toiicity of periodic 
"reinforcement" or "reinduction" chemotherapy in 
prolonging continuous complete remission; 3) lo 
prolong the duration of leukeaaa-f ree survival 
with combination chemotherapy and preventive 
central nervous system therapy; U) To analyze 
results to this study, in comparison to earlier 
results, to determine the reasons for differences, 
despite no apparent differences in therapy; 5) To 
continue studies of surviving patients for an 
indefinite period of time to detect late toxic 
effects of therapy such as growth impairment, the 
eaergence of secondary neoplasms and gonadal 
dysfunction. 

REFERENCES: Aur, 8. J. A.: Relapses in 
children with ALL off treatment. Letter to the 
Editor. NEJH 292;131, 1975. Simone, J.V., Aur, 
R.J. A., Hustu, H.O., Verzosa, B. and Pinkel, D. : 
Colbined modality therapy of acute lymphocytic 
leukemia. Cancer 35:25-35, 1975. 



73. IREAIMBHT OF ACUTE LmPHOCITIC LEOKEMIA IH 
CHILDHOOD - SFCC 73-01 

Camitta, B., Sallan, S. E., Jaffe, N., Traggis, 
D., Sidney Farber Cancer Institute, Kl Binney St. 
Boston, Hassachusetts, 02115, U.S.A. 

OBJECTIVE: Development of effective treat - 
»ent for childhood ALL. 

APPROACH: Protocol involves induction 
(vincristine plus prednisone) , consolidation 
(asparaginase) , early CNS prophylaxis (cranial 
irradiation plus intrathecal methotrexate) and 
intensive intermittent combination maintenance 
chemotherapy utilizing adriamycin as a major 
component. 

PROGRESS: Greater than 90X of patients are 
In remission at one year by lifetable analysis. 



71. ( CHEHOTHEEAPY of acute LYnPHOCTTIC LEUKEMIA 
gITH CMS RADIATIOH AND INTRATHECAL BETHOTREXATE) 
Uartmann, J. R., rhard, R. L. , Bleyer, H. A,, 
Bernstein, I. D. , Childrens orthopedic Hospital, 
Hematology, U800 Sand Point Way N.E., Seattle, 
Washington, 96105, U.S.A. 

CCSG 113-ALL/AUl Sanctuary TherapV for' 
patients with previously untreated acute lymph- 
ocytic leukemia. The study was opened in August 
of 19711. n will be closed in Barch of 1975. The 
study involves similar induction therapy and 
maintenance to CCSG 101, but the central nervous 
system prophylaxis was changed to only two arms 
with a different dose of irradiation. Randomi- 
zation is 1800 rads to the cranium and spinal axis 
versus 1800 rads to the cranium with intrathecal 
methotrexate. Thirteen patients have been entered 
from this institution. 



75. (COMBINATION CHEBOTHERAPY WITH CHS PROPHYLA- 
IIS) 

Hartmann, J. R. , Chard, R. L. , Bleyer, w. A., 
Bernstein, I. D. , Childrens Orthopedic Hospital, 
Hematology, 1800 Sand Point Way N.E., Seattle, 
Washington, 96105, U.S.A. 



The 



progr 



of 1972 

utilized 
inase for 



program was appro 
closed in August of 197it. 
prednisone and vincristine 
induction with a four arm randomization for t 
central nervous system prophylaxis and mainte 
With 6-MF, methotrexate and monthly pulses of 



nd 



prednisone and vincristine. The four arm randomi- 
zation for central nervous system treatment 
involved: a. 2000 rads to the cranial axis, plus 
1200 to liver, spleen and gonads, versus b. 2100 
rads to cranium, and spine, versus c. 2U00 rads to 
the cranium plus intrathecal methotrexate, versus 
d. intrathecal methotrexate alone. Sixty-three 
patients were entered on this study. 



76. EVAIDATION OF PODOPHYLLUM COBPOUNDS IN 
CHILDHOOD LEUKEMIA AND SOLID TUBORS (PHASE II) 

Jude Ch. 



Rivera, G., Pratt, C, Avery, I. 

Res. Hosp., Clinical Therapeutics, Box 318, 332 N. 

Lauaerdale St., Memphis, Tennessee, 38101, U.S.A. 

OBJECTIVE: The epipodophyllotolins, U'- 
demethylepipodophyllotoxin 9- (« ,6-0-2-thenylidene- 
Beta-D-glucopyranoside) (NSC-122ai9; Vfl-26) and 
U'-demethylepipodophyllotoxin 9- (a, 6-0-ethylidene- 
Beta-D-glucopyranoside (NSC-1 t 1 510 ; VP-16-213), ' 
are new chemotherapeutic agents with antitumor 
properties in experimental animal systems and in 
man. Excellent oncolytic activity by these agents 
has been reported in the treatment of murine 
tumors. with both drugs, promising results have 
been obtained in adult patients with advanced 
neoplasms. The objective of this study was to 
determine the therapeutic effectiveness of 
podophyllum compounds vn-26 6 VP-16-213 for 
childhood cancer patients. 

APPROACH: A "Clinical Protocol" for children 
with cancer was designed. These patients had 
advanced disease nonresponsi ve to therapy with 
conventional chemotherapeutic agents. Informed 
written consent of parents was requisite for 
admission into the study. Initially, subjects in 
each disease category were randomized to receive 
50 og/m2 of VB-26 intravenously twice weekly or 75 
mg/m2 of VP 16-213 intravenously twice weekly for 
1 weeks. If after 2-1 weeks no response or 
progressive disease was observed with the first 
agent, patients were given the alternate analog. 
Other antitumor therapy was not given during the 
administration of the epipodophyllotoxins. 

PROGRESS: Thirty-nine children with acute 
leukemia and solid tumors were studied. 17 
patients had acute lymphocytic leukemia (ALL) , 12 
had acute nonlymphocy tic leukemia (ANLL) , i> 10 had 
solid tumors. Although objective responses were 
not detected in the latter group, definite 
clinical responses were obtained in 9 of the 29 
patients with acute leukemia. The responses to 
the epipodophyllotoxins were noted in children 
with ALL as well as patients with ANLL. Toxic 
side effects included nausea, vomiting, diarrhea, 
fever, alpecia, leukopenia £ thrombocytopenia. 
These results, the first reported with botn VM-26 
and VP 16-213 in childhood cancer, indicate that 
these oncolytic agents are well tolerated and may 
be effective against acute leukemia. This study 
has been published. 

PRESENT STATUS: Only patients with solid 
tumors are being admitted. Leukemia patients are 
being registered in a study with VM-26 in com- 
bination chemotherapy. 



WITH CANCER, INCLUDING LEUKEMIA 
I, L., Burton, A. C. , Bar Memorial 
Hosp., pediatrics, 391 South St., 



Onta 



ada 



ated 



OBJECTIVE: Burton has demonst 
incidence of cancer of all types decreases 
significantly in people at higher altitudes. 
Aside from a relative polycythemia, the other 
known physiological change in people at high 
altitudes is a shift in their acid base balar 
which can be produced by use of the drug Dian 
A study reported by Evans indicated the use c 
Diamoz significantly reduced pain in patients 



134 



teninal cancer. Recent studies by Burton 
indicate that Diamox inhibits the growth of 
fibroblasts in tissue culture. Therefore, the 
objective is to use Diafflox in children with cancer 
to see if there is any decrease in syaptons or in 
tUBOr aass when Diamox alone is used without any 
other treatment. 

APPROACH: To select terminal patients with 
cancer or acute leukemia who have a measurable 
taaor or increasing blast cells in their periph- 
eral blood and who are receiving no other specific 
cheaotherapy. These patients would be treated with 
Diaaox, their acid base balance monitored to 
indicate that there have been specific changes, 
and the tumor mass or blast cells as well as the 
patient's symptoms would be noted. Since the 
ouaber of patients will be small, a control series 
will be difficult if not impossible and the 
results of this study will be anecdotal. 



78. COLLABORATIVE STDDIES IN THE SOUTHWEST 
ONCOLOGY GROUP - FOUR AR« AND TWO ARH BEGIHEM5 IN 
LEPKEMIA THERAPY 

HcHillan, C. H., Bryan, J. H., Johnson, A, H, , 
Oniv. of North Carolina, School of Hedicine, 
Pediatrics, Banning Dr., Chapel Hill, North 
Carolina, 2751^1, U.S.A. 



Part of this brcader project includes studies 
of acute leukemia in relapse and VB-26; testicular 
leukemia and radiotherapy; acute leukemia in 
relapse and streptozotocin. The following disease 
categories and treatments, respectively, are 
represented in registrations on Phase III studies: 
Hev cases of acute leukemia and the current u-Arm 
regimen for acute lymphoblastic leukemia, SWOG- 
7420; acute leukemia in relapse and a 2-ArB 
regiaen examining effects of adriaaycin alone 
versus added vincristine and prednisone. (Text 
Abridged.) 



79, A COHPARATIYE EVALOATIOH OF NEtf CHEHOTHEBA- 

PEDTIC DRUGS IK ACUTE LEUKEHIA IN CHILDREN - 

VB-26, STREPTOZOTOCIN AND ICRF 159 

Sutow, H. H., Sullivan, n. P., Cangir, A., Ried, 

B., Oniv. of Texas, H.D. Anderson Hosp. & Inst., 

Pediatrics, P.O. Box 20036, Houston, Texas, 77025, 

D.S.A. 

OBJECTIVE: To determine 1) the effectiveness 
of new chemotherapeutic agents in acute leukemia 
in children, and 2) optimum dosage schedules of 
the new agents. 

APPROACH: Children with acute leukemia who 
are resistant to conventional agents may receive 
investigative agents with parental consent. 
Starting doses are usually based on adult exp- 
erience; provision is made for dose escalations if 
no biological effects are produced. Drugs are 
obtained through the Southwest Oncology Group. 
Currently vn-26, streptozotocin and ICRF 159 are 
being studied. 



Ting 6-Hercaptopurane and Methotrexate continua- 
tion chemotherapy. Approximately 60 or more 
children with acute lymphoblastic leukemia will be 
admitted to the study. Initial therapy for all 
patients will consist of Prednisone, Vincristine 
and Asparaginase. Those in complete remission 
will receive preventive central nervous system 
therapy consisting of 2400 Rads cobal-t 60 cranial 
radiotherapy and concouitant intrathecally 
administered Methotrexate. Those in remission 
will be randomly divided into two groups to 
receive continuation chemotherapy. The first 
group will receive weekly Methotrexate and daily 
6-Hercaptopurine. The second group will receive 
one month of Cyclophosphamide given weekly and 
Adriamycin given every two weeks, thereafter 
receiving Htx and 6-nP as in the first group. The 
two groups of patients will be carefully followed 
and compared for significant differences in 
reaission duration, toxic effects and relapse 
rates. 



82. SECONDARY PROTOCOL FOR THE TREATHEBT OP ACUTE 

LYHPHOCYTIC LEUKEMIA IN CHILDHOOD BY THE USE OF 

BOLTIPLE AGENT, PULSE CHEMOTHERAPY 

Traggis, D., Jaffe, N., Camitta, B. , Sallan, S., 

Sidney Farber Cancer Institute, Clinical Sciences, 

**« Binney St., Boston, Massachusetts, 02115, 

U.S.A. 



OBJECTIVE: 1, Investigation of ACOAP 
remission induction in patients who fail primary 
treataent for a<;ute lymphoblastic leukemia. 2. 
Investigation o'f maintenance treatment with COAP 
after induction remission with ACOAP. 3. 
Investigation of COAP maintenance treatment 
following remission induction with primary 
treataent once the maximum cumulative dose of 
adriamycin has been attained. 

APPROACH: Induction comprises 5 days of 
therapy at 2-weekly intervals. This interval is 
aaintained for 2 courses after remission is 
induced. COAP maintenance is administered at 
3-weekly intervals with arabinosyl cytosine 
administered I.M. on an ambulatory basis. 

PROGRESS: Fifty-eight patients were entered 
into the protocol since 1971 and may be divided 
into 3 groups: 1. Eight patients without previous 
relapse oaintainea on COAP for 15 - 18 months. 
All are off therapy and in continuous remission. 
2. Seventeen patients with a previous celapse on 
prior single agent chemotherapy but not on 
multiple agent chemotherapy preceding introduct ion 
to COAP maintenance treatment. Nine relapsed and a 
10th died in remission from sepsis as a result of 
ayelcsuppression. Five of the remaining 7 remain 
in -A remission on COAP. Therapy was discontinued 
in 2 patients wnile in remission; both relapsed 2 
months later. 3. Thirty-five patients who failed 
previous single agent and/or multiple agent 
therapy entered ACOAP induction. Of 28 who 
entered remission, 22 relapsed on COAP maintenance 
and 6 remain in continuous remission. 



80. ICRF 159 CHEMOTHERAPY IN SOLID TOHORS AND 
ACUTE CHILDHOOD LEUKEHIA 

Vietti, T. J., Washington University, School of 
Bedicine, Radiology, 660 S. Euclid Ave., St. Louis, 
Hissouri, 63110, U.S.A. 

This is part of a ^|)roader project. A summary 
of this subproject is not available. 



81. COMBINATION CHEHOTHERAPY IN CHILDHOOD LEUKEHIA 
Thatcher, L. G., Pinkel, D., Rimm, A,, Medical 
Coll. of Wisconsin, School of Medicine, Pediatrics, 
561 N. 15th St., Milwaukee, Wisconsin, 53233, 
D.S.A. 

The objective of this study is to test 
whether the combination of two effective anti- 
leukeaic drugs - cyclophosphamide and Adriaaycin 
-adainistered early in complete remission will 
increase the eradication of leukemia cells and 
thus the duration and frequency of initial 
continuous coaplete reaission in patients recei- 



83. CHEMOTHERAPY OF ACUTE LYHPHOBLASTIC LEUKEMIA 
IH CHILDREN 

Yam, L. T., U.S. Veterans Administration, Hospital, 
Section of Hematology, 800 Zorn Ave., Louisville, 
Kentucky, M0202, U.S.A. 

Rational chemotherapy of acute leukemia 
consists of three phases: (1) Initial treatment 
phase or induction phase. The aim of treatment in 
this phase is to induce remission, (2) Conso- 
lidation phase: Treatment is given to patients 
who are recently in remission. The aim is to 
eradicate leukemic cells that may be undetectable 
clinically, and (3) Maintenance phase. The aim is 
to keep the leukemic cells at a minimum to prevent 
relapse of leukemia. In children with acute 
lymphoblastic leukemia, induction therapy with 
Methotrexate, Vincristine and Prednisone results 
in an 80-90X complete remission. Several the- 
rapeutic regimens have been used with some success 
both for consolidation and maintenance therapy. 
Agents used in these regimens include Cytosine 
Acaoinoside, Thioguanine, Asparaginase, Vincri- 



135 



6-neccaptopurine and 
n adults mth this 
ither with Methotrexa- 
any other regioeDS is 
therapeutic regimens 
nance therapy ha?e not 
e plan of this study 
istine-Preanisone for 



stine. Prednisone, Cytoia 

Intrathecal Methotrexate. 

disease, induction therap 

te- Vincristine- Prednisone 

less successful. Effect! 

for consolidation and oai 

been firnly established. 

is to use nethotrexate-Vi 

Induction therapy. Once 

will be treated with a consolidation regimen 

consisting of Thioguanine, Cytosine Atabinoside, 

tspacaginase. Vincristine and Prednisone. They 

ate randomized and treated with 6-(lercaptopurine 

Cytoxan, Bethotrexate and with inducing doses of 

Vincristine and Prednisone. 



81. PgOGNOSTIC FftCTOBS IH tCOTE lyWPHOCYTIC 
LEDKEBU m PREVIOUSLY USIREaTED CHIIDBEW - CCSG 

HI 

Hartmann, J. E. , Bernstein, I. D., Chard, E. L., 
Bleyer, H. J. , Childrens orthopedic Hospital, 
Hematology, 1800 Sand Point Hay N.3., Seattle, 
Bashington. 98105, U.S.A. 

This study was approved by the clinical 
investigations branch of the NCI in February of 
1975. The program involves the randomization to 
high risk and low risk groups on initial HBC count 
at diagnosis. Previous studies have shown that 
patients with a count of less than 20, COO do much 
better than patients with counts over 20,000. 
Patients with UBC counts of less than 20,000 
receive prednisone, vincristine, asparaginase 
Induction, cranial x-ray to 2400 rads plus 
intrathecal methotrexate central nervous system 
prophylaxis and maintained on methotrexate, 6-HP 
and monthly pulse doses of prednisone and vin- 
cristine for one year, at which time prednisone 
and vincristine will be discontinued. At two 
years all patients aisease-free will have therapy 
stopped or continued on a random basis. At three 
years all patients will have therapy stopped and 
on a random basis some will be assigned immunosti- 
Bulant therapy. Patients with WEC counts greater 
than 20,000 will be induced on a random basis with 
the same program as the low risk patients or will 
receive more intensive therapy with prednisone, 
vincristine and Cytoxan, asparaginase induction, 
the same cranial central nervous system prophy- 
laxis, but then will receive intermittent high 
dose therapy involving PGUP, (prednisone, oncovan, 
methotrexate and 6-I1P) in five day cycles every 
two weeks alternated with POCA (prednisone, 
vincristine, cytosine arabinoside and adriamycin) . 
After one year those patients remaining disease 
free will then be switched to a program identical 
to the low risk groups. Approximately thirty to 
forty new patients with acute lymphocytic leukemia 
are seen here yearly, so we would anticipate entry 
of about that many patients per annum on this 
study. At present four patients have been entered 
on a pilot basis. 



85. AI. L-BEIBDDCTION FOB PATIENTS BELAPSIMG FBOH 
CCG lai-CCG 152 

Hartmann, J. S. , Chard, B. L. , Bleyer, U. A., 
Bernstein, I. D., childrens Orthopedic Hospital, 
Hematology, UBOO Sand Point Kay N. E. , Seattle, 
Hashington, 98105, U.S.A. 



ALL Beinducti 
relapsing CCG im 
The protocol 



cc; 152- for all patients 
were low risk patients, 
ow under development. 



cytosine arabinoside or 6-iiercaptopurine with 
L-asparaginase being given at two different dose 
schedules with cytosine ana 6-mercaptopurine. "he 
study was approved in January 1971 and closed in 
October, 197il. Nine patients from this institu- 
tion have been entered on this study. 



87. CCSG 905 - UMHAINTAINED BEHISSIOM OF ACDTE 
LIHPHOCYTIC LEUKEMIA 111 CHILDBEM 
Hartmann, J. B. , chard, a. L., Bleyer, H. A., 
Bernstein, I. D., Childrens Orthopedic Hospital, 
Hematology, 1800 Sand Point Way N. E. , Seattle, 
Hashington, 98105, U.S.A. 

All children regardless of prior therapy who 
remain disease-free after three years or one 
thousand days with no incidence of bone narrow, 
central nervous system or other extramedullary 
relapse, are eligible to be entered on this study. 
On entry, patients on a random basis are assigned 
to continue their previous therapy or have it 
discontinued. Number of patients eligible at this 
institution are only one or two per year as all 
patients under previous Group A protocols have 
been entered. The present study started since 
1972. CCSG 101 and 1143 will maintain patients on 
that study after disease-free survival for three 
years. Number of patients entered at this institu- 
tion, six. 



88. NON ALL/AUL EEINDUCTION THEBAPY - CCSG 213 
Hartmann, J. E. , Chard, H. L., Bleyer, M. A., 
Bernstein, I. B. , Childrens Orthopedic Hospital, 
Hematology, 1800 Sand Point Hay N.3., Seattle, 
Bashington, 98105, U.S.A. 

This is for patients who will fail on CCSG 
2t 1 or cytosine arabinoside, 5 azacytosme, 
prednisone and vincristine. It is anticipated 
that the program of daunomycin and perhaps 
6-thioguanine or perhaps another agent will be 
utilized to reinduce these patients. This progra 
is now under development. 



89. (CYIOiAN, CYTOSINE AEABINOSIDE AND VINCBISTIHE 
IH ACUTE MYELOGENOUS AND ACUTE .10N0.1 Y ELOGENOUS 
LEUKEMIA - CCG 902) 

Hartmann, J. K. , Chard, E. L., Bleyer, H. A., 
Bernstein, I. D. , Childrens Orthopedic Hospital, 
Hematology, 14800 Sand Point Hay N.S., Seattle, 
Hashington, 98105, U.S.A. 

This is for patients previously untreated 
with acute myelogenous and acute monomyelcgenous 
leukemia. The study was opened July 1969 and 
closed January, 1972. Twelve patients were 
entered on this study from this institution. 



90. NON ALI/AUL PATCO THERAPY - CCSG 102 
Hartmann, J. E. , Chard, E. L. , Bleyer, u. A., 
Bernstein, I. D. , Childrens Orthopedic Hospital, 
Hematology, "4800 Sand Point Hay N.E., Seattle, 
Washington, 98105, U.S.A. 

This is for previously untreated patients 
with AMML. The study followed CCSG 902 and 
consisted of cytosine arabinoside, Cytoxan, 
vincristine, prednisone, thioguanine. The study 
was opened in January of 1972 and closed in 
October, 19714. This institution contributed 12 
patients to this study. 



86. ALL/AUL BEINDUCTION KITH L-tSPAEAGIN ASE ANP 
6-HEBCAPTOPUBINE - CCSG 002A 

Hartmann, J. f,. , Chard, R. L. , Bleyer, H. A., 
Bernstein, I. D. , childrens orthopedic Hospital, 
Hematology, 4800 sand point Hay N.E., Seattle, 
Hashington, 98105, U.S.A. 

ALL/AUL Eeinduction with L-asparaginase and 
6-«ercaptopurine CCSG 002A. This program involved 
a four arm randomization for patients relapsing 
from CCSG 903 with bone marrow relapse. This 
involved giving L-asp'araginase with either 



91. (COMBINATION CHEBOTHEEAPY FOB REINDUCTION III 
ACDTE LEUKEMIA) 

Hartmann, J. E., Chard, R. L. , Bleyer, H. A., 
Bernstein, I. D., Childrens Orthopedic Hospital, 
Hematology, 4800 Sand point Hay N. E. , Seattle, 
Hashington, 98105, U.S.A. 



a tre 



This invo 
therapy with daunomyci 
those patients failing 
cytosine arabinoside, 
date, two patients hav 



nd 5- 



nt of reinduction 



136 



progran and since CCSG 102 has been closed since 
October, 1975, no lore patients will be eligible 
to be entered on this program. 



92. CYIOSIIIE tR»BI>IOSIDE FOB HIELOBLASTIC LEDKEHIA 
laBpkin, B. C, Univ. or Cincinnati, Childrens 
Hosp. Hed. Ctr., Pediatrics, Elland o Bethesda 
lies., Cincinnati, Ohio, 145229, U.S.A. 



Thi 



s is part of a broader project, 
subproject is not available. 



ary 



93. CBEHOTHERAPT OF ACUTE LEUKEMIA 
Sinks, L. !., Freeman, A. I., Decastro, L. A., 
Suser, T., Brecher, B., Nakazaua, S., Roswell Park 
Bemorial Inst., Pediatrics, b66 Elm St., Buffalo, 
Hen York, 1K203, U.S.A. 

The cooperative chemotherapy studies of ALGB 
are conducted in a number of malignant disease 
entities, such as acute leukemia, chronic leuke- 
■ia, multiple myeloma, lymphoma, solid tumors of 
children and tumors ot adults. 

The Department of Pediatrics is particularly 
active in those studies appropriate for childhood 
malignancies. Such studies of comparative 
chemotherapeutic regimens continue to lead to 
improved survival in acute lymphoblastic leukemia 
of children, non-Hodgkin 's lymphoma, Hodgkin's 
disease, neuroblastoma, rhabdomyosarcoma, Ewing*s 
sarcoma, osteogenic sarcoma, CNS tumors, as Hell 
as Bilms" tumor of the kidney. 

It is anticipated that such studies vill be 
continued in the follouing year as well as new 
pilot studies yet to be designed. 

BEFEBENCES: Freeman, A. I., Pantazopoulos, 
B., Decastro, L., sinks, l.F.: Infections in 
Children with Acute leukemia. ned. and Fed. One. 
1: 167-173, 1975. Sinks, L.F. and Mindell, E.S.: 
Chemotherapy in Osteosarcoma. Clinical Orthop- 
aedics and Belated Besearch, Vol. Ill: 101-104, 
September 1975. 



9<l. IHVESTIGATIOH OF CHILDBOOD lEOKEMIA 
Nathan, D. G. , Eosen, F., Scher, C, Stossel, T., 
Parkoan, B., Sbelson, H., McCaffrey, B. , Forget, 
B., Childrens Hosp. Med. Ctr., ICO Longwood Ave., 
Boston, Massachusetts, 02115, U.S.A. 

This research program combines the resources 
of the Departments ot Medicine and Radiology of 
the Children's Hospital Kedical Center along with 
the Dept. of Biology of the Massachusetts Insti- 
tute ot Technology in a center of laboratory and 
clinical research into the problem of childhood 
leukemia. The clinical research deals with the 
therapeutic indications for total body radiation 
and bone transfusion in end stage leukemia and in 
non-malignant bone marrow failure. The research 
also investigates technigues tor replacement of 
phagocytes in patients with severe neutropenia. 
The laboratory research program includes investig- 



ati 



appro 



ch to cli 



cells, 

cells 

cancer chemotherapeutic 

of transforming virus g 

cription systems and tfi 



)nal selection of leukemia 
.on of specific targets of 
igents, the localization 
les in specific trans- 
effect of cell fusion on 



96. ABTIIEDItEllIA EFFECTIVENESS OF COHBIKED 
HETHOTBEIATE AND L-ASPABAGINASE 
KcIntoEh, L. S., Yale University, School of 
Medicine, Pediatrics, 333 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



97. BEMISSION mODCIIOM IH "HIGH RISK- CHIIDREII 
BITH ACUTE LYMPHOBLASTIC LEUKEMIA 
Bclntosh, L. S., Yale University, School of 
Medicine, Pediatrics, 3J3 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 



This is part of a broader project, 
of this subproject is not available. 



98. DADNOHYCIN IN CHILDHOOD LEUKEHIA 
Moreno, H., Univ. of Alabama, School of Medicine, 
Pediatrics, 1919 7th Ave. S., Birmingham, Alabama, 
35233, U.S.A. 



This is part of a broader project, 
of this subproject is not available. 



A sum 



iry 



99. C8EH0THEHAPI OF CHILDBOOD LEUKEMIA AND SOLID 

lOMOBS 

Kung, F.H., Univ. of California, school ot 

Medicine, Medicine, P.O. Box 109, San Diego, 

California, 92038, U.S.A. 

This is part of a broader project. A summary 
ot this subproject is not available. 



100. BADIATION TUEBAPY FOB CHILDHOOD ACUTE 
LYMPHOBLASTIC LEUKEMIA 

Kim, I., Univ. ot Minnesota, School of Medicine, 
Medicine, 1305 Mayo, Minneapolis, Minnesota, 
55155, U.S.A. 

This is part of a broader project. A sumaai 
of this subproject is not available. 



101. TREATMENT OF CHILDHOOD LEUKEMIA AND LYMPHOSA- 

ECOMA 

Moreno, H., Univ. ot Alabama, School of Medicine, 

Pediatrics, 1919 7th Ave. S., Birmingham, Alabama, 

35233, U.S.A. 

This part of a broader project. A summary of 
this subproject is not available. 



102. "TOTAL" THERAPY IN CHILDREN, YOUNG ADULTS 

BITH ACUTE LYMPHATIC LEUKEMIA 

Maldonado, N., Univ. of Puerto Rico, School of 

Medicine, P.O. Box 5067, San Juan, Puerto Pico, 

00936 



the 



immunogenicity ot tumor antigens 



This is part of a broader project. A summary 
of this Subproject is not available. 



D. THERAPY OF LEUKEMIAS IN ADULTS (OR UNSPECIFIED AGE 
GROUPS) 



95. COMBINATION CHEMOTHERAPY IN ACUTE LYMPHOCYTIC 

LEUKEMIA 

Pratt, C, St. Jude Ch. Hes. Hosp., Box 318, 332 

H. Lauderdale St., Memphis, Tennessee, 36101, 

U.S.A. 



Thi 



is part of 
ubproject is 



103. IMMUNOTHERAPY AND CHEMOTHEBAPY OF ACUTE 
MYELOGENOUS LEUKEMIA - COMPARISON OF BCG VS 
INJECTION OF IRRADIATED ALLOGENEIC LEUKEMIC CELLS 

lister, T. A., Oliver, R. T., Imperial Cancer 
Research Fund, Medical Oncology Unit, Lincolns Inn 
Fields, Bc2a 3px, London, England, United Kingdom 

A controlled trial involving fifty patients 
established a significantly better survival for 
patients receiving immunotherapy and chemotherapy 



137 



coBpared vith that of patients receiving chea- 
otherapy alone. However, despite this treatment 
indefinite control o£ disease vas not achieved. 
Aninal studies suggested that non-irradiated 
leukenic cells nixed uith BCG night stinulate a 
better iDioune response against leukesic cells. In 
a prelininary study, 18 patients received non- 
irradiated allogeneic leukemic blast cells and BCG 
given into a separate site. Nine other patients 
received allogeneic blast cells miied vith BCG 
injected at the same site. There was no signi- 
ficant difference in survival between these two 
groups, and the remission lengths were less for 
the patients who had received the cells mixed with 
BCG injected into the same site. 

In the original study allogeneic irradiated 
leukemic cells were injected into three limbs, and 
BCG into the fourth: this treatment was given 
once weekly. The median survival of patients 
receiving chemotherapy together with this treat- 
ment was 295 days, compared with 53C days for 
those receiving chemotherapy alcne. A new trial 
has been set up to compare remission duration and 
survival in patients receiving chemotherapy plus 
BCG alone, ti those receiving chemotherapy, BCG, 
and allogeneic irradiated leukemic cells. 



10«. (EVALBATIOH OF SPECIFIC >IID MOK-SPECIFIC 

mHONOTHEBAPI COMBINED WITH U-DBUG CH EHOTHEBAPI 
FOB ACOTE NOW-LYHfHOELASTIC LEUKEHIA) 
Jackson, J. (1., Herrmanr., R. P., aoyai Perth 
Hospital, Hematology, Hellington St., Perth, 
Western Australia, Australia 

OBJECTIVES: 1. To determine whether immunot- 
herapy (specific and non-specific) combined with 
intermittent chemotherapy for acute non-lymph- 
oblastic leukemia prolongs the duration of the 
first complete remission and or survival, compared 
with continuous intensive chemotherapy. 2. To 
Bonitor specific and non-specific immune parame- 
ters so that correlations of prognostic and/or 
other value can be made between these, the 
activity of the disease, and the two types of 
therapy. 3. To determine whether hypertransf usion 
might lessen bone marrow suppression during 
chemotherapy induction of remission. (Text 
Abridged.) 



105. AOTOIOGODS STEH CELL BEPLACEHENT CBEnOTHEliAPI 

Am TOTAL BODY IRBAEIAIIOll IH BESISIANT ACUTE 

lEOKEIlIA 

HcCredie, K. , Dicke, Lacgdren, Spitzer, Oniv. of 

Texas, M.D. Anderson Hosp. t Inst., Developmental 

Therapeutics, P.O. Box 20036, Houston, Texas, 

77025, U.S.A. 

OBJECTIVE: To study the effect of combined 
chemotherapy and total body irradiation followed 
by infusion of autologous stored remission 
haemopoietic stem cells in acute leukemia resis- 
tant to combined chemotherapy. 

APPROACH: To store the stem cells in vitro 
during a period of remission, and to infuse those 
stem cells for marrow engraptnent at a time 
further chemical remission seems unlikely. Upon 
relapse, the patients will be treated initially by 
chemotherapy, but when this fails to achieve or 
maintain remission, they will receive piperazidine 
and 850 rads of whole body irradiat ion in an 
attempt to destroy all leukemia cells. The 
incidentally ablated normal bone marrow will then 
be replaced from the stem cell separated previo- 
usly and stored in liyuid nitrogen. During this 
period between irradiation and restoration of 
normal levels of granulocytes, bacterial decontam- 
ination will be attempted. 



106. mHUMOLOGIC BEACTIVITI OF ACUTE LEOKEHIA 
PAIIEMTS TOWARDS THEIB OBII BLAST CELLS 
Jeannet, H., Cantonal Hospital, Transplantation 
Immunol Unit, 6i4 Av. de la Boseraie, Geneva u, 
Switzerland, 1211 

OBJECTIVE: To study the reactivity of 
patients* sera and lymphocytes towards their own 
blast cells using various humoral and cellular 
iaiunological tests. 

APPROACH: Humoral sensitization towards 
patients* own blast cells will be looked for usin 
the following techniques: complement dependent 
lymphocytotoxicity (NIH test) and lymphocyte 
dependent antibody (LDA) cytotoxicity. Evidence 
for a cellulr sensitization to autologous blast 
cells will be looked for using the cell-mediated 
lymphocytotoxicity (CML) assay, the lymphocyte 
blastogenesis test, and the JlIF assay. The effec 
of the patients' sera on these cellular assays 
will be studied in order to detect possible 
blocking substances. Humoral and cellular 
sensitization to autologous blast cells will be 
monitored at different periods of the disease: a 
the time of diagnosis, during remission and after 
relapse of the disease. The influence of chemoth 
erapy and possibly immunotherapy on the immun- 
ological reactivity of patients* lymphocytes will 
also be studied. If specific antibodies cr 
blocking substances are found active, serum will 
be fractionated and the various fractions screene 
for their ability to cause cytotoxicity or to 
block cell-mediated cytotoxicity or blastogenesis. 



107. SPECIFIC IBMUHOTHEBAPt IS ACUTE MYELCGESODS 

LEUKEMIA 

Zighelboim, J., Univ. of California, School of 

Bedicine, Medicine, 105 Hilgard Ave., Los Angeles, 

California, 90021, U.S.A. 

Evaluate the effects of immunizing patients 
with acute myelogenous leukemia or acute myelomon- 
ocytic leukemia with leukemia blast cells, 
modified in various ways. The studies will be 
undertaken in the context of clinical protocols 
which will include evaluation of the dose, route 
and schedule of administration, assessment of 
specific immunity appearing in response to the 
Immunotherapy regimen, ana evaluation of patients' 
general immunocompetence. 



108. ( IHBDIIOTHERAPY OF HUMAM L EUKEM IA - COMBIMED 
THEBAPEUTIC EFFECTS OF ALLOGENEIC LEUKEMIA CELLS 
AMD CHEMCTHERAPt ) 

Taub, P. N., Cuttner, J., Vila, J., City Univer- 
sity of New York, School of Medicine, Bedicine, 
5th Ave. at E. 100th St., New York, New York, 
10029, U.S.A. 



The intent of the ongoing and proposed 
clinical project is to study the feasibility and 
efficacy of immunotherapy with BCG and allogeneic 
leukemic cells given supplementary to chemotherap; 
in the treatment of human leukemia. Parameters o. 
non-specific immune competence and specific 
humoral immunity will be intensely monitored 
during the treatment. Special emphasis will be 
placed upon the development of humoral anti-blast 
antibody during immunotherapy of both acute and 
chronic myelogenous leukemia, the specificity of 
such antibody and its interaction in vitro witn 
cell-mediated immune assay systems. These studie 
will provide a basis for determining the progno- 
stic significance of immunological reactions to 
tuaoi antigens, and for refining current immunoth- 
erapeutic and inmunodiagnostic techniques. 



138 



109. CBEMOmHONOTHESAPI OF tCBTE IHELOCYTIC 

LEUKEHIt - CYCLIC ADnllllSTBATIOli OP ALLOGEMEIC 

lEDKEHIA CELLS AND BEB 

Holland, J. F., City University of New York, 

School of nedicine. Neoplastic Diseases, 5th Ave. 

at E. 100th St., New York, New Yoric, 10029, 

U.S.A. 

OBJECTIVE: To evaluate the therapeutic 
effectiveness of inoculation of allogeneic acute 
■yelogenous leukemia (ANL) cells and of BEB in 
acute Byelocytic leukemia. These modalities shall 
be tested in a protocol which will utilize 
cytosine arabinoside ana Daunorubicin for remis- 
sion induction followed by cycles of four diffe- 
rent designated combinations of chemotherapy 
administered intermittently. The immunotherapy 
shall be interspersed with eight cycles of the 
chemotherapy courses. After appropriate stratifi- 
cation, eligible patients shall be randomized to: 
no immunotherapy; immunotherapy with neuraminidas- 
e-treated allogeneic cells; or immunotherapy with 
HER and neuraminidase-treated cells. The no- 
therapy arm of this regimen corresponds to a 
similar control group to be evaluated by the acute 
leukemia group B, and for this reason, the 
relative numbers of patients to be allocated to 
each arm of this protocol will be 1:2:2 respe- 
ctively. 



110. IBHONOTHERAPY OF ACBTE LEHKEllIA - STUDIES TO 
OPIIHIZE SCHEDULE OF BCG AND LEUKEBIC CELL 
ADJOVABI THEHAPY 

Skeel, E. I., Mitchell, B. S., Bertino, J. R., 
Harsh, J., Capizzi, R. L., Yale University, School 
of Bedicine, Medicine, 333 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 

This application is for funds to initiate and 
develop a new research program in the immunothe- 
rapy of acute leukemia. We plan to investigate 
the effect of the schedule of aditiinistration of 
immunotherapy in relation to chemotherapy and the 
relative effect of adjuvants such as BCG vs. 
specific (leukemia cell) immunization on the 
stimulation of cellular and humoral determinants 
of immune responsiveness. At the same time we 
will determine whether such laboratory measut laents 
of immunological competence against the leukemia 
cell will be predictive of clinical control of 
disease. Cells will be collected from patients 
with acute leukemia using the NCI-IBB continuous 
flow centrifuge. These cells will be frozen and 
stored for testing and for later immunization of 
the same or other patients with histologically 
similar acute leukemia. Some patients will be 
given adjuvants alone or in combination with 
leukemia cells. The patients will be extensively 
studied for cellular and humoral immunity to 
leukemia associated antigens, to determine whether 
augmentation of presumed intrinsic rejection 
mechanisms is actually accomplished. Cellular 
immunity will be measured using lymphocyte- 
mediated cytotoiicity and mixed lymphocyte 
stimulation tests. Humoral antibodies to be 
studied include "blocking factor", cytotoxic 
antibodies, and cytopnilic antibodies. These 
studies will enable us to gather basic information 
about the response to immunotherapeutic maneuvers 
and help to clarify the relative roles of cellular 
mediated and humoral immunity in the rejection of 
human leukemia. 



111. TREATBEMT OF LYHPHOCYTIC AND LYHPHOBLASTIC 

LEDKEHIA WITH IMMUNE PLASBA 

Biller, D. S. , Duke University, School of Hedicin 

Surgery, Box 3711, Durham, North Carolina, 27706, 

D.S.A. 

This is part of a broader project. A summar 
of this subproject is not available. 



112. t BDLTIPLE CHEHOTHEBAPI COMBIHBD HITH C. 
^ABVDH IN TREATMENT OF ACUTE LEnKEMIAl 
Jacobs, P., Univ. of Cape Town, School of Medicine, 
Hematology, Private Bag C.P. 7700, C.P. 7700, Cape 
Town, Cape of Good Hope, Republic of South Africa 

He are prospectively testing a three-drug 
combination regimen for the induction of acute 
leukemia and, as part of the same progi^mme, 
evaluating immunotherapy with C. parvum in the 
maintenance Arm. 

A similar approach is being used in patients 
with chronic granulccytic leukemia following 
splenectomy at presentation. 



113. (MULTIPLE CHEHOTHERAPY PLCS BCG IN THERAPY OF 
ADULT ACUTE LEUKEBIA - SWOG 7315/73161 
Bottomley, R. H., Hampton, J. H., Grozea, P. N., 
Hoge, A. F., Ishmael, D. R. , Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 73101, U.S.A. 

OBJECTIVES: To test the remission induction 
efficacy of ten-day OAP in adult acute leukemia. 
The objective with lO-day OAP would be to clear 
the marrow of leukemic cells with the first or 
second induction course and in this way bring 
about an early complete remission. To compare the 
effectiveness of 5-day maintenance OAP with 5-day 
maintenance OAP plus BCG in prolonging the 
duration of complete remission of patients 
achieving a complete remission on lO-day OAP 
induction which was followed by 5-day OAP consoli- 
dation. Patients will be started on the following 
induction regimen: Oncovin 2 mg. intravenously on 
day 1 only; Ara-C 100 mg/B2day by 21 hour 
intravenous infusion x 10 days; Prednisone 100 
mg/day PO x 5 days. Every effort should be made 
to complete the first course regardless of the 
peripheral blood counts and bone marrow. Bone 
marrow aspirations (or biopsy if a dry tap is 
obtained) will be done on day 1 « and every « or 5 
days thereafter, to determine when the marrow is 
cleared of leukemic ceils and when recovery from 
the marrow hypoplasia has occurred sufficient to 
start the next course. It is important to start 
the second induction course as early as possible 
after completion of the first course. The 
induction phase (7315) of this protocol is closed 
to new patient entries. 



111. SH0G-7m6/17 - CHEBOIBHUNOTHERAPY OF ADULT 
ACUTE LEUKEBIA (CIAL) 

Bottomley, R, H,, Hampton, J, «,, Grozea, P. N., 
Hoge, A. F., Ishmael, D. B., Hussein, K. K,, 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310<l, U,S,A, 

OBJECTIVES: To determine whether with the 
use of sequential or simultaneous adriamycin and 
Ara-C there is significant difference in their 
ability to induce complete remission. To study 
the effects of combination chemotherapy and 
immunotherapy on the duration of remission and 
survival in patients with acute leukemia. To 
identify those patients with ALL vs AML who ate 
vincristine and prednisone responsive. 

TREATMENT OF CATEGORY 1 PATIENTS (GREATER 
THAN 30,000 BLASTS) : Vincristine and Prednisone: 
These patients will be started on vincristine and 
prednisone only. The dosage of vincristine will 
be 2 mg. IV on days 1, 7, m, 21 and 28, Pred- 
nisone will be given 200 mg, PO daily, days 1-10, 
then prednisone 60 mg, Po daily, days 11-28, 

TREATMENT OF CATEGORY 2 PATIENTS (LESS THAN 
30,000 BLASTS CU.BL): Chemotherapy with simult- 
aneous or sequential adriamycin and Ara-C will be 
started immediately. The vincristine and pred- 
nisone will be administered to patients receiving 
either simultaneous or sequential therapy: 
Vincristine 2 mg,IV on day 1, prednisone 100 mg , 
P0/dx5. 



139 



115. BtNEOHIZID CHEBOTHERtPI >MD IHHOIIOTHEIUPI FOB 
tCDTE LEUKEBIA EVtLUATION OF ALTERIIATIVE FOBHS OF 
BAIHTEMAIICE THERAPY 

lai, L. 1., U.S. Veterans AdDinistration, Hospital, 
Section o£ Hematology, eOC Zorn Ava. , Louisville, 
Kentucky, ii0202, U.S.A. 

Rational treataent for acute leukefflia can be 
divided into three phases: (1) Initial treatment 
phase or induction phase. The aim of treatment in 
this phase is to induce remission: (2) Consoli- 
dation phase. In this phase additional treatment 
is given to patients in remission to eradicate the 
leukemia cells which may not be clinically 
detectable; and (3) Maintenance phase. The aim of 
treatment in this phase is to prevent relapse of 
leukemia. Thioguanine, Cytosine Arabinoside, 
Daunorubicin have been used for treatment of acute 
leukemia. Experience of the Southeastern Group 
shoved that "Oi of adults vith acute myeloblastic 
leukemias did have remissions vhen treated with 
Cytosine, Arabinoside and 6-Thioguanine. The 
additional effect of Daunorubicin in those cases, 
however, is not clear. The aim of the study is to 
use these drugs and to establish the best treat- 
ment regimen for patients with acute leukemia. 
The plan is to use Thioguanine-Cytosine Arabinosi- 
de-Daunorbicin vs. Daunorubicin and Cytosine 
Arabinoside for induction therapy. Once remission 
is achieved, Thioguanine, Cytosine Arabinoside and 
Daunomycin will be used for consolidation trea- 
tment. After consolidation therapy, patients will 
be randomized into 3 groups to receive (1) no 
treatment, (2) immunotherapy with BCG, and (3) 
chemctberapy with fiCNU and Cytosina Arabinoside. 



116. PHASE III CHEBOIBnatlOTHEilAPY OF ADDLT ACUTE 
1EDKEHIA-IRDUCTI0II (CIALI - CCnfABE DRUG COBB- 
IHATIOHS IN ISDUCmG AHD SUSTAimUG REHISSIOS 
acCredie, K. , Hewlett, J., Solidoro, A., Vallejos, 
C. , Southwest Oncology Group, Suite 201, 3500 
Rainbow Blvd., Kansas City, Kansas, 66103, U.S.A. 

PBOIOCOL ENTBJ CRITERIA: All patients age 15 
or older with a diagnosis of acute leukemia who 
have received no extensive prior therapy will be 
eligible for this study. 

PURPOSE: 1. To determine whether with the 
use of sequential or simultaneous Adriamycin and 
Ara-C there is significant difference in their 
ability to induce complete remission; 2. To 
identify those patients with ALL vs. ABL who are 
Vincristine and Prednisone responsive. 

DOSE SCHEDULE: Induction Phase: Enter 
patients who have egual to or greater than 50A 
absolute leukemic cells in their marrow. Arm I: 
Enter Category I patients with greater than 30,000 
blasts/cu mm. 2-Drug combination chemotherapy 
with Vincristine plus Preanisone for » days. 

Be-randomize nonresponder s with increasing 
disease. Continue respondei with stable or 
decreasing disease on combination Vincristine plus 
Prednisone until day 10. 

Evaluate on day 10. Enter complete respon- 
ders into consolidation regimen. Continue partial 
responders with greater than 50* decrease in 
disease on 2-drug combination with Vincristine 
plus Prednisone. Serandomize non-responders with 
less than or egual to 50X decrease in disease. 

Conduct weekly evaluations on day 17. 
Continue complete responders on consolidation. 
Continue partial responders who show continued 
improvement on Vincristine plus Prednisone, then 
evaluate and re-randomize on day 29. Pe-randomize 
patients with stable or progressive disease. 



117. USE OF CMEHOTHERAPy AHP BCG IW OHRF 7U-02 - 
ACUTE MOM-LYBPHOCYTIC LEUKEBIA IN ADULTS - EFFECTS 
OF ACJUKCTIVE BCG IH SUSTAIHIMG REBISSIOII 
Bottomley, R. H., Hampton, J. W., Grozea, P. N., 
Hoge, A. F., Ishmael, D. R., Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310U, U.S.A. 

OBJECTIVES: To compare induction efficacy of 
(1) adriamycin plus OAP; (2) adriamycin plus 
Ara-C; (3) Cyclcphosphamide, Adriamycin, Ara-C 
and Thioguanine, in adults with acute non-lym- 
phocytic leukemia. The best regimen will be the 
most efficient in clearing the bone marrow of 
leukemic cells during the first and second 
courses, and thus improve the remission rate. To 
conpare the effectiveness of 5-day maintenance <1) 
OAP plus BCG; (2) Ara-C plus BCG; (3) Ara-C, 
Thioguanine and BCG, in prolonging the duration of 
complete remission. 

REBISSION INDUCTION: Eligible patients will 
be randomized to one of three treatment limbs, as 
follows: LIBB I: Adriamycin plus OAP; LIBE 11: 
Adriamycin plus Ara-C; LIBB III: Adriamycin, 
Cytoxan, Ara-C and Thioguanine. A bone marrow 
aspiration (or a biopsy if a dry tap is obtained) 
will be carried out on day 18 to determine whether 
the bone marrow is cleared of leukemic cells and 
if marrow hypoplasia has been reversed, so that a 
further course can be instituted. 

REBISSION CONSOLIDATION: Three consolidation 
courses will be administered at 1M-day intervals, 
as follows: LIBB I: Ara-C - 100 mg/B2/day x 5 
days, by constant IV infusion; Prednisone - 50 mg 
b.i.d., PO I 5 days; Vincristine - 1 mg IV on day 
1. LIBB II: Ara-C - 100 mg/B2/day x 5 days, by 
constant IV infusion. LIBB III: Ara-C 100 
mg/B2/'day x 5 days, by constant IV infusion; 
Thioguanine - 2 mg/Kg/day, PO, x 5 days. Dosage 
adjustments in Ara-C may be made when marrow 
hypoplasia occurs; the dose of subsequent courses 
can be reduced by 10 percent. 



118. OMRF 71-01 - ARA-C, VINCRISTINE, PREDNISONE 
AND BCG IN CHRONIC GRANULOCYTIC LEUKEBIA 
Bottomley, R. H. , Hampton, J. v., Grozea, P. N. , 
Hoge, A. F., Ishmael, D. E., Hussein, K. K., 
Oldham, F. B., U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310il, U.S.A. 

OBJECTIVES: To bring about adequate control 
of the clinical manifestations of chronic granulo- 
cytic leukemia (CGL) without the use of alkylating 
agents. Ara-C will be used tor this purpose and 
for maintenance. To attempt to prevent the 
accelerated .phase of the disease with intermittent 
doses of prednisone and vincristine, with or 
without BCG. (Text Abridged.) 



119. CHEHO-IHHUNOTHERAPY WITH SPLENECTOHY IN OB°F 
75-05 - PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC 
GRANULOCYTIC LEUKEBIA 

Bottomley, R. H. , Hampton, J. a., Grozea, P. N., 
Hoge, A. F., Ishmael, D. R. , Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310U, U.S.A. 

OBJECTIVES: To determine if the combined 
addition of splenectomy and immunotherapy with BCG 
to intermittent busulfan therapy: 1) delays the 
onset or reduces the incidence of blastic transfo- 
rmation, and b) improves the survival of previo- 
usly untreated patients with chronic granulocytic 
leukemia. 

TREAIBENT PLAN: Once entered on the study, 
all patients shall be treated with busulfan, given 
as a single daily dose, one-half hour before 
breakfast. The dose of busulfan shall be reduced 
as the leukocyte count falls during treatment, and 
discontinued when the total leukocyte count is 
5,000 - 9,000. 

Splenectomy shall be performed within 1-3 
weeks from cessation of induction therapy with 
busulfan, unless surgery has to be delayed for a 



140 



specific aedlcal reason. 

Balntenance therapy shall, start 2-3 weeks 
post-splenectony. naiutenance therapy shall 
consist of interaittent busulfao, alternating with 
BCS scarification. 



120. SPLEKECTOm IH CHB08IC BYEIOCITIC tiUKMlk 
Sokal, J. E., Rosvell Faric neiorial Inst., 666 Eli 
St.. Buffalo, New Yorlc, luJOJ, U.S.i. 

This is part of a broader project. A sunnary 
of this subproject is not available. 



121. (SPlEBECTOnl IH LtUKEBIAS AHP tlBPHOHtS) 
Bittelaan, A., Roswell Park Henorial Inst., 666 
El* St., Buffalo, New lork, 1u203, O.S.A. 

This is part of a broader project. A suonary 
of this subproject is not available. 



122. BOIi-SPECIFIC ACTIVE IBBBMOTHEii API IW CANCER 
PATIEBTS miH BCG C OTHER HON-SPECIFIC IBBOMOL- 
OGICAL SIIBULASTS 

Gutterian, J. u., Uersh, E. n. , navligit, G., Reed, 
B., Oniv. of Texas, B.D. Anderson Hosp. Inst., 
Bevelopiental Therapeutics, P.O. Box 20036, 
Bouston, Texas, 77025, U.S.A. 

OBJECTIVE: To develop a broad-scale proqra» 
of iBBUnctherapy and cheooinaiunotherapy for cancer 
patients. To use non-specific and specific 
iBBunological stimulation in patients with 
■alignant aelanona, carcinoma of the breast, 
carcinoma of the lung, colon carcinoma, adult 
acute leukemia, non-Hodgkin*s lymphoma and 
sarcomas of various types, Ihis will be compared 
to the presently accepted optimal medical and/or 
surgical treatment of these diseases. 

APPROACH AUD PROGRESS: He have demonstrated 
that BCG, when used in sufficient doses, can 
prolong disease free interval and survival in 
■elanoaa patients uith minimal residual disease. 
However, there are definite limitations of the 
efficacy of BCG; patients continue to relapse and 
die, suggesting that additional adjuvant iamunoth- 
erapeutic approaches need to be considered. 
Chemotherapy added to immunotherapy in melanoma 
appears to be additive. Exciting positive leads 
of iimunotherapy in a wide variety of tumors with 
BCG, other bacterial and mycobacterial agents as 
well as active specific and adoptive approaches 
clearly demonstrate the tremendous potential 
activity of immunotherapy and immunochemotherapy 
in Ban. The developmt -t of our program during the 
coBlng year will continue to focus on BCG and 
active specific iBmunotherapy. 



2. CHEMOTHERAPY AND/OR RADIOTHERAPY FOR LEUKEMIA 



125. COBFARISOII OF BETHOTREXATE DISTRIBUTION III 
SERDB AND C5F fOLLOMING INTRAVENTRICULAR A.ID 
INTRATHECAL ADHINISIBATION 

Shapiro, U. R., Hutchison, D. J., Sloan Kettering 
Inst. Can. Ses, Drug Resist 6 cyto Regulation, 1U5 
Boston Post Rd., Rye, New Jork, 10580, U.S.A. 

OBJECTIVE: To compare the distribution of 
Bethotrexate in the intrathecal space following 
Intrathecal and intraventricular administration. 

APPROACH: Patients suflering from meningeal 
leukemia and other intracranial neoplasms were 
given 6.25 mg/m2 methotrexate intrathecally 
(lumbar puncture) or intra ventricularly (via 
OBBaya Reservoir) . Blood ana cerebrospinal fluid 
(CSF) samples were obtained at definite intervals 
of 1,K, 16,2u,i4e and 72 hrs. Bethotrexate levels 
were determined in serum and CSF using microbiolo- 
gical assay techniques. 

PROGRESS: Uniform distribution of methot- 
rexate in the intrathecal space was obtained 
following Ommaya Reservoir administration, 
whereas, even after successful lumbar puncture 
administration, the methotrexate levels in 
cerebral ventricles were variable. This study 
needs further confirmation before recommending 
Ommaya Reservoir administration as a better route 
of administration. 



126. PHASE II - INTRATHECAL N,N', H",-TRIETHYLENE- 

THIOFH0SPHOHAHIDE (THIOIEPA-NSC-63961 IN MENINGEAL 

NEOPLASHS 

Walker, B. D. , Gutin, P. H., Levi, J. A., aiernik, 

P. H., U.S. Dept. o£ Hlth. Ed. E Uel., Natl. 

Cancer Institute, Neurosurgery Section, Baltimore, 

Maryland, U.S.A. 

Phase II evaluation of intrathecal thiotepa 
is being carried out in patients with meningeal 
leukemia and meningeal carcinomatosis. Thictepa 
represents the third intrathecal cnemotherapeutic 
agent available for the treatment of meningeal 
disease, and approilEatol y one-half of the 
patients showed a complete response with reduction 
in cerebrospinal fluid nlast count. It is 
anticipated that additional patients will be 
accrued and this study completed during the course 
of the next year. 



127. CLINICAL STDDT OF DESACEIIL VINBLASTINE ABIDE 

SDLFAIE 

Krakoff, 1. H., Tan, C, nemorial Hosp. for Can. 6 

Dis., Bedicine, 1275 york Ave., New York, New York, 

10021, U.S.A. 



123. LYMPHOCYTE TRANSFER FACTOR IN TREATBEMT OF 
iCDTE LEUKEMIA 

Betz, E. B., Ohio State University.. School of 
Medicine, obstetrics G Gynecology, 102 Admini- 
stration Bldg., 370 «. 9th Ave., Columbus, Ohio, 
113212, U.S.A. 

This is part of a broader project. A sumaa 
of this subproject is not available. 



121. CHEHOIBBUNOTHEBAPI OF ACUTE LEOKEBIA IN 

IDULIS 

Fefer, A., Univ. of Nashington, School of Bedic 

Medicine, 500 17th Ave., Seattle, nashington, 

9S122, U.S.A. 

This is part of a broader project. A susi 
of this subproject is not available. 



OBJECTIVE: The development of a new vinca 
alkaloid with useful activity in leukemias and 
lymphomas but without limiting neurotoxicity or 
bone narrow toxicity. 

PLAN: Desacetyl vinblastine amide sulfate 
(DVA) will be administered intravenously to 
patients with far-advanced, non-resectable 
neoplastic disease. The initial dose will be 0.5 
■g/fl2 I.V. once weekly. That dose will be 
increased stepwise with careful monitoring of 
hematopoietic parameters, liver function tests and 
neurologic status. Alternate dose schedules will 
also be evaluated, including administration of the 
compound twice weekly and administration daily. 

The Phase II (therapeutic) evaluation will 
Include patients with lymphomas and acute lymphob- 
lastic leukemia, initially those who have relapsed 
following initial combination therapy. It is 
anticipated that ultimately, following demonst- 
ration of Its activity and low order of tonicity, 
DVA will be administered as initial induction 
therapy to previously uittreated patients with 
acute lymphoblastic leukemia and that it will be 
added as a component of combination chemotherapy 
in other kinds of tumors. 

BACKGROUND: Antitumor studies of DVA in 
aniaals have revealed that it has a spectrum of 
activity identical with that of vincristine. 



141 



Bovever, it has not (reduced neurotoxicity either 
in intact laboratory animals (dog, cat, rat, mouse 
and chicXen) or in isolated nerve preparations 
from cats. Thus the evidence suggests that this 
compound nay be as useful as Vincristine but 
vithout limiting neurotoxicity and, therefore, 
might be used more intensively than Vincristine. 

SIGNIFICANCE OF STUDY: The potential 
development of a new eftective alkaloid without 
neurotoxicity or significant bone marrow toxicity. 



128. mPUCTIOM OF COMPLETE REHISSION IN ACnXE 

HTELOGENODS LEUKEMIA - INVESTIGATION OF CQBBINED 

IHERAPI 

lister, I. A., Whitehouse, J. II . , Beard, B. E., 

Imperial Cancer Research Fund, Medical Oncology 

nnit, lincolns Inn Fields, llc2a 3px, London, 

England, United Kingdom 



Previously reported stuaies at St. Barth- 
olomew's Hospital which use daunorubicin and 
cytosine arabinoside in combination have produced 
complete remission rates varying from 32-i9%. In 
an attempt to test the hypothesis that an S- 
phase-specif ic agent used before daunorubicin is 
■ore effective than the converse, a pilot study 
¥as carried out to compare these methods of 
administration. The preliminary results were 
discouraging, and did not permit adequate com- 
parison. A new protocol reported to produce 70% 
complete remission overall, combining vincristine, 
adriamycin, prednisolone, and cytosine arabinos- 
ide, is undergoing investigation at present. So 
far thirty patients have been treated in this 
trial, and the complete remission rate in 26 
analyzable cases is 50%. 



129. ATTEMPTED CELL SYNCHRONIZATION TO ENHANCE 
8ESP0WSIVENESS TO CHEMOTHERAPY OF ADULT LEUKEMIA 
Vincent, P. c, Gunz, F. W., Sydney Hospital, 
Sydney, New South Wales, Australia 

OBJECTIVE: Most chemotherapeutic agents 
effective against human acute leukemias act on 
cells during the DNA synthetic phase (S) . The aim 
of this study is to increase the proportion of 
cells in S by including synchronous cell division. 

APPROACH: Adult patients with acute leukemia 
are treated initially with 2 large doses of 
hydroxyurea 24 hours apart. Bone marrow samples 
obtained before and at intervals after hydroxyurea 
administration are analysed by autoradiography and 
nuclear microdensitcmetry to determine the 
proportion of cells, in s and in the other phases 
of the cell cycle. Further chemotherapy with 
cytosine arabinoside and thioguanine or daunor- 
ubicin is commenced at 88 hours from the first 
dose of hydroxyurea. More rapid methods of 
autoradiographic analysis are being assessed in 
the hope that cell synchrony can be detected in 
the individual patient and the timing of second 
chemotherapy altered accordingly. 

PROGRESS: 9 of the 19 patients in whom 
detailed analyses have been completed showed 
evidence consistent with the induction of syn- 
chronous cell division by hydroxyurea. The 
complete remission rate in this group was higher 
(5/9) than in the group in which there was no 
evidence of synchronization (2/10), although the 
numbers are small and the results do not yet reach 
the level of significance. 



130. STEROID METABOLITES AND ANDROGENS IN LEUKEMIA 
THERAPY - INCREASED SENSITIVITY TO CHEHOTHERAPI 
AND RADIOTHERAPY BY CELL S Y NCH B0NI2 AIION 
Gardner, F. H., Univ. of Pennsylvania, School of 
Medicine, Medicine, 36th £ Hamilton Walk, Philade- 
lphia, Pennsylvania, 19101, U.S.A. 



Control mechanisms in 
cells and tumor cells and i 
therapy will be studied. J 
Etetoid metabolites, nuclei 
will be used to alter tumoi 
stem cell cycling to defin* 
tion from nyelo-suppressior 



he regulation of stem 
eir relation to cancer 
drogens, beta 5-H 
ides, and hyperoxia 
cell and hematopoietic 
their use in protec- 



Eitivity during chemotherapy and irradiation. 
Later, when an IND for the steroid metabolite b 
5-H-pregnane-beta 3-hydroxy-20-one has been 
procured, clinical observation on the potential 
use of this compound along with androgenic 
hormones will be pursued. These objectives wil 
be in the animal models as well as clinical 
studies. The different stem cell compartments 
will be evaluated by the method of Till £ McCu- 
liough (Cru-S), Hetcalf (CFU-C) and Stephenson 
Axelrod (CFU-E) . The effect on the cell cyclin 
will be measured using combinations of CFU 
enumeration, Fe59 incorporation into RBC and H3 
thymidine uptake following interval treatment w 
chemotherapy, steroids, nucleotides and hyperox 

For the clinical studies, normal male 
volunteers will serve as controls, and various 
leukemic, pre-leukemic, and solid tumor patient; 
will be evaluated for the role of the agents 
previously enumerated during therapy. PreliminQ 
clinical observations relating to possible 
pyrogenicity or a steroid metabolite are plannec 
The potential application of the beta 5-H steroi 
metabolites for clinical use in bone marrow 
depression will be assessed as the different 
dosage schedules are defined. The synchronizati 
of tumor cells to cycle will be evaluated in 
Increasing susceptibility to cycle specific drug 
by the previously mentioned modalities. 

The effect of exposure to high levels of 
oxygen will be investigated in both normals and 
patients undergoing cancer therapy. This is part 
of a broader project. (Text Abridged.) 



131. PHASE II STUDY OF ARABIMOFUBANOSYLADENINE- 

5'-PU0SPHATE (ARA-A-5'-P) IN CHROMIC MYELOGENOUS 

LEUKEMIA 

Lepage, G. A., Khaliq, A., Univ. of Alberta, 

Cancer Research Unit, HcEachern Lab, T6g 2g7, 

Edmonton, Alberta, Canada 

OBJECTIVE: To determine the efficacy of 
Ara-A-5'-P in the treatment of selected hemat- 
ological malignancies. 

APPROACH: Selected hematological malignan- 
cies in patients who have not responded to other 
available therapy are to be treated daily for 5- 
days with Ara-A-5'-P i.v. as an isotonic solutioi 
Patients are studied first in regard to the 
enzymatic pattern of their peripheral and/or 
marrow KEC's (adenosine deaminase, kinases, DNA 
polymerase) . 

PROGRESS: Of t chronic myelogenous leukemic 
patients in blast crisis, 2 have responded and 2 
have not. one had a complete remission for 
approximately 6 months and then became refractor) 
Others have been entered but are not yet suitiblf 
for evaluation. 



Hossfeld, D. K., Schaefer, U. W., Schmidt, C. G., 
Univ. Clinic for Internal Med., 55 Hufelandstrass 
Essen, Federal Republic of Germany, U3 

OBJECTIVE: To increase the number of 
remissions and the duration of primary remissions 

APPROACH: The protocol follows closely the 
one designed by the "Acute Leukemia Group B". In 
addition, tfce methanol extraction residue of BCG 
will be given 14 days after maintenance therapy. 
For remission induction the patients are given 
daunomycin '45mg/m2 on 3 successive days and 
cytosine-arabinoside 100mg/m2 on 7 successive 
days. For maintenance 6-thioguanine 2CC/ig/u2, 
cyclophosphamide 1000Bg/m2, CCNU 100mg/m2, and 
daunomycin 90mg/m2, in addition to cytosine- 
araoinoside 200mg/m2 are given in 28-day interv- 
als. 



142 



133. CLIHICtL TRUL 0? COBBmATIOH OF MEIHYl-CCHB 

IMP CYCLOPHOSPKAnlljE IH ADULTS IIITH LEHKEHUS, 
LIMPHOnAS AND OTHER BALIGNAIICIES 
Krakoff, I. H., nemorial Hosp. for Can. S 01s., 
Bedicine, 1275 Tork Aie.. Sen York, Neii York, 
10021, U.S.A. 

OBJECTITE: To determine the tolerated dose 
and to evaluate the therapeutic activity and 
toxicity of the combination of Hethyl CCNU and 
Cyclophosphanide in patients with leukeaia, 
lyaphoaa and metastatic tumors abo are considered 
refractory to usual therapeutic measures. 

PLAN: Informed consent »ill be obtained. 
Pre-treatment studies: Physical examination, CBC, 
urinalysis, bone marrov aspiration, and screening 
profile. 

The initial dose of Methyl CCNO will be 
100mg/H2 orally given in the A.H. simultaneously 
vith Prochlorperazine lOmg P.O. or I.H. A second 
dose of Prochlorperazine will be given three hours 
later prior to administration of cyclophosphamide 
1000mg/n2; this is followed by hydration with 
D-5-B 1000ml to run in K-8 hours. Doses of Bethyl 
CCNU and Cyclophosphamide should be reduced for 
patients with recent chemotherapy or radiotherapy, 
fiepeat Prochlorperazine at 6-hour intervals for 3 
doses. Repeat urinalysis weekly. Repeat hemogram 
veekly. Repeat biochemical, radiological studies 
as indicated. The second drug administration 
could be repeated in 4-6 weeks in the absence of 
hematologic, oral and urinary toxicity. 

BACKGROUND: Bethyl CCSU has shown activity 
against the Lewis lung carcinoma implanted 
subcutaneously (6DF1 mice) , which has cell 
kinetics similar to human solid tumors. 

Resistance to individual alkylating agents 
such as BCNU, Methyl CCNU, and Cyclophosphamide 
■ay be circumvented by administering a combination 
of two of these drugs, from studies with murine 
lymphoma, they appear to complement each other and 
•ay in fact be synergistic. 



13<1. PROTOCOL (PHASE III) . CHEB0THB8APY Of ACDTE 
lEOKEBIA - DCWP VS. CCCMP 

Hosbino, A., Inagaki, J., Horikoshi, N. , Kuraishi, 
I., Cancer Chemotherapy Center, Div of Clinical 
Chemotherapy, 1-37-1 Kami Ikebukuro Toshima, 
Tokyo, Tokyo, Japan, 170 

PURPOSE OF STUDY: To compare the effecti- 
veness of Cyclocytidine in combination chemoth- 
erapy, tc that of Cytosine arabinoside in the sams 
combination in adult acute leukemia. Patient's 
eligibility: All patients less than 60 years old, 
without prior major chemotherapy, are eligible. 

PLAN CF TREATBENT: Patient will be random- 
ized to one of the two combinations. A. DCBP: a. 
Daunoaycin 'lO mg/m2 i.v. rapid infusion on day 1; 
b. Cytosine arabinoside uC mg/m2 day x u days, 
I.v., with each dose being divided into q 12 h 
injections; c. 6-mercaptopurine 80 mg/m2/day x 6 
days, P.O.; d. Prednisolone 100 mj/day x 1 days, 
f.o. B. DCcBP: Instead ^t Ara-C in the above 
combination, cyclocytidine is used, at a dose of 
700 mg/a2/day x ti days, i.v., with each dose being 
divided into g 12 h injections. This therapy will 
be repeated g 2 wks, depending upon the patient's 
response. 

A minimum of 3 courses of therapy should be 
completed before the patients are considered to 
have failed on thi^. therapy. 

After a patient achieved a complete remiss- 
ion, the cyclic maintenance therapy is used, with 
i-HP, BIX, Cyclophosphamide and Prednisolone, each 
£or 4 weeks. 



135. HAWAGEBENT OP CHRONIC HYBLCCTTIC LEUKEBU 

(CBL) BY SPLENECTOBY AND CYCLICAL INTENSIVE 

CBEMCIHEBAPI 

Bossfeld, D. K., Schmidt, C. G., Univ. Clinic for 

Internal Bed., Tumor Research, 5S Ilufelandstrassa, 

Essen, federal Republic of Germany, ii3 

OBJECTITE: To delay onset of the blastlc 
phase of CBL. 

APPROACH: After induction of remission by 



treatment with busulfan, the spleen is removed by 
splenectomy. Patients are then randomized into 
tvo protocols: a) continuation of busulfan 
treatment; b) courses with daunomycin 15 mg/m2, 
cytosine arabinoside 100mg/m2x5, vincristine 
1.2ag/2m, and prednisone 100mg/m2 every J months; 
busulfan is given if the UBC rises above 20,000 
■icrollter in the intervals. 



136. THE CBEBOTHERAPY OF ADULT ACUTE LEJUEBIA - 

CYTOSINE ARABINOSIDE, DAUNORUBICIN, EP 16-213, AND 

JEOCARZINOSTAIIN 

Uiernik, P. H., Aisner, J., Smyth, A. C. , Lic- 

htenfeld, J. L., Chabner, B., U.S. Dept. of Hlth. 

Ed. S wel., Natl. Cancer Institute, Bedicine 

Section, Baltimore, Maryland, U.S.A. 

A seven-day ccnticuous intravenous infusion 
of cytosine arabinoside in association with a 
three-day schedule of intermittent daily doses of 
daunorubicln has been shown to be a highly 
effective chemotherapeutic regimen for the 
induction of remission in adults with acute 
nonlymphocytic leukemia. A complete remission 
rate of 70X is being obtained with this combina- 
tion of agents, other newer agents such as the 
epipodophyllotoxin derivative of EP 16-213 and 
neocarzinostatin are under investigation lor their 
antileukemic activity and early indications are 
that these drugs have activity against this 
disease. 

Reverse transcriptase has been identified, in 
the bone marrow cells of leukemia patients prior 
to treatment and in morphologically normal 
peripheral cells during complete remission. One 
Interpretation of these data is that morpholog- 
ically normal and functionally normal granulocytes 
in the peripheral blood of leukemia patients in 
complete remission are derived from leukemic 
ceils. 



137. PgOTOCOL FOB RtBISSION INDUCTION Of ACUTE 
LEOKEBIA mTH DAUNORUBICIN (NSC 162151) AND 
CYIOSIBE ARABINOSIDE 

Kane, R. C, Bakary, A., Kough, R., Geisinger 
Medical Center, Hematology, Danville, Pennsylva 
17621, U.S.A. 



OBJECTIVE: To improve the remission induc- 
tion in acute myelogenous leukemia with the use of 
daunorubicln and cytosine arabinoside infusion. 

APPROACH: Patients with acute myelogenous 
leukemia, untreated or resistant to other drug 
regimens, who would appear to benefit frot 
treatment will be offered remission induction with 
drug combination listed. In recent studies, this 
combination has been the most effective drug 
regimen yet developed for remission induction of 
acute myelogenous leukemia. (Text Abridged.) 



138. CBEB0THE8APY IN ACDTE BYELCGENOUS LEUKEBIA 
Schrlet, S. L., Stanford University, School of 
Bedicine, Bedicine, Palo Alto, California, 91305, 
U.S.A. 

Therapy of ABL in remission: Patients with 
ABL In complete remission were randomly assigned 
to -groups either receiving or not receiving 
monthly courses of maintenance chemotherapy. 
Therapy consisted of monthly pulses of cytosine 
arabinoside and 6-thioguanine and prolonged the 
mean duration of remission from 5.8 to 11.7 
months; "46* of the treated patients have had 
zemlssions lasting longer than 11 months, of 
importance was the essential lack of morbidity of 
this form of therapy. These findings indicate tht 
efficacy of maintenance chemotherapy for prolon- 
ging remission durations in ABL. 



143 



139. 2,2'-»MHYDPO-1-E-D-ftBABIN0F»E>NOSri-5- 
riUOBOCITOSINE (AflFC) AND THIOGUAWINE COnBINATION 
Krakoff, I. H., Ian, C Haghbin, n., neniorial 
Hosp. for Can. 6 Dis., Medicine, 1275 York Ave., 
Ney York, New York, 10021, U.S.A. 

OBJECTIVE: To explore the synergistic effect 
in patients for tolerance and therapeutic effect 
of AAFC and thioguanine. 

BACKGROUND: Preliminary studies of AAFC (CIC 
protocol 173-23) in 35 patients (23 adults, 12 
children) have been sumaar ized . Adults tolerated 
doses up to 15 mg/kg b.i.d. and children up to «0 
ng/kg b.i.d. Side effects consisted of occasional 
nausea, vomiting, and diarrhea, and transient 
electrocardiographic changes. Therapeutic 

durations of response were short. In murine 
leukemia, the antileukemic effects of AAFC are 
potentiated by thioguanine, and in normal mice 
toxic effects of TG are decreased by AAFC, as well 
as by AFC. Also in man, combination of Ara-C and 
TG has produced remission in leukemia. 

SIGNIFICANCE OF STUDY: Possible development 
of a Sseful combination of two chemotherapeutic 
agents. In animals and trials in three patients, 
4AFC is active when administered orally and has a 
longer half-life than Ara-C. These would decrease 
hospitalizations and outpatient department visits. 
(Text Abridged.) 



110. MULTI-DHUG THEBAPY IN LEOKEHIA 
Eahim, B. A., Dacca Medical Coll. Hospital, 
Radiotherapy Unit, ug E, Azimput Govt. Estate, ■ 
Famna, Dacca, Bangladesh, 

OBJECTIVE: To evaluate the effectiveness of 
■ultiple anticancer drugs (six) in leukemia. 

PEOGEESS: 17 (seventeen) cases of leukemia 
have been collected in the series. This study 
Hill continue. 

Drugs used for leukemia: lEVSnp- - Leunase 
plus Endoxan plus Vincristine/Vinblastine plus 
Adriamycine plus Mitomycine plus Prednisolone 
(Endoxan is used last of all). This is part of a 
broader project. (Text Abridged.) 



111. PHASE II STUDY OF 5-AZftCYIIDINE ALONE OH IM 
COBEINATION BITB DAUNOEUBICIN IN ACUTE LEUKEHIAS 
Firat, D., Kucuksu, N. , Tekuzman, G. , Hacettepe 
University, Oncology, Ankara, Turkey 

PATIENT ENTRY CEITZEIA: Patients with acute 
non-lymphoblastic leukemias and with acute 
lymphoblastic leukemias resistant to prednisone 
and Oncovin are included in this study. 

TEEATHENT SCHEDULE: 2-drug combination 
chemotherapy with 5-Azacytidine and Daunorubicin, 
vs. single-agent chemotherapy with 5-Azacy t idine. 

The patients with acute lymphoblastic 
leukemias known to be resistant to the combination 
of steroids and Oncovin, and patients with acute 
non-lymphoblastic leukemias are randomly given 
either 5-Azacytidine 200-300 mg/m2 IV in 3 divided 
doses daily for 5 days or 5 Azacytidine 150-200 
lig/m2 H plus daunorubicin 15-25 mg/m2 IV daily 
for 5 days, repeated every 3 weeks depending or 
blood counts until complete remission or resist- 
ance or prohibitive toxicity. The patients in 
complete remission are put on a maintenance 
chemotherapy using 6-mercaptopur ine orally and are 
given prophylactic CNS irradiation. The major 
criteria for complete remission ate normal and 
peripheral blood smears and less than 5X blasts in 
the bone marrow. Patients with normal peripheral 
blood smears and over 5* blasts in bone marrow, 
are considered to have a partial response. 

Eight patients have been entered into this 
study to date. Two complete remissions for non 
lymphoblastic acute leukemias have been obtained. 
Ve are anticipating the inclusion of 25-30 
patients within 18-21 months, into this study. 



Bottomley, R. H., Hampton, J. W., Grozea, P. N., 
Boge, A. I., Ishmael, D. E., Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N. E. 13th St., 
Oklahoma City, Oklahoma, 7310U, U.S.A. 

OBJECTIVES: To determine the effectiveness of 
5-A2acytidine in the treatment of acute leukemia. 
(Text Abridged.) 



114 3. AZACYTIDINE THEBtPY OF PREVIOUSLY TREATED 
ADULT LEUKEBIA 

Levi, J. A., Uiernik, P. H., U.S. Dept. of Hlth. 
Ed. 6 Kel., Natl. Cancer Institute, Medicine 
Section, Baltimore, Maryland, U.S.A. 

The results of this study indicate that 
Azacytidine is a useful drug for the treatment o 
previously treated and relapsed patients with 
acute nonlymphocy tic leukemia. In such patients 
approximately 30X complete remission rates can b 
expected with this drug. Guanazole was shown to 
have no significant activity in such patients. 



Levi, J. A., Wiernik, P. H., U.S. Dept. of Hlth. 
Ed. 6 »el., Natl. Cancer Institute, Medicine 
Section, Baltimore, Maryland, U.S.A. 

In this study, methyl GAG was added to 
5-Azacytidine for induction therapy of patients 
With acute nonlymphocy tic leukemia who have becom 
refractory to more standard agents. It was 
determined that the addition of methyl GAG added 
nothing to the activity of 5-Azacytidine. 



115. PHASE II - AZACYTIDINE IN PATIENTS WITH ACUTE 

LEOgEMIA 

Saiki, J., McCredie, K., Sclidoro, A., Vallejos, 

C, Southwest oncology Group, Suite 20 1, 3500 

Rainbow Blvd., Kansas City, Kansas, 66103, U.S.A. 

PROTOCOL ENTRY CRITERIA: Patients with a 

ineligible for, or who have relapsed on, a 
leukemia protocol of higher priority. 

PURPOSE: To determine the effectiveness of 
5-Azacytidine in the treatment of acute leukemia. 

DOSE SCHEDULE: 5-Azacytidine 750 mg/m2 in a 
single dose. 

■CURRENT STATUS: Active. 

APPROXIMATE NUMBER OF PATIENTS: 20. 
■ DOSAGE F03M: 5-Azacytidine 500 mg vial. 
(Text Abridged.) 



116. PHASE I-II STUDY OF 5-AZACYTIDINE (5-AZACR) 
IN THE TREATBENT OF LEUKEMIA A H D SOLID TUMORS 
Krakoff, I. H., Tan, C, Memorial Hosp. for Can. 6 
Dis., Medicine, 1275 York Ave., New York, New York 
10021, U.S.A. 

OBJECTIVE: To evaluate the human toxicity 
and therapeutic effectiveness of 5-azacytidine. 

APPROACH: 5-azaCR will be given to children 
and adults with acute leukemia and other far- 
advanced, non-resectable malignant neoplastic 
diseases not amenable to conventional therapy. 
The initial dose in these studies, based on data 
supplied by Karon and Ueiss, will be 2mg/kg/d 
times 10 days :.V. push. Depending on the 
response, different doses and schedules may be 
used. 

The principal toxicity is expected to be 
hematologic and will be monitored by bone marrow 
examination and daily blood counts. In addition, 
liver function tests, BUS, uric acid and urinal- 
ysis will be done before, after and twice weekly 
during each study. 

BACKGROUND: 5-azaCR is effective against 
ascitic L1210 leukemia in mice. The best dose 
schedule has been single daily doses for 5 or 10 
days. Toxicity in animals has been largely to th 



144 



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bone larrow and liver. There were miniual effects BEDSIDE OBSERVATION: Ordinarily no special 

on the liver. This has also appeared to be the nursing care is necessary unless it is required by 

case in the early trials reported by Karon and by the patient's general condition. In special 

lejss. circuBstances, arrangements for closer supervision 

Hill be made by the physician in charge. 

FOLLOW-UP STUDIES: Chemistry routine, 

1147. SBG 920 - G-nP. VIHCEISTIHE. METHOTBIXITE AMD hematology routine, serum fibrinogen and L- 

PSEDHISOIIE (POBP) 111 ACUTE LEUKEdlA asparaginase levels, certain transplanted rodent 

BottoBley, R. H., Hanpton, J. k., 3rozea, P. N. , leukemias and tumors, primary dog lymphomas and 

Hoge, A. f., ishmael, D. B., Hussein, K. K., acute leukemia in man. The cells of leukemias^ tnat 

Oldhan, F. B., U.S. Veterans Administration, '' " ~" """ 

Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 73104, U.S.A. 

BACKGROUND: The combination of 6-nP (Purinet- 
hol) , Vincristine (Oncovin), Bethotreiate and 
Prednisone (POOP) has been used by the 3BCCSG 
since 1966. The rationale for the use of this 
Bodalitv of therapy vas based on the assumption 

that combinations of agents with anti-leukemic 150. CHRONIC LIBPHOCTTIC LEUKEBIA IHBBAPY WITH 

effect would result at least in additive effect in CHLOBABBUCIL A»D P?.EDNI50;IE AND SUBSEQU ENT THEStPt 

terms of ability to induce remission. It was also OF RESPONDEHS OR NOSPESPOKDEES 

anticipated that this combination of agents with Yam, L. I., U.S. Veterans Administration, Hospital, 

qualitatively different toxicity would result in Section of Hematology oncology, ooa Zorn Ave., 

less degree of limiting toxicity for the host. Louisville, Kentucky, 40202, U.S.A. 

The analysis from the results in 123 patients 
treated from 1966 through 1971 with the POBP study The most commonly used treatment is Chlo- 

has demonstrated the assumptions to be correct. rambucil in a small dose daily. Tne combination 

Consequently, this revised protocol intends to of Chlorambucil ad Prednisone has been shewn to be 

eaphasize the doses that are recommended for the better than chlorambucil alone. Preliminary 

continuation of the POBP study. (Text Abridged.) studies done by the Southern Ca 

shown that chlorambucil is less 
a larger dose every two weeks. -he aim of this 

1U8. BETHOIREXATE, ONCOVIN, L- ASPARAGINASE, AND study is to try to produce more complete remiss- 

DEXABETHASOME THERAPY FOR ADULTS iilTH ALL ions and then to observe whether the good effects 

Esterhay, E. J., Smyth, A. C, wiernik, P. H., last a Icng time. Initially, patients with CLL 

O.S. Dept. of Hlth. Ed. 6 wel., Natl. Cancer will be treated with intermittent chlorambucil- 

Institute, aedicine Section, Baltimore, Haryland, Prednisone in high uosages. Patients^responding 
U.S.A. " " " "" ' " 



to this treatment regimen will be randomized and 
treated either with the same regimen or with 
The purpose of this project is to improve the Cytoxan-Cy tosar . P'^'-^ents who donot respond to 



remission induction rate of acute lymphocytic Chlorambucil-Prednisone will be treated 

leukemia in adult patients utilizing vincristine Cytoxan and Cytosar. All the drugs proposed to be 

and deiamethasone with intermittent moderate doses used in this study have been used for CLL and will 

of methotrexate followed by L-asparaqinase. The be obtained through the Pharmacy at the Vf. 

second objective is to determine whether inte- Hospital. 

rmittent high dose methotrexate with leucovorum 

nrolonq^remission^duration. The third objective 151. HIGH DOSE 6-HEBCAPTOPDBIN E THERAPY FO R 

is to de-ermine the efficacy of moderate and high ADVANCED, BEFBACTOBY NEOPLASTIC DISEASE 

dose methotrexate in preventing meningeal leukemia Esternay, R. J., Aisr.er, J., Levi, J. A., iiiernik, 

and to correlate the clinical effectiveness with P. H., U.S. Dept. of Hlth. Ed. £ .el., Nati. 

the cerebrospinal fluid methotrexate levels. To Cancer Institute, Bedicine Section, Baltimore, 

date, no previously untreated patients have been Haryland, U.S.A. 

entered onto this study. Five previously treated .,»..- ^„. „„.= .- = 

patients have been entered on the study. Two There are few protocols that incorporate 

patients achieved a complete remission after one 6-Bercaptopurine at a dose level of 1.0-5.0 to the 

course, one patient obtained a partial remission 3rd power mg/B other than those tnat have been 

after three courses, and two patients are too used to treat acute lymphocytic leukemia in 

early to evaluate (they both have started their children and acute nonlymphocy tic leukemia in 

first course of therapy). adults. In such studies, count suppression, 

nausea and vomiting and moderately severe mucos- 
itis and stomatitis have occurred. 6-mercapto- 

149. CLINICAL TRIAL OF L-ASPABAGINASE purine has not been tested clinically as a single 

Krakoff, I. H., Clarkson, B. D. , Ian, C. , Gee, T. agent in high doses with respect to its antitumor 

S., Oettgen, H. F., Leeper, R. , Burphy, B. L. , effect. The objective of this study is to examine 

lalla', L., Biller, D. G. , Old, L. J., Boyse, E. the antitumor effect of high dcse 6-mercaptopur ine 

A., Campbell, H., Bemorial Hosp. for Can. 6 Dis., in a broad spectrum of disseminated refractory 

Hedicine, 1275 York Ave., New York, New York, neoplastic diseases. This is a Don-rand""i '<"i 



10021, U.S. A 



udy and all patients received high dose 6- 
•ercaptopurine 1.0 to the 4th power mg/H per day, 
OBJECTIVE: To'~evaluate the therapeutic given byrapid IV infusion on^thefirst^five days 



effect of L-asparaginase in patients with acute of each 21 day course. As of February, 1976, 20 

!e»ke.ia: lymphoma'and solid't umors. patients have been entered into this study The 

APPROACH: 1) Skin test: 0.5 lU (dilution of have been no complete responses and there have 

1:100 in saline of the asparaginase solution to be been no partial responses. Four patients, all 

used for the treatment of the patient) are had breast cancer, had objective responses (a 

injected intrader mally. If this test is negative response less than a partial response) , two 

after 30 minutes, L-asparaginase will be administ- patients, both with lung cancer, had stabilizat 

ered. 2) Dose schedule: L-asparaginase will be or no change in their disease and they had four 

administered i.v. for 28 consecutive days in doses more courses of therapy. None of the 20 patien 

of 200-5000 lU/kg daily. If therapy is interra- entered on this study are alive at this time. 

pted for three or more days, desensitiza tion Hematologic toxicity was uniformly severe with 
(according to 
out before therapy 



3l) must be carried count suppression occurring in all patients; 

addition, nausea and vomiting occurred '- -^ 



POSSIBLE SIDE EFFECTS: Fever, nausea, patients as well as moderate to severe mucositis 

woBiting, weight loss, mild anemia, abnormalities and stomatitis. 
o£ liver function tests, hypol ipidemia , hyperlipi- 
deaia, allergic reactions, acute pancreatitis. 



L4S, 



152. ODBIAHICm, VINCBISTIIIE >ND PBEDmSONE III 
ACnTE tinPHOCYIIC LEUKEnlAl 

Eottomley, R. H., Hanpton, J. u., Grozea, P. H. , 
Hoge, A. F., Ishmael, D. ?. . , Hussein, K. K., 
Oldhaa, F. B., U.S. Veterans Administration, 
Hospital, Heoatol Oncol Sects, 921 N.E. 13th St.. 
Oklahoia city, Oklahooa, 73101, U.S.A. 

OBJECTIVES: To evaluate the effectiveness of 
hydroxyldaunomycin (Adrian ycin) , vincristine 
(Oncovin) and prednisone in the induction of 
te»ission in acute lymphocytic leuHemia (ALL) in 
•dults. To evaluate the following remission 
■intenance program: Daily 6-nercaptopur ine and 
weekly methotrexate, plus periodic reinforcement 
with prednisone and vincristine. Semission 
Induction: Adriamycin 75 mg/H2 I.V. on day 1 and 
day 15; Vincristine l.i4 mg/n2 :.V. on days 1, 8, 
15 and 22 (naximum: 2 mg per dose) ; Prednisone HO 
«/B2/day P.O. for 28 days (tapering to zero during 
fifth week). After bone marrow aspiration on day 
28, patients not showing complete remission will 
receive a further treatment: Adriamycin 75 iig/n2 
on day 29; Vincristine 1 ag I. v., days 29 and 36; 
Continue predinisone, «0 my/n2 per day until day 
12, after which time the dose will be tapered to 
zero over two weeks. In this group of patients, 
if the bone marrow does not show complete remis- 
sion day 12, the patients will be removed from 
study. Those showing complete remission will 
enter the maintenance lioD of the trial. 



153. STUDY OF ADR IAWYCIH IN ADVAilCED LEUKEMIAS. 
lIHPHOnAS AND OT I JEH BEIASIATIC WALmilAKCIES 
Burkett, L. L., Heely, c. L., U.S. Veterans 
Adsinistration, Hospital, Hematology Service, 1030 
Jefferson Ave., nemphis, Tennessee, 381)5, U.S.A. 

The purpose of this study is to further 
define the spectrum in effectiveness of the newer 
anti-tumor agent, adriamyci 
response in patients witn a 
malignant disease not responsive to conventional 
therapy, and hopefully to prolong the life and 
improve the quality of life of patients with these 
nalignancies. 

Patients selected for this therapeutic 
program will include carcinoma of the thyroid, 
hepatoma, sarcoma, and carcinoma of the lung, and 
patients with responsive neoplasms wnich have 
become refractory to standard therapy, including 
lymphomas, acute leukemia, melanoma, ovarian 
tUBors, and carcinoma of the head and neck. 
Patients with histologically proven diagnoses, and 
a measureable lesion will be treated with a 
regimen consisting of adriamycin -- 75 mg/m2 iv., 
repeated every 21 days if side effects permit, for 
treatment totaling a dose of 525 mg/m2. 

Patients achieving this therapeutic goal will 
be evaluated for toxicity, objective response, and 
duration of response ic protocol on adriamycin. 



in producing 



15t. SBG-5145/576 - STUDY OF BUSULFAK IN CHBON IC 

GBANOLOCYTIC LEUKEHI A 

Bottomley, R. H., Hampton, J. v., Grozea, P. N., 

Hoge, A. p., Ishmael, D. B., Hussein, K. K. , 

Oldham, F. B. , U.S. Veterans Administration, 

Hospital, Hematol Oncol Sects 

Oklahoma City, Oklahoma, 7310 

Busulfan (Myleran, HSC-750) is the most 
widely used chemotherapeut ic agent in the treat- 
sent of chronic granulocytic leukemia. It is 
effective for initial remission induction in the 
previously untreated patient. The optimum scheme 
for maintenance therapy with busulfan has not bee 
delineated. Intermittent treatment, administered 
only upon relapse, and continuous therapy have 
both been advocated. Certain complications, 
including pulmonary fibrosis, Myelofibrosis and 
terminal myeloblastic transformation of the 
disease have been associated with ousulfan 
therapy, although the e;;act relationship of these 
complications specifically to intjtmittent or 
continuous treatment is :iot known. This study is 
designed to evaluate and cospare intermittent and 
continuous remission-maintenance tnerapy witn ora 



busulfan in chronic granulocytic leukemia. 
Special attention is devoted to (1) the magnito 
of iaprovement achieved; (2) the duration of 
reeissions induced; (3) the ease of patient 
lanagement; («) the number and type of complic- 
ations of the disease and/or therapy; (5) Icnge 
vity of treated patients; and (6) the freguency 
with which myeloblastic termination occurs. In 
addition, ancillary studies will be done regard 
serum vitamin B12 level, serum E12 binding 
capacity, leukocyte alualine phosphatase, and 
karyotype with reference to outcome in the two 
treatment groups. 

At present this project is ongoing but is 
closed tc new patient entries. 



155. CLmiCAL AND HEUATOLOGIC STUDIES OF IR KAD- 
lATION - CLimCAL AND LABOBATORY CHANGES tPTFlR 
TOIAL-BOCY IRRADIAIION 

Edwards, C. L., Vodopick, H. A., Goswitz, f. A. 
Hubner, K. F. , Oak Eidge Associated Univs., 
Bedical Division, Box 117, Oak Bidge, Tennessee 
37830, U.S.A. 

This study is directed at developing bette 
methods of therapy of malignant diseases of the 
blocd or bone marrow with total-body irradiatic 
Coincidentally important information is obtaint 
to more precisely define man's response to 
radiation at different dose rates for assessing 
and treating accidental radiation injury. 
Principal exposure rates of 0.8 R per hour, 1.5 
per hour, and 1.5 B per minute have been used. 

doses of 50 to 250 B or in daily fractions of 1 
or more per day. 

RESULTS: Total-body irradiation (TBI) 
appears to ^e an effective and well-tolerated 
treatment for chronic leunemia and polycythemia 
vera. The lower dose-rates are better tolerated 
because the gastrointestinal symptoms are less. 
Other than the residual effect of the lower dos 
rates on the platelet count .of patients with 
chronic granulocytic leukemia (CGL) , no decided 
effect of dose rate on the hes-.atoloy ic response 
radiation was seen. Survival rates of patients 
with CGL treated with TBI are comparable tc tho 
treated with drugs. dost of the patients aie i 
terminal blastic phase of their disease. 



UKEHIA With 



156. THERAPY OF LYMPHOBLASTIC 
ACCOHPANIED IPRADIAIlOil TO C! 
Velez, 3., Univ. of Puerto =ico. 
Medicine, P.O. Box 5067, San Juan 
00936 

Thi 



157. NEB COHBINATION CHE M OTHERA PY OF ACUTE 
LEUKEHIA - 5YSTEI1ATIC EXA'mI NAT ICN OF NE W D°') r 
COHBINATION HITH EXISTING THERA PY 
flcCredie, K. , Gutterman, J. u., freireich, E. 
Bodey, G. P., Univ. of Texas, B.D. Anderson •; 
6 Inst., Developmental Therapeutics, P.O. aox 
20035, Houston, Texas, 77025, U.S.A. 

OBJECTIVE: To develop techniques for 
inducing .-emission in more than 50* of adults 
acute leukemia. 

PROCEDURE: 1) By invest iaations of new 
agents. 2) studies of combination chei.otnora 
3) Alteration of therapy techniques such as n 
and schedule of treatment. 

PROGRESS: The combination of intensive 
chemotherapy, the utilization of the protec-.-- 
environment, prophylactic antibiotics, blood 
component therapy, tne early i ntroduct icr; c :' 
immunotherapy combined with cnemot nerapy , ar.i 
application of the therapy of cell kinetics " 
late intensification in those pati-;nts ■i:.th 
long-term maintained complete remission, ha.. 
significantly improved tne outicck to tne poi 
that in the future we will be looking at coii. 

30* of all patients. 



146 



158. PHASE I IHD II STUDY OF 1-HYDROPEBOlllfISOPHOS- 

PHAHIDE 

Ota, K., Ogawa, B. , Aichi Cancer Research Center, 

Rediclne, 81 1159 Kan.oleoden lashircho, Chikusa-ku, 

Nagoya, Aichi, Japan, 464 

U-hydroperoxyisophosphamide (HOI 97- S, 
IISC-22711U) , synthesized in the Shionogi Research 
Institute, is an active forn of ifosphamide 
(Z<l9it2) and has strong antitumor activity against 
11210 leukemia and Voshida sarcoma. It has no 
cross resistance to cyclophcsphamide in Yoshida 
sarcoma. Phase I and II study of this compound 
have been performed. 



159. THE STUDY OF CHRONIC LYHPHOCYTIC LEaKEHIA 
Johnson, R. E., Ruhl, U., U.S. Dept. of Hlth. Ed. 
t Hel., Natl. Cancer Institute, Radiation oncology 
Branch, Bethesda, Maryland, 20014, U.S.A. 

This is a long term, comprehensive study of 
the natural history of chronic lymphocytic 
leuXenia and includes efforts to develop effective 
■eans of treatment for patients in the "active" 
phase of disease. 



3. OTHER THERAPY OF LEUKEMIA 



VOTE: Each of the following projects is part of a 
broader clinical program. Summaries of these 
subprojects are not available. 



160. D.D.n.P. FOB HEHINGEAL 1EUKEHIA 
Stickney, D. S., Duke University, School of 
Hedicine, Surgery, Box 3711, Durham, North 
Carolina, 27706, U.S.A. 



161. TBEATBEHT OF lEUKEMIC ASCITES 
Baddell, U. R., Univ. of Colorado, School of 
Hedicine, nedlcine, 4200 E. 9th Ave., Denver, 
Colorado, 80220, U.S.A. 



162. ADRIAHYCIH THERAPY IN ACUTE LEUKEHIA 
Pearson, H. A., Yale University, School of 
Hedicine, Pediatrics, 333 Cedar St., New H 
Connecticut, 06510, U.S.A. 



Beard, V. S. , Univ. Hospitals of Cleveland, 
Hedicine, 2065 Adelbert Rd., Cleveland, Ohio, 
111106, U.S.A. 



leu. (COMBINATION 1- ASPARAGINASE- VINCRISIINE- 
DAUNOMYCIN-PREDNISONE IN PREVIOUSLY TREATED 
PATIENTS WITH ACUTE LEUKEMIA) 
Binder, R., Georgetown University, School of 
Hedicine, Medicine, 3900 Reservoir Rd. N.K., 
Bashington, District of Columbia, 20007, U.S.A. 



165. L-ASPARAGINASE THERAPY FOB ACUTE LYMPHOBLA- 
STIC LEUKEMIA 

Pearson, H. A., Yale University, School of 
Hedicine, Pediatrics, 333 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 



166. L-ASFARAGIIIASE IN ACUTE LEUKEMIA 
Velez, E., Univ. of Puerto Rico, Schoo 
Hedicine, P.O. Box 5067, San Juan, Pue 
00936 



168. ADULT ACUTE IIHPHOBLASTIC LEUKEMIA 
Omura, G. A., Univ. of Alabama, School of Medicine, 
Hedicine, 1919 7th Ave. S., Birmingham, Alabama, 
35233, U.S.A. 



169, 5-DAY INFUSION OF 5-AZACYTIDINE IN ADVANCED 
CAHCER AND ACUTE LEUKEMIA 

Oaura, G. A., Univ. ox Alabama, School .of Hedicine 
Hedicine, 1919 7th Ave. S. , Birmingham, Alabama, 
35233, U.S.A. 



170. 5-DAY INFUSIONS OF 5-AZACYTIDINE IN ADVANCED 

CANCER AND LEUKEMIA 

Miller, D. S., Duke University, School of Medicine 

Surgery, Box 3711, Durham, North Carolina, 27706, 

U.S.A. 



171. 5-AZACYTIDINE — NEH AGENT FOR TREATING ACUTE 

LEUKEMIA 

Nesbit, M. E. , Univ. of Minnesota, School of 

Medicine, Pediatrics, 1305 Mayo, Minneapolis, 

Minnesota, 55455, U.S.A. 



172. BETA-DEOXYTHIOGOAHOSINE IN REFRACTORY ACUTE 

LEUKEMIA 

Hiller, D. S., Duke University, School of Medicine 

Hedicine, Box 3711, Durham, North Carolina, 27706, 

U.S.A. 



173. BETA-DEOIIIHIOGUAHOSINE III ADULT ACUTE 

lEUKEHIA 

Onura, G. A., Univ. of Alabama, Scnool of Hedicin 

Hedicine, 1919 7th Ave. S. , Birmingham, Alabama, 

35233, U.S.A. 



171. EFFECT OF CYTOSINE ARABINOSIDE AND THIOGUA- 

KINE IN GRANULOCYTIC LEUKEMIA 

Hiller, D. S. , Duke University, School of Medicin 

Surgery, Box 3711, Durham, North Carolina, 27706, 

U.S.A. 



175. THIOGUAN I NE. CYTOSINE ARABINOSIDE, DAOSOHTCIN 
It LYMPHATIC LEUKEMIA 

Puerto Rico, School of 



Velez, E., Uni 

Medicine, P.O. 
00936 



167. THERAPY OF PBEVIOOSL Y 
ITHPHOCYIIC LEUKEMIA 
Velez, E., Univ. of Puerto 
Hedicine, P.O. Box 5067; sa 
00936 



NIREATED ACUTE 



176. SEQUENTIAL DAUNOHYCIK AND CYTOSINE ARABINO- 
SIDE IN ACUTE LEUKEMIA 

Omura, G. A., Univ. of Alabama, School of Medici 
Hedicine, 1919 7th Ave. S., Birmingham, Alabama, 
35233, U.S.A. 



177. CYTOSINE ARABINOSIDE IN TREATMENT OF ACUTE 

LEUKEMIA 

Cartwright, G. E., Univ. of Utah, School of 

Hedicine, Internal Medicine, 1400 E. 2nd S., Sal 

Lake City, Utah, 84112, U.S.A. 



178. CYTOSINE ARABINOSIDE LEUKEHIA THERAPY 
Moreno, H. , Univ. of Alabama, School of Medicine, 
Pediatrics, 1919 7th Ave. S., Birmingham, Alabama 
35233, U.S.A. 



179. DAUNOBYCIN IN TREATMENT OF PATIENTS BITH 

LEUKEMIA 

Quagliana, J. M. , Univ. of Utah, School of 

Hedicine, Internal Medicine, 1400 S. 2nd S. , Salt 

Lake City, Utah, 84112, U.S.A. 



180. EFFECT OF DADNORUBICIN Oil ACUTE LEUKEMIA AND. 
SOLID TUMORS 

Los Angeles Co. Karb. G. Hosp., 

Torrance, California, 90509, 



Bollinger 

1000 W. Carson St 

U.S.A. 



147 



181. COAP IH ACOTE BYEIOCYTIC LEUKEWIA 
?elez, E., Univ. of Puerto Rico, School of 
Bcdicine, P.O. Boi 5067, San Juan, Puerto Eico, 
00936 



182. TREAinEHT OF MIELOeLASTIC LEUKEHIA 
Kellernieyer, p. v., Univ. Hospitals of Cleveland. 
Hedicine, 2065 Adalbert 5d.^ Cleveland, Ohio, 
414106, U.S.A. 



183. CHEBOTHESAPI FOB MOW-LIBPHOCYTIC LEUKEHIA 
Bloomfield, c, Univ. of ninnesoxa. School of 
Hedicine, Medicine, 1J05 Mayo, Minneapolis, 
Hinnesota, 55155, U.S.A. 



184. ACUTE GBAKULOCYTIC LEUKEHIA IH THE EIDEBLY 
Bloonfield, C, Univ. of Hinnesota, School of 
Hedicine, Hedicine, 1305 Hayo, Hinneapolis, 
Hinnesota, 55u55, U.S.A. 



185. ADPLT ACUTE HYELOGEKOOS LEUKEHIA 
ODUra, G. A., Univ. cf Alabama, School of Hedici 
Hedicine, 1919 7th Ave. S., Birmingham, Alabama, 
35233, U.S.A. 



186. TBEBAPY OF ADULT ACUTE HYELOGEKOUS LEUKEMIA 
Bloonfield, C, Univ. or Minnesota, School of 
Hedicine, Medicine, 1305 Mayo, Minneapolis, 
Hinnesota, 55155, U.S.A. 



187. TREATBEHI OF ACUTE HYELOBLASTIC LEUKEHIA 
Hiller, D. S. , Duke University, School of Hedici 
Surgery, Box 3711, Durham, North Carolina, 27706 
U.S.A. 



188. TOTAL THERAPY OF CHBONIC GBANULOCYTIC 

LEUKEHIA 

Velez, E., Univ. of Puerto Bico, School of 

Hedicine, P.O. Eoi 5067, San Juan, Puerto B 

00936 



189. SE QUEHTIAL THEBAPY OF ACUTE LYHPHATIC 
LEUKEHIA IN ADULTS 

Bloomfield, c, Univ. of Hinnesota, school of 
Hedicine, Hedicine, 1305 Hayo, Hinneapolis, 
Hinnesota, 55155, U.S.A. 



i. COMPLICATIONS AND SIDE EFFECTS OF LEUKEMIA AND 
LEUKEMIA THERAPY 



190. PSYCHOLOGICAL ADAPTATIOHS TO CHILDHOOD 

LEUKEMIA 

Harten, G. K. , Powazelt, H., Goff, J. B. , Paulsen, 

H. A., Schyving, J., St. Jude Ch. Ses. Hosp., 332 



treatment outcoDe. 

Phase II of the study Kill consist of a 
coBtpariscn of treatment intervention modalities 
Kith the aid of determining the differential 
effectiveness of several remediation techniques 
Kith the aim of facilitating the psychological 
adjustment of leukemic children and their famil- 
ies. 



191. PSICHOLOGICAL EFFECTS CF CBANIAL IBPADIATIOM 
Harten, G. w. , Ponazek, n. , Pitner, s. E. , Goff, 
J. P., St. Juda Co. Pes. Hosp., Psychiatry Service, 
Bol 318, 332 N. Lauderdale St., Memphis, Tennessee, 
38101, U.S.A. 

Prolonged remissions of childhood acute 
lymphocytic leukemia are often terminated by 
central nervous system relapse of the disease. 
The use of 2100 rads of cobalt-60 craniospinal or 
cranial irradiation plus intrathecal methotrexate 
shortly after the initial hematological remission 
vas found to decrease considerably the incidence 
of central nervous system complication. Because 
children with leukemia now survive for many years 
and because the long-term effects of such inten- 
sive radiotherapy are unknown, a long-term study 
was planned by us to determine the neuropsych- 
ological effects of such therapy on relatively 
normal central nervous systems of children with 
leukemia. Serial neurological and psychological 
examinations were started in 2 groups of such 
children. In a retrospective study, 11 children 
Kith acute lymphocytic leukemia who received 2100 
rads of prophylactic craniospinal irradiation were 
compared with 12 children with the same illness 
who did not receive irradiation during initial 
treatment. In a prospective study, 31 acute 
lymphocytic leukemia patients receiving cranio- 
spinal irradiation or cranial irradiation plus 
intrathecal methotrexate were compared with a 
group of 27 children with solid tumors who 
received irradiation to parts of the body ether 
than the cranium. 

The objective of the repeated neurological 
and psychological examinations before irradiation 
and at intervals for several years after irrad- 
iation is to determine ppssible changes in 
intelligence, scholastic achievement, perceptual 
motor functioning and emotional adjustment. 



192. PATHOLOGIC STUDIES OF CNS LEUKEHIA IH 

CHILDHEN 

Price, B., St. Jude Ch. Res. Hosp., Pathology, Box 

318, 332 N. Lauderdale St., Memphis, Tennessee, 

381C1, U.S.J. 

The objective of this study is to determine 
the long-term effect of leukemia and therapy on 
the brain. The approach includes gross and 
histological examination of this organ removed at 
the time of autopsy. The results of our initial 
study are reported in CANCER, March 1973 and 
CANCER, Feb. 1975. 



Increased survival rates for children with 
leukemia have resulted in growing concerns about 
the effects of diagnosis and treatment upon the 
psychological well-being of the child with 
leukemia and his family. Ihe psychological status 
of the child, his parent, and the nature of the 
relationship between them has a great influence o 
the quality of the patient's life. Although it 
has long been assumed that psychological factors 
are an important area for investigation, there is 
a paucity of systematic research in the area. 

This research consists ot two phases to be 
carried out consecutively. The aims of Phase I 
are: (1) the development of reliable and valid 
methods for the early identification of psych- 
ological "high-risk" children and mothers, (2) a 
systematic examination of parent-child relatio- 
nships throughout the diagnosis and treatment 
periodsv and (3) an analysis of the inter-reiatio 
nship of parental adjustment, patient adjustment, 
mother-child relationship factors, and medical 



193. BRAIN NECROSIS AFTER RADIATION FOR ACUTE 
LYHPHOELASIIC LEUKEMIA 



a, Scho 
a polls. 



il of Medicine 



is part of 
ubproject is 



191. CLINICAL AND HEHATOLOGIC STUDIES OF IRRA D- 
IATION - CYTOKINETIC STUDIES OF THE EFFECTS OF 
TOTAL BODY lERADIATION 

Vodopick, H., Goswitz, F. A., Oak Ridge Associated 
Univs. , Medical Division, Box 117, Oak Ridge, 
Teinessce, 37830, U.S.A. 



The object of these studies 
the mechanism underlying the effe 
irradiation (TBI) on the hematopo 
Depending upon the dose of irradi 
white blood cell count and platel 



LS to 



rstand 
of total-body 
ic system. 



148 



Tbe in vivo disappearance of radioactively*labeled 
blood cells and the sites of their sequestration 
can be nonitored. Cytottinetic studies on patients 
■ith nyeloproliferat ive disorders after total-body 
irradiation suggest that the initial changes seen 
in the hematopoietic system are due to reduced 
input of new cells from a precursor pool. Why the 
white blood cell count should remain suppressed 
for months in some patients given TBI led us to 
search for another mechanism of hematopoietic 
control, A circulating humoral factor called 
chalone has been postulated as a regulator of 
■arrow proliferation. He are currently trying to 
find such a substance in the granulocytes of 
normal human volunteers and will then extend out 
studies to patients with myeloproliferative 
disorders who are treated with TBI. 

Lymphocytes from patients with chronic 
granulocytic leukemia will be studied in vitro to 
determine the effect of irradiation given to them 
at different doses and dose rates. Such data may 
be useful in predicting response of patients with 
chronic lymphocytic leukemia to radiation therapy. 

RESULTS TO DATE: Extracts from normal human 
granulocytes fractionated on Sephadex G-50 have 
caused decreased utilization of tritiated thymi- 
dine by rat marrow precursors, other studies of 
the properties of these extracts are now in 
progress. 



Craddock, C. G. , Ossorio, B. C, Tourtellotte, v., 
Oniv, of California, School of Medicine, Medicine, 
H05 Hilgard Ave., Los Angeles, California, 90024, 
D.5.A. 

OBJECTIVE: a) To assess the effects of 
certain chemotherapeutic regimens on marrow 
function. b) To assay cerebrospinal fluid from 
patients receiving prophylactic treatment for 
■eningeal leukemia, c) To assess marrow cellular 
levels for adriamycin and cytotoxic products 
thereof. 

APPROACH: a) Patients with normal hemopoi- 
esis and solid tumors receiving various forms of 
cancer treatment are assessed as to bone marrow 
function and histology. Particularly patients 
receiving the adjuvant C, parvum with adriamycin 
are assessed for marrow cytology and colony 
formation in culture, b) A bioassay for levels of 
cytosine arabinoside is being applied to the 
spinal fluid of subjects with acute leukemia 
receiving this agent for CNS prophylactic trea- 
tment, c) Marrow from rabbits and humans recei- 
ving adriamycin is being assayed for detectable 
cytotoxic amounts of the drug or its myelotoxic 
products, using a mouse marrow bioassay, 

PPOGRESS: Bone marrow removed from four 
patients with solid tumors who received C. parvum 
alone for non-specific immunological enhancement 
showed marked reduction in colony-forming capac- 
ity. Patients who received adriamycin alone also 
showed reduction. The same patients receiving 
both agents showed no reduction in colony form- 
ation. 



196. lEDKEaiA CHEHOTHERAPY AND NEUTROPHIL DYS- 
rUNCTION 

Craddock, P. R,, Jacob, H. S., Univ. of ninnesota. 
School of Medicine, Medicine, 1305 Mayo, Minne- 
apolis, Minnesota, 55455, U.S.A. 



These studies basic 
adhesion, motility, de£< 
of normal and abnormal c 
in vitro. The studies < 
the predictable future, 
closely related sets of 

(1) Determination 
acute granulocytopenia i 
occur immediately after 
microtubule inhibitors s 
vinblastine and colchic: 
mechanism and complicat] 
chronic, of hemodialysis 
modi f ication/ob via t ion c 



iluation of 


lenotaicis 


vivo and 


.me, and in 


.nto three 


1 of the 



ally inclade 
rmability an 
canulocytes. 



. (2) Evaluation of t 
s, both acute and 
eukopenia, including 
the leukopenic reac- 



tion. (3) Functional evaluation of granulocytes 
harvested fron donors for leukocyte transfusion 
into patients on high dose anti-leukemic therapy. 
Three methods of cell collection are under study: 
(a) nylon fiber filtration leukapharesis; (b) 
intermttent flow centrif ugation; (c) continuous 
flo» centrif ugation. 

REFEBENCSS: 1) Fehr, J., Craddock, P. a., 
Brighan, K.i., Jacob, H.S.: Pulnonary capillary 
leukostasis: A complement (C) mediated comp- 
lication of hemodialysis. Proc. International 
Soc. Nephrology. 1975 2) Boners, T.K., Craddock, 
P.B., Jacob, H.S.: Complement (C) induced 
granulocyte paralysis due to drug allergy. Clin. 
Res. 23:t89 (1975). 



197. ENIEBOCOI.ITIS ftSSOCHTED BIIH PROLONGED htlX-C 
(CTTOSIHE ARtBINOSinE) IREAIHENI 
Luna, M., Bodey, G. P., Rodriguez, v., Univ. of 
Texas, n.D. Anderson Hosp. e Inst., Pathology, 
P.O. Box 20036, Houston, Texas, 77025, U.S.A. 

OBJECTIVE: To characterize the morphology of 
the enterocolitis associated with prolonged ara-C 
treatment, to evaluate and correlate findings with 
the clinical picture, and to find out if this 
peculiar toxicity is dose related. 

APPROACH: Sixteen patients have been 
observed with clinical evidence of enterocolitis 
vhile under prolonged ara-C treatment for acute 
myelogenous leukemia, and these formed the basis 
for this retrospective clinicopathologic study. 

PSOGBESS: From this histological appearance 
it seems that the pseudomembranous appearance is 
due to a soluble toxin which diminishes in 
intensity as it penetrates the bowel wall. In all 
probability, the changes of pseudomembranous 
colitis can be elicited by a variety of toxins 
present in the lumen when the bowel is rendered 
susceptible by chronic cardio-renal diseases or 
other debilitating disorders. These mechanisms 
appear to be a commcn pathway for the production 
of enterocolitis regardless of the etiological 
agent, further research is planned. 



198. PNEDHATOSIS CISTOIDES IHTESTIHALIS IN 
LIHPHOMA AWO ACUTE LEUKE>IIA 

Humphrey, G. B. , Univ. of Oklahoma, School of 
Hedicine, Pediatrics, 800 N.E. 13th St., Oklahoma 
City, Oklahoma, 7310U, U.S.A. 



This is part of a broader project. A su 
of this subproject is not available. 



ary 



199. HISTOLOGICAL. BIOCHEHIOL AND IllHUNOLOGICAL. 

STUDIES IN PATIENTS HITH ACUTE MYELOID LEUKEMIA 

AND COMPLICATING OBAL LESIONS 

Basu, a. K., Univ. of Birmingham, School of 

Medicine 6 Dentistry, Oral Pathology, St. Chads 

Queensway, B« 6nn, Birmingham, England, United 

Kingdom 

Studies are being carried out on seruo, 
saliva and oral tissues of patients with acute 
myeloid leukemia with a view to understanding the 
pathogenesis of the oral lesions in this coniiit- 



200. BLOOD VISC05ITI FACTORS IN MALIGNANT MELAH- 
OBA, AND CHRONIC AND ACUTE LEUKEMIA 
Dintenfass, L. , Sydney Hospital, Sydney, New South 
Kales, Australia 

OBJECTIVE: (a) To define blood viscosity 
factors (that is, plasma and blood viscosities, 
aggregation and rigidity of blood cells, formation 
and apparent viscosity of artificial red/white and 
white thrombi) in patients with malignant melanoma 
(with metastases or free of metastases) , and with 
chronic or acute leukemia. (b) To define 
correlations between the blood viscosity factors 
and protein levels or ratios, and lipids. (c) lu 
the case of melanoma, to characterize the onset of 
metastasis by abnormality of blood viscosity 
factors. (d) To evaluate drugs which affect 



149 



blood viscosity factors, and to explore effect of 
these drugs on blood flox and tissue perfusion. 

APPROACH: The study is based on methods and 
tecbnic|ues which originated mostly in this 
laooratory, or were specially adapted. The 
folloving i.-istrunents are used: capillary 
Tisconeters; rotational rhombospheroid viscometer; 
variable frequency thromboviscomet er ; filtration 
pressure apparatus; erythrocyte sedimentation 
rates and sedimentation velocities at 20, 37 and 
140 degrees C, using Uestergren tubes, and EDTA 
blood without further dilution; estimations of 
aggregation of red ceils; estimations of rigidity 
of red cell fibrinogen assay; ABO blood group 
determination, etc. 

PROGSESS: So far 120 melanoma patients and 
20 leukemia patients have been studied, with 
results reported at international and national 
conferences and in the Medical Journal of Aust- 
ralia. All patients show abnormal blood viscosity 
factors. nelanoma patients with metastases show 
very significant elevation of plasma viscosity, 
elevation of blood viscosity {when adjusted to 
constant haematocrit) , a decrease of the albumin/- 
fibrinogen ratio, when compared to patients free 
of metastases. Significant differences are noted 
between patients suffering from acute as against 
chronic leukemia in their blood viscosity factors. 



201. OTILIZATIOS OF IBOH IN PATIENTS gITH LtHPH- 

OHAS 

Dealmeida, J. S., Fahel, V. G., Lessa, G. , 

Aristidas Baltez Hospital, ivenida D. Jose Vi-332 

Brotas, Salvador, Brazil 

OBJECIIVES: To learn whether the anemia 
found in patients with lymphomas is due to a 
deficiency in the bone marrow. Examination of the 
patients will be made with re59 before the 
initiation of any treatment. 



202. EVAIUATIOH OF LIVER FUNCTION AND HEPATIC 
FIBROSIS IN LEUKEHIC PATIENTS 

Patterson, S. B., Wake Forest University, School 
of Medicine, Medicine, Box 7323, Saynolda Station, 
Hinston Salem, North Carolina, 27103, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



203. OSTEOPOROSIS ASSOCIATED WITH ACUTE UMPH- 

OBIASTIC LEUKEMIA IN CHILDREN 

Glimcher, M. J., Childrens Hosp. Bed. Ctt., 300 

Longwood Ave., Boston, .Massachusetts, 02115, 

D.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



II. CLINICAL STUDIES OF LYMPHOMAS 



and among social contacts, A variety of assays, 
such as HLA typing, EBV serology, Concanavalin A 
tests of lymphocytes and other assays, are applied 
for evaluating susceptibility to various types of 
lyaphoma. A detailed study on childhood lymphoma 
is performed in order to identify immuno-epidemio- 
logic and laboratory parameters relating to 
Burkitt's lymphoma in Israel, Africa and the 
United States. Especially selected cell lines 
isolated from these lymphomas are characterized 
for markers specific to the lymphomas found in the 
Mediterranean region; these include cell surface 
characteristics, immunoglobulin, cytologic and 
karyctypic markers. 

PROGRESS: Is included in yearly and hal- 
f-yearly progress reports to the N.C.I. A new 
type of malignant lymphocyte was established in 
continuous culture which is the malignant cell of 
non-African, non-EBV genome carrying Burkitt's 
tumor. A diagnostic differential test for 
lymphoma has been developed using fluorescent 
Concanavalin A. 



205. HISTOLOGICAL, ULTRASIRUCTURAL AND IMMUNOL- 
OGICAL STUDIES ON LYMPH MODE LESIONS E0RDE5IiiG 
MALIGNANT LYMPHOMA 

Sucni, T., Sato, 7., Suzuki, R., Shamoto, M., 
Aichi Cancer Research Center, clinical Pathology, 
81 1159 Kanokoden Tasnircho, Chikusa-ku, Sagoya, 
Aichi, Japan, «6i| 

To contribute to making an accurate diagnosis 
in the early phase on the lymph noae lesions of 
eventually fatal outcome, (in whicn the histology 
is not that of outright malignant lymphomas) 
histological, ul trastructur al and immunological 

functional structures of the nodes. 



206. DETERM INATION, IN PEDIATRICS, O F THE EXTENT 
OF CANCER BY MEANS Of LYMPH ADENOGH A?HY 
Papendieck, C. M., Buenos Aires Cniidrens Hos?., 
Surgery, Gallo 1330, Capital Federal, Buenos Aire 
Argentina 



OBJECTIVES: To determine ganglionic (nodal) 

the metastases of tumors in childhood, and the 
retrograde or anterograde spreading of primitive 
tumors of the lymphatic system; by means of 
lymphography, and as complementary information in 
the methodology of study. 

APPROACH: Study of patients from 0-14 
years of age, registered at C.E.T.S.I., with 
tumoral pathology, and with special reference to: 
lymphomas, r haDdomyosarcomas, sympa thicoblastomas, 
Bilm's tumors, sarcomas/carcinomas, in general, 
and teratomas/teratocarcinomas, embryonal car- 
cinomas, with tne following aims: diagnosis, 
differential diagnosis, and diagnosis of the 
degree of extension. 

PROGRESS: Development of transganglion 
lymphography: bi-inguinal, manual and simultane- 
ous. 



A. DIAGNOSIS OF LYMPHOMAS 



201. MOLTIDISCIPLINARY STUDY OF HODGKIN'S DISEASE 
AND OTHER LYMPHOMAS, INCLUPING DEVELOPMEiiT OF 
DIAGNOSTIC lESTS AND MARKER IDENTIFICATION 
Goldblum, N., Hebrew University of Jerusalem, 
Hadassah Medical school, P.O. Box 1172, Jerusalem, 



OBJECTIVE: To investigate, evaluate and 
identify the relative roles played by various 
environmental and hereditary factors in the 
etiology and epidemiology of Hodgkin*s Disease and 
other types of lymphoma with an emphasis on the 
types which are indigenous to the Midule East. 

APPROACH: Includes an epidemiologic study of 
incidence of his-olcgic subtypes, the determina- 
tion of survival of cases of Hodgkin's Disease in 
relation to ethnic groups and evaluation of 
clustering of Hodgkin's Disease in space and time. 



STUDIES AND ELECIRON MICROSCOPY OF L YMPHC 
Bishop, M. B. , Davies, J. N., Vianna7 N. 
Veterans Administration, Hospital, Labora 
e., Albany, New Yo 



Precise diagnosis is an absolute lequireme 
for our ongoing, geographically based, epidemio 
gical studies of lymphoprol if erative discrders. 
This study seeks to obtain better definition of 
cell structure and interrelationships using 
ultrastructural, histochemical and imnunocytolo 
techniques. 

The first year of our project has been 
directed to: 1) estabi isnr.ent of techniques an 
control data for categorizing B £ I cells using 
the C3 5 Fc loci for B cells and the sheep 
erythrocyte receptor for T cells. 2) Their 
application to patients with chronic EBV mononu 



150 



eosls syndrone with repeat determination over a 9 
ttODth period. Preliminary results indicate 
persistent depression or B cells and fluctuation 
of T cells paralleling recurrence of symptonis. 
This expression of altered immune responsiveness 
■ay relate to the Icnoun predisposition of such 
patients to develop lymphoreticular disorders. 3) 
Oltrastructural and imnunof luorescent study of 
cell types, 103 peripheral blood or solid tumor 
sanples have been studied by EH (Hodgkin's Disease 
28, non-Hodykin's lymphomas 27, Leukemias 23, 
allied conditions 27), The diagnostic value of EH 
has been validated especially in tissues from 
extranodal sites where lymphoma was unsuspected by 
light microscopy. Immunofluorescence shows the 
Reed Sternberg cell to be immunoglobulin contai- 
ning and provides insignt into structural/func- 
tional relationships in nodular lymphomas. 

It is planned to confirm and extend the 
observations in 2), to complement the EN and 
iBBunof luorescent findings in 3) by immunoglobulin 
localization at the ultrasttuctural level and 
correlate all data with our clinical and epidemio- 
logical studies. 



208. EVAIUtTIOM OF GiLLIUH-67 AS A BADIOMUCLIPE 
TBiCEB IH DETECTION OF PRIHARI AND HEIASTATIC 
CARCINOHAS AND LYnPHOHAS 

Bilkinson, R. H, , Goodrich, J, K., Davidson, J. 
D., Workman, J., U,S, Veterans Administration, 
Hospital, 508 Fulton St,, Durham, North Carolina, 
27705, U.S.A. 

This study is currently being offered in 
order to provide the referring services with a 
neans for detecting the presence and location of 
soft tissue metastases. This study is currently 
employed at our medical center with varying 
degrees of freguency. Tee investigational project 
which initiated this study has been completed in 
terns of the acguisition of patient studies. 



209. COOPERATIVE PROJECT TO STODY DSE OF GAtLIUM 

67 IN THE DETECTION OF MALIGNANCY 

Sauerbrunn, B. J., U.S. Veterans Administration, 

Hospital, Nuclear Medicine Serv, 50 Irving St. 

U.K., Washington, District of Columbia, 20122, 

O.S.*. 

The Cooperative Group study has now acces- 
sioned 1300 case studies of malignancies and has 
completed a detailed study of the usefulness of 
gallium scanning in the detection of certain 
malignancies. 

In untreated Hodgkin's disease, 90% of 
patients had one or more positive sites on scan 
with a false positive rate of 5X. Thus, gallium 
scanning has a place in the staging of Hodgkin's 
disease but a negative scan does not exclude the 
presence of disease. 

In malignant lymphoma, 78* of patients had 
one or more positive scan sites. The degree of 
positivity is highest in histiocytic or the nixed 
cell variety of malignancy. Gallium is also of 
value in the clinical evaluation and staging in 
this disease. (Text Abridged.) 



210. EVALUATION OF GAUIOM 67 CITRATE AS A 

DIAGBOSTIC TOOL 

Claunch, B. C, Coleman, J. H., U.S. Veterans 

Administration, Hospital, Nuclear Medicine Service, 

ChaDtstone Ave., Providence, Rhode Island, 02908, 

D.S.A. 

An additional 41 cases have been done since 
last report. 

No adverse reactions have been experienced. 

The agent has been helpful in: (a) detecting 
recurrent lymphoma, (b) unsuspected metastasis to 
the mediastinum in bronchogenic carcinoma, (c) 
abdominal suppuration. 



211. DEVELOPMENT OF IMPROVED BEIHODS OF DIAGNOSING 
AND STUDYING HODGKIN'S DISEASE 

Stanford University, School of Medicine, Palo Alto, 
California, 9ii305, U.S.A. 

A summary is not available. 
B. PROGNOSTIC STUDIES OF LYMPHOMAS 

1. STAGING AND PROGNOSIS OF HODGKIN'S LYMPHOMA 



212. lAPABOSCOPY IH STAGING HODGKIN'S DISEASE 
Spinelli, P., Natl. Inst, for Study of Tumor, 
G Venezian 1, Milan, Italy, 20133 



OBJECTIVE: To study possibilities of 
replacing diagnostic laparotomy by laparoscopy i 
stating Hodgkin's disease (H.D.). 

APPROACH: Patients with H.D., previously 
treated or not, undergo laparoscopy with multipl 
biopsies from liver, spleen or other involved 
intraperitoneal sites. When laparoscopy and 
histology are negative, patients undergo a stagi 
laparotomy. 

PROGRESS: In H,D., laparoscopy plus needle 
narrow biopsy could substitute for the traditior 
exploratory laparotomy with splenectomy and 
multiple tissue biopsies in a large number of 
patients. 



213. INTENSIVE STAGING PROCEDURES FOR INVESTIGA- 
TION OF HODGKIN'S DISjASE PATIENTS - USE Of 
LAPABOTOHI, SPLENECTOMY AND LY BPHANGI OGR APUY 
Fairley, G, H., Sutcliffe, S. B. , Whitehouse, J. 
M., Imperial Cancer Research Fund, Medical 
oncology Unit, Lincolns Inn Fields, Wc2a 3px, 
london, England, United Kingdom 



Ninety-eight patients who have had an 
exploratory laparotomy and splenectomy have been 
evaluated in an attempt to assess the value of 
this procedure. Pre-operative lymphangicgraphic 
assessment was found to correlate well with 
subsequent histological assessment of the disease 
in the para-aortic and liiac nodes. It did not 
reliably indicate coeliac or mesenteric lymph-node 
involvement. Clinical assessment of spleen size 
was completely unreliaole in spleens of less than 
SOOg weight. 

Laparotomy modified the stage of disease in 
36% of cases, as therapy is entirely determined by 
the anatomical extent of disease; staging lapa- 
rotomy may alter management plans in as many as 
one out of three patients. 



Fischer, J. J., Prosnitz, L. R., Bertino, J. R., 
Forber, L. R. , Yale University, School of Medicine 
Therapeutic Radiology, 333 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



215. EVALUATION OF CELIOTOMY INCLUDING SPLENECTOMY 
IN THE STAGING OF PATIENTS WITH HODGKIN'S DISEASE 
AND OTHER MALIGNANT LYMPHOMAS 
Gamble, J. F. , Fuller, L. B. , Martin, R. G. , 
Butler, J. J., Univ. of Texas, B.D. Anderson Hosp. 
e Inst., Medicine, P.O. Box 20036, Houston, Texas, 
77025, U.S.A. 



OBJECTIVE: To 
initial staging in e 
non-Hodgkin' s lymphc 



increase the accuracy o 

arly Hodgkin's disease 

mas. To continue a Ion 

evaluation of these patients in regard to r 

free interval, pattern of relapse, and surv 

APPROACH: Unless medically or otherwi 

contraindicatcd, the following categories o 

patients will undergo exploratory laparoton 



15] 



' apfroacties 


significantly 


:. It has a: 


Lso been 


:s presentin. 


3 With Eupradia- 


.sease have ( 


Dccjlt disease 


splenic hili 


im and celiac 


ihich abdomil 


^al tumor uas 


ly. The resi 


Jits of these 


■taut in the 


subseguent 


.herapeutic | 


protocols for 


i IS to IIIA 


•Hodgkin's 



Including a splenectomy. A) Ke» patients clas- 217. CIXGNOSTIC laPAEOTOMY >KD SPLEWECTOBT FOR 

sified as stage I or II (localized disease) SIAGIMG HODGKIM'S DISEASE 

following routine investigation of Hodgkin's Wiernik, P. H., Levi, J. A., Sutherland, J., 

disease, including lymphangiography. This group Singer, J. A., Cooper, (I., Diggs, C, U.S. Dept. 

of patients would include patients not investig- of Hlth. Ed. S Wei., Natl. Cancer Institute, 

«ted by lyophangiograpby because of sensitivity to Clinical Branch, Baltimore, naryland, U.S.A. 
iodine dye, B) New patients classified as Stage I 

or II on the basis of all available facts or The purposes of this study have been to 

Euspected of having abdominal involvement by determine the value of staging laparotomy on 

reason of a) presence of systematic symptoms, b) evaluating the accuracy of the extent of abdominal 

equivocal lymphangiogram, c) other suggestive, but disease at the time of initial evaluation and what 

not diagnostic radiographic findings, e.g., upper influence this has on tne initial therapy for 

G.I., IVP, d) otherwise unexplained abdominal patients with early stage Hodgkin's disease. 175 

symptoms. patients with Hodgkin's disease have undergone 

SOBGERJ: Exploratory laparotomy will staging laparotomy and splenectomy, and this has 

include: 1) Biopsy of para-aortic, celiac and revealed that the pre-operative assessment of the 

mesenteric lymph nodes, also, nodes along the extended abdominal involvement uas incorrect in 

common bile duct and along the blood vessels of approximately UO percent of these cases. The 

the liver and spleen. The splenic pedicle and prediction of splenic involvement by Hodgkin's 

sites where nodes were removed will be marked with disease was incorrect in one-third of the patie- 

silver clips. If suspicious nodes are present by nts; approximately one-third of abnormal lympnang- 

lynphangiography, removal of these nodes will be iograms could not be confirmed at laparotomy and a 

assured by taking an x-ray of the abdomen, before number of cases of involvement of nodes in the 

the patient is removed from the operating table, porta hepatic region outside the usual radiation 

2) Splenectomy, 3) »edge and needle biopsies of therapy ports were discovered. A small number of 

both lobes of the liver, 1) Bone marrow biopsy, patients were also found to have documented liver 

and 5) Biopsies of other tissues as indicated. involvement which had not been suspected by 

PATHOLOGY: Histology of patients obtained on preoperative evaluation. These findings have 

laparotomy will be compared with the original altered the therapeu 

biopsy using the Rye modification of the Lukes and in a number of patie 

Butler method of classification. Findings on determined that pati 

abdominal exploration will be correlated with the phragmatic Hodgkin's 

interpretation of the initial lymphangiogram, limited to the spies 

other radiological studies, echograms and isotope axis in most cases i 

studies. The spleen, large nodes and wedge biopsy documented at laparc 

of the liver will be sectioned at 3 mm. intervals. studies have been in 

design of our furthe 
the treatment of sta 

216. STAGING LAPABOTOMI AMD COHBINED BODALIIY disease. 
THEKAPY IN EABLY HOBGKIN'S DISEASE 
Wiernik, P. H., Levi, J. A., Slawson, E. A., D.S. 
Dept. of Hlth. Ed. 6 Wei., Natl. Cancer Institute, 

Medicine Section, Baltimore, Maryland, U.S.A. 

DETECTION Of LUNG CANCEB 

The aims of this study were to determine the Benua, B. S., Laughlin, Hoodard, Tilbury, Memorial 

value of staging laparotomy in Stage I and II Hosp. for Can. £ Dis. , Medicine, 1275 York Ave., 

Hodgkin's Disease and further optimal initial New York, New York, 10021, U.S.A. 
therapy following laparotomy. Following the 

completion of initial clinical evaluation, OBJECTIVE: To define the clinical usefulness 

patients were randomized to receive laparotomy or of 67 Gallium in detecting cancers and following 

no laparotomy. These patients receiving no their progress. Collaboration wito the Coopera- 

laparotomy received extended field radiation tive Group to Study Localization and Sadiopharmac- 

alone. To date, 4 patients have been entered, all euticals and Oak Pidge Associated Universities 

have achieved complete remission and there have will include receipt of Ga67 for use in the study 

been no relapses to the present time (range 3 to of lung cancer and staging of Hodgkin's disease by 

19 months). 23 patients with pathologic stage I their protocol. 

to IIA disease were randomized following laparo- APPEOACH: 67 Gallium chloride complexes with 

tomy to one of the other 3 treatment arms and 1 sodium citrate will be supplied by CGSR or 

patients have received limited field radiation purchased from commercial suppliers. Patients 

alone, 11 patients extended radiation alone and 8 with untreated Hodgc.in's disease (niopsy proven), 

patients involved field radiation plus MOPP. untreated lung cancer (suspected and to be 

There have been 6 relapses, 2 among the patients operated upon or biopsied) will be selected for 

receiving involved field radiation alone, and 1 the furnished 67 Gallium. lie will study other 

among the patients receiving extended field patients with histologically proven evidence of 

radiation alone. There have been no relapses among malignancy at some time with clinical evidence of 

the involved field radiation plus MOPP. Patients some active tumor, without prior therapy except 

with E stage disease of the lung comprised 3 of radiation or surgery at a site different from the 

the 6 relapses and it has been decided that for one of current interest. 

the remainder of the study, patients with E stage The maximum dose will be "45 microcuries/kg. 

disease will be removed from this protocol. It is Scans will be performed at 48 to 72 hours after 

too early at this time to make any specific cleansing enemas. No pregnant women or infants 

assessments, although it does appear that patients will be studied (pediatric patients with malignant 

receiving irradiation plus chemotherapy are disease will be included if they can cooperate) . 

continuing to show improved results over those Whenever possible we will attempt to obtain 
receiving irradiation alone. It is too early to 
make any specific statements regarding the 
patients who received extended field irradiation 
alone without prior laparotomy. 

219. BLC GENES AND SURVIVAL IN HODGKIN'S DISEASE 
Oliver, E. T., Sutcliffe, S. B. , Burke, J., 
Imperial Cancer Eesearch Fund, Medical Oncology 
Unit, Lincolns Inn Fields, Wc2a 3px, London, 
England, United Kingdom 

Previously published results have suggested 
that there may be immune-response i;enes influen- 
cing survival in patients with Hodgkin's disease, 
and that these may be closely linked to the genes 
controlling MLC response. To investigate this 



1S2 



possibility all patients vith a diagnosis of 
Bodgkin's disease are being typed for their HLC 
genes using internationally standardized HLC 
typing cells. 



220. BECHimSBS OF THYHUS-IIEBIVED LYMPHOCYTE 
DISFDIiCIIOW IN HODGKIll'S DISEASE - IDENIIf ICATION 
OF BEVERSIBLE T-CELL DEfECT 

Bobrove, A. n., U.S. Veterans Administration, 
Hospital, Hheumatolcgy Section, 555 Hilliard Ave., 
Hartford, Connecticut, 06111, U.S.A. 

Be have recently reported that the depressed 
in Titro response of peripheral blood lymphocytes 
to phytohemagglutinin in patients with untreated 
Bodgkin's disease is not associated with a 
decrease in the percentage of I-cells but is 
correlated with inability of the T-cells to form 
non-imnune rosettes. Prelioinary evidence 
obtained in our laboratory, that short-term 
pre-incubation could reverse the defect in 
non-inBune rosette foruation and response to 
phytohemagglutinin, were confirmed by studies on a 
larger series of untreated patients. In similar 
studies of treated patients who were in long-term 
remission, we found that unlike the active, 
untreated patients there was a significant 
decrease in the percentage of peripheral blood 
T-lymphocytes. However, the capacity of their 
T-cells to form non-immune rosettes was not 
iapaired. Ue conclude, therefore, that there is a 
reversible defect in the T-lymphocytes of patients 
vith untreated Hodgkin's disease and that effec- 
tive treatment and long-term survival is associ- 
ated vith an amelioration of this defect. 



Bucher, W. C, Jones, s. E. , U.S. Veterans 
Administration, Hospital, 3601 S. 6th St., Tucson, 
»ri2ona, U5713, U.S.A. 

Recent reports have stimulated interest in 
the possible usefulness of selected laboratory 
tests as indicators of disease activity in 
Rodgkins* lymphoma. The results of these studies 
have shown that serum copper, serum zinc (espe- 
cially copper/zinc ratios) , and erythrocyte 
sedimentation rate values correlate best with 
fiodgkins* disease activity. 

It is the purpose of this pilot study to 
establish a longitudinal prospective study by 
obtaining pre- and post-treatment laboratory tests 
on individuals with Hodgkins' disease and other 
hematologic malignancies, wnose course ana care 
•ill be closely monitored by one of us (S.E.J.) , 
in an attempt to establish a useful index of 
disease activity and to evaluate the potential of 
these tests as prognostic monitors. 

One hundred blood samples, serially drawn 
from participating patients of the VA Hospital and 
Arizona Hedical College hematology-oncology 
clinics, will be tested for copper, zinc, magn- 
esium, iron and iron-binding capacity, and zeta 
sedimentation ratio. The results will Tihen be 
analyzed according to diagnosis, clinical activ- 
ity, and type of therapy, in an attempt to 
discover statistically significant correlations. 



2. PROGNOSTIC STUDIES OF NON HODGKIN'S LYMPHOMA 



222. BLOOD C LYIIPH GLAND nONOHOCLEAB CELLS OP 
PATIENTS WITH HON-HOCGKIN* S LYnPHOfiA - PHYSICO- 
CBEHICAL t, IllHDNOLOGICAL STUDIES OF LVnPHGCYIES 
Splinter, T., Feltkamp, c. i. , Vanunnik, J. A., 
Soners, P., Cleton, F. J., Netherlands Cancer 
Institute, Cancer Hospiral, Antoni Van Leeuwenhoek, 
Ziekenhuis Plesmanlaan 121, Amsterdam, Netherlands 

The classification of non-Hodgkin ' s type 
lymphomas on purely morphological criteria has 
been unsatisfactory. In the present study, 
■orphological criteria have been checked against 
functional characteristics of the cells found in 



lymphoma tissue and blood. 

The questions asked in this study were: 1. 
Is there a correlation between classification on 
the basis of functional characteristics, and 
classification based on conventional morphology or 
clinical course? 2. What is the nature of the 
immune deficiency of the blood lymphocytes? Does 
this deficiency correlate with the clinical course 
of the disease (longitudinal investigation)? 3. 
Bhat is the (clinical) relevance of the presence 
of these atypical cells in the circulation? 

To answer these guestions, a large number of 
investigations were carried out on lymphocytes 
obtained from patients with non-Hodgkin ' s lymphoma 
at regular intervals before and after clinical 
treatment. These included: cell separation on 
density and velocity gradients, morphology with 
light microscopy and electron microscopy, prolife- 
ration characteristics (DNA measurement, autoradi- 
ography) , immunological tests (rosette tests, 
membrane receptors, immunoglobulins) and functi- 
onal tests (antigenic stimulation, BLC, CtiL and K 
cell tests) . 

In the past 6 months, preliminary tests have 
been done on 3 patients. It is too early to give 
meaningful results. 

223. SEROH EACTOSS AFFECTISG PHA TBANSFOEnAIION OF 
BEBISSIOII LYUPHOCYTE? Of PAIIENTS WITH NON- 
BODGKIN'S LYMPHOID MALIGXANCY 

Lister, T. A., Pindar, A., whit ehouse, J. M., 
Imperial Cancer Sesearcn Fund, Medical Oncology 
Unit, Lincolns Inn Fields, Hc2a 3px, London, 
England, United Kingdom 

Remission lymphocytes from patients vith 
lymphomas in 'good' and 'poor' prognosis groups 
have been cultured in the presence of presentation 
and remission sera. One hundred experiments have 
been performed on 27 pa-ients in the 'good* 
prognosis group, and on 38 patients in the 'poor* 
prognosis group. 

There was increased transformation in almost 
all cases where these were cultured in the 
remission serum; this difference between transfor- 
mation in the paired sera (presentation and 
remission) may be expressed as a percentage 
inhibition, i.e.: * innibition equals 100 x A - 
E/A, where A equals c.p.m. in serum of patients 
before treatment and B equals c.p.m. in serum of 
patients after remission therapy. 

This inhibition does not affect either normal 
lymphocytes {.2i controls) or AKL remission 
lymphocytes (7 experiments) . Thirty-five exp- 
eriments have been performed in which the paired 
cells were tested with tne remission lymphocytes 
from other non-Hodgkin' s lymphomas, and inhibition 
vas again demonstrated. 

These preliminary experiments suggest that an 
inhibitor of PHA transformation may be present in 
the presentation serum and that it may be specific 
for non-Hodgkin's lymphoid malignancy. Further 
experiments are in progress to ascertain the 
nature of the inhibitor. 



221. SUPFACE-MARKER STUDIES IS PATIENTS WITH 
NON-HODGKIN'S DISEASE - - B 6 T CELL SURFACE 
BARKERS, SURFACE IMMUNOGLOBULINS A li D PROGNOSIS 
Catley, P., Lister, I. A., Hhitehouse, J. M., 
Imperial Cancer Research Fund, Medical Oncology 
Unit, Lincolns Inn Fields, Uc2a 3px, London, 
England, United Kingdom 



Use investigator index to locate a 
tion of this project elsewhere in this listing 



ip- 



153 



225. COBBEHTIOD OF COLCHICIHE SEHSITIVITI AKD 
JDHESIVEHESS KITH RESPOMSE ftND SUBUVftL IN 
FATIEHTS WITH LYH FdOPS01.IFEBAII VE DISORDEBS (LPHI 
Ihooson, A. E., Oconnor, T. H. , Wetherleymein , G. , 
iHperial Cancer Besearcft Fund, Cytochemistry, 
Llncolns Inn Fields, Uc2a 3px, London, England, 
Onited Kingdom 

Ongoing studies in patients vith CLL on 
lyiphocyte sub-populations characterized by 
colchicine ultrasensitivity, unaided death, 
abnoroal adhesiveness and other parameters, have 
continued. About 170 studies have been made in 60 
patients. Sufficient time has now elapsed to 
permit analysis of the cell-population data in 
terms of clinical and hematological features, vith 
particular reference to known duration of disease, 
reguirements for and response to treatment and 
patient life span. This analysis is in progress. 

Non-Hodgkin's lymphomas, including atypical 
lymphoprolif erative disorders, are increasingly 
being studied in terms of cell sub-population 
characteristics and it is already apparent that 
while in some the findings are similar to those in 
classical CLL, in others they are not. In this 
area the findings have had practical diagnostic 
value. Thirty-nine patients have been studied. 

Technigues for cell studies on simultaneous 
samples from bone marrow, spleen and lymph node 
have been developed and although the group of 21 
patients so far studied is still too small for 
definitive conclusions, the findings suggest that 
while in classical CLL consistent and typical 
abnormalities are found in all sites, (such as the 
bone marrow lymphocytes being always mostly 
colchicine ultrasensitive like the blood lymphocy- 
tes) , there are notable variations in other LPD 
patients. 



226. ASSOCIATIOll OF BAIIGMAHT LYBPHOHA BITH 
SCHISTOSOMA HAMSOmi 

Filho, S. Ci, Nascimento, E., Teixeira, J. A., 
Santa Casa de Hisericordia, Sao Paulo, Brazil 

OBJECTIVE: a) To test the association 
between malignant lymphoma and Schistosomiasis 
■ansonii. b) To test the influence of Schistose 
miasis on the surgico-clinical staging of lymp- 
homas, c) Testing of the evolution of cases of 
schistosomiasis in patients with lymphomas and 
Kith immunosuppression by radiological and 
chemical treatment. d) Testing of possible 
changes in the course of patients with lymphomas 
in their therapeutic response and survival which 
might be attributable to schistosomiasis. 

BATEBIAL: Patients with lymphomas registere 
in the Oncologic Cl'inic of Santa Casa de Hiserico 
rdia, and the Hospital of Santa nonica of Belo 
Horizonte. 

METHODS: All the patients are initially 
submitted to clinical and surgical staging, in 
addition to evaluation of immunological paramet- 
ers, having been evaluated and histologically 
classified in relation to their lymphomas and 
schistosomiasis. All cases will be followed with 
successive liver biopsies, along with immunolog- 
ical evaluation. 



227. KIHEIICS AND CIT0CHEHI5TBI OF HOM-HOCGKIN' S 

BALIGKANT IIMPHOMAS AND THEIB COHHELATION KITH 

aOBPHOLOGY 

Silvestrini, B., Piazza, R., Costa, A., Rilke, F., 

Natl. Inst, for study of Tumor, Via G Venezian 1, 

Bilan, Italy, 20133 

OBJECIIVE: To correlate proliferative 
profiles with clinical course of the disease, and 
to establish a morphological classification based 
on malignancy grade. 

APPROACH: The study is carried out by using 
a combined kinetic and cytochemical approach. 
Fresh lyffltJh node material is obtained by surgical 
excision, and divided into a portion tor histol- 

and autoradiographic analysis. Determinations of 
DMA content are carried out on imprints using a 
cytofluorometric method based on the fluorescence 



of the Feulgen reaction. Labeling index is 
determined on smears obtained from cell suspen- 
sions. The samples from 6 to 10 million cells, in 
2 ml of medium, are incubated at 37 degrees C for 
1 hour in slow agitation with H3 thymidine. The 
labeling index, DNA content, and cell distribution 
through the cell cycle are analyzed in malignant 
lymphomas diagnosed according to the Kiel classif- 
ication. 



228. PBOTOCOL FOB STAGING AMD IBEATHENT OF 
LIBPHOSABCOHA AND BETICllLUB CELL SABCOBA - BOLE OF 
LAPABOTOBI IN STAGING 

Wiernik, P. H., Levi, J. A., U.S. Dept. of Hlth. 
Ed. 6 Uel., Natl. Cancer Institute, Medicine 
Section, Baltimore, Maryland, U.S.A. 

The purposes of this study have been to 
assist the value of surgical staging in patients 
with apparently localized non-Hodgkin' s lymphoma 
and to determine whether or not adjuvant chem- 
otherapy will improve the treatment results in 
patients with localized non-Hodgkin ' s lymphomas 
who receive inital irradiation therapy. Patients 
with clinically localized stage I and :i non- 
Hodgkin's lymphoma are subjected to a staging 
laparotomy, and following this evaluation, the 
patients found to have pathologic stages I and II 
disease are then randomized to receive either 
extended field irradiation alone or extended field 
irradiation followed by six courses of chemothe- 
rapy utilizing Cytoxan, vincristine and prednis- 
one. Twelve patients whose staging laparotomies 
were entirely negative have been randomized to 
radiation therapy with or without adjuvant 
chemotherapy to this time. Relapses have been 
seen in both study groups. Too few patients have 
been accrued at this time to determine the value 
of adjuvant chemotherapy in treating localized 
malignant lymphomas. 



229. CHABACTEBIZATIGN OF B ANO T LrMPHOCYTES IN 
NON-HODGKIN'S LYMPHOMA 

Schur, P. H., Churchill, V. H. , Hunter, C. , Pinkus, 
G., Moloney, w. C. , cotran, R. S. , ailson, B. E. , 
Harvard University, Eobert Breck Brigham Hospital, 
Medicine, 125 Parker Hill Ave., Boston, Massa- 
chusetts, 02120, U.S.A. 

The purpose of this study is to improve the 
classification of non-Hodg kin ' s lymphoma patients 
by determining the cell surface markers of their 
cells in the peripheral oiood and lymph nodes. 
Patients with non-Hodgkin' s lymphoma, or suspected 
lymphoma, who are scheduled for diagnostic lymph 
node biopsy will have a portion of that lymph node 
analyzed, so as to determine the location and 
percentage of B, T, and Killer lymphocytes. These 
same patients, at the time of the biopsy, will 
have peripheral blood obtained and analyzed so as 
to determine the number and percentage of B, I and 
Killer cells therein. Approximately 50 patients 
will be so studied each year at the initial 
pre-treatment visit. After treatment is begun, 
serial analyses will be made of peripheral blood 
lymphocytes. These studies are aimed, not only to 
permit improved classification of patients with 
non-Hodgkin's lymphcna, but also to determine 
whether this classification will permit a better 
correlation with clinical course, prognosis, and 
response to therapy. 



230. BULIIVARIATE ANALYSIS OF PBOGNOSTIC FACTORS 
IN LYBFHOBAS 

Bloomfield, C, Univ. of Minnesota, School of 
Medicine, Medicine, 1305 Kayo, Minneapolis, 
Minnesota, 55155, U.S.A. 

This is part of a broader project. A summat 
of this subproject is not available. 



154 



3. OTHER PROGNOSTIC STUDtES OF LYMPHOPROLIFERATIVE 
DISORDERS 



231. HETEROGENEITY OF LIHPHOCTTE RAEIOSEWSITIVITY 
IH VITBO IB LynPHOPROLIFEBATIVE DISORDERS fLPD) 
VaughansDith, S,, Thomson, A. E. , WethGrieymein, 
G.( iDperial Cancer Research Fund, Cytocheuistry, 
LiDColns Inn Fields, Hc2a 3pz, LoDdon, England, 
United Kingdom 

Evidence to date suggests that the sensiti- 
vity in vitro to the killing action of X-rays of 
the B-lymfhocyte sub-population circulating in 
health is constant for different donors (20 
tested) and greater than the variable sensitivity 
displayed by the coexisting T lymphocyte sub- 
population in different donors. 

The colchicine-ultrasensitive lymphocytes 
(CUL) that predominate in patients with chronic 
lyapbocytic leukemia (CLL) , and which might be 
classed as B cells using immunological cell- 
surface Barkers alone, have proved more variable 
in radiosensitivity than B cells and their 
radiosensitivity varies widely between different 
patients (20 tested) . 

The radiosensitivity characteristics of 
IjBfhocytes circulating in 11 patients with 
lyiphoproliferative disorders other than CLL 
(non-Hodgkin* s lymphomas including diffuse and 
nodular lymphocytic lymphomas and unclassif iable 
forms) have conformed with the patterns expected 
for T cells, B cells and CUL coexisting in 
different relative proportions. However, one 
patient with nodular lymphocytic lymphoma and one 
mth unclassif iable LPD proved exceptional, A 
prominent radioresistant component denoted the 
presence of another lymphocyte type, different in 
each case, unrecognizable morphologically, and so 
far unidentified. Hairy cells from the one case 
of leukemic reticuloendotheliosis examined were 
likewise strikingly radioresistant compared to the 
accompanying other three defined lymphocyte types. 

Identification of lymphocyte sub-populations 
on the basis of radiosensitivity may have prac- 
tical, diagnostic, and predictive value in 
lymphoprolif erative diseases. 



232. DEFINITIOH OF IBBDHOLOGICAL STATDS OP 
PATIEMTS WITH L YHPHOPROLIFERATI VE DISEASES 
Cooper, I. A., Adams, P. B., Ding, J. C. , Kraft, 
v., Peter Haccallum Clinic, Immunobilogy, 481 
tittle Lonsdale St., Melbourne, Victoria, Austr- 
alia, 3000 

OBJECTIVE; The characterization of lymphoma 
and chronic lymphocytic leukemia patients by 
innunological parameters and their relation to 
prognosis. 

APPROACH: Lymphoid tissues are evaluated 
irith respect to thymus-derived and bone marrow- 
derived cells by fluorescent markers, resetting 
tests and mitogen studies. Cell surface antigens 
are labelled with radioactive tracers, extracted 
and analyzed by counter-immunoeleccrophoresis 
against patient sera. Cellular immunity is 
■onitored by cr51 release and microcytotoxicity 
assays against relevant tumor material. Patient 
iamune status will also be evaluated by in vitro 
capacity to mount a HLR, produce killer ceils 
against xenogeiieic antigens and the maintenance of 
aacrophage function in culture, 

PBOGBESS: Fluorescent marker studies are 
useful in diagnostic decisions, and preliminary 
results indicate that CLL patients can be divided 
into groups with different prognoses depending on 
the brightness of Anti-Ig fluorescence. 



233. RADIOIHHDHOASSAY OP SEROH FERRITIN IH 
iEOPI.ASTIC DISEASES INCLUDING LYHPHOHA 
Hiitsu, Y., Kohgo, Y., Ohtsuka, S., Urushizaki, 
I., Sapporo nedical College, Cancer Research 
Institute, Hedicine, S. 1, H, 17, Chuoku, Sapporo, 
Hokkaido, Japan, 060 

Ferritin in serum was guantitated by radioia- 
aanoassay to determine the usefulness of this 
assay in detecting malignancy. 

In aalignant diseases examined, elevated 
seruB ferritin values as high as 1.0 microgram 
were found in patients with acute myelogeneous 
leukeaia, myeloma, aplastic anemia, lymphoma, 
hepatoma, pancreatic carcinoma and uterine 
carcinoma in contrast to the normal subjects 
(20-150ng/ml) . 

The return of serum concentrations to normal 
in certain malignant diseases after successful 
chemotherapy suggested that ferritin concentration 
■ay be a useful index of active disease and may 
help in prognosis. 



231*. IHVESTIGATION OF DMA POLTflERASE INHIBITOR IH 
LEOKEBIA, HALIGNANT LYMPHOMA AND MYELOMA 
Trubowitz, S. , U.S. Veterans Administration, 
Hospital, Hematology Section, Tremont Ave, C S, 
Centre St., East Orange, New Jersey, 07019, 
D.S.A. 

About 50 sera were obtained from patients on 
the Hedical Service of the Veterans Administration 
Hospital in East Orange, New Jersey. These 
patients had malignancies of the lymphoreticular 
system, and were in various states of therapy and 
response. 

Ten sera were tested for their ability to 
inhibit the enzymatic action of a specific DNA 
polymerase (S-1) which had been recovered from 
murine myeloma cells. The results are expressed 
as a fraction of the uninhibited enzyme reaction, 
1.00 representing no inhibitor in the sera, and 
to 1.0 representing various degrees of inhibition. 

The results correlated well with the diagn- 
osis and clinical status of these patients, i.e. 
the levels of inhibitor were highest in the sera 
of patients with active (relapsing) disease as 
opposed to those who were in remission. 

In addition, a large amount of plasma 
obtained from one of the patients as a result of 
therapeutic plasmapheresis was used as a source 
for isolation and purification of the inhibitor. 



235. KINETICS OF CELL PROLIFERATIOg IH HDHAH 
BEBATOPOIETIC TUMORS INCLUDING LYMPHOMA 
Clarkson, B. D. , Fried, J., Gee, T. , Sloan 
Kettering Inst, Can. Res, Hematopoietic Cell 
Kinetics, 410 E. 68th St., New Yort, New York, 
10021, U.S.A. 

OBJECTIVE: The aim of tois work is to 
achieve a better understanding of the prolifera- 
tive behavior and related properties of the 
neoplastic cells in different hematopoietic 
tumors. It is hoped that more complete informa- 
tion about cellular kinetics will improve diag- 
nostic precision, permit formulation of more 
effective treatment schedules, and also lead to 
clearer definition of the fundamental abnormali- 
ties in the hematopoietic tumors and of the 
interrelationships between them. 

APPROACHES: Patients with acute leukemia and 
lymphoma will be studied before, during and 
following chemotherapy to determine what kinetic 
changes are caused by the different drugs and with 
the goal of devising improved treatment schedules. 
Both autoradiographic methods employing H3- 
thyaidine and continous flow oicrof luorooetric 
aethods using DNA specific fluorescent stains will 
be used. A variety of gradient and adherent cell 
separatory techniques and cloning methods in 
seai-solid media will also be used to separate 
pure subpopulations of cells and determine their 
clonogenic potential, cytochemical tests and 
electron microscopic studies will be used to help 
identify cell types. 

REFERENCES: Yataganas, X,, Hitoao, Y., 



155 



Traganas, T., Strife, X., and Clarkson, B. 
Evaluation of a feulgen-Type reaction in suspen- 
sion using flow micrcf luoronetcy and a cell 
separation technigue. Acta Cytologica., 19:71-78, 
1975. 



C. THERAPY OF HODGKIN'S DISEASE 



236. BtPIOIHERAPI AHC CHEHOIIIBDNOTHEBtPY IH 
BODGKH'S LYnPHOnA - COMPARISON OF THERAPEUTIC 
EFFECTS 

Solidoro, A., Zaharia, «., Vallejos, C, Natl. 
Inst, of Neoplastic Dis., Jvenida Alfonso Ugarte 
825, Lima, Peru 

OBJECTIVES: I. To coipare the efficacy of 
t¥0 sodalities of ccmbined therapy in remission 
induction in previously untreated HodgJcin's 
Lymphoma ^Jatients. To test the effectiveness of 
continued maintenance chemotherapy alone vs 
chemotherapy and BCG. II. All patients with any 
histologic type of stage III or IV HodgJcin's 
Lymphoma established by biopsy are eligible. 

PROTOCOL OUTLINE: Induction: Randomized 
Study, Arm I Radiotheraj-y, total nodal irradiation 
plus H-drug combination chemotherapy with nOPP for 
2 years. naintenance: Enter and re-randomize only 
patients who have attained complete remission. 
Am III: Combination coemotherapy with nOPP. Arm 
IV, Combination chemotherapy with :10PP plus 
immunotherapy with ECG. Dosage schedule: 
austargen, 6 Bg/[12/day 16 8.; Oncovin, ^.1 
lig/«2/day 1 6 8; Procarbazine, 100 mg/n2/day x H; 
Prednisone, 10 mg/(12/day x 11, only in series 1 
and 1. BCG: Bacillus Calmette Guerin - -6 i 10 
to the eth power live organisms by scarification g 
days e and 15 each nOPP. Courses repeated every 
28 days. 

237. NE» COMBINATION CBEHOTHERAPY IN ADVANCED 
HODGKIN'S DISEASE - STAGES IIB, IIIB. HIS (A E Bl 
AND IV 

Bonadonna, G. , Zucali, R. , Delena, n., Uslecghi, 
C, Natl. Inst, for study of Tumor, Via G Venezian 
1, Milan, Italy, 20133 

OBJECTIVE: To develop an effective non-cross 
resistant regimen which could be employed either 
in MOPP failure or in seguence with MOPP in the 
treatment of advanced Hodgkin's disease. 

APPROACH: Patients with histologically 
confirmed diagnosis of HodgJcin's disease were 
stratified according to stages and patterns of 
disease. After stratification, pat 
randomly allocated to receive 
BOPP or 6 cycles of a n 
adrianycin, bleomycin, 
(ABVD) . All patients a 
partial remission great 
uently irradiated. At 
further treatment was g 
ers, but to stage IV pa 

6 more cycles of either BOPP or ABVD every two 
months as maintenance treatment. 

PROGRESS: No difference was observed betw 
the two treatments in terms of complete remissi 
<7i4)l for MOPP; 77)1 for ABVD). The analysis of 
remission duration reveals that ABVD appears to 
as effective as MOPP. The results of secondary 
treatment after crossover revealed the absence 
cross-resistance between the two combinations. 



her 6 cycles of 
!W combination with 
■inblastine and DTIC 
hieving a complete or 
ir than 75* were subseg- 
he end of radiotherapy, l 
.ven to complete respond- 
ould receive 



238. CONTROLLED STUDY ON COMBINED CHEMOTHERAPY AND 

RADIOTHERAPY FOR ADVANCED HODGKIN'S DISEASE - 

EVALUATION OF ABVD 

Bonadonna, G., Banfi, A., Delena, H., Natl. Inst. 

for Study of Tumor, Via G Venezian 1, Milan, Italy, 

20133 

OBJECTIVE: Following the results of a recent 
experience carried out at our institute on a new 
combination chemotherapy with adriamycin, bleo- 
mycin, vinblastine and imidazole carboxamide 
(ABVD), this study was undertaken with the intent 
to explore new combined treatment approaches in 
advanced Hodgkin's disease. 

APPROACH: All patients with histologically 
proven diagnosis of HodgJcins's disease, with 
stages IIB, IIIB, HIS, IV (A6B) and I, not 
previously treated with chemotherapy, are suitable 
for this study. Patients are stratified according 
the four histologic subgroups. Patients with stage 
IIB, IIIB and HIS (A6B) are randomized to receive 
a) radiotherapy followed by 6 cycles of MOPP; b) 3 
cycles of MOPP followed by HT, followed by 3 
cycles of MOPP; c) 3 cycles of ABVD followed by 
RT, followed by 3 other cycles of ABVD. Patients 
in complete remission will receive r.o further 
chemotherapy until evidence of relapse; patients 
in partial remission or with no response will 
receive other 6 cycles of chemotherapy, alterna- 
ting the combination (ABVD for those treated with 
MOPP; MOPP for those given ABVD). Further 
treatments are planned upon progression. Patients 
with stage IV disease on the contrary will be 
randomized to receive either 1i cycles of BOPP or 
MOPP plus ABVD for 12 cycles (sequential combi- 
nation alternating cycles). Patients in complete 
remission will receive no further treatment after 
the 12th cycle, those in partial remission or with 
no response will receive ABVD if they were first 
treated only with MOPP, or CCSU if they were 
treated with seguential combination. 

PROGRESS: It is too early to carry out any 
evaluation. The series of cases is rtjported 
hereunder: Stages IIB-IIIB-IIIS (A6B) : Treatment 
A: 9 cases; Treatment B: 8 cases; Treatment C: 
10 cases. Stage IV: MOPP 12 cycles: 6 cases; 
MOPP plus ABVD: 6 cases. 



239. CHEBOTHEEAPY USING MOPP OR COPP SCHEDULE 
AFTER INITIAL RADIATION THERAPY IN STAGE I, II AND 
IIIA HODGKIN'S DISEASE IN YCUNG PATIENTS 
Shah, P. M., Gujarat Cancer Eesearch Ir.st., 
Medical Oncology, New Civil Hosp. Campus Asarwa, 
380 016, Ahmedabad, Gujarat, India 

OBJECTIVE: In patients with Hodgkin's 
disease, after traditional radiation therapy, 
evaluation of efficacy of chemotherapy on long 
term survival and cure is the aiE of this project. 

APPROACH: 6 courses of BOFP or COPP are 
given 1 month after radiation therapy. 

PROGEESSS: 25 cases at present. 



2lt0. SBG-160 - CHEMOTHERAPY AND RADIOTHERAPY FOR 
mTERBEDIATE STAGES OF HODGKIN'S DISEASE 
Bottomley, R. H., Hampton, J. v., :cozea, ?. N., 
Hoge, A. F., Ishmael, D. R., Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hemarol Oncol Sects, 921 N. E. 13th St., 
Oklahoma City, Oklahoma, 73101, U.S.A. 

Radiotherapy properly applied will cure 3U to 
80 percent of patients with localized Hodgkin's 
disease, and will produce substantial tumor-free 
survivals in patients with Stage IIIA disciase. 

Combined chemotherapy programs will produce 
complete remissions in tne majority of patients 
with disseminated Hodgkin's disease. These are 
followed by long durations of unmaintained 
remission. 

The two modalities of treatment are poten- 
tially supplemental, and limiting radiotherapy to 
localized disease and chemotherapy to dissoumated 
Stage IV disease may no longer be appropriate. 
Their combined use, particularly for the inte- 
rmediate stages of the disease (Stage IIB to Stage 
IIIB), is worthy of study. 



156 



It is the objective of the present study to 
detenine the safety and effectiveness uith «hich 
cheiotherapy followed by radiotherapy can be 
applied to these stages of Hodgkin's disease {IIB, 
IIIA, IIIB). The major criterion of evaluation 
will be the toxicity in the radiation therapy 
portion of the study, compared with toxicity of 
patients treated with radiotherapy alone and 
length of relapse-free interval for radiotherapy 
versus coabined groups. 

At present this project is ongoing but is 
closed to new patient entries. 



2141. SiG-nil/m - BODGKIH'S DISEASE - BI 

iBPacTioH »iiH nopp PLUS BiEonicm inopp 

Bottoaley, B. B., Hampton, J. W., Grozea, 
Hoge, A. f., Ishmael, D. E. , Hussein, K. 
Oldham, F. B., U.S. Veterans Administrati 
Hospital, Hematol Oncol Sects, 921 N.E. 1 
Oklahoma City, Oklahoma, 73104, U.S.A. 

OBJECTIVES: To determine the compar 
effectiveness of MOPP alone and in combin 
iiith two different dose schedules of Sleo 
complete remission induction in patients 
disseminated Hodgkin's Disease (IIIB, IVA 
1TB) . 

To determine the relative effectiven 
BOPP and radiation therapy (to the area 
disease involvement prior to noPP) folio 
BOPP and intensive BOPP in remission con 
in those patients achieving complete rem 

All patients with adequate pulmonar 
will be randomly assigned to either MOPP 
HOPP plus low dose Bleomycin; or BOPP p 
dose Bleomycin. Patients with signific 
compromise of pulmonary function will ge 
alone. All patients will initially rece 
treatment in full dose if they have adeq 
Barrow reserve, and half dose if they ha 
Boderately iopaired bone marrow reserve. 
courses of such treatment either with or 
Bleomycin will be given. If complete or 
response is not attained, the study 

At present this project is ong 
closed to new patient entries. 



,f major 
red by 
;olidation 
.ssion. 
y function 

us high 



partial 
erminated. 
but is 



2a2. COBBIHED USE OF MOPP CBEHOIBERAPI AHD 

BADItTIOll TUEEAPY IN THE IBEATMENI OF GEHEHA1.IZED 

HODGKIN'S DISEASE 

Gamble, J. F. , Fuller, L. M., Shullenberger , C. 

C, Univ. of Texas, fl.D. Anderson Hosp. £ Inst., 

Hedicine, P.O. Box 2C036, Houston, Texas, 77025, 

O.S.A. 

OBJECTIVE: To increase the remission rate, 
duration of remission and survival in Stage IIIA 
and IIIB Hodgkin's disease. 

APPEOACH: Patients admitted to this study 
receive 2 courses of MOPP (nitrogen mustard, 
Oncovin, prednisone and procarbazine) . Following 
recovery of the blood counts, which takes approxi- 
Bately 3 weeks, radiotherapy with Cobalt 60 is 
initiated. Our plan is to treat the mediastinum, 
aodomen, pelvis and peripheral node bearing 
regions in series. The sequence of scheduling is 
dependent on the clinical situation. In general, 
a rest of y to 8 weeks is planned between courses 
of radiotherapy for recovery of bone marrow 
function. For upper torso disease, radiotherapy 
is administered at the rate of 1000 rads tumor 
dose per week, for a minimum tumor dose of 3000 
rads. Additional treatment is given for residual 
disease. Lower torso disease is treated at 
somewhat slower dose rate, that is 30C0 rads 
delivered in 1 weeks. Additional treatment is 
given for residual disease when possible. Dosage 
to the kidneys is limited to approximately 2000 
rads by posterior shielding with two half value 
layers of lead. The liver is shielded after 2500 
rads. Treatment fields consist of the mantle, 
upper two thirds of the abdomen and pelvis. 

PROGEESS: In our experience preliminary 
cheaotherapy is essential for completion cf 
radiotherapy in patients with Stage III disease 
who have severe constitutional symptoms or 
extensive involvement of both nediastinum and 



abdoaen. Although the chemotherapy program has 
been effective in inducing a sufficiently long 
period of remission to permit completion of a 
planned program of radiotherapy, development of 
subsequent extra-nodal manifestation of Hodgkin' 
disease is still a problem. Hematologic toleran 
for combination treatment programs utilizing 
chemotherapy and radiotherapy for Stage III 
Hodgkin's disease is marginal. Uith escalation 
the BOPP dose to 3 courses, we have had difficul 
in completing our radiotherapy program. In Marc 
1973, our initial results were published. The 
overall survival figures for the entire group fo 
3 and 5 years were 70* and 68* respectively. A 
further publication will be forthcoming. 



2«3. RADIOIHEBAPI-CHEMOTHEBAPT FOR STAGE I AHD II 
- A AMD B HODGKIN'S DISEASE 

Fuller, L. B., Gamble, J. F., Shullenberger, C. 
C, Loh, K. K., Univ. of Texas, M.D. Anderson 
Bosp. 6 Inst., Radiotherapy, P.O. Box 20036, 
Houston, Texas, 77025, U.S.A. 

OBJECTIVE: To compare long-term results of 
"mantle" and para-aortic radiotherapy (total model 
when indicated) to Involved Field Radiotherapy 
(IF-XET) followed by six courses of combination 
cnemctherapy with Nitrogen Mustard, Vincristine, 
Procarbazine, and Prednisone (BOPP) in celiotomy 
staged patients with I and II, A and B disease in 
terms of: 1) Freedom from progression of 
disease; 2) survival. 

APPEOACH: Celiotomy staged patients between 
the ages of 15 and 65 are randomized to one of the 
treatment programs. Involved regions are treated 
to a total tumor dose of 3500 to 1000 rads at a 
rate of 1000 rads tumor dose per week. When 
applicable, additional treatment is given for 
residual disease. Prophylactic treatment is 
limited to 3500 rads as per details described in 
Southwest Oncology Group (SWOG) Protocol No. 781. 



2<lt. (BADIO-CHEMOTHEBAPy OF HODGKIN'S DISEASE — 
CCSG 5141) 

Hartmann, J. R. , Chard, R. L. , Eleyer, «. A., 
Bernstein, I. D., Childrens orthopedic Hospital, 
Hematology, U800 Sand Point Bay N.E., Seattle, 
Kashington, 98105, O.S.A. 

This protocol is in the developmental stage. 
Treatment for stage I and II disease involves 
random therapy between extended field radiotherapy 
only versus involved field radiotherapy plus MOPP, 
chemotherapy. For stage III disease, both stage A 
and B, staged by laparotomy and lymphangiography, 
all patients receive three courses of MOPP, 
followed then on a random basis by total nodal 
irradiation of 3500 rads versus total nodal 
irradiation of 2500 rads, with all patients 
receiving three courses of BOPP, following 
completion of radiotherapy. For stage IV disease, 
randomization for chemotherapy only between 
standard BOPP program versus ACOPP. The BOPP of 
course is nitrogen mustard, oncovan, vincristine, 
prednisone and procarbazine (matulane) versus 
ACOPP which is adriamycin, cyclophosphamide, 
oncovan and vincristine, prednisone and procar- 
bazine (matulane) , It is anticipated that this 
program will be in effect within the next year. 
This institution sees approximately eight to ten 
patients per year and in the past year, the 
Children's Cancer Study Group saw seventy such 
patients. 



215. STAGING LAPAROTOBT AND COBBISBD HODALITK 
THERAPY IN EARH HODGKIN'S DISEASE 
Niernik, P. H., Levi, J. A., slawson, E. A., U.S. 
Dept. of Hlth. Ed. 6 Uel., Natl. Cancer Institute, 
Hedicine Section, Baltimore, Baryland, U.S.A. 

The aims of this study were to determine the 
value of staging laparotomy in Stage I and II 
Hodgkin's Disease and furtner optimal initial 
therapy following laparotomy. Following the 
coBplotion of initial clinical evaluation, 
patients were randomized to receive laparotomy or 



157 



no la^arotoQy. These patients receiving no 
laparotomy received extended field radiation alone 
and to date; U patients have been entered and all 
have achieved cooflete remission and there have 
been no relapses to the present time (range 3 to 
19 months) . 23 patients with pathologic stage I 
to IIA disease were randomized following laparo- 
tomy to one of the other 3 treatment arms and 1 
patients have received limited field radiation 
alone, 11 patients extended radiation alone and 8 
patients involved field radiation plus noPP. There 
have been 6 relapses, 2 among the patients 
receiving involved field radiation alone, and u 
among the patients receiving extended field 
radiation alone. There have been no relapses 
among the involved field radiation plus flOPP. 
Patients with E stage disease of the lung compr- 
ised 3 of the 6 relapses and it has been decided 
that for the remainder of the study, patients with 
E stage disease will be removed from this proto- 
col. It is too early at this time to make any 
specific assessments, although it does appear that 
patients receiving irradiation plus chemotherapy 
are continuing to show improved results over those 
receiving irradiation alone. It is too early to 
make any specific statements regarding the 
patients who received extended field irradiation 
alone without prior laparotomy. 



216. ( RADIOTHEBAPI AMD CHEHCTHEBAP? IH £ARLI tSD 

ADYAIICED HODGKIM'S DISEASE! 

Kaplan, H. S., Glatstein, E. J., Rosenberg, S. A., 

Dorfman, R. F., Stanford University, School of 

Medicine, Radiology, Palo Alto, California, 94305, 

U.S.A. 



classified again by a group of pathologists. 
After this a reevaluation of the data will be 
■ade. 



250. COnPABISON OP SPLEMECTOnl AMD SPLENIC 
I8BACIATI0N FOR LIMITIMG HODGKIM'S DISEASE 
Burgers, J. H., Tierie, A. H., Breuer, K., Somers, 
R.. Cleton, F. J., Vanunnik, J. A., Netherlands 
Cancer Institute, 106-108 Sarphatistraat, Amste- 
rdam, Netherlands 

This trial is also carried out by the EORTC 
radio-chemotherapy group. 

The literature on laparotomy and splenectomy 
shows that in about 25 percent of the cases, 
non-suspected abdominal Hodgkin's localizations 
are found at operation, especially in the spleen. 
This is also the case in clinical stages I and II. 
This trial investigates the best way of treating 
the spleen localizations. After clinical staging, 
a randomization is made in two groups. one group 
is treated by laparotomy with splenectomy, the 
other group with spleen irradiation. The further 
treatment in both groups is identical: mantlefield 
irradiation and irradiation of the para-aortal 
nodes up to the level of LI. 

Since trial no. 1 had revealed the value of 
chemotherapy in patients with the unfavorable 
histology, in trial r.o. 2 these patients were 
again randomized in two groups. One group 
receives Velbe treatment only, the other group 
receives Velbe plus Natulan. There are 177 
patients in trial; after 250 cases the first 
conclusions can be drawn. 



Patients receive an extensive evaluation 
including bone marrow biopsy, lymphangiography and 
staging laparotomy if they do not have Stage IV 
disease. Patients who have Stage I and IIA 
disease receive either subtotal radiation therapy 
or local field irradiation plus intensive chemoth- 
erapy. Patients with more advanced disease 
receive either radiotherapy or radiotherapy plus 
intensive chemotherapy. 



251. COHBINATIOM THERAPY AND CHEHCTHERAPy IN 
HODGKIN'S DISEASE 

Durant, J. 5., Univ. of Alabama, School cf 
Oedicine, Medicine, 1919 7th Ave. S., Birmingham, 
Alabama, 3S233, U.S.A. 

This is part of a broader project, A summary 
of this subproject is not available. 



217. CHEHOTHERAPI AND LOB DOSE RADIOTBERAPI IN 
HODGKIN'S DISEASE 

Prosnitz, I., Yale University, School of nedici 
Therapeutic .Radiology, 333 Cedar St., New Haven 
Connecticut, C6510, U.S.A. 



This is part 
of this subproject 



brc 



A su 



218. CHEMOTHERAPY AND IRRADIATION OF HODGKIN'S 

BISEASE 

Velez, E., Univ. of Puerto Rico, School of 

Medicine, P.O. Box 5067, San Juan, Puerto Rico, 

00936 



Thi 



! is part of a broader project, 
subproject is not available. 



219. HODGKIM'S DISEASE, TRIAL NO. 1, VELBE IN 
CONTROLLED RADIO-CHEHOTHERAPY OF HODGKIN'S DISEASE 
Burgers, J. n., Tierie, A. H., Somers, R., 
Vanunnik, J. A., Antoni Van Leeuwenhoek Hosp., 
Plesmanlaan 121, Amsterdam, Netherlands 

This study was carried out during the period 
1961-1971. Patients in stage I and II (clinical 
stages) were treated with mantle field irradiat- 
ion, after which a randomization was made in two 
groups, one of which received Velbe treatment for 
two years, while the other did not receive further 
treatment. 

Follow-up for 10 years showed a better 
remission duration for the Velbe- treated miied- 
cellularity cases (60 percent after 5 years with 
no recurrence) compared with the non-Velbe group 
(25 percent at seven years). 

In the other histology groups no difference 
«as found. Due to changes in histological 
criteria over the years, the slides are being 



■The following types of treatment are being 
evaluated in retrospective studies: chemotherapy 
of non-Hodgkin' s lymphoma, gastro-in test inal 
lymphomas and staging laparotomies for Hodgkin's 
and non-Hodgkin' s lymphomas. 

In collaboration with the centers in Nijmegen 
and Rotterdam, the results of (lOPP chemotherapy in 
221 cases of Hodgkin's disease were studied: 55 
percent of the cases were in complete remission 
after 6 courses, 28 percent were m complete 
remission and in 17 percent treatment tailod. 
Patients with no prior treatment or those treated 
only with radiotherapy haa a better remission 
chance than patients treated with radiotherapy and 
chemotlierapy. Of the patients wno went into 
complete remission, 70 percent ate still in the 
first remission 1 years after the beginning of 
treatment. 

Survival in non-responders is very bad; less 
than 20 percent survive for 1 years after the 
beginning of treatment. 



158 



253. COBBIHED CHEMOTBERAPY (HOPP) IH THF IRE^IBENT 

OF tmAIICEE HODGKIN'S CISEASE — PBELmiNiBY 

STDDIES 

Falrley, G. H., Sutcliffe, S. B., Uhitehouse, J. 

B., Iipenal Cancer Beseaich Fund, nedical 

Oocology Unit, Lincolns Inn fields, llc2a 3px, 

London, England, United Kingdom 

Ontreated advanced Hodgkin's disease has a 
reij poor prognosis. Preliminary results o£ a 
trial using combination chemotherapy show a 
dcaiatic improvement in survival. 

Patients with Stage IIIB and IV Hodgkin's 
disease, together with cases which have relapsed 
after previous radiotherapy, were entered into a 
trial using the combination mustine hydrochloride, 
vinblastine, procarbazine, and prednisolone. 
These drugs were given together for two weeks and 
repeated after a four-week interval. Six such 
courses were given, then the freguency was 
reduced. 

Recently analyzed results show that the 
five-year survival of previously untreated and 
previously irradiated cases is 80*. Previous 
cheiotherapy and/or radiotherapy reduces the 
success rate to less than 10%. Comparisons with 
earlier trials of chemotherapy show a marked 
difference, the survival at five years using 
single drug chemotherapy being less than 25*. The 
prognosis for patients relapsing after combination 
cbeiotherapy is poor, with a median survival of 
anout 16 months. Several single agents appear 
proaising in the alleviation of disease, and it is 
proposed to conduct a controlled evaluation of a 
coabination of these agents to determine whether a 
second remission, and thus prolonged survival, can 
be obtained. 



25«. PHASE II STUDY OF THE COHBIKATION OF CCNU, 
TIHCRISIIME, PROCARBAZINE AMD PBEPmsOIIE (HOPP) IH 
BODGKIB'S DISEASE 

Cevik, N., lekinalp, G., Buyukpamukcu, H., Firat, 
D., Hacettepe University, Div of Pediatric 
Oncology, Ankara, Turkey 

PATIEHT ENTRY CRIIEEIA: Patients with Stage 
III or Stage IV Hodgkin's disease or patients with 
recurrent disease following extended field 
radiotherapy, conventional chemotherapy (HOPP) or 
both are eligible for the study, (Text Abridged.) 



255. STREPTOZOTOCIK, BLEOHYCIN, CCNO AND ACRIAB- 
ICIg FOB THE IREAIHENT OF ADVANCED HODGKIN'S 
DISEASE 



256. ADVANCED HODGKIN'S DISEASE - REHISSION 



Levi, J. A., Wiernik, P. H., Diggs, C, U.S. Dept. 
of Hlth. Ed. e Uel., Natl. Cancer Institute, 
Bedlclne Section, Baltimore, naryland, U.S.A. 

The purpose of this study was to determine 
the clinical usefulness of a new combination 
cheiotherapy for advanced Hodgkin's disease which 
la no longer responsive to conventional chemo- 
therapy. Patients with advanced Hodgkin's disease 
have received treatment with streptozotocin 
0.5Bg/H2 daily for five days, CCNU 100mg/H2 on day 
1, bleomycin 15mg/H2 IH on days 1 and 8, and 
adriamycin i45mg/H2 on day 1 with cycles repeated 
each 28 days it blood counts permit. Seventeen 
patients have been currently entered onto this 
study. Three are too early for evaluation and 
aaong the remaining 14 patients, there have been u 
coaplete remissions, 5 partial remissions and 5 
failures, a remission rate of greater than 50». 
The duration of the unaaintained complete remi- 
ssions have been 20 plus, 12, 9, and 6 months. 
This combination of agents appears to have 
definite efficacy in this previously treated group 
of patients and may, therefore, be of a value in 
the subseguent treatment of all patients with 
advanced stage Hodgkin's disease whether or not 
thej received prior chemotherapy. 



Bottomley, R. H., Hampton, J. w., Grozea, P. N., 
Hoge, A. F., Ishmael, D. R. , Hussein, K. K. , 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
OJclahoma City, Oklahoma, 73104, U.S.A- 

OBJECTIVES: To compare the effectiveness of 
2 nOPP plus bleomycin plus adriamycin combinations 
against HOPP plus bleomycin for remission induc- 
tion in patients with advanced Hodgkin's disease 
without prior chemotherapy. To evaluate system- 
atic restaging of patients in apparent complete 
remission. To assess the length of unmaintained 
remission after intensive induction with 10 
courses of treatment and after documentation of CR 
status by careful restaging. To evaluate by 
crossover design the remission induction potential 
of the other study combinations for patients who 
relapse during unmaintained remission. 

Remission induction: Ten courses cf treat- 
Bent at U-week intervals will constitute remission 
induction. If inductior results in a CB and this 
is confirmed by restaging, then no further 
treatment will be given. If restaging after 10 
courses of the induction regimen indicates at 
least a PR but residual Hodgkin's disease, another 
t Jourses will be administered in a second attempt 
to achieve a CB. Persistence of disease after 11 
courses will constitute an "induction failure" and 
the patient will be taken off study. 



257. HODGKIN'S DISEASE — CBEHCTHEBAPY BITU HOPP 
PLUS BLEOHYCIN 

Vietti, I. J., Washington University, School of 
Bedicine, Radiology, 660 S. Euclid Ave., St. loui 
Hissouri, 63110, U.S.A. 

This is part of a broader project. A summar 
of this subproject is not available. 



258. TBEATHENT OF "C-HOPP" IHEBAPY-BESISIANT 
HODGKIN'S DISEASE »ITH ADBIAHYCIN. DTIC, CCNU AND 
BLEOHYCIN 

Osieka, E., Seeber, S., Bruntsch, U., Gallmeier, 
B. n., Univ. Clinic for Internal Had. , 55 Hufelan- 
dstrasse, Essen, Federal Republic of Germany, 
13 

Clinical Protocol, Phase II - III: Patients 
with evidence of progressive disease under 
adequate "C-HOPP" chemotherapy are eligible for 
this protocol, Adriamycin (NSC- 1231 27) , bleomycin 
(125066), DTIC (15368), CCNU (79037). (Text 
Abridged.) 



259. TREATHEHI OF HODGKIN'S PATIENTS III BCYPP 
INDUCED REHISSION. USING MO THERAPY. HOPP. OR 
INDUCING COBBINATIOH 

Yam, L. I., U.S. Veterans Administration, Hospital, 
Section of Hematology, 800 Zorn Ave., Louisville, 
Kentucky, "40202, U.S.A. 

Great strides have recently been made in the 
treatment of Hodgkin's disease. Combination 
chemotherapy using BCVPP (BCNU, Cytoxan, vinb- 
lastine, procarbazine, prednisone) or HOPP 
(nitrogen mustard, vincristine, procarbazine, 
prednisone) have been tried on Hodgkin's disease 
with success. Sixty to eighty percent of patients 
with advanced Hodgkin's disease respond to nOPP. 
The complete remission rate of BCVPP in advanced 
Hodgkin's disease has not been determined. After 
six courses of combined chemotherapy with either 
BCVPP or HOPP, it is not certain whether further 
■aintenance chemotherapy is better than no 
maintenance at all. The aim of this study is to 
answer these guestions. In each patient with 
advanced Hodgkin's disease, six courses of BCVPP 
will be given. Patients with remission will be 
randomized into three groups: (a) No therapy; (b) 
six courses of standard HOPP treatment; and (c) 
six courses of BCVPP. 



159 



Krantz, S. B. , Zaer.tz, 3. D., Graber, S. E., U.S. 
Veterans Admnistration, Hospital, Hematology Unit, 
1310 2ilth Jve. S., Nashville, Tennessee, 37203, 
U.S.*. 

Daunomycin, CCNU and Bleomycin represent new 
drugs which are currently being administered to 
patients with acute leukemia or malignant lymphoma 
Including Hodgltin's Disease. Another protocol has 
been added, which uses daunomycin and prednisone 
for erythroleukemia. One patient was treated with 
this protocol who had erythroleukemia, but no 
remission of the disease was produced. This 
patient died of infection subsequent to drug 
therapy. Use of Bleomycin by itself has been 
superseded by another protocol which has added to 
this research study. This protocol is titled "The 
Use of E-Dopa for Hodgkin's Disease witn noPP 
Failure." Two patients nave been treated with the 
B-Dopa program: one has done very well with a 
complete remission of his disease and the other 
failed on this program and subseguently died. At 
the present time, insufficient numbers of patients 
bave been treated with these drugs to draw any 
general conclusions and the study is proceeding as 
outlined. 



study was undertaken since 1972 in cur department 
and the Southwest oncology Group to compare the 
efficacy of CHOP vs HOP for remission induction. 

PROGRESS: Doctor acKelvey has recently 
completed the analysis of 129 evaluable patients 
and found that the regimens are equally effective. 
The overall response in the 208 patients who 
received CHOP was 95 percent with 67 percent of 
them in complete remissions (CB) . In the 221 
patients receiving HOP, the overall response was 
88 percent with 61 percent of them in CR. The 
lowest response rate occurred in patients with 
unclassified lymphomas (5C percent CR) . However, 
patients with histiocytic and lympnocytic lymph- 
omas had CR rates greater than 50 percent. Best 
CR rates were obtained in nodular disease. 
However, in diffuse histiocytic lymphoma, complete 
remission rates of 70 percent (CHOP) and 63 
percent (HOP) were obtained. The projected 1 year 
survival for all patieniis on CHOP and HOP chemoth- 
erapy is 73 percent and 66 percent respectively. 
The survival appears superior for patients wirh 
nodular disease. 

Our investigations in malignant lymphomas 
have also concentrated on the maintenance therapy 
for these diseases. Thus, two maintenance 
regimens have been investigated after induction 
with CHOP vs. HOP. (Text Abridged.) 



261. COHEIHATIOH CHEMOTHEHAPy FOR STAGE IIIB AMD 
IV aODGKIN'S DISEASE — USE OF CVPP 
Kiernik, P. H., Levi, J. A., Diggs, C. H., U.S. 
Oept. of Hlth. Ed. 6 Wei., Natl. Cancer Institute, 
Hedicine Section, Baltimore, flaryland, U.S.A. 

Fifty patients with advanced Hodgkin's 
Disease were treated with a combination of 
cyclophosphamide, vinolastine, procarbazine, and 
prednisone (CirPP) in every three-week regimen. 
Patients who achieved complete remission were 
randomized to receive maintenance therapy cons- 
isting of monthly alternating CCNU and vinblastine 
or to be followed on no therapy. Thirty-one 
patients (62)i) achieved complete remission with 
the fewest remissions being seen (3/8) in those 
patients who had previously both chemotherapy and 
radiation therapy. Maintenance therapy to date 
has no significantly prolonged remission duration 
or survival. Patients who received more than six 
courses of induction therapy have had longer 
remissions and fewer relapses than those receiving 
only six courses regardless of maintenance therapy 
status. CVPP IS an effective regimen for inducing 
remissions in advanced Hodgkin's disease. Mai- 
ntenance therapy has not yet been shown to be 
beneficial. 



262. CHEMOTHERAPY OF HODGKIN'S DISEASE AND 
BAIIGNANI LYMPHOMA 

Rodriguez, v., Bodey, G. P., McKelvey, E., Univ. 
of Texas, M.D. Anderson Hosp. B Inst., Develop- 
mental Therapeutics, P.O. Box 20036, Houston, 
Texas, 77025, U.S.A. 

OBJECTIVE: The objective of th .s study is to 
Improve the remission induction rate and duration 
of remission in patients with malignant lymphomas, 
with conventional agents by modification of dose, 
schedule, duration of treatment and with combined 
chemotherapy. Also, to determine tne utility of 
new agents and of new methods using conventional 
agents in patients with lymphoma who are refrac- 
tory to conventional agents and conventional 
methods. 

APPROACH: In the past, we have been actively 
investigating new modalities of chemotherapy of 
malignant lymphoma and have participated in such 
studies with the Southwest Oncology Group. These 
studies have continued. Recently, hydroxydaunoru- 
bicin (Adriamycin) was demonstrated to be very 
effective in patients with advanced malignant 
lymphoma refractory to other regimens. Accord- 
ingly, Drs. Gottlieb and Gutterman in our depa- 
rtment designed a ccmbina t icn chemotherapy regimen 
for remission induction of advanced malignant 
lymphoma with cyclophosphamide, hydroxydaunoru- 
bicin, vincristine and prednisone (CHOP) . The 



263. BECCNU IN HODGKIN'S DISEASE 

Bottomley, R. H. , Hampton, J. M., Grozea, P. N., 
Hoge, A. F. , Ishmael, D. R. , Hussein, K. K. , 
Oldham, F. B., U.S. Veterans Administration, 
Hospital, Hematol Oncol sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 73104, U.S.A. 

OBJECTIVES: To evaluate the effectiveness of 
intermittent oral methyl CCNU in the treatment of 
various sclid tumors. This protocol is open only 
for treatment of patienrs with Hodgkin's disease. 
(Text Abridged.) 



2611. COMBINATION CHEMOTHERAPY OF HODGKIN'S DISEASE 

Presant, C, Washington University, School of 

Medicine, Internal Medicine, 660 S. Euclid Ave., 
St. Louis, Missouri, 63110, U.S.A. 



This is part of a broader project, 
of this subproject is not available. 



265. CHEMOTHERAPY FOR LYMPHOMA AND HODGKIN'S 

DISEASE 

Bloomfield, C, Univ. of Minnesota, School of 

Medicine, Medicine, 1305 Mayo, Minneapolis, 

Min 



marv 



sota, 55h55, U.S.A. 



This is part of a broader project. A summary 
of this subproject is not available. 



266. COWPAR I SOH OF RADIOTHERAPY AND CHEMOTHERAPY 
IN THE MANAGEMENT OF PATIENTS WITH SIAGE-IIIA 
HODGKIN'S DISEASE 

Fairley, G. H., Sutcliffe, s. B., Hhitehouse, J. 
M., Imperial Cancer Eesearcn Fund, Medical 
oncology Unit, Lincolns Inn Fields, llc2a 3px, 
London, England, United Kingdom 

Patients with pathological Stage IIIA 
Hodgkin's disease have been entered into a 
co-operative study with the Medical Research 
Council which is designed to compare the role of 
combination chemotherapy or radiotherapy in the 
treatment of advanced nodal disease. 

So far eight cases have received chemotherapy 
(MVPP) and 16 have been treated by radiotherapy. 
The remission rates are 88% and lOOX respectively. 
To date there have been no relapses in the 
combination chemotherapy group, but six have 
relapsed in the radiotherapy group. One death due 
to infection has occurred. The minimum follow-up 
of this series is thirteen months. 



160 



267. RADIATIOII VS CHEnlCiL IBEBAPI FOB STAGE III 
HODGKIN'S DISEASE 

elooifield, C, Univ. of Klnnesota, School of 
Bedicice, Hediclne, 1305 nayo, Dinneapolis, 
BiDoesota, SSUSS, U.S.A. 

This is part of a broader project. A suomary 
of this subproject is cot available. 

3. OTHER THERAPY FOR HODGKIN'S LYMPHOMA 



272. THE STDPT OF HODGKIN'S DISEASE 
JohQSOQ, B. E.« Greco, F. A., nerrill, J. N.# 
ZiBbler, H., U.S. Dept. of Hlth. Ed. £ Wei., Natl. 
Cancer Institute, Radiation Oncology Branch, 
Bethesda, Harylaod, 200114, U.S.A. 

This study involves long-term, continuous 
observation of patients treated between 1965 and 
1969 for Hodgkin's disease. Information is being 
collected and periodically evaluated with respect 
to not only survival but delayed consequences of 
the disease and its treatment in these patients. 



268. COOPEHATITE HODGKIN'S DISEASE CLINICAL 
TmAL— TEW YEAB FOLLCB-OP OF EFFECTIVENESS OF 
EXTENDED FIELD BADIOTHEHAPY 

Hutchison, G. B. , NicKson, J. J.. Fuller, L. B., 
Kaplan, H. S. , Peters, v., Rapt^aport, H., Viaaonte, 
B., lee, B. J., Shalek, H. J., Harvard University, 
School of Public Health, Epidemiology, 55 Sbattucic 
St., Boston, Hassachusetts, 02115, U.S.A. 

A group of patients with Hodgkin's disease of 
stages 1 and 2 who were enrolled in the years 1967 
to 1973 in a collaborative clinical trial compa- 
ring involved and eitended field radiotherapy will 
be followed to determine mortality and morbidity 
through 10 years following enrollment. 

Outcome measures include survival, extension 
of disease, distant eitension of disease, and 
complications. 

Initial descriptive variables include age, 
sex, histologic type, use of diagnostic laparot- 
omy, stage, systemic symptoms. 

continued follow-up will serve to refine 
outcome measures at the early intervals since 
treatment and to obtain measures of outcome at 
longer intervals. Treatment effects significantly 
different from zero have been seen in frequencies 
of extensions and complications but not in 
frequency of distant extensions or in mortality up 
to the present date. It is desired to determine 
whether effects follow this same pattern in later 
follow-up years or whetner early extensions serve 
as predictors of later distant extensions or 
death. 

Twenty institutions have enrolled at least 
one patient each, and at least one survivor 
remains under follow-up in each center. Continued 
follow-up will be obtained through collaboration 
between these centers and the coordinating center, 
Boston. A total of tOU patients remain active at 
this time. It is estimated that 270 patients will 
survive to 10 years after enrollment. 



269. FOLLOBUP ON RADIOTHERAPY OF HODGKIN'S DISEASE 
Prosnitz, L. , Yale Uriiversi'y, School of nedicine. 
Therapeutic Radiology, 333 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 



This is part of a broader project. A summary 
of this subproject is not available. 



270. TREATING HODGKIN'S DISEASE NIIH EXTENDED 
FIELD RADIATION 

Bong, H. H., Univ. of Minnesota, School of 
Bedicine, Therapeutic Radiology, 1305 nayo, 
Binneapolis, Hinnescta, 55155, U.S.A. 



This is part 
of this subproject 



broade 



271. ANTIBODY RESPONSE TO IBHUNIZATION IN HODGK- 
IN'S DISEASE 

Holton, C. P., Childrens Hosp., 1056 E. 19th Ave 
Denver, Colorado, 80218, U.S.A. 

This is part of a broader project. A summa 
of this subproject is not available. 



273. HODGKIN'S DISEASE — COMPARISON OF TREATBENT 
Kellermeyer, R., Univ. Hospitals of Cleveland, 
2065 Adelbert Ed., Cleveland, Ohio, UU106, U.S.A. 

This is part of a broader project. A sumaary 
of this subproject is not available. 



2711. HODGKIN'S DISEASE IN CHILDREN 

Smith, K., St. Jude Cn. Hes. Hosp., Box 318, 332 

N. Lauderdale St., Memphis, Tennessee, 38101, 

U.S.A. 

This is part of a oroader project. A summary 
of this subproject is not available. 



0. THERAPY OF NON-HODGKIN'S LYMPHOMA (OR UNSPECI- 
FIED LYMPHOMAS) 



1. MULTIMODAL THERAPY FOR NON-HODGKIN'S LYMPHOMA 



275. NON-HODGKIN'S LYMPHOMA. TRIAL NO. 3 — 

EXTENSIVE STAGING FOLLOWED BY RANDOMIZED BADI- 

OTHERAPY AND C HEMOTHERAPY 

Burgers, J. H., lierie, A. H., Cleton, F. J., 

Vanunnik, J. A., Breuer, K., Somers, B., Antoni 

Tan Leeuwenhoek Hosp., Plesmanlaan 121, Amsterdam, 

Netherlands 

The results of treatment of the non-Bodgkin's 
lymphomas are worse than those or Hodgkin's 
disease. 

In the EORTC radio-chemotherapy group, a 
trial has been started which includes extensive 
staging procedures and an aggressive treatment for 
all stages. Staging procedures include bone 
biopsies and laparoscopy with liver biopsy. The 
staging procedure is planned to exclude stage IV 
with each successive procedure. For the patients 
who are not stage IV after clinical staging, a 
laparatomy is carried out with splenectomy and 
liver biopsy; multiple mesenteric nodes are also 
removed. 

Treatment differs per stage: Stage I: A 
randomization is made between mantle field (or 
inverted Y) versus the same radiotherapy with one 
year adjuvant chemotherapy with a Vincristine- 
Prednisone-Cytoxan combination. 

Stage II: a) Above diaphragm: randomiz- 
ation, one group only receiving mantle field, the 
other group receiving mantle field with abdominal 
radiotherapy. Both groups are treated with one 
year chemotherapy after radiotherapy. b) Below 
diaphragm: randomization was carried out berween 
abdominal bath radiotherapy versus a combination 
of abdominal bath with mantle field. 

Both groups receive chemotherapy. 

Stage. Ill and IV: The randomization is 
between two forms of intensive remission induction 
chemotherapy, i.e., different combinations of 
VB26, Adriamycin, Cytoxan and Prednisone. 

After this remission induction treatment, 
radiotherapy is given to the biggest tumor area or 
residual areas, followed by a maintenance chemoth- 
erapy. Some centers will treat stage IV patients 
with total body irradiation. 

It is hoped that the prognosis will be 
Improved by this intensive program. In this trial 
no difference in treatment will be made in advance 
between the histological types. This will 



41 

161 



therefore be a unique opportunity to estinate the 
value of the different histological classificat- 
ions in a prospective study. At the moment 15 
patients are included from our Institute. 



276. COHIBOLLED STODV III THE TREtTBEm OF HOB- 

HODGKIU'S DISEASE -BtPIOTHEBAPI BND/OR CHEHOTHE- 

RAPt 

Banfi, A., Bonadonna, G. , Lattuad<t, A., nilani, 

F., Natl. Inst, for Study of Tumor, Via G Venezi 

1, nilan, Italy, 2013J 



OBJECTIVE: To determine the optimal the- 
rapeutic approach in the treatment of different 
stages of non-Hodgkin' s lymphomas. 

APPROACH: Patients with a histologically 
confirmed diagnosis cf non-Hodgkin* s disease are 
eligible for this study. Different treatments are 
planned for every stage and patients are strati- 
fied according to histologic subgroups and 
patterns and type of staging. In stage I and II, 
patients are randomized to receive either radioth- 
erapy alone or RT plus CVP (cyclophosphamide, 
vincristine, prednisone) for 6 cycles (in stage 

III they uill receive either BI followed by 6 
cycles of CVP or 6 cycles of CVP followed by RT; 
in stage :v they are randomly allocated to receive 
either CVP or ABP (adriamycin, bleomycin and 
prednisone). 

PROGRESS: An analysis carried out on 
patients presenting with stage I-II disease failed 
to demonstrate the advantage of adding chemothe- 
rapy to irradiation in early stages of non- 
Hodgkin's disease. In stage III patients our 
preliminary updated results fail to indicate that 
after t'he combined modality approach, the incid- 
ence of CB, the median duration of complete 
response and the relapse rate were significantly 
affected by either sequential program. In stage 

IV patients, where the aim of study was to explore 
the therapeutic effects and the lac)t of cross- 
resistance of the two combinations, both treatm- 
ents appear equally effective in terms of CR (CVP 
Kit percent, ABP "46 percent). The secondary 
treatment upon progression or relapse (crossover) 
yielded complete plus partial remission in 28 
percent of patients treated with CVP and in 33 
percent of those given ABP. 



277. RADIOTHERAPY AND/OR COHBIBATIOH CBEBOTHEBAPIf 
or KOB-HODGKIM'S LYKPHOHAS IH CHILDREM (ALL 
STAGES) AND IN ADULTS (LEUKEMIC PHASE) 
Bellani, F. f., Gasparini, n. , Natl. Inst, for 
Study of Tumor, Via G Venezian 1, nilan, Italy, 
20133 

OBJECTIVE: To determine an optimal thera- 
peutic approach in the treatment of non-Hodgkin* s 
lymphomas in childhood and in adults with leukemic 
phase. 

APPROACH: All children with histologically 
confirmed diagnosis of malignant lymphoma, not 
previously treated with drugs used in this study 
are eligible, while for adults only those in 
leukemic phase are treated under this protocol. 
Children with stage :-II diseases are first 
treated with radiotherapy, followed by 6 cycles of 
CVP (cyclophosphamide, vincristine and predniso- 
ne). Chemotherapy will start one week before the 
end of radiotherapy. Children with stage III and 
IV and adults are given a combination chemotherapy 
(adriamycin, cyclophosphamide, vincristine, 
prednisone plus methotrexate) tor a period of 2 
months (remission induction phase). After 
induction, consolidation is planned (6-nP plus HTX 
p.o. or i.m. plus BLH) . A reinduction phase is 
also planned. 

PROGRESS: It is too early to carry out a 
proper evaluation. Actually our series of evalu- 
able cases consists of 17 patients, namely 15 
children and 2 adults. 



278. MON-HODGKIS'S LinPHOID MALIGNANCI - CHEB- 
OTHEBAPY WITH AND UITHOUT CBAMIAL IBHADIATION 
Lister, T. A., Uhitehouse, J. «., Beard, (1. E. , 
Imperial Cancer Research Fund, (ledical Oncology 
Onit, lincolns Inn Fields, Uc2a 3pi, London, 
England, United Kingdom 

One hundred and fifty patients with gener- 
alized disease (including acute lymphoblastic 
leukemia) have been allocated to either a good or 
a poor prognosis group on the basis of histology 
(Rappaport classification) or morphology (BGG 
stain) . 

Those in the good prognosis group have b6en 
randomized to receive either- chlorambucil or 
intermittent cyclophosphamide, vincristine, and 
prednisolone (CVP) for remission induction, and no 
maintenance. The response rate is approximately 
the same in both groups and the pattern of relapse 
is being studied. 

All patients in the poor prognosis group are 
being treated intensively with adriamycin, 
vincristine, prednisolone, and asparaginase. 
Those achieving complete remission are given early 
central nervous system therapy, i.e. cranial 
irradiation and intrathecal chemotherapy. 
Haintenance therapy is given using cyclophosph- 
amide, methotrexate and 6-jiercaptopurine. The 
complete remission rate is about 60 percent for 
all patients, being higher in those with acute 
leukemia. 

The pattern of both hematological and CNS 
disease is being studied and related to a battery 
of presentation parameters. The median complete 
remission length is about 13 months and median 
survival of the remitters over 21 months. 



279. (mVESIIGATIVE STUDIES IH IREATBENT OF 

BUBKITI'S LYBPHOBA) 

Kyolwazi, S., Bakerere University College, Kampala, 

Uganda 

This part of a broader project includes 
investigations in Burkitt's tumor, as follows: 1. 
Treatment protocol studies for remission induction 
with cyclophosphamide followed by immunotherapy 
with BCG in a randomized, controlled trial. 2. 
Investigation of new agents in resistant Burkitt's 
lymphoma patients. 3. Continued investigation of 
central nervous system treatment with CCNU and 
irradiation therapy. (Text Abridged.) 



280. NEW BULTinODALITY PROTOCOL FOR IBSAIIIIG 
NON-HODGKIN'S BALIGBANT LYBFHOIIAS 

Bonesana, A. C. , Schvartzman, E. , Papendieck, C, 
Pavlovsky, S. , Degarcia, C. P., Sackmann, F., 
Penchasky, L. , C. E.T.N. I., Oncology, Gallo 133C, 
Capital Federal, Buenos Aires, Argentina 

OBJECTIVES: To determine that the combina- 
tion of surgery, radiotherapy and chemotherapy 
improves post- treatment status, in comparison wit 
prior experiences; to evaluate two maintenance 
plans. 

APPROACH: Study of children with non- 
Hodgkin's lymphomas, between 0-15 years of age. 



281. NON-HODGKIN' S LYBPHOBA, L2 GROUP STUDY 
PROGBAB — SE(jU£NTIAL CQHBXNAIIOJ CHEBOIHEBAPY 
MODERATE RADIOTHERAPY 

Hartmann, J. B., Cnard, 5. ].., Bleyer, w. A., 
Bernstein, I. D., Childrens orthopedic Hospit 
Hematology, UBOO Sand Point Way B.E., Seattle 
Washington, 98105, U.S.A. 



This institution is presently using the 
program called the L2 program used at Sloan 
Kettering Institute and to date we have place 
four patients under this program. This progr 
utilizes multiple chemotherapy drugs in a seg 
ential fashion with only moderate amounts of 
to the primary lesion. Ihe program is starte 
with high dose cyclophosphamide, prednisone a 
vincristine, followed at that tine with radia 
administered to the local area, ranging from 
to 2500 rads. The patient then receives intr 



162 



thecal Bethotrerate approxinate 
daunonycin is given in two dos 
six weeks for the induction pa 
Follcwing this is consolidation 
of daily cytosine arabinoside 
Following completion of that, 
receives twelve doses of 1-asp 
this tine another two doses of 
■ethottexate. Maintenance the 
of five different cycles of dru 
days with a fourteen day rest 
Cycle one is 6-thioguanine for 
on the fifth day by intravenou 
Cycle two is oral hydroxyurea 
followed on the fifth day by i 
■ycin. Cycle three is oral met 
days followed by intravenous BC 
day. Cycle four is cytosine 
days with intravenous vincri, 
day; and cycle five is intra 
two doses three to four days 
therapy is carried on for a > 
Initial data presented at a i 
Park indicated that with sue. 
Kettering had seen 70 percent d 
at one year. The Childre 
has fifty such patients. 



ly monthly; 

s within the first 

t of the program. 

th fifteen doses 
ith 6-thioguanine. 
he patient then 
raginase and during 
intrathecal 
apy then consists 
gs given for five 
eriod in between* 
four days followed 
cyclophosphamide, 
or four days 
travenous dauno- 
hotrexate for four 

the fifth 
abinoside for four 
ne on the fifth 
cal methotrexate 
art. The latter 
ation of two years, 
ting in Boswell 
program, Sloan 
sease free results 
ncer Study Group 



282. COHBIHATIOH RADIOTHERAPY, CHEHOTHERiPY AHD 
IMHUMOTHERAPY IN THE HAttAGEBENT OF STAGES I AND II 
NON-HODGKIH*S LYHfHOfIA 

Fuller, L. (1., Gamble, J, F. , Sinkovics, J. G., 
Shullenberger, C. C, Univ. of Texas, n.D. 
Anderson Hosp. 6 Inst. , Radiotherapy, P.O. Box 
20036, Houston, Texas, 77025, U.S.A. 



nd 



OBJECTIVES: To see whether the incidence < 
duration of remission can be improved in Stage ] 
and II non-Hodgkin's lymphoma patients by: 1) 
celiotomy and splenectomy for more accurate 
staging in patients with nodal and/or extranodaJ 
disease, 2) the addition of systemic treatment 
following local radiotherapy utilizing: a) a 
multi-drug program and b) immunotherapy. 

APPROACH: Celiotomy staged I and II non- 
Hodgkin's lymphoma patients less than 65 years c 
receive radiotherapy to involved regions includi 
the abdomen. Those patients remaining in comple 
remission are randomized to either chemotherapy, 
immunotherapy, or no therapy. Chemotherapy of 
Cytoxan, Adriamycin, Oncovin, Prednisone, and 
Bleomycin (CHOP Bleo) is maintained for twelve 
nonths. Immunotherapy consists of BCG scarifi- 
cation followed by lymphoma viral oncolysate 
vaccination over a twelve month period, Patiem 
in the no therapy or immunotherapy maintenance 
arns receive chemotherapy or immunotherapy at th 
first sign of relapse. 



283. CpHBINED RADIOTHERAPY, CHEHOTHERAPY AND 
IHMUHOTHERAPY IH THE HRNAGEHENT OF STAGE III 
MOH-HODGKIW'S LYMPHOMA - A PROSPECTIVE CONTROLLED 



Fulle 



STUDY 

Gamble, 

C, Sinkovics, J. G., 

Anderson Hosp. & Inst. 

Houston, Texas, 77025, 



L. H., Shullenberger, C. 
rniv, of Texas, H.D. 
. Medicine, P.O. Box 20036, 

U.S.A. 



OBJECTIVE: To determine if inten 
combination chemotherapy and radi other 
feasible in Stage III lymphoma patient 
such a program will improve remission 
rates and prolong survival. To conpar 
otherapy with no therapy after the pat 
achieved a complete remission and dete 
whether immunotherapy will prolong rem 



APPROACH: The basic desi 
Bent of Stage III non-Hodgkin' 
ding Stage II diffuse lymphoma 
intra-abdominal involvement, w 
The patients will be divided a 



> lymphoma, incl 
with massive 
.11 be as follow 
:cording to the 
pathological classification into nodular and 
diffuse lymphoma. Nodular lymphoma will be 
treated with 2 courses of CHOP plus Bleomycin 
(Adriamycin, Cytoxan, Oncovin, Prednisone and 
Bleomycin) followed by total abdoninal X-ray 



■let count 


lamed for 2 


le neck or 


■e 6 farther 


a complete 


It will be 


,0 therapy. 


It of 


ise of 


. lymphomas. 


lemotherapy. 


ibed as a 


.ation 


licated by 


reec courses 


Its with 


illy to the 


.her 


will be 


.ed. 


be placed 


Patients 


: induction 


randomized 



therapy. After the leukocyte and plate 
has recovered, chemotherapy will be res 
courses followed by x-ray therapy to th 
axillae. The patients will then receiv 
courses ol CHOP plus Bleomycin, and if 
remission has been obtained, the patien 
randomized either to immunotherapy or n 
Ihe CHOP treatment used in the treatmen 
nodular lymphoma will have a reduced do 
Adriamycin and Cytoxan. In the diffuse 
the major emphasis will be placed on ch 
The patients will receive what is descr 
full dose of CHOP plus Bleomycin. Radi 
therapy to the abdomen and neck, as ind 
the bulk of disease, will be given betw 
of chemotherapy. Stage I and II patien 
large neck nodes will be treated initia 
head and neck with x-ray therapy. Furt 
work-up, to include staging celiotomy, 
delayed until neck lesions are controll 
Patients will, after surgical staging, 
in the appropriate treatment program, 
will receive approximately 18 months of 
and consolidation treatment. Patiants 
to immunotherapy will receive 12 months 
remission maintenance. 



281. S80G 7133 - RftPIOTHERAPI BITH AMD BITHOHT 
CHEBOIHEBAPY FOR STAGE I AND II WON-HODGKIM ' S 
ITMFHOHA 

Bottomley, R. H. , Hampton, J. U., Grozea, P. 11., 
Hoge, A. F., Ishmael, 0. R., Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Bematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310U, U.S.A. 

OBJECTIVE: To compare the remission rate, 
remission duration and survival in patients with 
non-Hodgkin' s lymphoma, pathologic stages I, IE, 
II and HE treated with extended field radiothe- 
rapy (supradiaphragmatic mantle or abdominal 
field) alone, with extended field radiotherapy 
plus combination chemotherapy (CHOP) . 

TREATBENT PLAN: Patients will be randomized 
to either radiation therapy or radiation therapy 
plus chemotherapy. The only exception will be 
patients presenting with the histologic diagnosis 
of diffuse lymphoma below the diaphragm, who will 
not be randomized for this study. (Text Abridg- 
ed.) 



285. PHASE III - CBEHOIHWONOTHEHAPI IN MON- 
HODGKIN' S HHPHOMA 

Jones, S., Salmon, S., Solidoro, A., Vallejos, C, 
Southwest Oncology Group, Suite 20 1, 3500 Rainbow 
Blvd., Kansas City, Kansas, 66103, U.S.A. 

PROTOCOL ENTRY CRITERIA: All patients with 
any histologic type of stage III or IV non- 
Hodgkin's lymphoma established by biopsy are 
eligible. Patients with chronic lymphocytic 
leukemia are ineligible. 

PURPOSE: 1. To compare the effectiveness of 2 
chemotherapy regimens or chemoimounotherapy for 
remission conduction in previously untreated 
non-Hodgkin's lymphoma patients; 2. to evaluate 
systematic restaging of CR's; 3. to test the value 
of continued maintenance immunotherapy vs nonmain- 
tenance treatment for ca's; «. to test the 
effectiveness of continued treatment with chemoim- 
munotherapy for PR's. 

PROTOCOL OUTLINE: Induction (8 courses), 
randomized: Arm 1, CHOP and Bleo (x8) q. 21 days. 
Arm II CHOP and BCG (x8) g. 21 days. Arm HI, COP 
and Bleo (x8) g. 28 days. Restaging, NF - Off 
study Documentel CR, 3 cycles, same induction Rx. 
Randomized, Maintenance: Arm IV, no maintenance 
Rx. Arm IV, BCG q 28 days x 18 m. Arm V, chemoim- 
■unotherapy COP (or CAP) and BCG g. 28 days. 

DOSAGE SCHEDULE: Arm I: Cyclophosphamide, 
750 mg/m2 i.v. day 1. Hydroxyldaunorubicin, 50 
mg/m2 I.V. day 1. Oncovin, 1.U mg/m2 I.V. day 1. 
Predisone, 100 mg/d PO day 1-5. Bleomycin, t mg/m2 
I.V. day I. BCG 2-3 xlO to the 8th power organisms 
by scarification on days 8 and 15 of each CHOP. 
Courses to be repeated every 21 days. Arm II: 
Cyclophosphamide, 125 mg/m2 PO day 1-1<t. Oncovin, 



163 



1.1 tq/Kl 1.1. day 1-8. Prednisone, 100 tq PO day 2. CHEMOTHERAPY FOR NONHODGKIN'S LYMPHOMA 
1-5. Bleoycin, 14 nig/m2 I.V. day 1 i8. Courses 
repeated every 28 days. 

269. CHEHOIHEBAPT of MON-HODGKIll'S LYBFHOnAS 

286. SIIOG-T426/27 - CHEHOTHEBAPT OB CHEnomMaBOTH- freedman. A., HiBfoo, B. , Lavrin, L. , Harstiall, 
tBAPI roB BON-HODGKIN'S STAGES III AND IV R, , New South Wales St. Can. Coun. , challis House 
Bottomlej, R. H., Hamtiton, J. U., Grozea, P. N., 10 Bartin PI., Sydney, Neu South Bales, Australia, 
Boge, A. f., Ishmael, D. P., Hussein, K. K., 2000 

OldhaB, F. B., U.S. Veterans Administration, 

Hospital, Hematol Oncol Sects, 921 N.E. 13th St., OBJECTIVE: A new protocol, COBEA, for 

OfclahoBa City, Oklahoma, 73101, U.S.A. therapy of stage 3 6 4 non-Hodg kin ' s lymfhoma, to 

be compared with c.o.P.P. protocol. 
OBJECTIVES: To compare the effectiveness of APPROACH: Cyclophosphamide, Vincristine, 
2 chemotherapy regimens {CHOP plus Bleomycin; COP then high dose oral Bethotrexate with oral folinic 
plus Bleomycin) or chemoimmunotherapy (CHOP plus acid rescue, on an outpatient basis -I.V.I. 
BCG) for remission induction in previously cytosine arabinoside and completion of Bethotre- 
untreated patients with non-Hodgkin's lymphomas. late and folate rescue. 
To establish baseline and serial data on immun- 
ologic status in both chemotherapy and chemoimmun- 
otherapy groups. To evaluate systematic restaging 290. CONTBOIIED STDDI BITH SEQUENTIAL BULTIPLE 
of patients judged to be in complete clinical DRUG conBINATIOllS IN APVANCED NON-HODGKIN'S 
remission. For patients proven to oe in complete DISEASE 

remission after induction, to test the value of Bonadonna, G. , nonfardini, S., Delena, n., Natl, 

continued maintenance inmunot herapy (BCG) vs no Inst, for Study of Tumor, Via G Venezian 1, Milan, 

naintenance treatment. For patients who only Italy, 20133 
achieve a partial remission during induction, to 

test the effectiveness of continued treatment with OBJECTIVE: Following the results achieved in 

chemoimmunotherapy. a previous controlled study, this trial was 

PEBISSION INDUCTION: Eight courses of undertaken with the intent to determine a more 

treatment will constitute remission induction. If aggressive chemotherapeu tic treatment in stage IV 

induction results in a CR and this is confirmed by non-Hod j kin's lymphomas. 

restaging, then the patient is eligible for a APPF04CH: All patients, aged more than 15 

second randomization into the maintenance phase of' years, with histologically confirmed diagnosis of 

this study. If residual lymphoma is detected non-Hodgkin' s lymphomas, with stage IV disease, 

during restaging, an additional 3 courses of are judged eligible for this study. Patients will 

treatment will be administered, restaging repea- receive one cycle of CVP alternated with ABP every 

ted, and patients in CR will be eligible after 11 three weeks (seguential treatment) for a total of 

courses of induction for the maintenance phase. 6 cycles (CVP 3 cycles, ABP 3 cycles). Patients 

Patients who are only in a partial remission after in complete remission after 6 cycles will receive 

11 courses of treatment ate eligible for continued 6 more cycles of sequential combinations ' but every 

treatment with chemoimmunotherapy. 6 weeks, at which point, if there is still 

complete remission, treatment is stopped and 
resumed only in presence of relapse. Patients in 

287. CHEBOIBBONOIHEBAPY OF CANCEB BY IBBUNIZAIION good partial remission (greater than 5C») at the 
BITH CULTURED TU BOR CELLS end of the first phase (first 6 cycles) will 
Sinkovics, J. G. , Shullennerget , C. C. , Univ. of receive 6 more cycles of CVP followed by ABP every 
Texas, B.D. Anderson Hosp. 6 Inst., Bedicine, P.O. 3 weeks until they reach CR. In presence of 

Box 20036, Houston, Texas, 77025, U.S.A. progression between 6th and 12th cycles, CCNU 6 

VLB will be administered. The same treatment will 

OBJECTIVE: Patients with malignant lymphoma, be given to non-responsive patients, 
sarcomas or malignant melanoma receive chemoimmun- PROGRESS: It is too early to carry on any 

otherapy. Immunotherapy consists of either analysis which, in any case, will take into 

scarified live BCG or tumor lysates or both. consideration each histological subgroup. Our 

APPBOACH: The clinical status and in vitro series consists of 20 cases; not less than 50 

tunor-specif ic immune reactions of the patients cases are required for a preliminary evaluation. 
are evaluated. 

291. CHEBOTHERAPT OF HISTIOCYTIC LTBFHOBA 

288. EFFECT OF INTERFERON THERAPY ON NON-HODGKIN'S Jacobs, P., Univ. of Cape Town, School of Bedicine, 
LiaPHOBA -- COflPABISON AND COBBINATION WIIU Hematology, Private Bag C.P. 77C0, C.P. 77C0, Cape 
COMVENIIONAL THERAPY Town, Cape of Good Hope, Republic of South Africa 
Berigan, I. c, Rosenberg, S. A., Breeden, J. H. , 

Valle, B. J., Brodeur, B., Stanford University, A randomised, prospective three-Arm trial is 

School of Bedicine, Bedicine, Palo Alto, Califo- presently in progress to evaluate VP 16-213 as a 

rnia, 9il305. U.S.A. single agent against this Epipodophyllot oxin 

combined either with cyclophosphamide or adria- 
an mycin. 

292. IBIAL OF COP VEBSUS PEP IN NON-HODGKIN'S 
LYBPHOHA 

re Jackson, J. H., Herrmann, R., Boyal Perth Hospital, 

erth. Western 

This hospital is participating in this trial 
which is a multi-centre trial ,in.volving hospitals 
in New South Wales, Victoria, South Australia, 
Western Australia and New Zealand. 

OBJECTIVE: To compare remission and survival 
in advanced non-Hodgkin's lymphoma between 
cyclophosphamide/vincristine/prednisolone and 
cyclophosphamide/VB26 (Sandoz) /prednisolone. 

Either regimen given in 3 weekly cycles ot 5 
days each until complete remission achieved. If 
there is no improvement after 3 courses, patients 
are crossed over to alternative regimen. Three 
consolidation courses are given at 3 weekly 





This study will evaluate 


the effect of hur 


leukc 


jcyte interferon on severa. 


1 stages and typ* 


of nt 


)n-Hodgkin's lymfh( 


3ma. Th. 


3 initial studie; 


will 


be doi 


3e on patieni 


ts with , 


advanced but 


objectivel' 


( measurable 


disease 


who have failed 


other convi 


jntional therapy. T 


hen, if results ; 


encoi 


iraging, patients i 


<ith "go. 


Dd" risk and "poc 


risk 


types 


of histolog: 


really a, 


nd clinically sti 


disease wi. 


11 be utilized to ev. 


Jluate, on a 


controlled 


basis, the effect o: 


£, short-term but 


intei 


isive ; 


interferon therapy oi 


n disease status 


recurrence, 


. This will 


be done 


both by contrasi 


with 


and i) 


1 concert with conve) 


^tional therapy. 


Careful ob: 


servation of 


interfei 


con pharmacokinel 


Ics, 


effect 


t of treatmei 


It on cl: 


inical course anc 


possible s: 


ide effects will be carried out thro- 


ughout the 


trials. 







164 



lntei>als after Ca, then aalntenance courses of 
saae legisen at 6 weekly intervals for 1B Bonths 



293. A DOUBLE >RM COOPEBATITE CHEBOIHEtlAPt STUDI 
H 1108-HODGKIII'S HBPHOWA 

Cooper, I. A., Gunz, F. v., Penington, D., Pitney, 
1. P., Stephens, E. J., Herrmann, S., Dale, B. , 
Cancer Institute, Haematology Lynphona Unit, USI 
little Lonsdale St., Melbourne, Victoria, Austr- 
alia, 3000 

In 1973 a group of clinical investigators 
£ro« nine Institutions situated in four of the 
seven states of Australia agreed to establish a 
Cooperative Chenotherapy Study Group. The first 
project vas to conpare the efficacy and toxicity 
of tvo drug combinations used in the management of 
non-Hodgkin's lymphoma. The two drug combination 
C.V.P. and P.E.P. vary in only one respect, » 
equals vincristine and E equals the epipodophyllo- 
toxin V(126, the other drugs being cyclophosphamide 
and prednisolone. The statistically controlled 
trial has been in progress since July 1st 197U, 
and 15 Bonths later 75 patients have been reg- 
istered. The trial had not been in progress for 
long enough to permit any conclusions. It is, 
however, expected that by the end of 1976 there 
Bay be sufficient data. 



2911. SOG 7107 - TB-lt IH aODGKIM'S AlP HOW- 

aocGHii's lyHPHonT 

Bottoiley, R. H.; Hampton, J. W., Grozea, P. N., 
B09e, A. F., Ishmael, D. B., Hussein, K. K. , 
Oldham, F. B., U.S. veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoaa City, Oklahoma, 731014, U.S.A. 

OBJICIIVE: To determine the efficacy of 
»P-16 in adult patients vith Hodgkin's disease and 
non-Bodgkin's lymphoma. All patients shall 
receive the same initial dose of VP 16-213: 100 
ag aapule, dissolved in a combination of organic 
solvents and diluted vith physiologic saline for 
IV infusion over 30 minutes - one hour. Courses 
vill be administered at 3-week intervals as 
tolerated. subsequent courses should not be 
repeated until the nadir of blood counts has been 
reached and the counts are recovering. If at the 
end of 3 weeks, the nadir in the UBC and/or 
platelets has hot been reached and evidence of 
bone aarrov recovery present, these counts should 
be obtained biweekly until recovery is evident so 
that the next course can be administered as soon 
as possible. At present this project is ongoing 
but is closed to new patient entries. 



died toward the completion of their induction. 
One patient is currently too early for evaluation. 
Ihe durations of remissions for the two pathologi- 
cally confirmed complete responses have been 25 
plus montns and 10 months, the second patient 
having eventually succumbed to cumulative cardiac 
toxicity from adriamycin therapy. Although the 
results of this study suggest that if patients are 
unable to achieve complete response then long tern 
duration of remission may be good, but the therapy 
is very aggressive and it still remains to be 
deteained whether such approaches are justified. 

296. SWOG 780 - COP lU FOB NON-HODGKIN'S LYaPHOHA 
Bottomley, 8. H., Hampton, J. «., Grozea, P. N., 
Hoge, A. ?., Ishmael, D. R., Hussein, K. K., 
Oldham, I. B., U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 73104, U.S.A. 

OBJECTIVES: To study the efficacy of a 
combination of cyclophosphamide, vincristine, 
prednisone and bleomycin in patients with states 
III and IV non-Hodgkin's malignant lymphoma. To 
determine the side effects and toxicity of that 
coabination. 

TEEAIHENT PLAN: General: Patients with 
non-Hodgkin's lymphoma will receive the below 
described combination of bleomycin, cyclophos- 
phamide, vincristine, and prednisone once every H 
weeks. (Text Abridged.) 



Bottomley, R. H. , Hampton, J. «., Grozea, P. N., 
Boge, A. F., Ishmael, D. R., Hussein, K. K., 
Oldham, F. B., U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma city, Oklahoma, 73101, U.S.A. 

OBJECTIVES: To compare the remission inducing 
effectiveness of the four-drug regimen — Cytoxan, 
hydroxyldaunomycin (adriamycin) , Oncovin and 
prednisone (CHOP) to the three-drug regimen 

hydroxyldaunomycin, Oncovin, prednisone (HOP) 

given by similar schedules. 

To compare two maintenance arms after 
complete remission induction and remission 
consolidation. One arm will utilize cyclophospha- 
mide, vincristine, and prednisone (COP) and the 
other arm, cytosine arabinoside (also referred to 
as ara-C or arabinosyl cytosine), vincristine and 
prednisone (CAP). (Text Abridged.) 



295. CATP VERSUS CVP FOB DISSEWIgAIED HOM-HODGK- 
H'S LYMPHOllA 

Levi, J. A., uiernik, P. H. , Diggs, C. , Schiffer, 
C, Schimpff, S., U.S. Dept. of Hlth. Ed. £ Bel., 
latl. Cancer Institute, Medicine Section, Balti- 
Bore, Maryland, U.S.A. 

The purpose of this study has been to 
determine the value cf high dose intensive 
coabination chemotherapy for patients with diffuse 
histiocytic lymphomas utilizing measures to 
prevent infection which include laminar air flow 
isolation and prophylactic oral non-absorbable 
antibiotics. Patients with stage III and IV 
diffuse histiocytic lymphoma have been placed in 
reverse isolation in a laminar air flow unit, have 
coaaenced on prophylactic non-absorbable ^ral 
antibiotics, and given high dose chemotherapy with 
cyclophosphamide, adriamycin, vincristine and 
prednisone. Seven patients have been entered to 
date and in general, the tolerance to the high 
doses of cnemotherapy have been good. Myelosuppr- 
cssion has generally occurred on days 10-1U, after 
the initial administration of agents and, though 
often severe, has generally been brief. Besults 
to date have been two pathologically confirmed 
coaplete responses and two patients who clinically 
achieved complete remission, but died as a result 
of sepsis during myelosuppression. There have 
teen two failures on therapy, both patients having 



Sheehan, R. G., U.S. Veterans Administration, 
Hospital, Hematology oncology Section, H500 S. 
Lancaster Rd., Dallas, Texas, 75216, U.S.A. 

This is a cooperative protocol for the 
cheaotherapeutic management of stages III and IV 
histiocytic diffuse malignant lymphoma. Patients 
with no prior therapy, or only limited radiothe- 
rapy with clinical stage III or IV disease of the 
above histologic subclass (Bappaport classific- 
ation) will be treated with combination, cyclic 
chemotherapy including Cytoxan, methotrexate, 
cytosine arabinoside and folinic acid. 

Previous experience with the treatment of 
this disease is generally poor, both in regards to 
complete remission rates and survival. Analysis of 
data will primarily relate to remission rates, 
duration of remissions, survival and toxicity. 



299. RANDOHIZED STDDT OF BCNU, CITOIAN, VINCRIS- 
TINE AND PREDNISONE VS CYTOXAN, VINCRISTINE AND 
PREDNISONE IN NOK-HODGKIN ' 5 LYBPHOHA 
Yam, 1. I., U.S. Veterans Administration, Hospital, 
Section of Hematology, 800 Zorn Ave., Louisville, 
Kentucky, 40202, U.S.A. 

This study is conducted to compare the result 
of treatment of the combination of BCNU, Cytoxan, 
Vincristine and Prednisone regiaen with Cytoxan, 



165 



Vincristine and prednisone in Don-Hodglcin*s 
lymphomas. These two regimens have been shown to 
be effective for 160 non-Hodgkin "s lymfhomas. The 
drugs used in these two regimens have been 
approved by, and are being used in this institute 
lor patients with these diseases. 



300. IIATURAL HISTORI OT NON-HODGKIll' S LYBPHOHA AHD 
BOLE or RADICAL AND PALLIATIVE THERAPY 
Prosnitz, I., lale University, School of nedicine. 
Therapeutic Radiology, 3J3 Cedar St., New Haven, 
Connecticut, 06510, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



301. THE STUDY OF NON-HODGKIN' S LIUPHOWAS 
Johnson, R. E., Brereton, H. D., U.S. Dept. of 
Hlth. Ed. 6 Wei., Natl. Cancer Institute, Radia- 
tion oncology Branch, Bethesda, Maryland, 20011, 
U.S.A. 

The purpose of this study is to increase our 
understanding of the natural history of the 
various malignant lymphomas, to define which 
diagnostic (staging) methods are requisite for 
Baking treatment decisions, and to evaluate 
various therapeutic approaches which might improve 
the survival and quality of life for patients with 
these diseases. 



3. OTHER CHEMOTHERAPY FOR MALIGNANT LYMPHOMA 



302. ETALOATION OF VII-26,IN SUBSTITUTION OF VINCA 
ALKALOIDS IN THE TREATMENT OF LYWPHOHAS 
Filho, 3. C. , Santa Casa de Misericordia, Clinical 
Oncol £ Radiotherapy, Sao Paulo, Brazil 

OBJECTIVES: To test the efficacy of vn-26 as 
a substitute of Vinca Alkaloids in combination 
chemotherapy protocols for lymphomas. 

MATERIAL: Malignant lymphomas of Stages EC 
HI and IV, registered in the Santa Casa de 
Bisericordia de Belc Horizonte and the Santa 
Monica Hospitals. 

METHODS: VB-26 has been used as a substitute 
for vinca alkaloids in the classical MOPP and COP 
protocols, and there has been a control group 
submitted to standard protocols. 

STAGE: 50 cases have already beer, studied 
and up to the present no differences have been 
observed. 



303. AN EVALUATION OF THE EFFECTIVENESS OF 
CHEMOIHERAPEUTIC AGENTS IN THE TREATMENT OF 
CHILDREN WITH MALIGNANT LYMPHOMAS 
Sullivan, M. p., Sutow, w. u., cangir. A., Univ. 
of Texas, M.D. Anderson Hosp. 6 Inst., Pediatrics, 
P.O. Box 20036, Houston, Texas, 77025, U.S.A. 

OBJECTIVE: To determine the effectiveness of 
new chemotherapeutic agents and treatment regimens 
in children with lymphoma. 

APPROACH: Children with lymphoma of any 
histology who have become resistant to or in-o- 
letant of conventional therapy are eligible for 
evaluation of new treatmer.t regimens. Agents 
under investigation at present include BCNU, CCNU, 
VM-26 and Bleomycin as an adjuvant as well as a 
synchronizing agent. Studies of MOPP plus "low 
Bleomycin" are contemplated in Stage III disease 
with a view to determining immeaiate, intermeiiate 
and late effects of chemotherapy, especially when 
given in combination with radiotherapy to the 
upper thorax. 



Firat, D., lekuzman, G., Hacettepe University, 
Oncology, Ankara, Turkey 

Adult patients with inoperable, recurrent or 
■etastatic solid tumors, soft tissue sarcomas, 
primary brain tumors and lymphomas unresponsive tc^ 
previous chemotherapy are accepted for this study,' 
Methyl-CCNU is administered orally in one daily 
dose of 200 mg/m2 every 6 weeks until relapse or 
progression of the disease. The dosage is 
adjusted up or down by 25 mg/m2 depending on 
leukocyte and platelet counts. Treatments are 
continued until death or prohibitive toxicity in 
patients with primary brain tumors regardless of 
response. The objective regression of the 
■easurable tumor or disease parameters by 25-50X, 
over 5C», and 100* are considered partially fair, 
partially good or complete responses. 125 
patients are entered into this study. He are 
continuing to enter only patients with the primary 
brain tumors and lymphomas refractory to known 
chemotherapeutic agents into this protocol. In 
other tumors, Methyl-CCNU appears to have no 
significant superiority. 



305. THERAPEUTIC TRIAL OF BCNU (1, 3-BIS (2-CHLOROE- 
THYLl- 1-NITBOSOUREA) IN PAIIENIS MITH ADVANCED 
NEOPLASTIC DISEASE 

Krakoff, 1. H., Lee, Tan, C. T. , Young, C. W. , 
Seller, L. , Memorial Hosp. for Can. 6 Dis., ~--~-^ 
Medicine, 1275 York Ave., New York, New York, 
10021, U.S.A. 



the Clin 



cal 



adults 



childr 



ility 



OBJECTIVE: To . 
BCSU in the manageme 
advanced neoplastic disease. 

APPROACH: The drug is supplied in sterile 
vials containing ICC mg BCNU plus 300 mg nannitol. 
The vials are accompanied by a diluent which 
contains 3.5 ml of absolute ethanol. The drug is 
prepared by injecting 3 ml of ethanol into the 
sterile vial, thoroughly wetting the contents, and 
then injecting 27 ml of "sterile water for 
injection". The vial is then shaken, producing a 
3.3 »g/ml solution of BCNU, 10 mg/ml solution of 
mannitol, and a 10 percent solution of ethanol. 
This is injected directly intravenously and is 
used within ten minutes of formulating. 

SELECTION OF PATIENTS AND DOSAGE: The drug 
will be given initially to patients with advanced 
neoplastic disease resistant to conventional 
therapy. It will be given on both an inpatient 
and outpatient basis. In our initial studies, the 
following dosage schedule will be used: for 
patients without evidence of impaired marrow 
function, a dosage of 2.5 mg/kg intravenously on 2 
successive days followed by a four week rest 
period will oe used. If response is seen, 
maintenance dosage of 2.5 mg/kg intravenously 
approximately at two week intervals will be given 
as tolerated. If the patient under consideration 



has 



sted by peripheral count depression, the dosag 
administered will be cut in half. Hemoglcbin, 
white count, and platelet count will be folic 
at least weekly in all patients, until the 
patient's response to the drug has been defined 
Blood urea nitrogen and serum creatinine, bili- 
rubin, SGOI, alkaline phosphatase, and prcthrom 
time will be monitored at weekly intervals to 
assess the incidence of hepatic and renal toxic 
ity. 

BACKGROUND; Nitrosourea derivatives are o 



ed 



3f the 



abili 



perimental a 
to penetrate 



mals 



Repo 



spectr 
and be: 
blood-brain Carrier. 

SIGNIFICANCE Of STUDY: 
centers indicate that BCNU is active in the 
treatment of Hodgkin's aisease. The drug has 
produced thereapeutic response in patients 
considered to be refractory to therapy with 
alkylating agents. 



166 



306. HIGH DOSE JETHOTBEIATE (HPHTI) FOR THE 
THEBAPT OF LYMPHOMA 

Schiffer, c. A., Levi, J. A., wiernik, P. H. , 
Beich, S. D., Bachur, N., U.S. Dept. of Hlth. Ed. 
e Bel., Natl. Cancer Institute, Baltisore Cancer 
Bes Center, Baltiiote, naryland, U.S.A. 

High Dose nethotreiate folloxed by citrovoruB 
factor "rescue" has been administered to patients 
with refractory lymthooa and advanced sarcoma. In 
order to decrease toxicity, bicarbonate is 
administed orally and urinary pH is monitored. 
Badioimmunoassay for methotrexate has been used 
and will hopefully be of assistance in regulating 
dosage in the future. 7o date, 2 patients with 
advanced lymphoma have been treated and neither 
have responded to therapy. There have been no 
objective responses in patients with metastatic 
soft tissue sarcomas. 



307, SBOG-71435 - PIPERAZINEDIOIIE III BALIGNAKT 
imPHOIlA OR BtELCBA 

Bottomley, R. H. , Hampton, J. »., Grozea, P. N. , 
Hoge, A. F., Ishmael, D. R. , Hussein, K. K. , 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310"4, U.S.A. 

OBJECTIVES: To establish the objective tumor 
cesponse rates, both partial and complete, for 
patients with refractory lymphomas, and the 
duration cf such responses; and to establish the 
objective tumor response rates and their durations 
in patients with refractory multiple myeloma, 

TREAIdENT PLAN: All patients will receive 
the same initial dose of Piperazinedione : 
12Bg/ll2, administered by I.V. infusion over 10-20 
minutes. Courses will be administered at 3-weelt 
intervals as tolerated. Subsequent courses will 
not be repeated until the naair of blood counts 
has been reached and the counts are recovering. 
If at the end of 3 weeks the nadir in the WBC 
and/or platelets has not been reached and evidence 
of bone marrow recovery is not present, these 
counts should be obtained twice weekly until 
recovery is evident so that the next course can be 
administered as soon as possible. Subsequent 
doses of Piperazinedione will be adjusted in 
relation to nadir blood counts. If an antitumor 
response is noted or if there is no tumor growth 
after 2 courses of therapy, administration of the 
drug will be continued in 3-week courses until 
relapse occurs. Dose adjustments will be made so 
as to maintain the patients on the highest dose 
possible to produce modest myelosuppression. If 
the patient demonstrates a 50* increase in tumor 
while receiving a myelosuppressive dose of drug, 
treatment will be discontinued after 2 courses of 
therapy have been given. If the patient demo- 
nstrates tumor growth while receiving a non- 
myelosuppressive dose of drug, treatment will be 
continued, with the dose of drug being increased 
as indicated above until myelosuppression occurs. 

Patients may receive other therapies as 
necessary to control reversible medical complicat- 
ions. 

Closed for entry of myeloma patients 10-8-75. 



308. SBOG 7113 - CIS-PLATIlinH IM LIHPHOHAS AMD 
HDITIPLE HYELOHA 

Bottomley, R. H., Hampton, J. «., Grozea, P. N., 
Boge, A. F., Ishmael, D. R., Hussein, K. K., 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 73101, U.S.A. 

OBJECTIVES: To evaluate the activity of 
cis-diamminedichloroplatinum (II) (NSC-1 19875, 
CACP) in patients with refractory Hodgkin's and 
non-Hodgkin's lymphomas and in refractory multiple 
myeloma. 

TREATHENT PLAN: CACP, 75 mg/m2, will be 
given as a single rapid intravenous injection 
every three weeks. An adequate trial will consist 
of 2 courses and all patients will be followed for 
the six-week period. If there is evidence of a 
tumor response or stable disease the drug may be 



continued at 3-week intervals indefinitely, with 
evidence of progression after two courses of the 
agent, the patient will go off the study. 
Supportive therapy: Patients may receive other 
therapy as necessary to control reversible medical 
complications such as hyperuricemia, hypercalce- 
mia, infection, pain, anemia, etc. 



BOTE; The following projects are part of broad 
clinical programs. Summaries of individual 
projects are not available. 



309. ORAL HETHYL CCNO IN TREATMENT OF LIMPHOIIAS 



AHD SOLID lUHOSS 
Kellermeyer, R. U., U 
Medicine, 2065 Adelbe 
11)106, U.S.A. 



t. Hospitals of Clevela 
Bd. , Cleveland, Ohio, 



310. CCND III LYMPHOMAS AHD SOLID TUMORS 
Velez, E., Univ. of Puerto Rico, School of 
Medicine, P.O. Box 5067, San Juan, Puerto Ri 
00936 



311. BCNH. CYTOXAH, TIHCRISTIHE IH SARCOMA AND 

LYMPHOMA 

Valez, E., Univ. of Puerto Rico, School of 

Medicine, P.O. Box 5067, San Juan, Puerto Rico, 

00936 



312. BLEOMYCIN AND OTHER ANTITUMOR AGENTS IN 
IREATBENI OF LYMPHOMA AMD OIHIJB NEOPLASMS 
Kaplan, B., Yeshiva University, School of Medicine 
Medicine, 1300 Morns Park Ave., Bronx, New York, 
10161, U.S.A. 



313. TREATMENT OF SOLID TUMORS AHD LYMPHOMA HITH 
5-AZACYTIDINE INSC-1028161 

Ouagliana, J. X. , Univ. of Utah, School of 
Medicine, Internal Medicine, 1100 E. 2nd S. , Salt 
Lake City, Utah, 81112, U.S.A. 



311. COMBINATION CHEMOTHERAPY OF ACUTE MYELOCYTIC 
AND ACUTE LYMPHOCYTIC LEUKEMIA, MULTIPLE MYELOMA. 
AHD LYMPHOMA 

;well Park Memorial Inst 
r York, 11203, U.S.A. 



666 



4. OTHER THERAPY FOR MALIGNANT LYMPHOMAS 



lOTE: The following projects are part of liroad 
clinical programs. Summaries of individual 
projects are not available. 



315. DIAGNOSTIC STUDIES AND SELECTION OF INITIAL 

TREATMENT PROGRAMS FOB PATIENTS BITH MALIGNANT 

IIMPHOMAS 

Binder, R. , Georgetown University, School of 

Medicine, Medicine, 3900 Reservoir Rd. N.W., 

Bashington, District of Columbia, 20007, U.S.A. 



316. SPLENECTOMY IN MALIGNANT LYMPHOMA 

Sokal. J. E., Roswell Park Memorial Inst., 666 Elm 

St., Buffalo, New York, 11203, U.S.A. 



317. TREATMENT OF SOLID TDBOBS AHD BEPBACTOBI 

LYMPHOMAS 

Beard, N. S. , Univ. Hospitals of Cleveland, 

Medicine, 2065 Adelbert Bd., Cleveland, Ohio, 

11106, U.S.A. 



167 



318. auMAGEaEm of ltmphoha 

Silverstein, n. N., Univ. of ninnesota. School of 

Hedicine, Internal Medicine, 200 1st St. S.V., 

Eochester, Hinnesota, 55901, U.S.A. 



319. ACVAHCep LYHPHOHA TBEAIIIENT 
Bill, J., Univ. o£ Hinnesota, School of nedici 
Hedicine, 1305 Hayo, Minneapolis, Minnesota, 
55155, U.S.A. 



320. CAHCEB THEBAPY — LYMPHOMA 

Henderson, E. S., Roswell Park Menorial Inst., 666 

ElB St., Buffalo, New YorX, 14203, U.S.A. 



III. SUPPORTIVE THERAPY OF PATIENTS 

WITH LEUKEMIAS, LYMPHOMAS AND 

OTHER LYMPHOPROLIFERATIVE DISORDERS 



therefore nodified to include 60 ng/kg cyclophosp- 
haBide plus irradiation. The patient is supported 
through the first few weeks of pancytopenia by 
platelet and granulocyte transfusions. Patients 
are randonized into laminar air-flow isolation 
rooms, where they receive a sterile diet and gut 
sterilization. Methotrexate is given post 
grafting to prevent graft- versus-host disease. 
Antithymocyte globulin is being studied to 
determine its efficacy in treating early GVHD. 

PROGRESS: More than 100 patients with acute 
leukemia have been treated on these protocols, 
Ihere has been a steady improvement in survival 
rates over the past 5 years, probably reflecting 
improvements particularly in supportive care. The 
present 1 year complete remission rate off all 
therapy is about 25X. Those who ate long-term 
survivors are leading essentially normal lives and 
receive no additional anti-leukemic tnerapy. Two 
patients have now passed the 5th year post- 
transplant. 



A. MARROW TRANSPLANT 



321. TREATMEHT OF ACUTE LEUKEMIA — BONE MAB80II 
IRAllSPLANTAIIOM AMD IIS COM FLIC AIIONS 
Thomas, E. D. , Univ. o£ Washington, School of 
Medicine, Medicine, 500 17th Ave., Seattle, 
Hashington, 98122, U.S.A. 

The Adult Leukemia Eesearch Center is engaged 
in a oulti-facetea research program with major 
emphasis on marrow transplantation and ensuing 
complications. Since its opening in 1969, 153 
allogeneic or syngeneic marrow transplantations 
have been performed for restoration of marrow 
function in patients with marrow aplasia or for 
treatment of hematologic malignancies. The 
long-term survival of a number of these patients 
has been encouraging, leading to intensification 
of studies to overcome some of the associated 
problems. Ongoing studies include: evaluation of 
ultra-isolation and gut sterilization in preven- 
tion of infection, use of anti- thymocyte globulin 
and other immunosuppressive drug regimens to 
prevent or ameliorate graf t-versus-host disease 
and support of the pancytopenic patient with 
granulocyte and platelet infusions using the 
NCI-IBM blood cell separator or the LeuKo-Pak 
technique. A randomized trial using a procarbazi- 
ne-ATG preparatory regimen to abrogate prior 
sensitization by blood transfusion is underway. 
Chemoimmunctherapy to achieve more effective 
eradication of malignant cell lines is also under 
study. 

Ancillary programs involve cytogenetic 
studies for confirmation of engraftment, immun- 
ologic evaluation of long-term marrow graft 
recipients, evaluation of the role of HL-A 
antigens in platelet transfusions, and the 
efficacy of high-dose chemotherapy followed by 
autologous marrow infusion for a variety of 
malignant diseases. 



322. (EVALUATION OF MARROB TBANSPLASTATIOM IN 

LEUKEMIA! 

Thomas, E. D. , Buckner, C. D., Fefer, A., Fred 

Hutchinson Cancer Res. Ct, oncology, 1102 Columbia 

St., Seattle, Washington, 981014, U.S.A. 

OBJECTIVE: To evaluate the role of marrow 
transplantation in the treatment of acute lym- 
phocytic and acute myelocytic leukemia. 

APPROACH: Most patients referred to the 
Adult Leukemia Center have exhausted all conv- 
entional chemotherapy and are in relapse. Harrow 
from an Hl-A matched, MLC non-reactive donor is 
infused into the immunosuppressed recipient. In 
the first series of 10 patients, 100 rad total 
body irradiation was used to condition the 
patient. Four patients died of infection too 
early to be evaluated. Five of the remaining six 
showed recurrent leukemia. Cytogenetic studies 
demonstrated clearly that the recurrent leukemia 
was in donor-type cells. The protocol was 



323. (GBAFT-YEBSaS-aoST DISEASE IN PATIENTS AFTER 
HA8R01I TBANSPLANTS) 

Thomas, E. D.. Buckner, C. D., Fefer, A., Fred 
Hutchinson Cancer Res. Ct, Oncology, 1102 Columbia 
St., Seattle, Hashington, 98101, U.S.A. 

OBJECTIVE: To study graf t-versus-host disease 
(GTHD) in patients who have received marrow 
transplants. 

APPROACH: Despite the use of HL-A, MLC 
identical marrow donor's immunologically competent 
cells in the marrow infusion may react against the 
host, resulting in the syndrome known as GVHD. 
Our studies have focused on two aspects of the 
disease, i.e., recognition and characterization of 
GVHD both clinically and by biopsy studies, and 
methods of treating established GVHD. The role of 
ultraisolation on GVHD is also being evaluated. 

PROGRESS: The histopathologic changes 
associated with GVHD of the skin, liver and gut in 
105 HL-A matched sibling marrow transplantations 
have been studied by light and electronmicroscopy, 
and a grading system has been devised. A new 
study is underway to study skin biopsies on 
non-transplant patients on chemotherapy for a 
variety of tumors, to help distinguish changes due 
to GVHD from changes due to chemotherapy. 

A protocol for early treatment of patients 
with Grade I biopsy-proven GVHD is now underway to 
evaluate the efficacy of antithymocyte globulin. 
A second protocol involving randomization into the 
ultraisolation study will evaluate the role of a 
protective environment on prevention and/or . 
modification of seveifity of GVHD. A third study 
will evaluate the role of prophylactic antithy- 
mocyte globulin. 



3214. PROTECTIVE ENVIRONMENT IN INTENSIVE CANCER 
IBEBAPI FOLLOHING ALLOGENIC MARaoM GRAF TS 
Thomas, E. D. , Clift, H., Buckner, c. D., Fred 
Hutchinson Cancer Res. Ct, Oncology, 1102 Columbia 
St., Seattle, Washington, 98101, U.S.A. 

OBJECTIVE: To determine the effect of a 
protective environment on 1) the control of 
Infection in immunosuppressed recipients of 
allogeneic marrow grafts, 2) the incidence and 
severity of grafts, and 3) the incidence and 
severity of graf t-versus-host disease post 
transplantation. 

APPROACH: Patients receiving allogeneic 
narrow transplants from HL-A and MLC matched 
siblings as therapy for acute leukemia or aplastic 
anemia will be randomized into laminar airflow 
(LAF) or conventional isolation. LAF patients 
will receive oral nor-absotbable antibiotics to 
suppress the gut flora, and will be served sterile 
food. They will remain in isolation for 50 days 
or until all signs of graf t-versus-host disease 
have disappeared. Both groups of patients will be 
monitored for infections and graf t-versus-host 
disease. 

PROGRESS: At present 26 patients have been 
randomized into the study, but it is as yet too 
early to analyze results. 



168 



325. (PPLnONA?! STUTnS OF fUTIHTS FOLLOglNG 
BlBHOa IBANSPIANIS) 

Tbonas, I. D. , Bucxner, C D. , Fefer, A., Fred 
Hutchinson Cancer Hes. Ct, Oncology, 1102 Columbia 
St., Seattle, Uashington, 98104, U.S.A. 

OBJFCIITFS: To deteraine the pulnonary 
status of narrow transplant patients pre-which 
■igfat predispose patients to subsequent develop- 
ment of interstitial pneunonia. 

iPPBOACH: The following studies will be 
carried out and entered into the data collection 
center records on transplant patients at specified 
intervals: Arterial blood gases and alveolar- 
arterial oxygen differences, spirometry, diffusing 
capacity (single breath carbon monoxide method) , 
total lung capacity (helium dilution method), 
physiological dead space, and shunt (Qs/QT) , chest 
X-rays at routine intervals. 

Transbronchial lung biopsy through the 
fiberoptic bronchoscope will be carried out for 
those patients who develop acute interstitial lung 
disease meeting the current indications for open 
lung biopsy. 



326. SEPARATION AMD CHTOPBESIBYATIOS OF HFMOPOI- 
ETIC cms FOE DS£ IH nARROM IBANSPLAliTATION 
Schaefer, U. ». , Bcecker, W., beyer, J. H. , 
Schnidt, C. G., Univ. clinic for Internal (led.. 
Clinical oncology, 55 Hufelandstrasse, Essen, 
Federal Republic of Germany, 43 

OBJICIIVE: 1. Separation and cryopreserva- 
■tion of hemopoietic stem cells of normal indiv- 
iduals and leukemic patients. 2. Cryopreservat ion 
of nomal platelets. 3. CFD-C proliferation of 
lenkeaic bone marrow. 

iPPROiCH: In mice, healthy human beings and 
IcuJceaic patients, normal bone marrow and stem 
cell rich bone marrow fractions obtained by 
albumin gradient centrif ugation are tested for 
proliferative capacity before and after cryoprese- 
rvation in liguid nitrogen. Viability assays; 
CFO-S assay, CFU-C assay, diffusion chamber. In 
rabbits and in men in vivo survival of fresh and 
cryopreserved labelled platelets is investigated. 

PEDGBESS: In mice and in nen hemopoietic 
stem cells can be cryopreserved without marked 
loss of viability. The phase after thawing is 
significant. Inxracellular protectants of high 
osBolarity nave to be removed alter thawing by a 
slow stepwise dilution technique in order to avoid 
an osBOtic cell death. Preliminary data give 
evidence that the same phenomenon is significant 
for platelet survival. 

Feaission bone marrow of leukemic patients is 
collected and cryopreserved in DBSO. In the 
relapse the stored autologous bone marrow cells 
•ill be transplanted after total body irradiation. 



327. CXimcAl BDBE BABROB IPAMSPLAHTATIOH 
Schaefer, U. W. , Beyer, J. «., Hossfeld, D. , 
Schmidt, C. G., Boecker, v.. Dniv. clinic for 
Internal Bed., Clinical Oncology, 55 Hufelands- 
trasse, Essen, Federal Republic of Germany, 43 

OBJECTIVE: Clinical bone marrow transpl- 
AStation in leukemia and aplastic anemia. 

APPBOACH: 1) In the relapse phase of acute 
lenkemias, fresh allogeneic bone marrow of HLA and 
■LC-compatible family members or autologous bone 
•arrow collected and frozen in DHSO during the 
xeaission phase will be transplanted after total 
body irradiation. 2) In aplastic anemias, fresh 
Allogeneic bone marrow of HIA and aLC-compatible 
fasily members will be transplanted after total 
body irradiation or after conditioning by Cycloph- 
osphaaide. 



Nathan, D. G. , Camitta, B. , Parkman, R. , Sappeport, 
J., Sidney Farber Cancer Institute, Pediatric 
Oncology, 44 Binney St., Boston, Massachusetts, 
02115, U.S.A. 

OBJECTIVE: Definition of the role of 
transplantation in treatment of hematologic 
malignancies. 

APPROACH: Use of cyclophosphamide and total 
body irradiation as pregrafting immunosuf pression 
and methotrexate for post-grafting amelioration of 
graft vs host disease (GvH) . The study focuses in 
two major areas: A. Immunologic parameters 
determining transplant success, GvH and immune 
reconstitution. B. The appropriate timing of 
transplantation in the course of the illnesses, 

PROGRESS: Three patients have been succ- 
essfully engrafted in the past year. One is 
surviving disease-free after 8 months. The other 
two died of interstitial pneumonitis and chronic 
GvH. 



329. EVALDATION OF IIPIIIG TECHmQUES IM CLINICAL 

HOBOTRANSPLAillATIOS 

Thomas, E. 0., Fred Hutchinson Cancer Res. Ct, Div 

of Oncology, 1102 Columbia St., Seattle, Uashin- 

gton, 98104, O.S.A. 

OBJECTIVE: To utilize in vitro cytotoxicity 
testing to select the best possible donor-recip- 
ient combinations for marrow transplantation and 
to evaluate immune responses to histocompatibility 
antigens after transplantation. 

APPROACH: Potential marrow graft recipients 
and members of their families are Hl-A typed using 
NIB trays and trays prepared in the Adult Leukemia 
Center laboratory. 212 anti-sera are routinely 
used to determine 29 specificities. Genotypic 
analysis is done when possible. Patients found to 
have an ABO compatible, HL-A identical match are 
then tested by a two-way mixed leukocyte culture 
test. 

PROGRESS: In the past year, 43 patients 
received allogeneic marrow transplants for 
treatment or marrow failure, acute leukemia or 
HodgXin's disease. The HL-A and HLC matched 
sibling pairs involved were selected by typing 613 
patients and family members. 87C sera from these 

and leukoagglutinating antibodies and it is 
apparent that, despite their generally immunodefi- 
cient state, these patients were able to mobilize 
immune responses to histocompatibility antigens 
soon after transplantation. Despite HL-A identity 
and HLC non-reactivity between patients and 
siblings, donor graft rejection and graft-ver- 
sus-host disease occur frequently following marrow 
transplantation, suggesting that antigenic systems 
controlled by genetic regions on chromosomes other 
than C-6 are involved. Attempts have continued to 
demonstrate and characterize these antigens using 
accepted techniques and other investigational 
approaches, including cell-mediated lympholysis 
and antibody-dependent cell-mediated cytotoxicity. 
Be are still unable to identify the antigenic 
systems involved. Studies on one and two-way HLC 
reactivity between genot ypically HL-A matched 
siblings have continued in an attempt to detect 
leukemia-associated antigens. 



330. (ROLE OF MtBROg TBAHSPLANTS IS ACUTE LEDKE- 

BIA) 

Thomas, E. D. , Buckner, C. D. , Fefer, A., Fred 

Hutchinson Cancer Pes. Ct, Oncology, 1102 Columbi 

St., Seattle, Washington, 98104, U.S.A. 

OBJECTIVE: To evaluate the role of marrow 
transplantation in the treatment of acute lym- 
phocytic and acute myelocytic leukemia. 

APPROACH: (lost patients referred to the 
Adult Leukemia Center have exhausted all conv- 
entional chemotherapy ^nd are in relapse. narrow 
from an HL-A matched, HLC non-reactive donor is 
infused into the immunosuppressed recipient. In 
the first series of 10 patients, 100 rad total 



169 



body irradiation was used to condition the 
patient. Four patients died of infection too 
early to be evaluated. Five of the renaining six 
showed recurrent leukemia. Cytogenetic studies 
deaonstrated clearly that the recurrent leukeaia 
was in donor-type cells. The protocol Mas 
therefore oodified to include 60 og/kg cyclophosp- 
haaide plus irradiation. The patient is supported 
through the first feu weeks of pancytopenia by 
platelet and granulocyte transfusions. Patients 
are randomized into laminar air-flow isolation 
rooss, where they receive a sterile diet and gut 
sterilization. Methotrexate is given post 
grafting to prevent graf t-versus-host disease. 
Ant ithymocyte globulin is being studied to 
deternine its efficacy in treating early GVHD. 

PEOGEESS: More than 100 patients with acute 
leukemia have been treated on these protocols. 
There has been a steady icprovement in survival 
rates over the past 5 years, probaoly reflecting 
inproveBients particularly in supportive care. The 
present 1 year complete remission rate off ail 
therapy is about 2b%. Those who are long-term 
survivors are leading essentially normal lives and 
receive no additional anti -leukemic therapy. Two 
t-atients have now passed the 5th year post- 
transplant. 



331, (AUTOLOGOUS MABRQW TFANSPLAWTS IH CHROHIC 
HYELOGENOUS LEUKEMIA) 

Thomas, E. D. , Buckner, C. D. , Fefer, A., Univ. of 
Hashir.gton, Scnool of Medicine, Medicine, 500 17th 
Ave., Seattle, Washington, &8122, U.S.A. 

OBJECTIVE: To evaluate the role of autolo- 
gous marrow transplantation in chronic myelogenous 
leukemia. 

APPEOACH: During the benign phase of chronic 
myelogenous leukemia, marrow is aspirated from the 
patient, frozen in DHSO and stored. When the 
disease progresses into blast crisis, which is a 
form of disease relatively resistant to most forms 
of cnenotherapy and rapidly fatal, the patient is 
treated with cyclophosphamide and total body 
irradiation and is given his own storea marrow 
back in an attempt to revert the disease to the 
chronic phase. 

PROGBESS: A large bank of stored marrow is 
preserved at the Adult Leukemia Center. Three 
patients have received their marrow back. One 
patient achieved engraftment of myeloid, erythroid 
and megakaryocytic elements but not lymphoid 
elements and died of cardiopulmonary complications 
on day 83 post-grafting. A second patient had 
extensive myelofibrosis and engraftnent was 
incomplete. He died of infection 48 days post- ' 
grafting. A third patient is doing well with 
apparent complete restoration of marrow function 
but it is too early to comment on disease status. 
Similar marrow storage programs are being utilized 
for other hematologic malignancies, such as 
Hodgkin* s disease. 



332, AUTOLOGOUS STEM CELL REPLACEHFNT WITH 
CHEMOTHERAPY AND TOTAL BODY IRRADi;v ION 
HcCredie, K., Dicke, Langdren, SpitL^r, Univ, of 
Texas, M.D. Anderson Hosp, C Inst., Developmental 
Therapeutics, P.O. Box 20C36, Houston, Texas, 
77025, U.S.A. 

OBJECTIVE: To study the effect of combined 
chemotherapy and total body irradiation followed 
by infusion of autologous stored remission 
haemopoietic stem "cells in acute leukemia resis- 
tant to combined chemotherapy. 

APPROACH: To store the stem cells in vitro 
during a period of remission, end to infuse those 
stem cells for marrow engraftnent at a time 
further chemical remission seems unlikely. Upon 
relapse, the patients will be treated initially by 
chemotherapy, but when this fails to achieve or 
Maintain remission, they will receive piperazidine 
"and 850 rads of whole body irtadiat ion in an 
attempt to sterilize all leukemia cells. The 
incidentally ablated normal bone -narrow will then 
be replaced from the stem cell separated previo- 
usly and stored in liquid nitrogen. During this 



period between irradiation and restoration of 
normal levels of granulocytes, bacterial decontam- 
ination will be attempted. 



333. HDHAM HABBOH TRAWSPLANTATIOH IM LEUKEHIA ASP 
OTHER CASES OF BOHE HAR-JQW FAILURE 
Edwards, C. L., VodopicK, H. A., Hubner, K. F. , 
Oak Bidge Associated Univs., Medical Division, Box 
117, Oak Ridge, Tennessee, 37830, U.S.A. 

The objective of this study is to develop 
techniques for human allogeneic bone marrow 
transplantation as treatment for persons with bone 
■arrov failure due to potentially lethal accide- 
ntal total-body irradiation or other natural 
causes as aplastic anemia, leukemia, and other 
incurable blood diseases. The initial clinical 
trials are oeing carried out in patients with 
leukemia in the later stages of their disease. 
The patients are prepared for the transplant by 
treating them with antinuman lymphocyte gamma 
globulin followed by hign-dose-rate (40 R/min) 
total- body irradiation. The immunosuppressed 
patients are kept in the protected environment of 
the ultra-clean laminar-air-flow rooms. Donors are 
selected from among healthy siblings based on 
leukocyte antigen typing and mixed lymphocyte 
testing for histoccrapatioility . 

RESULTS: Four aduit patients with acute 
leukemia were treated with bone narrow transplants 
from siblings. The first patient survived 11 
weeks before succumbing to a pulmonary infection 
complicated by pulmonary embolism and myocardial 
ischemia. The second patient died 92 days after 
the transplant with a systemic yeast infection and 
recurrence of her leukemia. The third and fourth 
patients failed to achieve a hematologic graft. 
Only the fourth patient showed a significant 
graf t-versus-host reaction. 



33«. BLOOD COMPONENT TRANSFUSION ASP BONE BABROW 
TRANSPLANTATION IN CANCEP. AND APLASTIC ANEMIA 
Graw, R. G., Bull, .1. I., herzig, ?. H., Kauffmanr., 
J. C, Appelbaum, F. 3., Fay, J, H. , Grathwohl, 
A,, Gorin, N. C, Penland, W. Z., Krueger, G. F., 
Alter, H. J., Pomeroy, T. C, U.S. Dept. of Hlth. 
Ed. & Mel., Natl. Cancer Institute, Experimental 
Hematology Sect, Bethesda, Maryland, 20014, 
U.S.A. 

In this project, blood components are 
transfused into patients with depressed bone 
marrow function; emphasis is on the development of 
improved procurement and transfusion techniques 
for platelets and granulocytes. "he utility of 
these various supportive care techniques is 
assessed in conjunction with chemotherapy and 
other primary cancer treatment, A second aspect 
of the project concerns allogeneic, autologous, 
and isogeneic bone marrow grafting in patients 
with hematologic malignancies ar.d solid tumors. 
Various preparative and post-transplant treatments 
(e.g., anti-thymocyte globulin) are tried in 
graf t-versus-host syndrome. Autologous transplan- 
tation is pursued in various solid tumors and 
non-Hodgkin*s lymphorras. In preclinical studies, 
we examine the effectiveness or combined modality 
treatment (chemotherapy, radiotherapy, immuno- 
therapy, and supportive care) in lymphosarcoma 
dogs; the dog is also utilized to investigate new 
supportive care techniques and bona marrow 
transplantation. 



335. BOHE MABBOM TBANSPLAHTATION PROGRAM IN HUMAN 

DISEASE 

Santos, G. w. , Sensenbrenner, L. L. , Humphrey, R. 

L., Burke, P. J., Anderson, P. N. , Slavin, R. E., 

Borgaonkar, D, S., Schacter, B. Z, , Johns Hopkins 

University, School cf Medicine, Medicine, 725 N. 

Holfe St., Baltimore, Maryland, 21205, U.S.A. 



The principal objective o 
obtain scientific information 
establishment, survival, funct 
effects of bono marrow grafts m pat 
malignancy and various forms of bone 



his project is to 
ative to the 
and th<^tapeutic 



170 



failure. Hore specifxcally, ve plan to study; 1} 
■etbods of histocoBf atibility matching and 
prediction of graft versus host disease (GVH) ; 2) 
■ethcds of preparing individuals for transplan- 
tation (i.e., iamunosuppression and cytoreduct ive 
therapy with drugs and serum products; 3) methods 
for preventing, detecting and eliminating the 
prcsensitized state; 4) the pathogenesis of and 
recovery from GVH; 5) the immunoincompetent state 
following marrow grafting; 6) the recurrence of 
leukemia in donor cells; 7) the therapeutic 
potential of marrow transplantation m various 
forms of malignancy and bone marrow failure. 

REFERENCES: Tutschka, P.J. and Santos, G.H.: 
Bone larrow transplantation in the busulfan- 
treated rat. I, Effect of cyclo-phosphamide and 
rabbit antirat thymocyte serum as immunosuppre- 
ssion. Transplantation 19: August, 1975. 
Tutschka, P.J. and Santos, G.W.: Bone marrow 
transplantation in the busulf an-treated rat. II. 
Effect of cyclophosphamide and antithymic serum on 
the presensitized state. Transplantation 19: 
August, 1975. 



336. BOWE HARROW TR AHSPLA WTflTIOM IN TRERTHEMT OP 
HEgATOLOGIC MALIGNANCIES 

Gale, R. P., Fahey, J. L. , Univ. of California, 
School of Hedicme, Microbiology C Immunology, t*05 
Hilgard Ave., Los Angeles, California, 90024, 
0.5. A. 

OBJECTIVES: (A) The establishment of 
iaptoved techniques in the elimination of recip- 
ient neoplastic tissue prior to transplantation 
including aggressive combination chemotherapy and 
x-irradiation. (B) Immunologic modulations both 
pre- and post-transplantation in an attempt to 
prevent or modify allograft rejection and GvHD and 
thereby permit allogeneic bone marrow transpl- 
antation in man across conventional (HL-A and 
■ixed lymphocyte reaction HLR) histocompatibility 
barriers. (C) Establish the value of bone marrow 
transplantation in the treatment of: Hematologic 
■alignancies including acute leukemia, Hodgkin's 
and non-Hodgkin' s lymphoma, and multiple myeloma, 
and advanced chronic leukemia. (D) Establish the 
value of "non-specific" modification of donor 
■arrow, i.e. , reduction of thymus-de pendent (T) 
cells or enrichment of bursa equivalent (B) cells, 
or as a modality for the improvement of patient 
survival in allogeneic bone marrow transplantation 
and/or as a basis of understanding the rejection 
and GvUD phenomena. 

APPROACH: Bone marrow transplantation is 
increasingly employed in the treatment of patients 
with leukemia. The proposed program is concerned 
with two areas of transplantation: (1) Develop- 
■ent of more effective chemoradiotherapeutic 
reginens to eradicate leukemic cells pre-trans- 
plant; and (2J continued investigation of a rat 
■odel of transplantation of marrow from "incompat- 
ible" donors and extension of this model to 
preliminary clinical trials in patients with 
leukemia who lack "histocoDpatible'* donors. 



337, IHMDHOLOGIC STDDIES IW HARROM GRAFTIHG FOR 
TREATBEHT OF HEnATOLOGIC HALIGNANCIES 
Storb, R.. Weiden, P. L., Fefer, A., Thomas, E. 
D., Fred Hutchinson Cancer Pes. Ct , Oncology, 1102 
Columbia St., Seattle, Washington, 98101, O.S.A. 

Over the past years the Division of oncology 
has been involved in a continuing program of 
experimental and clinical marrow transplantation 
directed toward the treatment of patients with 
otherwise fatal hematologic diseases. The 
clinical studies have involved conditioning of the 
patient with high doses of cyclophosphamide, or 
total body irradiation, or a combination of both 
followed by infusion of marrow from either a 
syngeneic sibling (monozygous twin) donor, or a 
sibling matched with the recipient at the major 
human histocompatibility complex. A number of 
patients have become long-term survivors with 
neither recurrence of their original disease nor 
with occurrence of graf t-vs-host disease (GVHD) . 
Many patients, however, have died either from 



recurrent disease, or more frequently, from 
complications related to the transplant. Further 
improvement of clinical marrow grafting results 
hinges upon progress and better understanding in 
at least four areas of study: (1) Recovery of 
immunologic reactivity in marrow graft recipients. 
(2) Elucidation of mechanisms of stable graft-host 
tolerance and of GVHD. (3) .lethods of recogni- 
zing and overcoming sensitization to transplan- 
tation antigens due to blood transfusions. («) 
Detection of cell-mediated immunity to' leukemia- 
associated antigens and use of marrow grafting as 
immunotherapy. 



338. ADOPTIVE IHHDNOTHERAPY OF CAHCER BY ALLOGE- 
HEIC MARROW 

Emeson, E. E. , Montefiore Hosp. S !ied, Ctr, , 
Pathology, 111 E. 210th St., Bronx, New York, 
10U6?, U.S.A. 

OBJECTIVE: To eliminate graft versus host 
reactivity (GVH) from allogeneic murine bone 
■arrow and utilize this marrow in ccmbination with 
chemotherapy and/or irradiation to treat several 
models of murine leukemia and lymphoma. 

APPROACH: Recruit (or trap) recirculating 
lymphocytes with specific GVH reactivity in the 
marrow donor's lymphoid organs (other than marrow) 
thereby deleting these cells frcm his marrow. 
Lymphocytes with specific GVH reactivity will be 
recruited to the appropriate lymphoid organ by 
challenging this organ with allogeneic cells. 
Initially we will define the optional conditions 
to recruit the maximum number of specifically 
reactive lymphocytes, and then use these condit- 
ions to delete the donor's marrow of specific GVH 
reactivity as defined by the popliteal lymph node 
GVH and GVH mortality assays. This marrow will 
then be used to reconstitute and possibly mount a 
graft versus leukemia reaction in leukemic 
allogeneic recipients previously treated with 
chemotherapy and/or irradiation. 



339. CARDIAC LESIONS IN BONE HARROW TRANSPLANTA- 
TION 

Buja, L, H,, Ferrans, V. J., Graw, ?. G. , 0,S. 
Dept. of Hlth. Ed. & Wei,, Natl. Haart & Lung 
Institute, Section of Pathology, Bethesda, 
Maryland, 20014, U.S.A. 





Cardiac pathologic 


findings 


were a 


inalyzed : 


20 nccrofsied patients : 


Crom a series of 


: 26 


patients with leuXemia, 


aplastic 


anemia 


1, iDoune 


defii 


:iency disease or nn 


Btastatic 


cancel 


: who had 


been 


treated with bone i 


.arrow tra^splar 


itation. 


nost 


cardiac alteration; 




niiar t 


;o those 


wbici 


a occur in patients 


witn henatologi 


.c and 


neop. 


lastic diseases who 


have not 


been t 


ireated w: 


bone 


marrow transplanta' 


cion. Other car 


dlac 



alterations were more specifically related to bone 
■arrow transplantation. Six patients exhibited a 
distinctive interstitial reactive change characte- 
rized by the presence of a pleomorpnic population 
of lymphoid, histiocytic and AnitschJcow cells. 
This alteration may have been induced by abnormal 
iiBune mechanisms. Two patients developed fatal 
cardiac failure in the post-transplcnt period, and 
exhibited myocardial damage with histologic and 
ultrastructural features i:,dicative of severe 
acute injury. Clinicopathologic analysis strongly 
suggested that the fatal cardiotoxicit y in both 
patients resulted primarily from effects of high 
doses of cyclophosphamide (180 mg/kg and 270 
■g/Kg) which were administered as part of a newly 
developed regimen of combination chemotherapy- 
im.unosuppression (B.A.C.T.). 



340. (EVaLUtTIOH OF BABBQg TRtBSPLAllTATIOB IN 
inHOWOSUPPaESSED RECIPIENTS) 

Thomas, E. D. , Buckner, C. D. , Fefer, A., Fred 
Hutchinson Cancer 5es. Ct, oncology, 1102 Columbia 
St., Seattle, Washington, 981014, U.S.A. 

OBJECTIVE: To evaluate the efficacy of 
■arrow transplantation in the treatment of severe 
aplastic anenia. 



171 



APFBOACH: Harrow from an HL-A matched, HLC 
Don- reactive donor is infused into the immunosupp- 
ressed recipient. The patient is protected during 
the one- to three-week, period of pancytopenia by 
platelet transfusions, white cell transfusions and 
in some patients on a randomized study, isolation 
in a laminar air-flow room. Patients on the 
isolation protocol undergo gut sterilization and 
are on a sterile diet. Methotrexate is given post 
grafting to prevent or ameliorate graf t-versus- 
host disease. The role of antithymocyte globulin 
in reversing the effects of graf t-versus-host 
disease is also being studied. Cytogenetic 
studies are carried out whenever donor and 
recipient are of opposite sex to document engraft- 
aent. Patients who have received olood products 
from family members will be prepared for marrow 
transplant with a regimen utilizing procarbazine, 
antithymocyte globulin and cyclcphosphamide. 
Patients who have had no previous transfusions 
will be prepared with cyclophosphamide only. 
Patients who have had blood t^roducts from random 
donors will be randomized to Cy only or Cy plus 
ATG and procarbazine, 

PBOGSESS: More than 60 patients with severe 
aplastic anemia have been treated with narrow 
transplantation at the Adult Leu)temia Center. The 
survival rate has improved steadily as a result of 
iaprovements in supportive and nursing care. The 
current rate for survival in the aplastic cases is 
SOX. 



B. PLATELET- AND PLASMAPHERESIS 



3a 1. ftLTERHATE-DAY GRANULOCYTE AND PLATELET 
IRAN5FUSIOH5 IS ACUTE L£UKEHIA 
Cullen, n. H., Delves, P. J,, Ford, J. M., 
Inperial Cancer Research Fund, Medical Oncology 
Unit, Lincolns Inn Fields, Wc2a 3px. London, 
England, United Kingdom 

Hemorrhage and infection, either alone or in 
combination, are responsible for the high morta- 
lity rate observed during the initial phases of 
reiQissioi.-induction treatment in adult acute 
myelogenous leukemia. In an attempt to reduce the 
freguency of these early deaths, a randomized 
contrcl trial has been designed in which half the 
patients receive a combined granulocyte and 
platelet transfusion on alternate days during 
their initial period of neutropenia (absolute 
neutrophil count 500 per cu. mm.) 

The cells are collected from normal donors 
using the Hemonetics Blood Cell Processor, model 
30, A battery of tests are being used tc monitor 
the development of anti-white-cell and anti- 
platelet antibodies in the recipients. 

In-vitro and in-vivo function of the plate- 
lets collected by the Hemonetics Blood Cell 
Processor has been investigated. They have proved 
clinically effective although a slight defect in 
platelet aggregation is detectable. 



312. EXTRACOBPOBEAL COWTIHUOUS FLOW THPOHPOPHER- 
E5TS AND LEUKOPHERESIS IN LEUKEHIA 
Beyer, J. H. , Schmidt, C. G. , Scnaefer, U. W, , 
Luboldt, W., Univ. Clinic for Internal Med., 
Clinical Oncology, 55 Huf elandstrasse , Essen, 
Federal Republic of Germany, U3 

OBJECIIVE: To prevent bleeding from thrombo- 
cytopenia and infections from granulocytopenia 
caused by gram negative bacilli in patients with 
these blood components 



APPROACH: The separ 
done by the IBM blood eel 
ana scientific use. The 
labelled fresh thronbocyt 
donors was normal. The u 
concentrates of one donor 
of the IBM blood cell sep 
sufficient amount of gran 
oning the donor was unsuc 
the continous flow filtra 



ion of thrombocytes is 

separator for clinical 

timation of CR51 
of normal blood bank 
of these thrombocyte 

s successful. The use 



Djerassi- 

PROGRESS: He are now trying to estinate the 
half life of frozen (minus 196 degrees C) tbroabo- 
cytes and their clinical effectiveness. In the 
same way we are trying to collect a sufficient 
anount of granulocytes and obtain their storage at 
Binus 196 degrees c. In these granulocytes, 
function and clinical effectiveness will be 
studied. 



3«3. (PLATELET SOPPOFT FOR THROHBOCYTOPEMIC 
LEUKEMIA PATIENTS) 

Thomas, E. D. , BucKner, C. D., Fefer, A., Univ. of 
Washington, School of Medicine, Medicine, 500 17th 
Ave,, Seattle, Washington, - 98122, U.S.A. 



OBJECTIVE; To 
and storage procedu 
to the thrombocytop 

APPROACH: All 
Leukemia Center go 
as a result of thei 
chemotherapy or rad 
support these patie 
their marrow functi 
recovery of their o 
nsplant. Short-term 
has been achieved, 
recoveries of 38% a 
Long-term preservat 
lide has been studi 
give post-transf usi 
survival of 6,7 day 
transfusion refract 
utilizing Cr51 labe 
and 131 labeled pla 
screening for plate 
best data obtained 
assay developed in 
patients with eithe 
dies, all have been 
irregardless of dru 



develop platelet procureaent 
res to provide platelet support 
enic patient. 

of the patients in the Adult 
through periods of pancytopenia 
r disease process or intensive 
iation. It is essential to 
nts through this period until 
on is restored, either by 
wn marrow or by marrow tra- 

platelet storage (72 hours) 
giving in vivo platelet 
nd survivals of 7.a days. 
ion using 10S dimethyl sulfo- 
ed and technigues refined to 
on recoveries of 35* with 
s. The etiology of platelet 
oriness has been studied 
lling, 1125 labeled fibrinogen 
sminogen. In vitro methods of 
let antibodies are used. The 
have been with the radioimmuno- 
hemostasis laboratory. In 20 
r alloantibodies or autoantibo- 

positive by this technique 
g treatment. 



itho 



ssfui. 



thod described by 



34*t. (PLATELET TRAHSFDSION THERAPY IN LEUKEMIC 

PATIEMTS) 

Leikin, S. L. , Movassaghi, N. , Childrens Hosp. 

Natl. Wed. Ctr, 2125 13th St. N,W., Washington, 

District of Columbia, 20009, U.S.A. 

As part of our efforts in pediatric oncology 
and hematology, we plan to study the role of 
immune and coagulopathic mechanisms in platelet 
transfusion therapy. We will perform platelet 
antibody studies by the serotonin release and 
complement fixation methods, HLA typing and 
coagulation studies in patients receiving platelet 
and other types of transfusions. The results of 
these studies will be correlated with platelet 
unresponsiveness. This information will be used 
to search for donors for platelet transfusions 
among family members and unrelated individuals. 
In addition, in vitro platelet function studies 
will be performed on donor platelets and on 
recipients' platelets before and after infusion. 
He will attempt to correlate these with platelet 
rise and platelet survival, control of hemorrhage 
and other untoward reactions. 

These studies will be performed in order to 
■aximize the benefit of platelet transfusion 
therapy in patients with the thrombocytopenia 
associated with malignant disease and to determine 
the effect of platelet transfusions on overall 
survival of patients with aalignani disorders. 



34 5. (ROLE OF PLATELETS IN SUPPRESSING INFECTIOBS 

IN LEUKEMIC PATIENTS) 

Krivit, W., Clawson, C. c, , White, J, G., Pernan, 
v., Blooofield, C, Nesbit, M., Gerrard, J., 
HcCullough, J., Univ, of Minnesota, School of 
Medicine, Pediatrics, 1305 Mayo, Minneapolis, 
Minnesota, 55455, U.S.A. 

Infusions of platelets are being given to 
patients with leukemia who have sepsis in a 
uniform, but random, manner at the present. This 
data tfiil be studied further in a controlled 



172 



■a&ner to test the hypothesis as to vhether 
platelets can be effective in suppressing bacte- 
rial infection. This is part of a broader 
project. (Text Abridged.) 



31(6. IPHIELET SOPPOBT FOB lEOUBBIC C8ILDBEIII 
Chard, R. 1., Hartaann, J. B., Calderon, C. S., 
rusener, J., childrens orthopedic Hospital, aeOO 
Sand Point Way N.E., Seattle, Uashington, 98105, 
O.S.I. 

OBJECTIVES: To iaprove platelet support for 
children with malignant diseases and to investi- 
gate the causes of abnoraal bleeding in these 
patients. 

Investigations to define and characterize 
heaostatic abnormalities associated with malign- 
ancy should permit identification of mechanisms of 
platelet transfusion refractoriness and their 
appropriate management. Thus far, these studies 
have indicated the extensive consumption associ- 
ated vith acute leukemias in childhood nith 
turnovers up to 6 times the normal and the high 
incidence of autoantibodies (57S) in acute 
lymphocytic leukemia. In addition, the studies of 
the incidence of alloimmunization vill define the 
risk for the development of this cause of platelet 
transfusion refractoriness, further studies are 
needed to identify the potential value of antithr- 
oibotic therapy to reverse the consumptive 
process. 

Since platelet support in acute leuxemia is 
one of the most difficult problems because of the 
development of refractoriness, furtner definition 
of the role of blood product administration as the 
cause of sensitization and its potential preven- 
tion with antileukemic drugs is needed. Theref- 
ore, samples of platelet antibody detection will 
be collected weekly through remission induction 
and maintenance regimens. Platelet donor selection 
for the alloimounized recipient is essential. When 
patients become refractory to random donor 
platelet transfusions on the basis of alloimmuniz- 
ation, a crossmatch will be performed using the 
patients' serum or plasma and that of available 
family members or random platelet donors, using 
the C1U labeled adenine release or radioimmunoa- 
ssay technigues. 

In almost 50* of the newly diagnosed children 
with acute lymphoblastic leukemia, platelet 
antibodies are present at the onset. The sign- 
ificance of this finding is under continuing 
investigation. (Text Abridged.) 



3117. (ETALUATIOB OP PIATEIEI SOPPOBI IV LEOKEBIC 

PHIEBTSl 

Slichter, S. J., Barker, I. A., Storb, B. r. , 

Thcmas, E. D. , Puget Sound Blood Center, Terry 

Ave. at Badison St., Seattle, Hashington, 981011, 

O.S.A. 

These studies are designed to evaluate 
several aspects of platelet support. Included are 
investigations of platelet preparation: i.e. 
-optimize platelet yield while ensuring viability 
and function of platelets obtained by plateletpho- 
resis, and develop simple techniques to determine 
viability and sterility of room temperature stored 
platelets. In addition, an evaluation of indic- 
ations for platelet transfusions (prevention of 
CrSI labeled stool blood loss) and their effectiv- 
eness (appropriate reduction of the bleeding time 
for the number of circulating platelets) are 
planned. Platelet transfusion refractoriness is 
usually a manifestation of infection (viral or 
bacterial) or alloimmunization. Animal models 
•ill be used to determine whether available 
antithrombotic agents can prevent consumption 
associated with infection. Histocompatibility 
typing and platelet typing techniques (Cli-labeled 
adenine release, platelet Factor 3 release, 
radioimmunoassay and platelet-lymphocyte react- 
ivity) will be used to screen for compatible 
donor-recipient combinations for platelet transfu- 
sions. As an alternative approach to donor 
selection, the effects of recipient immunosup- 
pression on preventing, delaying or reversing 



allolBBunization will be studied. For the 
refractory recipient, methods which will allow 
fiubscguent bone-marrow-grafting from related or 
non-related donors as an ultimate solution to 
platelet support will be investigated. 



3«e. (STODIES OB PLAIEIETS AND PLATELET TBANSF- 

DSIOBS m LEaKEHIC PATIENTS) 

Gardner, F. H. , aurphy, S. , Evans, A., Donaldson, 

I. H., Stathakis, N. E., Koch, P. A., Univ. of 

Pennsylvania, School of Medicine, Bedicine, 36th & 

Hamilton Halk, Philadelphia, Pennsylvania, 1910ii, 

O.S.A. 

He are studying the optimal methods for the 
storage of platelet concentrates and the indic- 
ations for their use. studies of storage at room 
temperature are emphasized. Currently emphasis is 
on the type of plastic from which the container is 
constructed and the gas concentration in the 
surrounding air. He plan administration to 
thrombocytopenic patients with measurements of 
increments in platelet count and serial bleeding 
times. Also, we are engaged in a prospective, 
randomized study of the indications for platelet 
transfusion in children with Acute Leukemia. 
Patients are randomized to receive either prophyl- 
actic or therapeutic transfusion. In addition, we 
will re-evaluate the clinical efficacy of refrige- 
rated storage of platelets in raising the platelet 
count and shortening the bleeding time in thrombo- 
cytopenic recipients. 



3«9. PIASBA IBAKSFOSIOll IH LIBPHOCTTIC LEOKEBIA 
Kattlove, H. , Los Angeles Co. Harb. G. Hosp., 1000 
H. Carson St., Torrance, California, 9C509, 
O.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



350. EAPIC PLASHA EICHAKGE HITH COHTISDODS FLOH 
CEBTBIFDGE 

BcCullough, J., Univ. of Binnesota, School of 
Bedicine, Bedicine, 1305 Bayo, Binneapolis, 
Binnesota, 55155, U.S.A. 

This is part of a broader project. A summar 
of this subproject is not available. 

351. BLOOB COBPOMEBT TBEBAPT— PLATELETS 
Holland, J. F., City University of New lork. 
School of Bedicine, Neoplastic Diseases, 5th Ave. 
at E. 100th St., New lork. New York, 10029, 
O.S.A. 

This is part of a broader project.' A summai 
of this subproject is not available. 



352. ( SDBYIYAL OF CEIL COBPOBEBTS IB TRANSFUSED 

PATIEBTS) 

Spurr, C. L., Cooper, B. B. , flcCall, C. E. , 

Dechatelet, L. E., Heise, E. B., Kaufmann, J. S., 

Richards, F., Hake Forest University, School of 

Bedicine, Bedicine, Box 7323, Beynolda Station, 

Hinston Salem, North Carolina, 27103, U.S.A. 

This study will evaluate the survival of 
leukocyte transfusions by use of DFP-labeled 
leukocytes, and will utilize specific parameters 
of leukocyte metabolism to evaluate the effective 
survival of the leukocyte in transfusion recip- 
ients. Platelet survival data will be obtained by 
the use of Cr51 labeled donor platelets and 
physiological survival of platelets as evidenced 
by a coagulation survey. 



173 



C. lEUKAPHERESIS 



353. THE IBEAIIIEIII OF CHROMIC LEaKEnlA B? LEOKAPH- 

EBESIS 

BcCreoie, K. , Guttcrman, Hester, Univ. of Teias, 

H.D. Anderson Hosp. S Inst., Developmental 

Therapeutics, P.O. Box 20036, Houston, Texas, 

77025, U.S.A. 



OBJECTIVES: (a) To improve the manageaent o£ 
the stable phase of chronic leuKemia by utilizing 
leukapheresis. (b) To evaluate the effectiveness 
of leukapheresis itself for the control of the 
signs and symptoms of the stable phase of chronic 
leukemia. (c) To evaluate the role of therapy 
during the stable phase in the evolution of the 
■ore serious complications of the advanced phase 
of chronic leukemia. 

APPSOACH: Patients who have had minimal or 
no prior chemotherapy have leukapheresis performed 
intensively with the objective of reducing the 
accumulative phase of chronic leukemia. Hhere 
possible, periods of intensive leukapheresis will 
be separated by periods of no treatment where the 
patient will be allowed to continue without 
therapy until signs cr symptoms of disease recur. 

PROGBZSS: Based on preliminary studies, it 
appears that intensive leukapheresis over a two to 
three week period can result in regression of 
leukacytosis and tissue infiltration on liver and 
spleen lyofh nodes. In a small number of patients 
it requires "4-6 months without leukapheresis for 
the signs and symptoms to recur. Therefore, it is 
conceivable that intensive pheresis over 2-3 week 
periods administered 2-3 times annually could 
control all the symptomatic phase of the stable 
phase of chronic leukemia. 



35«. (CLINICAL APPLICATIOM OF lEH 2990 HODEL 6 
EIPEFilMEmAL BLOOD CELL SEPARATOR IN LEUKEMIA ) 
Oettgen, H. F., Clifford, G. 0., Clarkson, E. D. , 
Reich, Bemorial Hosp. for Can. 6 Dis., Medicine, 
1275 Jork Ave., New York, New York, 10021, U.S.A. 

The IBB Cell Separator was used in studies of 
the following categories: 1. Leukapheresis of 
patients with acute myeloblastic leukemia - (6 
cases) . This is an attempt to stimulate the 
leukemic cells to go into "S" phase and, theref- 
ore, render them susceptible to chemotherapy. 
Though preliminary studies showed no therapeutic 
effects, in vitro, there is a slight indication 
that these changes might occur. 2. Leukapheresis 
of patients with chronic lymphocytic leukemia 
aiming to lower their WBC and perhaps "disiT.pact" 
their marrow (n cases) . A distinct decrease in 
adenopathy and/or spleen size is noted, but it is 
of short duration. This is part of a broader 
project. (Text Abridged.) 



355. HEBAIOLOGY SUPPORT CARE FOR LEUKAPHERESIS OF 
LEUKEBIA PATIENTS 

Irapani, P. J., Microbiological kssoc. Inc.; U733 
Bethesda Ave., Bethesda, naryland, 2001"l, U.S.A. 

Conduct hematology support care and perform 
the following tasks: Conduct a variety of leukoag- 
glutination assays of prospective human recipient 
sera against prospective donor peripheral leu- 
kocytes; Conduct microlymphocy to+oxicit y assays on 
serum samples from patients; Ascertain the 
granulocyte phenotype of patients and prospective 
donors, eJifloying reference granulocyte typi;.g 
sera in a modified microlymphocytotoxicity type of 
procedure; Conduct microgianulocyte cytotoxicity 
screening assays and absorption studies on serum 
samples from patients; and maintain a systematic 
frozen repository of all serum and/or plasma 
samples obtained from patients, relatives, and 
normal donors under study in this program. 



356. ( EFFICACY OF CEIIULAB SOPPOBT IN LEOKEMIC 

PAIIEHIS) ' 

yankee, E. A., Horner, S., Sichman, c, Sidney 
Farber Cancer Institute, «U Binney St., Boston, 
nassachusstts, 02115, U.S.A. 

This project will provide experimental 
information on the efficacy of various aspects of 
cellular support in patients undergoing chemot- 
herapy for cancer. Procurement of granulocytes by 
filtration leukapheresis induces a granulocytosis 
in donors. Post filtration pheresis plasma 
obtained from an animal model produces a consis- 
tent granulocytosis in non-pheresed recipient 
animals. Humoral regulators of stem cell prolife- 
ration and maturation may influence the degree of 
toxicity experienced with various chemotherapeutic 
agents. -Both in vitro and in vivo assays are 
utilized to evaluate regulators and to establish 
their importance on the level of circulating 
cellular components during chemotherapy. 

Committed granulocyte progenitor cells 
circulate in the peripheral blood and we have 
observed a profound increase in the number of stem 
cells during recovery from myelosuppression. 
These cells may be useful for autologous stem cell 
reconstitution in patients undergoing intensive 
chemotherapy. This is part of a broader project. 
(Text Abridged.) 



357. (FILTRATION LEUKAPHERESIS IN LEUKEHIA 

PATIENTS) 

Djerassi, I., Cooper, R., Kim, J. S., Root, R. , 

Hsieh, Y., Nayak, N., Shreiber, A., Alavi, J. B., 

Guerry, D., Burphy, S., Bercy Catholic Bedical 

Center, Philadelphia, Pennsylvania, U.S.A. 

Studies on the clinical effectiveness of 
transfusions of granulocytes collected by Filt- 
ration Leukapheresis will be carried out in 
leukopenic and infected patients. The viability 
and functional adeguacy or filtered granulocytes 
in-vitro and in-vivo will be evaluated. Improved 
methods for collection of granulocytes and 
monocytes by Filtra tion-Leukapheresis will be 
explored. The value of supportive granulocyte 
transfusions in enlarging the scope of currently 
available therapeutic modalities for malignant 
disorders will be determined. 



35 8. SEPARATION OF BLOOD BY CONTINUOUS FLOW 

CENTRIFUGE 

Thomas, E. D. , Buckner, c. D., Clift, R. A., Fred 

Hutchinson Cancer Res. Ct, Div of Bed Oncology, 

1102 Columbia St., Seattle, Washington, 9eiOU, 

U.S.A. 

OBJECTIVE: To develop and evaluate granu- 
locyte transfusion therapy as a life-support 
procedure in the treatment of idiopathic and 
iatrogenic agranulocytosis. 

APPROACH: Hethods or granulocyte procurement 
from normal donors will be compared for dcnor 
safety and harvesting efficiency. The value of 
granulocyte transfusions in the treatment of 
existing bacterial injection in agranulocytic 
patients will be assessed. A prospectively 
randomized study of the value of granulocyte 
transfusions in prophylaxis against bacterial 
infection of agranulocytic patients is being made. 
Uninfected patients are randomized to transfused 
and non-transfused groups. These studies are 
being undertaken in patients receiving allogeneic 
marrow transplants as part of the treatment of 
leukemia or marrow aplasia. 



359. FILTBATION-LEUKAPHERESIS FEB GR ANULOCYTE 

TRANSFUSIONS 

Huggins, C. B., Pataki, J., Univ. of Chicago, 

School of Bedicine, Cancer Research, 5801 S. Elli 

Ave., Chicago, Illinois, 60637, U.S.A. 

OBJECTIVE: a) TO perform in vitro studies 
of granulocytes prepared by different methods for 
transfusion into patients and, b) to determine 
the efficacy of granulocyte transfusions as 



174 



supportive therapy in addition to antibiosis in 
the sanagemeDt of sepsis in leukopenic patients. 

AFPROACH: Granulocytes have been separated 
fros heparinized blcod of noroal donors using the 
technique of continuous flo« filtration leuka- 
pheresis (CPPL) . CffL cells are then tested in 
vitro for their aOility to respond to chenotactlc 
stinuli« to adhere to surfaces, to phagocytize and 
kill bacteria « and to perform a variety of 
different oxygen-dependent netabolic functions 
relevant to the bactericidal process. The 
Bodification of these processes by ABO incompat- 
ible leukagglutinin positive and recipient secua 
Is also under investigation. Leukopenic patients 
vith presumed sepsis are assigned randomly to 
receive antibiotics and granulocytes or antibio- 
tics alone as management and are compared to 
survival ajid other parameters of clinical respo- 
nse. 

FROGBESS 
cm technigu 
respects save for a 
ability to adhere tc 
bactericidal functic 

incompatible serum, c) Initial data from the 
clinical trial of leukocyte transfusion therapy 
does not indicate a clear benefit to transfusion 
therapy vith CFFL cells above and beyond the 
appropriate choice of antibiotics. 



a) VBCs prepared by a modified 
unction well in vitro in all 
r a mild diminution in their 

surfaces, b) Phagocytic and 
ns are not modified by the 



360. LEUKOCYTE TBAHSFUSIOHS AHD IligUH0THE8>PI IH 

XEDKEtllA 

Vogler, u. R. , Binton, E. F., Gordon, D. S. , Emory 

Dnlversity, School of nedicine, nedicine, 1364 

Clifton Bd. H.E., Atlanta, Georgia, 3C322, D.S.A. 

The purposes of this project are: 1) to 
assess, by means of a randomized study, the role 
of granulocyte transfusions in the management of 
Infected granulocytic patients; 2) to determine 
the effect of leukapheresis on plasma and urinary 
factors KnovD to affect granulopoiesis; 3) to 
procure sufficient quantities of human leukemic 
blast cells by means of leukapheresis for the 
purposes of: a) extracting tumor specific 
antigens for skin testing and b) testing the 
usefulness of allogeneic cells and BCG in a 
randomized immunoiberapy protocol; and H) to 
establish the antibody dependent lymphocyte 
cytotoxicity test for the detection of leukemia 
associated antigens in patients undergoing 
isBUnotherapy. 



361. BLOOP COHPOMEMT THERAPY — GHA8PL0CYTES 
Holland, J. p., city University of Hew York, 
School of Medicine, Neoplastic Diseases, 5th Ave. 
at E. 100th St., Sav York, Ken York, 10029, 
D.S.A. 

This is part of a broader project. A sumiary 
of this subproject is not available. 



362. CELL COHPATIBILITY BETWEEM DOHOB AND GHi- 
BDLOCIIE TBAKSFOSIOH BECIPIEm 
Hadlock, D., Univ. of Minnesota, School of 
nedicine. Medicine, 1305 Kayo, Minneapolis, 
Hinnesota, 55455, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



363. EFFECTS OP GBASUI.OCYTE IRABSPPSIOMS 0» ACOTE 
lEOHEBIA PATIEHIS 

Deinard, A., Univ. of ninnesota. School of 
Hedicine, nedicine, 1305 (layo, Minneapolis, 
Binnesota, 55455, U.S.A. 



This is part of a broader project. 
of this subproject is not available. 



uiaary 



36«. 1.I0KAPHERESIS FOR CYCLIC LEOKCCYIOSIS IN 
CHBOmC MYELOGEIIOaS LEUKEMIA 
Fortuny, I., Univ. of Hinnesota, School of 
Medicine, Medicine, 1305 Mayo, Minneapolis, 
Rinnesota, 55455, U.S.A. 

This is part of a broader project. A sum 
of this subproject is sot available. 



365. IHFDSIOilS OF GRAHULOCYTES IN GBAUDLOCYTIC 

lEUKEHIA 

Robinson, R. A., Univ. of Colorado, School of 

Medicine, Medicine, 4200 E. 9th Ave., Denver, 

Colorado, 80220, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



366. HISIOCOMPATIBLE LEUKOCYTE TRAMSFHSIOK TO 
PREVENT AHE CONTROL INfECTION 

Cooper, M. H. , wake Forest University, School of 
Hedicine, Medicine, Box 7323, Reynolda Station, 
■inston Salem, North Carolina, 27103, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



367. SPPPOBTIVE CARE — IMPROVING GRANULOCYTE 
COLLECTION TECHNIQUES 

Higby, D. J., Rosvell Park Memorial Inst., 666 Elm 
St., Buffalo, Sev York, 14203, U.S.A. 



This Is part of a broader project, 
of this subproject is not available. 



A summary 



D. TREATMENT AND PREVENTION OF INFECTIONS IN 
IMMUNOSUPPRESSED PATIENTS 



368. ALTERATIONS OF ORAL FLORA IN CHILDREN 
RECEIVING CHI30THERAPY FOR LEUKEMIA 
Turner, J. E. , Halker, R. D., Univ. of Tennessee, 
School of Dentistry, oral Pathology, 62 S. Dunlap 
St., Memphis, Tennessee, 36103, U.S.A. 



Hicroorganism 
source for systemi' 
leukemia receiving 
incur life-threaten 
such as Pseudcm 
and Candida Spp 
healthy persons 
tion is to evaluate 
certain pathogens 
the dorsal tongue 
correlate the occ 
the development o 
from the dorsum o 
• sterile swab. Sa 
will be obtained 
(J.A.D.A. 85: 1349- 
igfat incubation in 
«ill be streaked on 
Hill be obtained pr 
erapy, during indue 
continuation therap 
atlon is awaiting 
pation Committee, S 
Bospital. 



from the oral cavity may be a 

infections in children with 

hemotherapy. These patients 
ing infections by organisms 

aeruginosa, Escherichia coli, 
ich do not ordinarily endanger 
he purpose of this investiga- 

qualitative alterations among 
nd opportunistic organisms of 
nd dental plague and to 
rence of these organisms with 
systemic infections. Samples 
the tongue will be obtained via 
mples from the dental plaque 

described by Hoerman, et al 
1352, 1972) . Following overn- 
thioglycollate, viable growth 

appropriate media. Samples 
lor to the onset of chemoth- 
tion of remission and during 
y. The onset of this investig- 
pproval by the Patient Partici- 
t. Jude Children's Research 



369. SNOIOEIOTIC RESEARCH OF CANCER AND LEUKEMIA 
Beyer, J., linzenmeier, G., Hantschke, D., 
Vanderwaaij, D. , Univ. clinic for Internal Med., 
Clinical Oncology, 55 Huf elandstrasse, Essen, 
Federal Republic of Germany, 43 

OBJECTIVE: TO reduce the rate of infections 
in patients vith acute leukemias undergoing 
intensive cytostatic chemotherapy. Isolation of 
these patients in 2 laminar down flow tents with 
decontaainaticn of the skin, oropharynx and gut. 

APPROACH: He are members of the EORTC 
Gnotobiotic Project Group, which studies in 



175 



iOCC 


imial 


infeciic 


ns, (2) 


their ability 


the 


! acti 


vity o£. 


or pre> 


tent energence 


li t 


esist 




other drugs when used 


lion 


. Si 


nee rece 


ht studi 


.es have shonn 


: hi 


ghly 


effectiv 


e in the control of 


li 1 


nfect 


ior.s pro 


duced bj 


■ Pseudomonas 


!l# 


Saino 


nella ty 


Fhimuriu 


im. Listeria 



randomised prospective trials the isolation and 372. COHBIBEP DBDGS IH KEOPLASII-iiEHTSD BOSPITAL 

iecontajiinaticii of patients nith acute leukemias. mfECIION 

The bacteriological and fungal surveillance is Hobby, G. I., Lcnert, T. F. , U.S. Veterans 

done by our local bacteriologist and mycologist Administration, Hospital, Special aesearch 

and by the central laboratory of the EOBTC laboratory, Iremont Ave. t S. centre St., East 

Gnotobiotic project Group (Rijswiilt, Netherlands). Crane, "en Jorsej, C7019, U.S.A. 

PEOGEESS: The duration of infections under 
neutropenic conditions in patients undergoing The goal of this study is to determine the 

isolation and decontamination is decreased extent of the problem, with respect to nosocomial 

compared with patients treated in open wards. infections, within VS hospitals and establish 

Until now there is no complete absence of bacteria methods for the treatment of hcspital-acguired 

in the oropharyni and sometimes in the gut. The infections, particularly those occurring in 

new protocol of another randomised trial of the transplant patients and in patients with neopla- 

EOBIC has special interests in this field. stic disease, commonly due to strains of Esche- 
richia coli, Pseudomonas aeruginosa, staphyloco- 
ccus aureus, Proteus and Klebsiella. It has oeen 

370. TBANSfEB FACTOB FOE THE PBOPHyiAlCIS AND clearly established that carefully selected drug 
THEBAPl IN INFECTIOUS IN CAMCE-i PATIENTS UNDEBG- combinations are more effective than single drugs 
CIKG CHlnOTHEEAPY in the treatment of tuberculosis. Jet little 
Bodriguez, v., Bodey, G. P., Gutterman, J. U., attention has been directed to the rational use of 
Hersh, E. H., Univ. of Texas, n.D. Anderson Hosp. drug combinations for treatment of most other 

6 Inst., Developmental Therapeutics, P.O. Box infections. The present study is designed 

20036, Houston, Texas, 77025, U.S.A. therefore to provide a routine survey of acute 

infections in patients with chronic pulmonary 

OBJECTIVES: (a) To assess the effectiveness disease, within selected VA hospitals, to evaluate 

of transfer factor in the prevention and therapy the nature of the organisms responsible fcr such 

of infections in cancer patients. (b) To infections, and to evaluate in vitro and in 

investigate the various parameters of cell- experimental animals (1) the ability of aitim- 

mediated immunity in cancer patients undergoing icrobial agents to inhibit growth of organisms 

chemotherapy before and after the administration causing no 

cf transfer factor. to enhance 

APPROACH: This project has been established of microbi 

to assess the effectiveness of Transfer Factor in combina 

(TF) therapy of infections in cancer patients, and that BCG i 

to investigate the various parameters of cell- experiment 

mediated immunity in cancer patients undergoing pseudomall 

chemotherapy before and after the administration monocytogenes, and other organisms and suggest 

of TF. Since TF has been shown to be capable of also that BCG may be effective in lowering 

transferring cell-mediated -immunity to bacterial mortality among leukemic patients, the present 

and fungal antigen, it appears to be uniguely study is designed also, tc evaluate the extent to 

suited for immunotherapy of cell-mediated immunod- which increased levels of non-specific immunity 

eficiencles. Infection constitutes the major will enhance effects cf antimicrobial therapy. 
cause of morbidity and mortality in patients with This is a long-range study and is important, 

hematological malignancies and also in solid tumor for a reduction in the incidence and severity of 

patients; a progressive increase in fungal and nosocomial infections should significantly reduce 

other unusual infections has been observed. This mortality in hospitalized patients receiving 

in part occurs because of the patients' immun- immuno-suppressive drugs for organ transplants or 

ological derangement, and also because of the neoplastic disease. 
effects of the therapy that they undergo. 
Patients with acute leukemia frequently develop 

fungal infections mainly caused by Candida spp. 373. DEIECIIOH OF INFECTION IN PATIENTS gITH 

and Aspergillus spp. Infections caused by HALIGNAHCt 

Cryptococcus, herpes simplex and herpes zoster are Hamilton, J. D., U.S. Veterans Administration, 

not uncommon in patients with malignant lymphoma. Hospital, 508 Fulton St., Durham, North Carolina, 

Patients with bronchogenic carcinomas and with 27705, U.S.A. 
hematological malignancies are also susceptible to 

developing mycobacterial infections which can be In order to investigate the reasons for the 

caused by Kycobacter ium tuberculosis or any of the difficulty in identifying bacterial infections in 

atypical mycobacteria. Protozoal infections are patients with leukemia, in vitro and in vivo 

becoming more frequent in patients undergoing studies have been designed. Purified standard 

intensive chemotherapy, thus the incidence of samples have been obtained from the manufacturers 

Pneumocystis and Toxoplasma gondii, as causative and will be tested against a battery of clinically 

organisms of infections in these patients, is significant microorganisms for their inhibitory or 

becoming recognized more frequently. Resistance cidal capacity. 

to pathogens which are able to survive within In addition, patients presenting to the 

•acrophages is largely dependent on cellular Hematology Clinic who are in chemotherapy are 

immunity. Cellular immunity is also of clinical having bloods drawn before treatment and at 30 

importance in preventing fungal infections and minute intervals thereafter for 1-2 hours. These 

terminating many viral infections. The fact that sera will be tested for inhibitory capacity 

leukocyte extracts can activate cellular immunity against other organisms. 

in patients who are congenitally deficient in T These data, along with knowledge of the 

lymphocytes suggests not only that the material is metabolic fate of many of these agents will be 

capable of supplying lymphocytes with certain useful in assessing the problem originally 

receptor specificities, but also that they might identified, 
somehow promote the differentiation of T lympho- 
cyte precursors. (Text Abridged.) 

371. A SIDDI OF INFECTIONS IH IREADIAIEP PATIENTS 
Tyndall, E., lankersley, u., chaskes, S., Colyer, 

371. PREVENTION OF INFECTIOUS COHPLICAIIONS IH S. , Oak Eidge Associated Univs., Bedical Division, 
1EUKEHIA BOX 117, Oilk Bidge, Tennessee, J7830, U.S.A. 
Klastersky, J., Tagnon, H. , Cappel, E., Debusscher, 

L., Henry, A., Free University of Brussels, 50 Infection is one of the most serious complic- 

Ave. Franklin Eoosevelt, Campus Plaine, Brussels, ations of leukemia and associated therapeutic 

Belgium, 1050 total-body irradiation (7B1) . This increased 

susceptibility to infection has been studied in 

A Euiiary is not available. some detail in experimental animals; nowever, 

little information is available on humans. The 
purpose of this study is to examine the underlying 
causes of altered resistance in irradiated human 



176 



Dd cellular 



:plore Vf 


:s and ii 


.ntly we 


!S folloi 


Pseudomc 


lacteric. 



syste. 
itudying 
BI to ki 


the 
11 


eraginos 
lotential 


of 


ariou; 






lly, .e 


are 


ictive 


dr 


uqs 


1 the eff 


ect 



rophil's 




.coccus 01 




■riments 




,n prevent 




, help 




lysis of 


c 


r transplan' 



subjects. Our principle g 
the effects of irradiation 
defense lechanisis; (2) ex 
the host's natural defense 
daring irradiation. Curre 
ability of human leukocyte 
Staphylococcus aureus and 
ie are also studying the b 
£eruB frou TBI patients on £. coli at v 
Intervals after irradiation. Additiona 
investigating the ability of radioprote 
to prevent iopairoent of leukocyte func 
following TBI. lastly, we are studying 
of TBI on the ability of hunan leukocyt 
produce interferon in response to virus 
BESDLIS: Data to date indicate th 
TBI depresses the total number of perip 
leukocytes but does not impair the neut 
ability to kill Pseudomonas or Stapbylo 
per cell basis. The data in mouse expe 
also show that radioprotective drugs ca 
depression of peripheral leukocytes and 
prevent TBI-associated infections. Ana 
reactive protein levels of three marrow 
patients showed good correlation with t 
csifi of this protein and microbial infe 
following transplantation. 



375. STDEIES OH PSEBPOBOHAS AEBDGIHOSt III * CtHCEH 
BESEARCH CEHTEB 

■oody, M. B., Young, V. II., Borris, «., Friedman, 
B. R., U.S. Dept. of Hlth. Ed. 6 Bel., Natl. 
Cancer Institute, Baltimore Cancer Res Center, 
Baltimore. Baryland, U.S.A. 

The studies on Pseudomonas aeruginosa were 
designed to investigate the influence of extrinsic 
factors on the pathogenicity of this organism to 
provide insight into mechanisms by which the 
infections they cause can be eliminated. 

P. aeruginosa was recovered from 26» (199) of 
762 cancer patients. Recovery rates were highest 
in acute leukemias (52X) (P less than .001). Types 
« and 7 were freguently isolated from cancer 
patients but rarely from noncancer patients. Type 
3 was more likely to be recovered from lymphoma 
patients and Type 6 from solid tumor patients. 
Colonization rate was highest in acute leukemias. 
Icute leukemic and CNS patients were colonized 
•est often by Type 7, Hodgkins' non-CVS solid 
tumor and noncancer patients by Type 6, non- 
Bodgkins' lymphoma patients by Type 1 and myeloma 
patients by Type 2. P. aeruginosa were acquired 
by 65* of the patients (P less than .001). Type 7 
was the most frequently acquired strain (P less 
than .001) and Type 2 was most commonly present at 
admission (P .01). Colonization and infection 
rates were higher with acquired strains. Over 6551 
of the colonized patients btcame infected. 
Acquired Types 1 and 7 caused more infections than 
did other types. 

Immunoglobulin levels to P. aeruginosa were 
highest in solid tumor patients and lowest in 
lymphoma patients. Ig level to the causative 
organism increased following urinary tract 
infections and pneumonias. Among solid tumor and 
lymphoma patients, the average titer was highest 
in non-colonized patients. It was highest in the 
aon-colonized, non-infected leukemic patients. 

P. maltophilia and P. cepacia, which were 
freguently recovered from patients and their 
environs and were resistant to most antibiotics, 
«ere susceptible to trimethoprim-sulfamethoxazole. 



more rapid and/or accurate diagnosis of infection. 
This program has been in progress for over 5 years 
and has allowed meaningful evaluation of the types 
of infection occurring in different types of tumor 
patients. Further, specific problems have been 
identified such that appropriate intensive 
preventive measures could be devised and enforced 
with consequent marked reduction in Infection 
morbidity. 



377. IBFECIIOM III CAMCER PATIEMTS 

Bodey, G. P., Univ. of Texas, Cancer Center, P.O. 

Box 20036, Houston, Texas, 77025, U.S.A. 

Infections are a frequent complication of 
patients undergoing cancer chemotherapy. The 
Protected Environment-Prophylactic Antibiotic 
Program has been developed to reduce the risk of 
infection in these patients. He are evaluating 
this program in patients with acute leukemia 
receiving chemotherapy, using a randomized 
controlled study. In addition, new methods for the 
diagnosis and treatment of bacterial, fungal, 
viral and protozoal infections will be developed. 
Also, new antibacterial, antifungal and antiviral 
antibiotics will be evaluated for their value in 
the treatment of infections in cancer patients. 



378. SUPPRESSIOH OF ESTABLISHEC LEUKEBIA VIRUS 

IHFECIIOWS 

Uheelock, E. F. , Ban, P. A., Goldstein, L. , 

Thomas Jefferson University, School of Bedicine, 

Bicrobiology, 1025 Halnut St., Philadelphia, 

Pennsylvania, 19107, U.S.A. 

The objective of this research is to define 
and understand the role of humoral immunity in the 
maintenance of a dormant Friend leukemia virus 
(FLV) infection. We will study a unique leukemia 
virus model in which we can restore normal levels 
of humoral immunity to FLV-infected mice with a 
single injection of statolon, an extract of 
Penicillium stolonif er um. Statolon converts a 
rapidly fatal leukemia virus infection to a 
dormant state with prolonged clinical remission. 
He plan to study two phases of the humoral immune 
response which may maintain the dormancy of Friend 
leukemia. First, we will identify the Fiv-virion 
polypeptides that bind antibodies obtained from 
uninfected mice, and from mice with either overt 
leukemia or a dormant FLV infection. We will use 
radioimmune precipitation and polyacrylamide gel 
electrophoresis. Our aim is to detect differences 
in the humoral inmune response in the three groups 
of mice. Secondly, we will identify antibodies 
that react with the spleen cells of these mice. 
In these studies, extracts of radioact ively 
labeled spleen cells from uninfected, FlV-leuxeaic 
and FLV-dormant infection mice will be tested for 
their ability to combine with antibodies from 
dormant infection mice and the antigens identified 
by polyacrylamide gel electrophoresis. 

In other studies, we will search for ant- 
i-virion antibodies obtained from FLV-dormant 
infection mice, that bind to the surface of spleen 
cells from uninfected, FLV-leukemic and FLV- 
dormant infection mice. A full description of the 
target antigens of humoral antibodies in FLV- 
dormant infection mice will enable us to unders- 
tand the potential of these antibodies for 
maintaining the suppression of Friend virus 
leukemia. 



376. EYALDATIOII OF THE TYPES ARD CAUSES OF 
IBFECIIOOS DISEASES IN CAliCEB PATIENTS 
Schimpff, S. C, Aisner, J., Brouiilet, B. , Hahn, 
D. «., niernik, P. H., young, V. B., U.S. Dept. of 
Blth. Ed. e »el., Natl. Cancer Institute, Bedicine 
Sect, Baltimore, Baryland, U.S.A. 

Infection is the leading cause of morbidity 
and mortality in patients with acute leukemia and 
a aajor cause in other types of advanced malignan- 
cies. The aims of this project are to catalogue 
and identify the infections, identify the predisp- 
osing factors, and evaluate new techniques for 



379. LAMINAR FLOU ISOLATION III ACUTE LEUKEBIA 
Irwin, I. E., Univ. of Southern California, Scho 
of Bedicine, Pediatrics, 2025 Zonal Ave., los 
Angeles, California, 90033, U.S.A. 

This is part of a broader project. A suiaa 
of this EUbproject is not available. 



177 



380. ETIOLOGIC HCEHIS OF PHEUHOIIITIS IK LEUKEHIA 

f UTIEHIS 

Siitb, J., St. Jude Ch. Bes. Hosp. , Box 318, 332 

K. Lauderddle St., Heapbls, Tennessee, 36101, 

D.S.A. 

This is part of a broader project, t susaacy 
of this subproject is not available. 



Hugbes, H., St. Jude Cb. Bes. Hosp., Box 318, 332 
N. Lauderdale St., Hemphis, Tennessee, 38101, 
U.S.A. 

This is part of a broader project. A sunnary 
of this subproject is not available. 



382. BICBOFLORA IB lEUKEBIC AMD IllllUSODEf ICIEST 
PAIIEms AND LABOBAIORlf AMIIIALS 

Hilson, B. , Baylor College, School of Medicine, 
Pediatrics, 1200 Houcsund Ave., Houston, Texas, 
77025, U.S.A. 

This is part of a broader project. A suBitary 
of this subproject is not available. 

IV. COOPERATIVE GROUP STUDIES 



A. MEMBERS OF THE ACUTE LEUKEMIA GROUP B 



386. CHEBOTHEBAPI OF CAMCER - ACUTE LEUKEHIA GBODP 

£ 

Ellison, B. B. , Hattern, J., Dayeo, U. , Goldberg, 

B., State University of New York, School of 

Hediclne, Medicine, 3435 Hain St., Buffalo, Nev 

Tork, 1'(21i(, U.S.A. 



387. ACDIE lEUKEHIA GROOP B 
Spurr, C. L., Patterson, R. B. , Cooper, B. 
Hayes, D. n., Bichards, F., Buss, H. B., U 
D. «., Sterchi, J. M. , Homesley, H. D. , «a 
Forest University, School of Medicine, Bed 
Box 7323, Reynolda Station, Winston Saleo, 
Carolina, 27103, U.S.A. 



388. ACUTE LEUKEMIA COOPEBATIVE-STUDI GROUP B 
Baurani, F. I., Erslev, A. J., ThCBas Jefferson 
University, School of Medicine, Bedicine, 1025 
Malnut St., Philadelphia, Pennsylvania, 19107, 
U.S.A. 



389. ACUTE lEOKBMIA GROUP B 

Bassermac, 1. R. , Holland, J. F., Cuttr-er, J. 
City University of New York, School of Medici 
Medicine, 5th Ave. at E. 100th St., New York, 
York, 10029, U.S.A. 



390. ACUTE LEUKEMIA GROUP B 
Henry, P. H., Univ. of Missouri, School of 
Medicine, Bedicine, B228 Medical Sciences, 
ColuBbia, Bissouri, 66201, U.S.A. 



NOTE: The aims of this group are to screen ne 
chemotherapeutic agents in patients with 
leukemia (Phase I studies) and to explore 
the clinical pharmacology of known effective 
drugs (Phase II studies). This includes stu- 
dies of optimal dose, freguency of adminis- 
tration, sequence of administration, combin- 
ation of agents, and route of administration. 
Emphasis will be on the importance of consol- 
idation and reinduction to the duration of 
remission and survival. 



ill 



Progr 

radiotherapy, immunoth 
otherapy and surgery. Ancilla 
which includes platelet trans 
cyte transfusion, sterile env 
antibiotics will be evaluated 
Baries of individual projects 



iloped to include 
y, anti-viral ch 
llarv treatment 



vailable.) 



391. COOPEBATION HITH ALGB 

Bernard, J., Jacguillat, C, Ueil, B., Gemonauc- 
lerc, B., Auclerc, G. , Chastang, C. , St. Louis 
Hospital, 2 PI. du Docteur Fournter, Paris, Cedex 
10, France 



392. ACUTE LEUKEBIA GROUP B 
Henry, P. H., flrubaker, L. H. , Sam 
Veterans Administration, Hospital, 
Services, 800 Stadium Rd. , Columbi 
65201, U.S.A. 



393. ACUTE LEUKEBIA COOPERATIVE GROUP B 
Kung, F. H., Nyhan, «. L., Vonessen, C. , Mullere 
erhard, U. , Lang, J., Bendelson, J., Univ. of 
California, School of Bedicine, Pediatrics, P.O. 
Box 109, San Diego, California, 92038, U.S.A. 



383. ACUTE LEUKEBIA GROUP B OPERATIONS OFFICE 
Holland, J. F., City University of New York, 
School of Bedicine, Neoplastic Diseases, 5th Ave. 
at E. 100th St., New York, Hew York, 10029, 
U.S.A. 

It is the objective of this project to 
conduct the Operations Office of the Acute 
Leukemia Group B in its new location in Scarsdale, 
New York under the official sponsorship of the 
Mount Sinai School of Bedicine. The Operations 
nerve center of the Group and is 
th the coordination, organization, 
nalysis of research of the Group 



Office is 
associated 
conduct an 
members in 



394. ACUTE LEUKEMIA GROUP B 



26506, U.S.A. 



;, S. B., Klingber 
5rsity, School of 



the the 



apy of cance 



395. ACUTE LEUKEBIA GROUP B STUDIES 
Bank, A., Marks, P. A., Hyman, G. A., Grossbard 
L., Bifkind, R. A., Kritzler, E., Debellis, B., 
Karanas, A., Goldstone, J., Kovach, J., Tretter 
P., Columbia University, School oi Medicine, 
Bedicine, 630 W. 16Bth St. , New York, New York, 
10032, U.S.A. 



384. CO-OPERftllTE STUDIES WITH ACUTE LEUKEMIA 
GROUP B 

Falkson, G., Vandyk, J. J., Vaneden, E. . B. , 
Vandermerwe, A. M., Falkson, H. C, H.F. Verwoer 
Hospital, Cancer Chemotherapy, Private Bag X169, 
Pretoria, Transvaal, Republic of South Africa, 
0001 



385. CHEBOTHERAPY OF LEUKEMIA AND NEOPLASTIC 

DISEASES 

Sawitsky, A., Long Island Jew. Hillside Ctr., 

Division of Hematology, 207-05 76th Ave., New Hyde 

Park, New York, 11040, U.S.A. 



396. CANCER AND LEUKEMIA GROUP B 
Henderson, E. S., Stutzman, L. , Fridman, M. , 
BoEwell Park Memorial Inst., Bedicine A, 666 Elm 
St., Buffalo, New York, 14203, U.S.A. 



397. ACUTE LEUKEMIA GROUP B CHEMOTHERAPY PROGRAMS 
James, G. w. , Flaherty, M. J., Baurer, H. M., 
McWilliams, N., Virginia Commonwealth Univ., 
School of Medicine, Medicine, 1200 E. Broad St., 
Richmond, Virginia, 23298, U.S.A. 



178 



398. ACUTE LEDKEBU GBOUP B 

Hclntyre, 0. R. , Haurer, L. H., Cornvell, G. G. , 
Seibert, D. J., Storrs, B. C. , Zacharski, L. B., 
forcier, B. J., Crichlow, E., Tulloh, K. E., Grace, 
H. 8., Burke, G., Hills, C, Dartmouth College, 
School of Bedicine, (ledicine, P.O. Box 83J, 
Hanover, Nex Hampshire, 03755, O.S.A. 



399. CHEMOTHEBAPY OF ACniE lEBKEIIH AND BELATEP 

PISOBDEBS 

Kjle, B. A., Burgert, E. 0., Boagla&d, H. C, 

Gilchrist, G. s., Soule, E. H., Univ. of Hinnesota, 

School of Bedicine, Internal Bedicine, 200 1st St. 

S.H., Bochester, Binnesota, 55901, 0.5. A. 



«00. ACUTE LEOKEBIA GBODP B - BOSTOH GBOBP 
Carey, B. H., Necheles, I. f., Greenberg, H., 
Paris, U., Brauer, B. J., ShattucJc, L. , Bass. 
General Hospital, 32 Fruit St., Boston, Bassa- 
chasetts, 0211U, U.S.A. 



«01. ACUTE lEDKEBIA G800P B 

lee, S. 1,, Jeuish Hospital 6 fled. Ctr. , 555 

FEOspect PI., Brooklyn, Nen York, 11238, U.S.A. 



»02. ACUTE LEUKEHIA GBOUP B 
Koch, K. , Univ. of .liami, Scho 
Pediatrics, 1U00 N.w. 10th Ave 
33124, O.S.A. 



dose with more selectivity and less cardiotoxic- 
ity. In practice it turned out to be very 
difficult to make a Daunomycin-DNA preparation for 
use in patients. Pilot studies with some patients 
in Brussels showed a negative result in leukemic 
patients. A more extensive clinical trial was 
therefore abandoned. (2) The screening of a 
combination of Adriamycin, DTIC, Actinomycin D and 
Cytoxan in the treatment of soft tissue sarcomas. 
A number of chemotherapists of Dutch cancer 
centers have drawn up a protocol for an intensive 
chemotherapy program combined with immunotherapy 
for the treatment of soft tissue sarcomas. In a 
projected trial, two combinations will be used; 
Adriamycin-Actinomycin-DIIC and Cytoxan given 
together on the same day as a pulse dose, followed 
by DTIC and Actinomycin the next four days. The 
other combination is an alternating scheme of 
Adriamycin combined with DTIC one week, and 
Cytoxan with Actinomycin 3 weeks later. As second 
randomization an adjuvant immunotherapy with 
coryne bacterium parvum will be made. The 
definite protocol is in preparation. So far, 
experience has been gained in pilot studies with 
this very intensive chemotherapy. About 20 
patients were treated. The toxicity seemed 
acceptable to the patients. In ISJ of the 
patients it was necessary to interrupt treatment, 
especially because of complaints concerning the 
gastro-interstitial tract. In some cases a good 
effect was seen. 

The follow-up is still too short to give more 
definite results. 



•103. ACUTE LEDKEBIA GROUP B - flIHNESOTA BEDICAl 

OgCOLOGY 

Kennedy, B. J., Theologides, A., Fortuny, I. E. , 

Bloomfield, C. B., Kiang, D. T., Vosika, G. J., 

Dniv. of Hinnesota, School of Bedicine, Bedicine 

1305 Bayo, Hinneapolis, Hinnesota, 55455, U.S.A. 



104. ACUTE LEUKEBIA GROUP B LAHCEB CHEBOIHEBAPI 

PKOTOCgi 

Benry, P. H. , Univ. of Hissouri, School of 

Medicine, Bedicine, B228 Hedical Sciences, 

Columbia, Hissouri, 65201, U.S.A. 



<405. LEDIIEHIA, LYHPBOHA AMD MTEIOBA CHEBOTHEBAPI 
Silver, R. I., Nachman, S. L. , Beksler, E., 
Gottfried, E. 1., Harpel, P., Coleman, n., 
Pasmantier, H. , Hoore, A., Cornell University, 
School of Bedicine, Bedicine, '1300 York Ave., Sew 
lork. New York, 10021, U.S.A. 



«06. ACUTE LEOKEBIA GBODP B 

Spurr, C. L., Patterson, B. B. , Cooper, B. B. , 
Bayes, D. B., Bichards, F., Huss, H. B. , White, 
P. H., Sterchi, J. H., Homesley, H. D. , Sake 
Forest University, School of Bedicine, Bedicine, 
Seynolda Station, Box 7323, Winston Salem, North 
Carolina, 27103, U.S.A. 



B. OTHER COOPERATIVE AND COMPREHENSIVE STUDIES 



407. EORIC - EARLY CLINICAL TRIAL GROUP 
Cleton, f. J., Heyster, H. , Netherlands Cancer 
Institute, Cancer Hospital, Antoni Van Leeuwenhoek, 
Ziekenhuis Plesmanlaan 121, Amsterdam, Netherlands 

This is a new branch of the EOEIC. It was 
established because of the need for a screening 
sethod for new cytostatic drugs, and combination 
of cytostatics. 

Some reference tumors were selected: lung 
cancer as an example of a resistant tumor, and 
Balignant lymphoma, chronic myeloid leukemia and 
breast cancer as more se.-sitive malignancies. 

The investigations involved: (1) The 
screening of Daunomycin linked with DNA. It was 
hoped from animal experiments that tumor cells 
■ould selectively take up Daunomycin-DNA complex, 
and that it would be possible to give a higher 



408. SOUTHEASTERN CANCER STUDY GBOUP 
Knospe 



H., Irobaugh 
. J., Hester 
Lukes Bed. Ctr, Profess 
Congress Parkway, Chica 
U.S.A. 



E., Gregory, S. A., 
n. F., Bush Presb. : 

1 Bldg. 907, 1753 H. 

Illinois, 60612, 



The majority of studies are directed against 
hematological malignancies, especially Hodgkin's 
disease, acute leukemia in adults, chronic 
lymphocytic leukemia and lymphomas. Emphasis is 
now shifting toward solid tumors. Phase I studies 
are done in patients with solid tumors ana Phase 
II and III studies are being devised for solid 
tumors in which there is some evidence of effect. 
We deal primarily with chemotherape'utic drugs, but 
are now incorporating the use of radiotherapy in 
comparison with chemotherapy or in combination 
with chemotherapy, ImmunotherapeuL ic approaches 
are being explored. 

Protocols we participate in are: Phase I.T, 
Protocol 245: oral methyl-CCNU E prednisone 
(pred) in myeloma (non-randomized) , H patients 
studied between 6/72, to present; Phase II, 
Protocol 248; betadeoxy thioguanosine in adult 
acute leukemia 6 blast crisis, CGL (non-random- 
ized), 6 patients studied between 5/73 to present; 
Phase II, Protocol 250; cytosine arabinoside 
(AraC) 6 thioguanine (TG) on Ph 1 plus clone in 
CGL in remission (non-randomized), 1 patient 
studied 2/75 to present; Phase II, Protocol 252: 
Twice weekly azacytidine in signal 6 other tumors 
(non-randomized, 1 patient studied 11/73 to 
present; Phase III, Protocol 340: BCNU vinblas- 
tine (VLB) , CTX, procarbazine S pred in stage IIIB 
e IV Hodgkin's (randomization; None for induction; 
maintenance by card), 11 patients studied 11/7 1 to 
present; Phase III, Protocol 343: Intermittent 
BCNU, CTX, pred vs intermittent melphalan (L-PAM) 
6 pred in myeloma (randomization: induction and 
maintenance by phone) , 30 patients studied 6/72 to 
present; Phase III, Protocol 346: BTX, VCR 6 pred 
in all consolidating remissions w/AraC E TG 
followed by asparaginase, VCR 6 pred randomizing 
to 6-mercaptopurine (6-BP) , CTX, plus or minus 
cranial radiation £ intrathecal MIX followed by 
6-BP, CTX, BTX, VCR E pred (randomization: None 
for induction E consolidation; maintenance by 
phone), 30 patients studied, 6/72 to present; 
Phase III, Protocol 346: BTX, VCR E pred in all 
consolidating remissions w/AraC 6 TG followed by 
asparaginase, VCB £ pred. (Text Abridged.) 



179 



<I09. OMCtB CHEHOTHEBftPt COOPEBtllVE CBUG STDDIES 111. BISCOWSIH HEMATOLOGY STODY GROOP - COOPERA- 

Krener, W. B. , Cchen, H. J., Huang, A. T., U.S. THE IREATnEWI OF ACUTE LEUKEalA AMD LYHFHOHAS 

Jeterans Administration, Hospital, 508 Fulton St., nacXinney, A. A., Schilling, B. F. , Korst, D., 

Durham, North Carolina, 27705, U.S.A. Eisner, E., Baich, P., Azen, £. , Cronell, E., U.S. 

Veterans Administration, Hospital, Hematology 

Clinical chemotherapy protocol studies Here Service, 2500 Overlook Ter., Madison, Wisconsin, 

carried out this past year at the Durham, VA 53705, U.S.A. 
Hospital in association with the Southeastern 

cancer Chemotherapy Study Group and the National A study of the treatment of adult acute 

Cancer Institute. leukemia using synchronization and recruitment is 

New agents: a. Phase I studies of platinum, in progress. Synchronization refers to the 

diammine-dichloro, cis (NSC* 1 19875) , are nearing selective blocking of cells in DNA synthesis by 

coDifleticn. The major toxicity experienced has cytosine arabinoside leading to partial synchroni- 

been renal failure and we have noted severe zation of the cell cycle. Death of some cells in 

worsening ot renal function in the face of DNA synthesis is also believed to enhance the 

hypercalcemia. To date no significant responses likelihood of resting cells entering the cell 

and a variety of tumors has been seen. b. Beta cycle (recruitment) . The technique of pulse 

deoxythicguanosine in acute leukemia. This cytosine arabinoside followed by 9 to 12 hour 

analogue of deoxy guanosine is being studied to infusions was developed by Mauer. It has induced 

determine its activity in patients with acute remission in more than 90 per cent of AML patients 

leukemia. We have had some success in the in his series of approximately 20 patients. Host 

treatment of blastic crisis of chronic granuloc- of these patients were children. 

ytic leukemia with this agent and some partial We have entered 19 adult patients between the 

responses in patients who have been refractory to ages of 18 and 60 in a program of treatment using 

more conventional mcdes of therapy. Bauer's method. There were 10 remissions (55 per 

Acute leukemia: Cur recently completed cent) and 8 failures. Of the 10 remissions 5 were 

protocol comparing cytosine arabinoside and complete and "4 patients are still living with 

thioguanine vs. cytosine arabinoside, thioguanine complete remission. One other complete remission 

and dauncmycin in inducing complete remissions in was obtained after multiple inductions. There 

acute myeloblastic leukemia is now being analyzed. were 1 partial remissions. Four patients are 

It appears that we are acnievirg a t0-50» rate of alive but not in complete remission. Of 8 

complete remissions with both regimens. Our failures, 6 died during induction and 2 died 

current protocol compares the three drug approach without remission. 

previously mentioned with a kinetic approach that The treatment program has not proved unduly 

we had worked out previously atQ has been submi- toxic but has not been as beneficial in our hands 

tted for publication. as in Bauer's. Part of the difference can be 

Bodgkin's disease: We are achieving a 75S attributed to differences in age of the patients, 

complete remission rate with combination chemothe- We conclude, tentatively, that synchronization and 

rapy. This protocol involves randomization after recruitment is an improvement ever conventional 

complete remission ana studying means of prolon- cytosine arabinoside and thioguanine therapy which 

ging the duration of remission. induced 13 per cent remissions in our previous 

Cancer: Numerous metastatic solid tumors are study, 
beivg investigated with combinations of adriamy- 
cin, methotrexate and Cytoxan, but these are 

preliminary. 1112. CHIIJBEN'S CANCER STUDY GROUP A 

Involvement in the treatment of patients with Newton, W. A., Ohio State University, Childrens 

cancer has allowed us to study several patients Hosp., Laboratory Medicine, 561 5. 17th St. 6 

with unusual characteristics in detail, with the Livingston Pike, Columbus, Ohio, 143205, U.S.A. 
hope of understanding the biology of the tumor 

involved a little tetter. In addition, our This is a continuation of a cooperative 

program of chemotherapy has allowed us to publish inter-institutional study of cancer in children 

several review articles dealing with clinical utilizing multidisciplinar y approach to treatment 

aspects of cancer and cancer chemotherapy. of those types of cancer which are suited to 

scientific analysis in a reasonable period of 
time. The studies are designed to provide answers 

110. WESTERN CANCER STUDY GROUP to questions concerning optimum management: and at 

Erook, J., U.S. Veterans Administration, Hospital, the same time provide the individual institutions 

Medical Service, 59C1 E. 7th St., Long Beach, with the added strengths to provide exemplary 

California, 90822, U.S.A. demonstrative care for its patients and an 

outreach to provide its community with a referral 

We will continue clinical drug trials in center for childhood cancer, 
patients with acute and chronic leukemia, lymp- At the time of writing, there are seven 

homas, Hcdgkin's disease, multiple myeloma, and active protocols dealing with leukemia and twelve 

other disseminated solid tumors within the dealing with solid tumor 

guidelines of the cooperative study group prot- for ILL/AUL is designed 

ocols. Survival data of patients entered into a effectiveness of four regimens to minimize the 

randomized contemfoiary controlled study comparing theoretic "sanctuary" of leukemic cells presen 

the effects of single agents given sequentially the time of initial induction of complete clin 

otherapy (MOPP) will continue remission utilizing both chemotherapy and radi 

nalyzed. We initiated a tion therapy, 
cooperative group protocol for the treatment of A specific protocol is available for wilm 

multiple myeloma comparing the action of seguences tumor, localized and disseminated neuroblastom 

of cycle dependent and non-cycle dependent agents. histiocytosis, osteosarcoma for the group alon 

One drug regimen employs non-cycle dependent as well as for rhabdomyosarcoma, Swing's tumor 

agents at monthly intervals (Melphalan and an intergroup basis. Additional protocols for 

Prednisone) while the other drug regimen employs study of hepatoma, histiocytosis, and Hodgkin' 

cycle dependent agents followed by non-cycle disease are being formulated. 

dependent agents given at monthly intervals In addition. Phase II studies are on-goin 

(Methotrexate, Vincristine and nelphalan) . utilizing a succession of agents and combiaati 

Cellular kinetics will te monitored with tritiated such as DTIC, and 5-A2acy tidine. 
thymidine to correlate cell destruction with 
response rate and survival in these groups of 
patients. The effect of chemot herapeut ic agents 
on the stathmokinetics of bone marrow blast cells 
in acute leukemia will also be correlated with 
response rates. As in the past, the education of 
physicians and paramedical personnel in the care 
of patients with cancer will be a vital part of 
the activities iupported. 



180 



«13. CHILDBEII'S CmCEB STUDI GBOPP 
Pinklestein, J. Z. , Sieger, L. , Lukens, J., 
Byfield, J., Univ. of California, ios Angeles Co 
Bat. Gen. Kosp, Pediatrics, 1000 w. Carson St., 
Toirance, California, 90509, U.S.A. 

The Division of Pediatric Hematology and 
Oncology of UCLA-Harbor General Hospital nas 
elected to full eembership in Children's Cancer 
Study Group A in June 1972 and becaie funded by 
tha KCI on June 1, 1973. 

The purpose of this project is to continue 
deTSlop and increase the participation of the un 
«t Harbor General Hospital and affiliated instit 
tions in all phases of the national cooperative 
progran of clinical cancer investigation of 
children. Investigators associated nith this 
prograD are located in the major referral center 
for a population of 3.3 million people. The 
purpose of the Children's Cancer Study Group is 
design and coordinate clinical investigations in 
various neoplastic disorders of children. 



tin. CBIIDBED'S CASCEB STODI GBODP A 
Sart«ann, J. P., Childrens Orthopedic Hospital, 
11800 Sand Point Hay N. E. , Seattle, Hashington, 
98105, U.S.A. 

To investigate etiology, detection, specific 
treatient aodalities of jialignant diseases in 
children. 

As a member of children's Cancer Study Group 
1, a broad program in pediatric oncology which 
•ncompasses the Pacific Northiiest, a regional 
center has been developed at this institution 
under the aegis of the above program. Children 
with acute lymphoblastic leukemia are placed on 
the group-vide protocol (which is being reported 
separately) vi4»h a current induction rate over the 
last three years of complete remission in 99» of 
the patients. According to present projected 
studies, it is anticipated that 50» of these 
children who undergo cranial spinal radiation 
continue maintenance therapy for three years will 
be in complete remission off the therapy at the 
end of five years. Similar programs in acute 
Bonlymphoblastic leukemia presently give an 
induction rate of approximately 50* of the median 
survival of one year. In addition, studies are 
underway in the treatment of Wilm's Tumors 
according to the National Wilm's Study Project, 
neuroblastoma, osteogenic sarcoma with high dose 
Bethotreiate and Citrovorum rescue, Swing's 
sarcoma, rhabdomyosarcoma, Hodgkin's Disease, 
lymphosarcoma and a newly inaugurated program in 
the chemotherapy of brain tumors. Approximately 
100 new patients with malignant diseases are seen 
at this institution annually of which UO-SO 
patients have leukemia. A patient load of 
approximately 300 patients constitutes an ongoing 
study. Approximately 85* of all patients are 
placed on specific protocol study. In addition, a 
large supportive program in plateiet transfusion, 
antibiotic therapy, and a psychosocial rehabi- 
litation of children with malignant aiseases is 
underway. A continuing improvement in the 
treatment of children with malignant diseases has 
been evident during the course of this project. 



al5. CHILDBtM'S CAHCEB STODI GBOUP 
Biller; D. F., Canale, V. C, Bilgartner, B. »., 
Sergis, E., Salk, L., Dangio, G., Gray, G. P., 
Bedo, S. P., Cornell Oniversity, School of 
Bedicine, Pediatrics, 1300 York Ave., New York, 
lew lork, 10021, U.S.A. 

The purpose of this project is to support the 
cooperative group studies at an established 
children's cancer treatment center at the Sew York 
Bospital-Cornell Bedical Center. The general 
goals are to improve patient care through the 
collaborative chemotherapeutic , surgical and 
radiotherapy protocols of Children's Cancer Study 
Group of which the principal investigator has been 
a sember since January 1967. Active protocols 
Include studies in acute lymphoblastic and 
non-ly«phoblastic leukeaias, and solid tumors 



(neuroblastoma, rhabdomyosarcoma, uilms' tumor, 
histiocytosis I, Ewing's sarcoma and osteogenic 
sarcoma) . The aim of using new approaches in 
cancer therapy will hopefully prolong survival in 
acute lymphoblastic leukemia. The use of new 
combinations of drugs will hopefully improve 
remission rates and therefore prolong survival in 
other less responsive leukemias. Through partici- 
pation in cooperative studies, the entire medical 
community engaged in the treatment of children 
with cancer will have a focal point to provide not 
only improved patient care, but also mul t idiscipl- 
inary teaching and education in the diagnosis and 
management of malignancies ir. childhood. This 
approach will involve medical and nursing stude- 
nts, house officers, staff nurses, hematology- 
oncology trainees and practicing pediatricians. 

New approaches will include prospective 
evaluation of prognostic factors in remission 
induction and maintenance. The contributions of 
such factors as the initial WBC at diagnosis, 
immunocompetence, morphologic and histochemical 
characteristics and other front end prognostic 
factors will evaluated in the new ALL stuoy. 
Immunotherapy with BCG and allogenic leukemia 
cells will be used in non-ALL. Phase II studies 
in patients with refractory leukemias and solid 
tumors will be performed as well. 



1116. STODI 0? ADVANCED BALIGSA8T DISEASES 
Kennedy, B. J., Univ. or ninnesota. School of 
aedicine, Hedicine, 1305 Bayo, Binneapolis, 
Binnesota, 55it55, U.S.A. 

The Basonic Bemorial Hospital is a clinical 
center for the care of patients with advanced 
■alignant diseases. A program representing a 
variety of medical disciplines has been developed 
to study the basic mechanisms of cancer and growth 
and to conduct clinical investigations relative to 
problems of advanced cancer witn the aim of 
improving patient care. These include the 
pathogenesis of decreased resistance to infection 
in cancer patients, the immunological competence 
of patients with acute leukemia, tne glycoprotein 
content of cell membranes and white blood cell 
kinetics. Bodels of immunotherapy have been 
developed in experimental animals and in man. 
Studies are being done of immune responses in 
patients against their tumors. Immunosurveiliance 
of patients with cancer is a newly established 
program. Consideration has been given to the 
theoretical and basic mechanisms of radiotherapy, 
radiobiology, and radiological physics with 
clinical studies including comnination therapy. 
The study of chemotherapeutic agents has included 
the evaluation of mithramycin, hydroxyurea, 
daunorubicin, bleomycin, adriamycin, and the role 
of leukapheresis in chronic leukemia and the 
support of patients undergoing intensive chemothe- 
rapy. Under the aegis of this grant, a lymphoma 
Task Porce formed to coordinate the study, staging 
and treatment of lymphomas. The Kasonic Leukemia 
Treatment Center was established to coordinate the 
Adult Leukemia Treatment Program, Pediatric 
Leukemia Treatment Program (including participa- 
tion in the Children's Leukemia Group A), Leukaph- 
eresis Unit, Basonic Research Clinic, and the 
leukemia Immunology Program. The Brain Tumor lask 
force was formed to coordinate the treatment of 
brain tumors. Such interdisciplinary projects 
correlate several modalities of study or therapy 
aimed at providing improved patient care. 



1117. BEGIOSAL CENTEB FOB PEDIATBIC OMCOLOGI 
Bartmann, J. R., Chara, R. L. , Bleyer, v. A., 
Bernstein, I. D. , Fred Hutchinson Cancer Bes. Ct, 
Div of Pediatric Oncology, 1102 Columbia St., 
Seattle, Hashington, 98101, U.S.A. 

TO improve the screening, diagnosis, treat- 
ment and rehabilitation of children with malignant 
diseases, providing services to regional center 
for the Pacific Northwest including treatment of 
malignant diseases with bone marrow transplant- 
ation. 

As an integrated regional pediatric oncology 



181 



unit, for the Fred Hutchinson Cancer Research Kith new agents and neii cojnbinatioas for patients 

Center, this division has developed a broad Kith chronic lymphocytic leukemia Based on recent 

indepth program in pediatric oncology. Support advances and treatment of lymphocytic lymphomas 

for key professional personnel and activities of are anticipated. Intensive chemotherapy uith cell 

the unit are provided under the grant mechanism. cycle and non-cell cycle specific drugs will be 

Over half of the funding available is for bed undertaken for patients with chronic granulocytic 

support, patients undergoing bone marroii transpla- leukemia. Continuing investigations of new agents 

ntation from siblings for the treatment of their for remission induction and maintenance, evalua- 

acute leukemia or severe aplastic anemia. This tion of early and late remission intensification 

program is performed in conjunction with that of chemotherapy, and continued evaluation of the role 

Dr. E.D. Thomas of the Adult Leukemia Center here of infection control measures as well as platelet 

in Seattle. In addition to the 16 patients who and granulocyte transfusion studies will be 

now have had marrow transplantations at this integrated with the program. 
Institution, a broad ongoing program for the 
treatment of acute leukemia and various other 

solid tumors under protocol studies is underway. H20. CLIHICAL CHEnOTHEBtpy PBOGRAn IN CANCER 

In addition, a heavy teaching program in pediatric CONTROL " ~ 

oncology education and a program in the psycho- lampkin, B. C, Childrens Hosp. Med. Ctr. , 32<t5 

social rehabilitation of the children with Burnet Ave., Cincinnati, Onio, 15229, D.S.A. 
malignant disease has been inaugurated. 

As noted above, improved survival and even OBJECTIVE: The objective of this project is 

cure rates have been striking in children with that progress in chemotherapy and in combined 

acute lymphoblastic leukemia, Uilm's Tumor, modality therapy be extended widely, utilizing 

rhabdomyosarcoma, osteogenic sarcoma, Swing's existing centers with the ability to bring modern 

sarcoma and other newly inaugurated programs for combined modality therapy to susceptible tumors in 

lue chemotherapy of brain tumors. children and/or adults and hospitals with the 

ability to provide high-guality combined modality 
therapy for one or more of the susceptible tumors. 
lie. PROTOIIPE CLINICAL CHEMOTHEBAPI PBOGRAB IN PROPOSED COURSE: Develop a prototype 

CANCER CONTROL clinical chemotherapy network program by recru- 

Hasserman, L. , City University of New York, School itment of hematologists and oncologists practicing 

of Bedicine, Microbiology, 5th Ave. at E. 100th in community hospitals around the primary ins- 

St.. New York, New York, 10029, D.S.A. titution and by utilization of a system of 

treatment protocols, education programs and data 

OBJECTIVE: The objective of this project is monitoring' 
that progress in chemotherapy and in combined PROGRESS: Development of a network of over 

•odality therapy be extended widely, utilizing 30 hospitals, of which most are community hospi- 

existing centers with the ability to bring modern tals in rural areas. The network's primary 

combined modality therapy to susceptible tumors in hospitals include Children's of Cincinnati 

children and/or adults and hospitals with the University Hospital in Cincinnati and several 

ability to provide high quality combined modality hospitals in Bayton, Ohio. The network encompa- 

therapy for one or more of the susceptible tumors. sses an area serving Southwestern Ohio and extends 

PROPOSED COURSE: Develop a prototype to Dayton on the northern, to Huntington, West 

clinical chemotherapy network program by recru- Virginia on the eastern, and into northern 

Itment of hematologists and oncologists practicing Kentucky and eastern Indiana on the southo-n >n/i 

in community hospitals around the primary ins- western edges, respectively. A central d 



sloped 



titution and by utili 

treatment protocols, education programs and data and a pathology review panel hasbeen 

monitoring. operation for uniform diagnosis and classificat- 

PBOGBESS: Development of 6 networks with ion. Some 68 children with !.Ll have been entered 

subnetworks of 30 institutions that surround on the CCP protocols in the first 2 years, with an 

primary hospitals. The network covers New York increase in the entry rate projected for the third 

City, Westchester County, Long Island and New year. In addition to those on protocols, the 

Jersey, but dees not compete with the New York network has treated 10 more children with acute 

Hospital/Cornell University Hedical School's lymphocytic leukemia. Hodgkins' Disease and the 

participating institutions and physicians. They other malignant lymphoma protocols have been 

have developed a pathology review mechanism and a operational for less than one year. In tnat time, 

radiation therapy quality control program that has li3 adults have been treated in the network. The 

been effective. Of the 166 patients treated in potential of the network and the cancers treated 

the network to date, 26 children and 330 adults has not been fully tested. For this reason, the 

have been entered on developed protocols for ALL, program is being considered for expansion to all 

Hodgkins' stages I, II, IIIA, IIIB, and IV, and pediatric cancers, and additional support to 

malignant lymphoma, lymphocytic and histocytic hospitals in Layton, Ohio and Huntington, west 

types. The Project has oeen effective in establi- Virginia, 
shing networks in a major city and surburban 
areas. Two new extensions are being negotiated 

further evaluation and broadenii.g of patient 142I. SUPPORT FOR CLINICAL CHEMOTHERAPY PROGRAM 



types entered. 



Karon, M. B., childrens Hosp. 01 Los Angeles, "4650 
Sunset Blvd., Los Angeles, California, 90051, 
U.S.A. 



119. SOUTHWEST ONCOLOGY GROUP 
Preireich, E. J., Univ. of Texas, Cancer Center, n OEJECIIVE: The objective of this project 

D Anderson Hosp Turner Inst, P.O. Box 2C036, that progress in chemotherapy and in combined 

Houston, lexas, 77025, U.S.A. modality therapy be extended widely, utilizing 

existing centers with the ability to bring node 

Research for patients with Adult combined modality therapy to susceptible tumors 

111 emphasize chemotherapy and children and/or adults and hospitals with the 

ppropriate supportive therapy, as well as ability to provide high-quality combined modali 

,.»..r,«»k = ,.„„ . ,..._ .. cooperative Group therapy for one or more 01 the susceptible tumo 



Dunoth 
research. Complete remission rates of 50 p 



PROPOSED COURSE: 



or greater have now been established for adult clinical chemotherapy network program hy t 

acute leukemia. Research will be directed toward itment of hematologists ana oncologists pr 



ing the 



ty ho 



sing the inadequate trials from early deaths titution, and oy utilization of a system of 

during chemotherapy. A median remission duration treatment protocols, edhcation programs and da 

of approximately 1 year has been demonstrated in 3 monitoring. 

consecutive studies. Efforts are being made to PROGRESS: USC-LA Children's Hospital 

l^rt^r.11 '^^^"'"^""apy and immunotherapy for the developed a network cf the physicians associat 

purpose of remission prolongation. Chemotherapy with 14 hosptials in five southern California 



182 



counties. Protocols for t 
in children were developed 
Chenotherapy Program. The 
Hospital enters their acut 
Cancer Study Group Protoco 
can be nade between childr 
institutions and those tre 
Cooperative Group Protocol 
have been entered on these 
conparisons show that the 
sion duration, and surviva 
groups. This indicates th 
ion, with protocols adapte 
cooperative network config 
These hospi\:als are enteri 
60 children per year. The 
coming under well-defined 
Bent can be doubled. For 
success of the network, th 
expanded to include all pe 
extension in contract dura 
to accommodate field testi 
expanded program. 



reating acute leuKeaia 

by the Clinical 

Los Angeles Children's 
e leuicemia on Children's 
Is, so that coiparisons 
en treated in network 
ated on a major Clinical 
To date, 102 patients 

protocols and initial 



tion 



rate 



are the same for both 
t the network operat- 
d to be operative in the 
ration, is successful, 
g patients at, a rate of 
umber of children 
nd controlled manage- 
his reason, and lor the 

work scope has been 
iatric cancers. An 
ion is being considered 
g and evaluation of an 



tl22. 50PPORT FOR CHEMOTHERAPY PROGRAH 
Durant, J. R, , Univ. of Alabama, School of 
Medicine, Comprehensive cancer Center, 1919 7th 
Ave. S., Birmingham, Alabama, 35233, U.S.A. 

OBJECTIVE: The objective of this project is 
that progress in chemotherapy and in combined 
■odality therapy be extended widely, utilizing 
existing centers with the ability to bring Bodern 
combined modality therapy to susceptible tumors in 
children and/or adults and hospitals with the 
ability to provide high-quality combined modality 
therapy for one or more of the susceptible tunors. 

PROPOSED COURSE: Develop a prototype 
clinical chemotherapy network program by recru- 
itment of hematologists and oncologists practicing 
in comnunity hospitals around the primary ins- 
titution and by utilization of a system of 
treatment protocols, education programs and data 
monitoring. 

PROGKESS: Development of a network of 10 
cooperating institutions covering this State and a 
western portion of Georgia. It provided coor- 
dination and treatment education in use of 
protocols for acute lymphatic leukemia, Hodgkins* 
Disease and non-Hodgkins* Disease Lymphoma. 3^ 
children and 1 adult have been treated in the 
network so far. The contractor's primary emphasis 
has been providing educational materials to 
physicians and hospitals on use of protocols in 
the network. Established referral patterns for 
involved disease were not significantly changed. 
The greatest effect occurred in the early prograi 
efiphasis in ALL. 



H23. SUPfOfrX-ilOR CLIMICAL CHEMOTHERAPY PROGRAM 
flclntyre, 0, B., TTaxtBOuii^College, school of 
Medicine, Medicine, P. 0. Box 63l7~-tfanove r, Hew 
Haapshire, 03755, U.S.A. 

OBJECTIVE: The objective of this project is 
that progress in chemotherapy and in combined 
modality therapy be extended widely, utilizing 
existing centers with the ability to bring aodern 
combined modality therapy to susceptible tumors in 
children and/or adults and hospitals with the 
ability to provide high quality combined modality 
therapy for one or more of the susceptible tumors. 

PROPOSED COURSE: Develop a prototype 
clinical chemotherapy network program by recru- 
itsent of hematologists and oncologists practicing 
in community hospitals around the primary ins- 
titution and by utilization of a system of 
treataent protocols, education programs and data 
Bonitoring. 

PROGRESS: Dartmouth Medical School dcTeloped 
a network comprised of the University of Veraont's 
College of Medicine and several coaaunity hospi- 
tals that included both small, rural hospitals and 
urban community hospitals. Due to regional 
characteristics, the network evolved in basically 
a primary hospital-direct-to-physician type of 
structure. Protocols were developed for acute 



lyaphocytic leukeaia, Hodgkin's Disease, and other 
aalignant lyaphoaas, A total of 153 patients, 
including 18 children and 135 adults, have been 
entered in the treataent program and most received 
their initial treataent in one of the two medical 
centers, with some patients receiving maintenance 
by their community physicians. The rural nature 
of this State and the inadequate resources of the 
involved rural, small size hospitals, limited the 
aggressiveness of patient management at the local 
level and a true network was not possible. 
Information gained by this project, particularly 
in relation to the probleas encountered in rural, 
coaaunity-level treataent, will be valuable to 
future programs. Time has been allowed for 
evaluation of project results specifically for 
noo-Hodgkin's lyaphoaas. 



ll2«. SDPPOBT FOR CUBICAL CAHCER CHEMOTHERAPY 



versity. School of 



PROGRAH 

Silver, B. T. , Cornel 
Medicine, Medicine, 1300 York A 
York, 10021, U.S.A. 

OBJECTIVE: The objective of this project is 
that progress in chemotherapy and in combined 
sodality therapy be extended widely, utilizing 
existing centers with the ability to bring modern 
coabined modality therapy to susceptibile tumors 
in children and/or adults and hospitals with the 
ability to provide high quality combined modality 
therapy for one or more of the susceptible tumors. 

PROPOSED COURSE: Develop a prototype 
clinical chemotherapy network program by recru- 
itaent of hematologists and oncologists practicing 
in coaaunity hospitals around the primary ins- 
titution and by utilization of a system of 
treataent protocols, education programs and data 
aonitoring. ' 

PROGRESS: Development of a network of 23 
institutions in New York City, Westchester County 
and Northern New Jersey Areas. This network 
involves much of the same area as the Ht. Sinai 
Network, but does not compete for institutions, 
physicians, or patients. The network was devel- 
oped through the hematologists and oncologists 
trained at the New York Hospital who have gene 
into practice in these areas. Patient accrual has 
been excellent, with 622 patients entered to date. 
This figure is more than twice the number cont- 
racted to be entered in the network and includes 
55 children with acute lyaphocytic leukemia and 
182 adults with Hodgkins' lymphoma. 355 of these 
patients were treated under defined network 
protocols. This project has demonstrated effecti- 
veness in developing multi-hospital cooperation 
and physician involvement in high quality proto- 
cols in a major city setting. Protocols for CML, 
CLL and multiple ayeloma have been developed in a 
contract expansion and are being implemented. 
Project IS being considered for extension while 
finding alternate sources of support and for 
coBpletion of its e-v-aXuat.ion. 

V. THERAPY AND OTHER CLINICAL ASPECTS 
OF MYELOMAS 



1125. CHBOIIOBIOIOGICH STUDIES OH nULTIPLE BIELOnA 
ASP »G>IIHtG1.0BULIllEMH 

Zinne.an, H. H. , Halberg, F., U.S. Veterans 
AdBinistration, Hospital, 5Uth St. £ uSth Ave. S., 
Hinneapolis, ninnesota, 55117, U.S.A. 

Chroncbiological studies on humans are 
continuing, »ainly in cooperation with Profs. 
CagnoDi and Guglielmo of Florence, Italy. Thus 
far ve could observe the circadian rhytho of 
L-chain excretion in the najority of patients. 
Ihe observations covered one weeK in each case, 
»ith 3-hourly urine collections around the clock. 

our first observations on LOU-rat uyeloaa 
have been published and show circadian rbythn in 
this tuaor also. At present we are exploring the 
effect of tined feeding plus timed cytotoxic 
therapy on. tumor activity and on the normal bone 
BarroH. 



183 



Kcasurement of L-chains in lat urine is Bore 
cooplicated than in huaans, because of nornally 
occurring peptides in rat urine. Concentrations of 
rat-k-chains is measured by single radial imnunod- 
iffusion, using purified rabbit-anti-rat k-cbain 
seruD. All neasurements are done in quadruplic- 
ate, which means that each rat tumor study 
requires about 800 tests. 

Assuming that low serum iron levels indicate 
the time of maximal Fe-uptaJte, in other words, 
naiimal activity of normal bone narrow, and high 
serum iron levels mean lowest activity, it may be 
sound strategy to administer cytotoxic drugs to be 
effective at the time of maximal serum iron 
levels. This plus the activity of cytotoxic 
drugs, other than adrianycin, will be the subject 
of our next inquiries. 



«30. BCNO. CYTOIAM AIID PBEDHISONE III BIELOIH 
Velez, E., Univ. of Puerto Rico, School of 
Medicine, P.O. Box 5067, san Juan, Puerto Bico, 
00936 

This is part of a broader project. A sunaary 
of this subproject is not available. 



131. CCND-PgECNISOIlE III MDLTIPLE MIELOIIA RESISIAHT 

TO OTHER BODES OF IHEHAPf 

Velez, E., Univ. of Puerto Rico, School of 

nedicine, P.O. Box 5067, San Juan, Puerto Rico, 

00936 

This is part of a broader project. A suamary 
of this subproject is cot available. 



126. AGGRESSIVE CHEMOTHERAPI Of HYELOWA 
Jacobs, P., Univ. of Cape Town, School of Medicine 
Hematology, Private Bag C. P. 77C0, C. P. 7700, Cape 
Town, Cape of Good Hope, Republic of South Africa 

A prospective study is in progress to 
document changes in tumor kinetics following 
induction therapy with four drugs in patients with 
myeloma and then, as laoelling indices rise, to 
switch to cycle-specific agents. 



127. COWTROLIED STUDI IM BUITIPLE MYELOMA — 

CCHPARISOW OF EFFECTS OF COBBIIIATIOll CHEBOTBERA- 

PIES 

Bajetta, t., Bonadonna, G., Monfardini, S., Natl. 

Inst, for study of Tumor, Via G Venezian 1, Milan, 

Italy, 20133 

OBJECTIVE: To compare, the effectiveness of 
two different combinations in the treatment of 
multiple myeloma. 

APPROACH: All patients with a histologically 
confirmed diagnosis of myeloma and not previously 
treated are randomized to receive either a 
combination of melphalan, prednisone and proc- 
arbazine or a combination of adriamycin and 
prednisone. Upon regression, patients are 
switched to alternate treatment. (Text Abridged.) 



128. SWOG 7313 - MAINTEWAKCE CHEMOTHERAPY OF 
RESPOMSIVE PATIENTS WITH MULTIPLE MYELOMA 
BottoBley, R. H., Hampton, J. w., Grozea, P. N., 
Hoge, A. F., Ishmael, D. R., Hussein, K. K. , 
Oldham, F. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 K.E. 13th St., 
Oklahoma City, Oklahoma, 73101, U.S.A. 

OBJECTIVES: To compare a combination of 
uelphalan-cytoxan-BCNU-prednisone (MCBP) with 
azathioprine-prednisone plus MCBP reinduction in 
the long-term remission maintenance of responsive 
patients with multiple myeloma. (Text Abridged.) 



129. PHASE III STDDY OF COMBINATIOg CHEMOTHERAPI 
IN MULTIPLE MYELOMA 

Yam, L. I., U.S. Veterans Administration, Hospital, 
Section of Hematology, BOC Zorn Ave., Louisville, 
Kentucky, 10202, U.S.A. 

Although our current treatment of myeloma is 
more effective than 10 years ago, the median 
survival of responders is only two to four years. 
The need for a better treatment of myeloma is 
obvious. The aim of this study is to compare the 
response rate and survival of myeloma patients 
with an induction regimen of either a BCNU- 
cytoxan-prednisone or a melphalan-prednisone 
combination, and to determine if after six courses 
of the induction regimen, the quality of response 
IS improved by the addition of f luoxymesterone, 
sodium fluoride, calcium gluconate and vitamins 
for 18 months. In patients who fail to improve 
from either regimen, studies will be made to 
determine the effect of either regimen by crossing 
over to the other combination after six courses of 
therapy. 



132. CHEHOTHERAPI FOB MOLTIPLE HIELOMA 
Alexanian, R., Univ. of Texas, Cancer Center, 
Medicine, P.O. Box 20036, Houston, Texas, 77025, 
U.S.A. 

OBJECTIVE: To improve the therapy of 
patients with multiple myeloma in a Phase III 
Clinical Trial. 

APPROACH: Combinations of alkylators, 
adriamycin, and vincristine are under study. 
Tumor regression is assessed from changes in 
■yeloma protein production rate in order to 
compare the frequency and duration of remission 
from different treatments. Patients are strati- 
fied to different treatments in accordance with 
their tumor mass grade, and the kinetics of serial 
changes in tumor mass are assessed. Patients who 
achieve remission are treated with a chemoimmunot- 
herapy program that utilizes BCG in order to 
reduce tumor mass maximally. • 

PROGRESS: With about 20 patients receiving 
each of the treatments currently under evaluation, 
about 55X of patients achieve remission as defined 
by a 75X reduction in myeloma proteins. Previo- 
usly untreated patients are still accepted. The 
survival time for large groups of patients on 
recently completed protocols is improving slightly 
so that the median survival for all patients is 
now about 28 months, cycle active agents have not 
reduced tumor mass further in patients achieving 
remission. BCG maintenance therapy is well 
tolerated. 



133. THERAPEUTIC TRIAL OF ANILINE MUSTARD, NSC 
18129, IH PATIENTS WITH BYELOMA AND OTHER ADVANCED 
NEOPLASTIC DISEASE 

Krakoff, I. H., Young, C. W., Yagoda, A., Memorial 
Jlosp. for Can. 6 Dis., Medicine, 1275 York Ave., 
New York, New York, 10021, U.S.A. 

OBJECTIVE: 1. To assess the clinical 
utility of aniline mustard (NSC 181429) in patients 
with advanced neoplastic disease. 2. To assess 
whether antineoplastic activity can be correlated 
with levels of beta-glucuronidase activity within 
the tumor. 3. To assess whether tumor content of 
beta-glucuronidase can be increased, and concomit- 
antly therapeutic response to aniline mustard be 
enhanced by hormonal manipulation, i.e. androgens 
in prostate and renal carcinoma, estrogens and 
androgens in breast carcinoma. 

APPROACH: Patient selection: Any patient 
with advanced neoplastic disease is a candidate 
for inclusion in the drug trial. Actual selection 
will be based upon the patient's clinical status 
and the presence of evaluable disease. Particular 
emphasis will be given to patients with multiple 
nyeloma, prostate carcinoma, breast carcinoma and 
patients with biopsiable lesions in which levels 
of beta-glucuronidase can be measured by bioch- 
emical and/or histochemical techniques. Drug 
dosage: The drug is supplied in 25mg capsules 
containing mannitol and magnesium stearate as 
excipients. In initial studies the drug will be 
given orally at a dosage of 0.5 to 1 mg/kg/day. 
For combination with androgens, halotestin will be 
used at a dose of lOmg p.o., t.i.d.; For combi- 
nation with estrogens, diethylstilbestrol 5mg 
P.O., t.i.d. The initial combined studies will be 



184 



done on hospitalized patients with close Bonito- 
ting of serum calciuo levels. Possible toxicity: 
G.I.: »noreiia, nausea and vomiting; diarrhea may 
be seen at high dosage. Liver: Elevation of 
transaminase and B5P at high dosage. Bone marrow: 
Lenkopenia and thrombocytopenia. Informed consent 
•ill be reguired for trial of aniline mustard. 
SIGBIf ICANCE OF STUDY: Clinical trial of 
aniline mustard vill help assess tne utility of 
the murine plasma cell tumors as models for human 
neoplasms. In addition it may permit rational 
exploitation for therapeutic purposes of one of 
the enzymatic constituents present in some tumors. 
Since early studies suggest that a correlation 
does exist between tumor response to aniline 
Bustard and tissue levels of beta-glucuronidase, 
efforts to increase these levels become imperat- 
ive. 



U3lt. SBOG 71113 - CIS-PlAimOB IM LTMPHOIHS AMD 
gPLIIPI-E BYELOMA 

Bottomley, R. H., Hampton, J. »., Grozea, P. N., 
Hoge, A. P., Ishmael, D. K., Hussein, K. K., 
01dha«, P. B., U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310U, U.S.A. 

Ose investigator index to locate a descrip- 
tion of this project elsevere in this listing. 



1135. SHOG-71123 - CHBOBOBTCIH A3 III ADVASCED 
HULTIPLE BYELOBA 

Bottomley, B. H. , Hampton, J. K. , Grozea, P. N., 
Boge, A. P., Ishmael, D. P., Hussein, K. K., 
Oldham, P. B. , U.S. Veterans Administration, 
Hospital, Hematol Oncol Sects, 921 N.E. 13th St., 
Oklahoma City, Oklahoma, 7310<i, U.S.A. 

OBJECTIVE: To investigate the effectiveness 
of Chromomycin A3 in the treatment of advanced 
Bultiple myeloma. (Text Abridged.) 

436. AMDBOGEIIS POU BBITIPIE BYELOBA 
Kiang, D. I., Univ. of Binnesota, School of 
Bedicine, Medicine, 1305 Bayo, Binneapolis, 
Hinnesota, 55155, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



1137. C0BBI8ATI0H CHEBOTHEBAPY III BULTIPLE BYELOBA 
Kiang, D. I., Univ. of Minnesota, School of 
Bedicine, Bedicine, 1305 Mayo, Minneapolis, 
Binnesota, 55U55, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



1136. PLASBAPHORESIS— EFFECT OS BYELOBA 
Franklin, E. C, Ne» York University, School of 
Bedicine, Bedicine, 550 1st Ave., New York, New 
York, 10016, U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 

«39. BULTIPLE BYELOBA AND BENIGN MONOCLONAL 
CABHOPATHY — COBPABISON OF IMMUNOLOGICAL ALT- 
EBATIONS AND NATURAL HISTORY 

BaranduD, S. , Morell, A., skvaril. P., Swiss Natl. 
rdn. for Sci. Res., Immunology, 20 Uildhainweg, 
Bern, Switzerland, 3001 

OBJECTIVE: Differentiation between malignant 
and benign paraproteinemias. 

APPROACH: 1. Follow-up of clinical par- 
ameters. 2. Repeated analyses of a. Monoclonal 
Ig in serum and urine of patients. b. Normal Ig 
("backgrcund Ig") in serum and urine of patients. 
c. Honoclonal Ig producing cells in bone marrow of 
patients (immunofluorescence studies) . d. Normal 
Ig ("background Ig") producing cells in bone 
■arrow of patients (immunofluorescence) . e. 



Bltogenic stimulation 

phocytes of patients. 

for lynphoblasts synthesizing monoclonal 

polyclonal Ig . 3. Analysis of the influ 

chemotherapy on points (2) a through d. 

PROGRESS: At the present time, abou 
patients are under investigation. This c 
only points 1 and 2 a through d, and 3. S 
point 2.e will start 
reports will be publj 



>ripheral blood 1) 



thi 



UUO. TARIODS ASPECTS OF BYELCBATOSIS — NATDHAL 
HISTORY. COINCIDENT PROBLEMS AND IBMUNOLOGIC 
ALTERATIONS 

Zawadzki, Z. A., Kapadia, S. B. , Brandon, J. B., 
Fujimaki, B., Ukita, fl., U.S. Veterans Admini- 
stration, Hospital, Hematology C Oncology Section, 
University Dr. C, Pittsburgh, Pennsylvania, 15210, 
U.S.A. 

The case material of 150 patients with 
myelomatosis in this study consists of 83 patients 
observed in the Pittsburgh veterans Administration 
Hospital, 31 patients seen in consultation in 
other hospitals and 36 patients who were hosp- 
italized and came to autopsy in Presbyterian- 
University Hospital. 

The aims of the this study are: 1. The 
evaluation of the natural history of myelcmatosis 
in patients hospitalized in this institution, in 
whom the diagnosis was frequently established at 
the lantbanic, i.e., preclinical, stage of the 
disease, in comparison to a population of patients 
in general hospitals. 2. The correlations of the 
survival of patients with various immunologic 
types of paraproteinemias- and their cytomorph- 
ological features. 3. The evaluation of certain 
clinical conditions and pathological findings in 
myelomatosis: antecedent respiratory infections: 
predisposing factors; mode of detection and 
diagnosis; association with cancer, aoylcidcsis, 
chronic disorders; incidence or skeletal invol- 
vement and extramedullary localizations of 
■yelcmatcus lesions, etc. 

A computer analysis is being performed in 
this large series of patients in relation to the 
survival of patients with variojs immunologic 
types, stage of disease, and possible predisposinc 
factors to the development of plasma cell myeloma. 



mil. GElltTICS OF THE IDIOTYPE OF A HUBAN GAMMA A 
BYELOBA PROTEIN 

Sachs, D. H., Eicks, J. E. , Terry, ». D., U.S. 

Dept. of Hlth. Ed. 6 Wei., Natl. Cancer Institute, 

Transplantation Biol Sect, Bethesda, Baryland, 
20011, U.S.A. 

The goals of this project are to determine 
where on the immunoglobulin molecule the idiotypic 
antigenic determinants measured in the previously 
described radioimmunoassay reside; to determine 
whether a human myeloma protein contains, restri- 
cted allotypes and/or idiotypes which are shared 
with, and can be detected in the serum of, related 
individuals; and to assess the use of myeloma 
idiotype as a TSTA (Tumor Specific Transplantation 
Antigen) for following clinical course of multiple 
myeloma. 

No idiotype activity could be found in the 
sera of 17 other patients with IgA myeloma, nor 
could any be detected in the patient's parents or 
11 siblings. The patient continues in clinical 
remission, but low idiotype levels are still 
detectable in his serum. 

Further characterization of the genetics of 
this patient's idiotype and restricted allotypes 
will be carried out by multiple specific absor- 
ptions on affinity chromatography columns. 
Attempts at in vitro specific tumor cell killing 
will be made. The RIA will continue to be used as 
a tool to follow the course of the patient's 
disease. 



185 



IHI2. BIClOmL KltLOKIi SCBEEIIIIIC 
Sledge, C, Calif. Inst, of Technology, Craduata 
School, Biology, 1201 E. California Bl»d., 
Pasadena, California, 911C9, U.S.A. 

This is part of a broader project. A sunaary 
of this subproject is not available. 



KM3. IHU'JMODI A GNOSIS of HUHAH aAlIgWAIICY — 
rmOBESCEKT BEAGENIS FOB AWALtSIS OF HYELOMA 

PBoitms 

Voods, E., iieloy Laboratories Inc., 6715 Electr- 
onic Dr., Springfield, Virginia, 22151, O.S.A. 

Ismunodiagnostic Tests for Iinunoglobulins - 
Perform immunodiagnostic tests on serum froB 
patients uith multiple myeloma, nacroglobulinemia, 
and imDiuii£ deficiency diseases. Production of 
riuorescer.t Antibody aeajents and Analysis of 
Nyeloma Proteins - Screen all sera shown to 
contain homogeneous proteins by SDS acrylamide gel 
to look for proteins of unusual size or those with 
non-covalently linked light chains. Proteins with 
unusual characteristics shall be investigated 
structurally. All sera referred to the Reference 
Center and shown to contain homogeneous proteins 
shall be screened by precipitation in agar for 
activity against bacterial antigens and polysacch- 
arides. This is part of a broader project. (Text 
Abridged.) 



1111. STAGIMG StSTEB FOB PATIEMIS gITH MDlTIPLt 
HtELOIlA ~~ 

Salmon, S. E. , Univ. of Arizona, School of 
Medicine, Pharmacol, 1501 N. Campbell Ave., Tucson, 
Arizona, 65721, U.S.A. 

This project will establish a special center 
for the study of Human Tumor Kinetics and for 
subsequent institution of predictive cancer 
chemotherapeutic trials in patients with multiple 
myeloma. Specifically, we will develop a useful 
staging system for multiple myeloma patients, and 
hopefully set the stage for broadening the 
application of msrker kinetics and cytokinetics to 
other tumors for which this .approach is feasible. 



It 15. KINETICS OF MULTIPLE nyELCHA 
Brown, B. H., Thompson, J. s., Hokanson, J. i. , 
Univ. of Texas, M.D. Anderson Hosp, C Inst., 
Biomathematics, P.O. Box 20036, Houston, Texas, 
77025, U.S.A. 

OBJECTIVE: To examine and attempt to develop 
a hypothesis for the time course of this disease 
under treatment. Based on such a model, to 
examine some treatme'nt strategies. 

APPBOACH: Eata on selected patients was 
obtained. based on this data, several simple 
models of the time course were developed. From 
these models overall kinetic parameters were 
inferred and the effect of tuoor size growth rate 
inhibiticn was examined. Following this, effects 
of possible mechanisis fcr drug resistance were 
examined. In particular, both resistance through 
cell kinetic parameters and resistance independent 
of these parameters is being investigated. In 
both cases, there is a correlation (in the model) 
between resistance of daughter cells and those of 
the parent. 

VI. THERAPY AND OTHER CLINICAL ASPECTS 
OF MYCOSIS FUNGOIDES 



"IS. mcOSIS FUNGOIDES COuPERATTvr S Tiinv - PILOT 

PHASE "~" ' ^ 

Lamberg, S. I., Johns Hopkins University, School 
of Medicine, Medicine, 725 N. Wolfe St., Baltimor 
Maryland, 21205, U.S.A. 

.'>urinc; tl.r y^st year an effort to determine 
xi.". f^^asiljiiity ,it.d likelihood of success of a 
national cocij.'rr.t ive study of uycosis fungoides 



has been in progress. This narrative will outline 
(1) the problems that we see inherent to a 
cooperative study of mycosis fungoides, (2) the 
reasons that such a cooperative study is, neverth- 
eless, imperative, (3) work so far completed and 
(1) our plan for implementation of such a study. 

Mycosis fungoides is an uncommon but not rare 
■alignancy of the lympho-reticular system acco- 
unting for about 1 percent of the lymphoma deaths 
in the U.S.A. There are perhaps 2,000 to u.OOO 
new cases per year; with the larger institutions 
seeing 10 to 30 new cases per year. As the disease 
■ay last for many years a fairly large reservoir 
of total cases, therefore, exists. In addition to 
the incidence of this condition, there has been 
interest in mycosis fungoides because of obse- 
rvations charging the delayed hypersensitivity 
system in the control of this neoplasm. 

Any cooperative effort, particularly where 
protocol therapy is concerned, will reguire 
standardization of histologic and clinical 
criteria as a matter of first importance. 
Although definitive therapy for mycosis fungoides 
is not yet available, reports on small series of 
patients and many individual case reports have 
clarified, at least, the present most useful 
treatment modalities. A study to determine which 
is superior has not been done. Yet unresolved is 
the intriguing matter that most of the therapies 
presently used interfere with immunologic defen- 
ses. 

Two formal meetings were held in Chicago 
during the project period for the purpose of 
examining the application of mycosis fungoides to 
a national cooperative effort. The first was on 
September 8-9, 1971; the second was on December 3, 
1971. 



"OT- MYCOSIS FUNGOIDES, A PBOSPECTIVE EVALOAIIOll 

Beinstein, G. D., Sigel, «., Univ. of Miami, 

School of Medicine, Dermatology, 1400 N.w. 10th 
Ave., Miami, Florida, 33121, U.S.A. 

Mycosis fungoides is an uncommon, but not 
rare, malignancy whose relative sparsity of 
patients has prevented the systemic evaluation of 
this disease. Studies of the natural history, 
diagnostic, pathologic, immunologic, and thera- 
peutic aspects of mycosis fungoides are still in 
their infancy as compared to the more common 
lymphogenous malignancies such as Hodgkin's 
disease and the leukemias. That mycosis fungoides 
offers a unique opportunity for the investigation 
of lymphogenous malignancy in general can be 
easily supported. 1. The gradual onset of this 
disease, coupled with a long pre-maligna nt state 
presents an opportunity to study host immunologic, 
pathologic, and biochemical status prior to the 
onset of frank malignancy. 2. Ihe target organ 
(skin) is simply studied clinically, pathologi- 
cally, immunologically, and biochemically. 3. 
Likewise, investigational therapy may be evaluated 
visibly, pathologically, immunologically and 
biochemically with relative ease. 

Ihe treatment of mycosis fungoides has been 
unsatisfactory to date because it has not improved 
patient survival time. An extensive chemothe- 
rapeutic approach on a national cooperative 
program basis will offer the greatest chance of 
significantly influencing this disease. 



tie. ADBIABYCIN THEBAPY FOB ADVANCED MYCOSIS 

FUNGOIDES 

Levi, J. A., Hiernik, P. H., Diggs, C. , Slawson, 

R. A., U.S. Dept. of Hlth. Ed. £ Wei., Natl. 

Cancer Institute, Medicine Section, Baltimore, 

Maryland, U.S.A. 

The purpose of this study has been to 
determine the efficacy of adriamycin therapy for 
the treatment of advanced mycosis fungoides. 
Adriamycin has been administered to patients with 
a biopsy-proven diagnosis of mycosis fungoides who 
were refractory to any prior therapy. Disease 
status was advanced in all patients with extensive 
skin involvement and lymph adenopathy and frequent 
visceral disease. Adriamycin was administered in a 



186 



dose of 60Eg/H2 IV every three weeks and a Blnilua 
of three courses given beyond conpiete response. 
Haintenance therapy consisted of aethotrexate 
I5»g/I12 III twice weekly and cytoian 750 mq/n2 I? 
every three weeks. Thirteen patients have been 
entered into this study and there have been three 
coaplete responses (23*) , five partial responses 
(39%), three improvements (23X) , and two failures. 
The median duration of responses for the complete 
responders has been 32-plus weeks and improvement 
18 weeks. Toxicity has been mild, and it appears 
that adriamycin is an active agent for the 
treatment of advanced mycosis fungoides. 



ins. lOPICtL mlHOSOOBEAS IH MICOSIS FUNGOIDES 
ZackheiD, H. S. , Univ. of California, School of 
Hedlcine, Dermatology, 551 Parnassus Ave., San 
Francisco, California, 914122, U.S.A. 

Patients with early and moderately advanced 
■jcosls fungoides (HF) are treated topically with 
solutions of 3-nitrosourea (NU) compounds in a 
continuing evaluation of the efficacy and safety 
of such therapy. To date 26 such patients have 
been treated topically with 3-NU compounds: 
1,3-bis(2-cnloroethyl)-1-NU (BCHU) , 1- (2-chloroet- 
hyl)-3-cyclohexyl-1-NU (CCNU) , and 1-methyl-1-NU 
(UNO). Good to excellent results have been 
obtained in a high percentage of cases. Patients 
allergic to topical mecnlorethamine can be treated 
with NU compounds without danger of cross-sen- 
sitivity reactions. Bone marrow depression 
occurred in 2 patients and was attributed to CCHO. 
No hematopoietic or other toxicity was noted in 
patients treated with BCNU alone, and BCNU is 
presently the preferred NU compound in the 
treatment of HF. The percutaneous absorption of 
BCNU is in the range of 20-30X. Eesults of 
long-term painting of mice with NU compounds 
indicate that BCNU and CCNU are weak topical 
carcinogens, whereas MNU is a strong topical 
carcinogen. 



USD. TOPICAL NITROSOUREAS III HTCOSIS PDNGOIDZS - 
CLINICAL TRIAL PHASE III 

Zackheim, H. S. , Epstein, E. H., Univ. of Cali- 
fornia, School of aedicine. Dermatology, 551 
Parnassus Ave., San Francisco, California, 9H122, 
U.S.A. 

He are studying patients who have histol- 
ogically confirmed mycosis fungoides (BF) . 
Treatment is limited to those with plague stage 
HF. Agents used: 1,3-bis (2-chloroethyl) -1-nit- 
rosourea (BCNU); 1- (2-chloroethyl) -3-cycloheiyl- 
1-nitrosourea (CCNU); 1-methyl- 1-nitrosourea 
(BNU). These are applied topically in weak 
alcoholic solution to the entire body surface in 
extensive disease, or to lesions only in limited 
involvement. The trial is controlled. The most 
favorable results with least toxicity have been 
obtained with BCNU and present treatment schedules 
are limited to that compound. The overall results 
compare favorably with those obtained with topical 
mechlorethamine and the incidence of allergic 
reactions is much lower than with mechlorethamine. 
Approximately 35 patients have been treated with 
HU compounds. New patients are being accepted. 



«51. PERCUTA N EOUS PENETRATION OF BCNU IH PATIENTS 
IITH BICOSIS FUNGOIDES 

Zackheim, H. s. , Epstein, E. H., Univ. of Cali- 
fornia, School of Medicine, Dermatology, 551 
Parnassus Ave., San Francisco, California, 9U122, 
O.S.A. 



1152. DEVELOPaEMT OF TOPICAL CHEBOTBEBAPEUTIC 
AGENTS FOR HTCOSIS FUNGOIDES 

Lemberg, S. I., Johns Hopkins University, School 
of Hedicine, Bedicine, 725 N. Wolfe St., Baltimore, 
Haryland, 2120S, O.S.A. 

Evaluate existing cancer chemotherapeutic 
agents for use in the treatment of mycosis 
fungoides when applied topically. Th^ project 
will consist of two phases; patch testing to 
determine relative effectiveness of approximately 
thirty existing cancer drugs on lesions of the 
disease; and clinical trials of the most promising 
drugs, applied widely and for extended periods, 
for effectiveness and safety. 



«53. TRANSIENT DIABETES HELLIIOS SECONDARY TO 
1,-ASPARAGINASE IN ACUTE LEUKEBIA 
Gillette, P. C, Baylor College, School of 
Hedicine, Pediatrics, 120C Hoursund Ave., Houston, 
Texas, 77025, U.S.A. 

This is part of a broader project. A sumaary 
of this subproject is not available. 



USt. CARDIOPDLHOllAgl DYNAHICS IS LEUKEBIA AND 

SEVERE INFECTION 

Ainger, L. E. , St. Jude Ch. Res. Hosp. , Box 318, 

332 N. Lauderdale St., Beapbis, Tennessee, 38101, 

U.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



155. BONE HARROW TBAHSPLANTATIOH III IDENTICAL 

TglllS 

Fernbach, D. J. , Baylor College, School of 

Hedicine, Pediatrics, 1200 Hoursund Ave., Hous 

lexas, 77025, U.S.A. 

This is part of a broader project. A sum 
of this subproject is not available. 



1156. CARBOIIPEPTIDASE G1 IN LEUKEBIA 
Pearson, H. A., lale University, School of 
Bedicine, Pediatrics, 333 Cedar St., New Ka 
Connecticut, 06510, U.S.A. 

This is part of a broader project. A 
of this subproject is not available. 



»57. RADIATION AND CHEBICAL THEBAPI OF ACUTE 
LTBPHOBLASTIC LEUKEBIA 

Humphrey, G., Univ. of flinnesota. School of 
aedicine, Bedicine, 1305 Kayo, Hinneapolis, 
Hinnesota, S5it55, U.S.A. 



APPROACH: C1U-BCN0 is applied to the foreara 
skin in lesion-free area in patients with aycosis 
fungoides. Total daily urine collections are 
obtained for 5 consecutive days. The amount of 
CIM activity is determined in the urine. This is 
regarded as a measure of percutaneous penetration 
of BCNU. 

PROGRESS: In 2 patients the range of 
percutaneous penetration is 20-301 of the applied 
dose. 



This is part of a broader project, 
of this subproject is not available. 



use. TBEATHENI OF ACUTE BYELOCITIC LEUKEBIA 
Halters, I., St. Jude Ch. Res. Hosp., Box 318, 332 
N. Lauderdale St., Bemphis, Tennessee, 38101, 
O.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



159. PERIODIC REINFORCEMENT THE8API IN CHILDREN 
ilTH ACUTE LEUKEBIA 

Fernbach, D. J., Baylor College, School of 
Hedicine, Pediatrics, 1200 Hoursund Ave., Houston, 
Texas, 77025, O.S.A. 

This is part of a broader project. A summary 
of this subproject is not available. 



187 



«60. CYT0KI8EIICS, CITOCHEHICAL «HD IHHnilOLOGIC 
SIDDIES IM LEaKEBIC CEILS 
Shav, fl. T., Ishnael, V. B., U.S. Veterans 
Jdiinistration, Hospital, 921 N.E. 13th St., 
Oklaboaa City, Oklahoaa, 7310it; U.S.A. 

3C0 cases of acute leukeaia have been studied 
in regard to cytochemical variability of the blast 
cells. The stains enployed have been previously 
outlined. The correlation with remission rate and 
survival is at present being analyzed by the 
Southwest Oncology Group biostatisticians. 

Several interesting, unexpected findings have 
been discovered, including sub-classifications of 
acute lymphocytic and acute monocytic leukemia. 
The blastic phase of chronic granulocytic leukemia 
has also shown great heterogeneity. 



«61. GIICOLIPID CELI, SDBFACE AMTIGEHS III ACUTE AMD 
CHBOmc LEUKEnlA 

Krivit, u., Cesnick, B. J., Univ. of ninnesota. 
School of Hedicine, Pediatrics, 1305 Mayo, 
Hinneapolis, ninnesota, 55U55, U.S.A. 

The previous investigations have demonstrated 
abnormalities and changes of glycolipid content in 
human and animal tissue fibroblast cultures when 



Incubated with viruses. Also, there have been 
abnormalities noted in the leukocytes in patients 
with leukemia that relate to the above in vitro 
studies. These human in vitro studies have 
indicated depression and/or elevation of sphi- 
ngolipid hydrolases depending upon the type of 
leukemia noted. The purpose of this study will be 
to observe in a seguential manner the changes of 
the glycolipid enzymes and the glycolipid levels 
in patients with acute lymphatic and myelogenous 
leukemia and the patients with chronic myelogenous 
and lymphatic leukemia as the therapy progresses. 
The knowledge obtained from this research will 
permit more precise attack on the leukemic cell. 
Therapeutic consideration of neuraminidase (or 
other specific sphingolipid hydrolase) treatment 
of leukemic cells will be gained. The capability 
of predicting diagnosis, response to therapy and 
possible immunological treatment with these 
altered cells will be obtained. 



INVESTIGATOR INDEX 



AbelsoD, H., 914 
Adams, P. B., 232 
Ahearn, H. J., 33 
Alnger, 1. E., USU 
Aisner, J., 136, 151, 376 
Alavi, J. B., 357 
Alexanian, Fl. , ii32 
Alter, B. J., 33ii 
Anderson, P. N., 335 
Appelbaum, F. R., 33i( 
Aroesty, J., 25, Ul, ii5 
Auclerc, G., 391 
Aur, B. J., 72 
Avery, T., 76 
Azen, £. , mi 
Bachur, M., 306 
Bajetta, E., it27 
Baker, (1. *., 39 
Balkwill, F. B., 36 
Banfi, A., ;38, 276 
Bank, A., 395 
Barandun, S., 039 
Basu, n. K., 199 
Bath, D. W., S 
Beard, n. E., 126, 278 
Beard, N. .s., 163, 317 
Bellani, T. ?., 277 
Benedict, U. F., 31 
Benua, R. S. , 216 
Bernard, J., 391 
Bernstein, I. D. , 58, 63, 

6U, 71, m, 75, et, 85, 

86, 87, 88, 69, 90, 91, 

2ltU, 281, 1(17 
Bertino, J. R., 110, 214 
Beyer, J., 369 
Beyer, J. H., 326, 327, 

302 
Bigelow, J., 25, uu 
Binder, R., 16<t, 315 
Bishop, B. B., 207 
Bleyet, V. »., 56, 63, 6«, 

67, 68, 69, 71, 711, 75, 

61, 85, 86, 87, 88, 89, 

9C, 91, 2114, 281, 1417 
Blootfield, c, 183, 181, 

186, 189, 230, 265, 

267, 315 
Bloomfield, c. B., 103 
Bobrove, A. B., 220 
Bodey, G. p., 157, 197, 

262, 370, 377 
Boecker. W., 326, 327 



Bonadonna, G., 237, 2 

276, 290, 127 
Bonesana, A. C, 280 
Borella, L. 0., 36 
Borgaonkar, D. S. , 33 
Bottomley, 8. H., 113 

111, 117, lie, 119 

112, 117, 152, 151 
210, 211, 256, 263 
281, 286, 291, 296 
297, 307, 308, 128 
131, 135 

Boyse, E. A., 119 
Brandon, J. B., 110 
Brandt, I., 26 
Brauer, B. J., 100 
Brecher, fl., 93 
Breeden, J. H., 288 
Brenner, J. F. , 10 
Brereton, H. D., 301 
Breuer, K. , 250, 275 
Brodeur, B., 266 
Brook, J., 110 
Brouillet, «., 376 
Brown, B. U., 115 
Grubaker, L. H.. 21, 
Bruntsch, U., 258 
Bryan, J. H., 78 
Bucher, W. C. , 221 
Buckner, C. D., 322, 
321, 325, 330, 331 
310, 313, 358 



275 
Burgert, 
Burke, G. 



. 0., 399 
398 
J., 219 
P. J., 335 
, I. I., 153 
A. C, 77 
J. J., 215 



Buyukp 
Byf i 
Caba 
Cald 



Id, 



113 



lias. 



C. S., 316 
Clmitta, B., 73, 62, 
Campbell, H., 119 
Canale, V. C, 115 
Cangit, A., 79, 303 
Capizzi, B. L., 110 
C^ppel, R., 371 



Carey, R. »., 100 

Carter, G. , 25, 11 

Cartwright, G. E., 177 

Catley, P., 37, 221 

Catley, P. T.. 36 

Cevik, :J., 251 

Chabncr, B., 136 

Chan, J. Y., 11 

Chard, B. L., 58, 63, 61, 
71, 71, 75, 81, 85, 66, 
87, 88, 89, 90, 91, 
211, 281, 316, 117 

Chaskes, S., 371 

Chastang, C, 391 

Churchill, V. H., 229 

Clarkson, B. D., 119, 235, 
351 

Claunch, B. C. , 210 

Clawson, C. C. , 315 

Cleton, F. J., 222, 250, 
275, 107 

Clifford, G. 0., 351 

Clift, R., 321 

Clift, R. A., 358 

Cohen, H. J., 109 

Colebatch, J. H., 16, 66 

Coleman, J. H., 210 

Coleman, fl., 105 

colyer, S., 371 

Cooper, 1. A., 232, 293 

Cooper, B., 217 

Cooper, B. B., 352, 366, 
387, 106 

Cooper, R. , 357 

Cornwell, G. G., 398 

Costa, A., 227 

Cotran, B. S., 229 

Craddock, C. G., 195 

craddock, P. E., 196 

Crichlow, R., 398 

Crowell, E., Ill 

Cullen, fl. H., 311 

Cuttner, J., 108, 369 

Dale, B., 293 

Dangio, G., 115 

Davidson, J. D., 208 

Davies, J. N., 207 

Davis, W., 100 

Dayem, H., 386 

Dealmeida, J. S. , 201 

Debellis. R., 395 

Debusscher, L. , 371 

Oecastro, L. A., 93 



Dechatelet, L. R. , 352 
Degarcia, c. R., 260 
Bernard, A., 363 
Delena, fl., 237, 238, 290 
Delves, P. J., 311 
Desnick, R. J., 161 
Deveber, L. 1. , 17, 62, 

77 
De»ter, T. B., 15 
Dicke, 105, 332 
Diggs, C, 217, 255, 295, 

116 
Diggs, C. H., 261 
Ding, J. C, 232 
Dintenfass, L. , 200 
Djerassi, I., 357 
Doilinger, B., 180 
Donaldson, fl. H., 318 
Dotfman, R. F. , 216 
Dow, L. , 20 
Drewinko, B. , 7, 13 
Durant, J. R., 251, 122 
Edwards, C. L. , 155, 333 
Eisner, E. , 111 
Ekert, H., 16, 19, 56, 57, 

59, 66 
Elias, L., 50 
Ellison, E. R., 366 
tmeson, E. E. , 338 
Emmelot, P., 1 
Epstein, E. H. , 150, 151 
Erslev, A. J., 368 
Esterhay, B. J., 116, 151 
Evans, A., 318 
Fahel, V. G., 201 
Pahey, J. I., 336 
Fairley, G. K. , 213, 253, 

266 
Palkson, G. , 381 
Falkson, H. C, 381 
Fay, J. v.. 331 
Pefer, A., 121, 322, 323, 

325, 330, 331, 337, 

310, 313 
Feltkamp, C. A., 222 
Fernbach, D. J., 155, 159 
Ferrans, v. J., 339 
Filho, S. C, 226, 302 
Finklestein, J. Z., 113 
Firat, D., Ill, 251, 301 
Fischer, J. J., 211 
Flaherty, fl. J., 397 
Foiber, I.. B.. 211 



188 



rorcier, B. J., 398 
Pord, J. n., 3111 
lorget, B., 9<i 
fortuny, I., 361 
lortuny, :. E., 103 
rranklin, E. c. , ii38 
freednan, »., 289 
f reenan, A. I. , 93 
rieireich, E. J., 157, 

■819 
freireich, E., 7, 22, 
rrid«aL, B., 396 
Tried, J., 235 
rriedman, N. R. , 375 
FojiBaki, n., MUC 
Fuller, L. n., 215, 21 

Its. 268, 282, 263 
Fusecer, J., 3U6 
eale, K. P., 336 
eallaeier, u. a., 258 
saible, J. F., 215, 21 

213, 282, 283 
Bams, X. , le 
Gardner, F. H., 130, 3 
easpariDi, R, , 277 
Gazley, C, 25, «« 
eee, T., 235 
See, T. s., 1119 
Gehan, £. A., 42 
Geller, I., 305 
Geiooauclerc, H. , 391 
Gesdel, B. B., 5 
eerrard, J., 3^5 
Gilchrist, G. s., 399 
Gillette.. P. C, 153 
eiatstein, E. J., 2U6 
Click, A, D., u 
elincher, fl. J., 203 
Goff, J. S., 190, 191 
Goldberg, P., 386 
ebldbluD, N., 20U 
Goldstein, L., 376 
Goldstone, J., 395 
eoKez, G., 19 
Goodrich, J. K. , 208 
Gordon, P. S., 360 
Gcrin, N. c, 33U 
GosKitz, F. A., 155, 1 
Gottfried, E. L., u05 
Gottlieb, J. A., 28 
Grabet, s. E., 260 
Grace, . U. B., 398 
Grathvohl, -A. , 33U 
Grav, B. S., 331, 339 
Gray, G. F. , "415 
Greaves, n. F., 2 
Greco, F. A. , 272 
Gr^en, A. A., 38 
Grecnberg, (1., UCO 
Greenberg, P. L., 50 
Gregory, S. A., 108 
Gross, J. F., 25. uu 
Grossbard, L. , 395 
Grozea, P. N., 113, 11 
117, 118, 119, 112, 
117, 152, 151, 210, 
ill, 256, 263, 281, 
286, 291, 296, 297, 
307, 306, 128, 131, 
435 
Goerry, D. , 357 
Gunz, F. U., 129, 293 
Gotin, P. H. , 126 
Gutterian, 353 
Gotternan, J. U. , 122, 

157, 370 
Badlock, D., 362 
Bagiibin, n., 139 
Bahn, D. n., 376 
flalberg, F., 125 
Banilton, J. D. , 373 
Baapton, J. v., 113, 1 
117, 118, 119, 112, 
117, 152, 151, 210, 
211, 256, 263, 281, 
266, 291, 296, 297, 
307, 308, 128, 131, 
<13S 
Eantschke, D., 369 



Barker, 1. ». , 317 

Harpel, P., 105 

Hart, A. A., 252 

Hart, J., 7, 22, 33 

Bartmann, J. B. , 58, 63, 
61, 68, 71, 71, 75, 81, 
85, 86, 87, 88, 89, 90, 
91, 211, 281, 316, 111, 
117 

Uaurani, F. I., 388 

Hayes, A., 20 

Hayes, D. (1., 387, 106 

Haynie, T. P., 7 

Beise, E. B., 352 

Henderson, E. S., 311, 
320, 356 

Henry, A., 371 

Henry, P. H., 390, 392, 
101 

Herriann, P., 292, 293 

Herrmann, B. P., 101 

Bersh, E. n., 122, 370 

Herzig, R. H. , 331 

Hester, 353 

Hester, E. H., 22 

Bealett, J., 116 

Heyn, B. H., 70 

Heyster, H., 007 

Higby, D. J., 367 

Hilgartner, H. »., 115 

Hill, J., 319 

Binpoo, B., 269 

Hittelaan, V. N., 28 

Ho, D., 22 

Hoagland, H. C. , 399 

Hobby, G. I., 372 

Hoge, A. F., 113, 111, 
117, 118, 119, 112, 
117, 152, 151, 210, 
211, 256, 263, 281, 
286, 291, 296, 297, 
307, 308, 128, 131, 
135 

Hogg, v., 2 

Hokanson, J. A., 115 

Holland, J. F., 109, 351, 
361, 383, 389 

Holland, B., 70 

Bolton, C. P., 271 

Hoaesley, H. D., 387, 106 

Horikoshi, N. , 131 

Horner, B. , 356 

Hoshino, A., 131 

Hossfeld, D., 327 

Bossfeld, D. K., 29, 132, 
135 

Hsieh, I., 357 

Huang, A. T., 109 

Bubner, K. T., 155, 333 

Buggins, C. B., 359 

Hughes, H. , 381 

BuDbert, J. B., 30 

Huaphrey, G., 157 

HuBphrey, G. B., 21, 55, 
198 

Humphrey, E. L., 335 

Humphreys, E. E., 6 

Hunter, C, 229 

Hussein, K. K. , 113, 111, 
117, lie, 119, 112, 
117, 152, 151, 210, 
211, 256, 263, 281, 
286, 291, 296, 297, 
307, 306, 128, 131, 
135 

Hustu, 0., 72 

Hutchison, D. J., 125 

Hutchison, G. B., 268 

Butter, J. J., 30 

Hyaan, G. A., 395 

Inagaki, J., 131 

Irvin, L. E., 379 

Ishaael, D. B. , 113, 111, 
117, 118, 119, 112, 
117, 152, 151, 210, 
211, 256, 263, 281, 
286, 291, 296, 297, 
307, 308, 128, 131, 
135, 160 



Jackson, J. ». , 101, 292 
Jacob, H. S., 196 
Jacobs, P., 112, 291, 126 
Jacguillat, C, 391 
Jaffe, H. , 73, 82 
James, G. V., 397 
Janossy, G., 2 
Jeannet, II., 106 
Johnson, A. H. , 78 
Johnson, B. £., 159, 272, 

301 
Johnston, 0. A., 13 
Jones, B., 394 
Jones, S., 285 
Jones, S. E., 221 
Jose, 0. G., 16, 59 
Juncosa, H., 25, 11 
Kagivada, H., 25, 11 
Kane, B. C, 137 
Kapadia, S. B. , 110 
Kaplan, B., 312 
Kaplan, H. S., 216, 268 
Karanas, A., 395 
Karon, n. B. , 121 
Kattlove, B., 319 
Kauffiann, J. c. , 331 
Kaufaann, J. S., 352 
Kellermeyer, E. , 273 
Kellermeyer, B. v., 162, 

309 
Kennedy, B. J., 103, 116 
Khaliq, A., 131 
Kiang, D. I., 103, 136, 

137 
Kia, J. S., 357 
Kia, T., 100, 193 
Klasterskj, J., 371 
Klingberg, u. G. , 391 
Knospe, «. B., 1C8 
Koch, K., 102 
Koch, P. A., 318 
Kongo, I., 233 
Korst, D., Ill 
Kough, B. , 137 
Kovach, J., 395 
Koyama, B. , 3 
Kraft, v., 232 
Krakoff, I. H., 127, 133, 

139, 116, 119, 305, 

133 
Krantz, S. B., 260 
Kreaer, V. B. , 1C9 
Kritzler, B., 395 
Krivit, «. , 315, 161 
Krueger, G. F., 331 
Kucuksu, N., Ill 
Kundu, D., 52 
Kung, F. H., 99, 393 
Kuraishi, t., 131 
Kyle, B. A., 399 
Kyolwazi, S., 279 
laaberg, S. I., 116 
laapkin, B. C, 65, 92, 

120 
Lang, J., 393 
Langdten, 105, 332 
Lankford, J. A., 21 
lattuada. A., 276 
Laughlin, 218 
Lavrin, L. , 289 
Lawler, S. , 35 
Lay, H. H., 66 
Leahy, R. A., 60 
Lee. 305 
Lee, B. J. , 268 
Lee, S., 36 
lee, S. 1., 1C1 
Leeper, R. , 119 
Leikin, s. L., 311 
Lemberg, S. I., 152 
lenert, T. F., 372 
Lepage, G. A., 131 
Lessa, G., 201 
Levan, G. , 26 
Levi, J. A., 126, 113, 

111, 151, 216, 217, 

228, 215, 255, 261, 

295, 306, 118 
Lichtenfeld, J. L. , 136 



Lincoln, T., 25, 10 
Linzenaeier, G., 369 
Lister, T. A., 37, 103, 

128, 223, 221, 278 
loh, K. K., 213 
Lozzio, B. B., 11 
Lozzio, C. B., 11 
Luboldt, w., 312 
Lukens, J., 113 
Luna, n., 197 
Lundguist, C, 25, 11 
Hackinney, A. A., Ill 
Hakary, A., 137 
naldonado, B., 102 
narks, P. A., 395 
narmor, J., 50 
Harsh, J., 110 
narshall, )!., 269 
Barten, G. »., 190, 191 
Hartin, R. G., 215 
Harx, P. A., 378 
Hattern, J., 386 
Battheus, B. N., 16 
nauer, A. n., 20, 72 
Hauger, D. c, 61 
Baurer, H. n., 397 
Haurer, L. H., 398 
navligit, G., 122 
BcCaftrey, P., 9i 
Hccall, C. E., 352 
HcCredie, K., 105, 116, 

115, 157, 332, 353 
HcCullough, J., 315, 350 
Hclntosh, L. S., 96, 97 
nclntyre, 0. f... 396, 123 
BcKelvey, E. , 262 
ncBillan, c. «., 78 
ncwilliams, N., 397 
Heier, G., 25, 11 
Hendelson, J., 393 
Nerigan, T. C, 288 
Berrill, J. M. , 272 
Hetcalf, D., 8, 23 
Hetz, E. B., 123 
netzgar, R. S., 10 
Hilani, F. , 276 
Hiller, D. G., 119 
Biller, D. E., 115 
Hiller, D. S., 10, 111, 

170, 172, 171, 187 
Bills, C, 398 
ainty, c. J., 66 
Bitchell, B. S., 110 
Bitelman, F. , 26 
Bittelman, A., 121 
Hcayeri, H., 19 
gohanakumar, I., 00 
Boloney, W. C. , 229 
Honfardini, s., 290, 127 
Boody, B. B., 375 
Boore, A., 105 
Boore, B. A., 51 
Borell, A., 139 
Boreno, H., 98, 101, 178 
Bortis, H. , 375 
Borrison, P., 25, 11 
Borse, B. G., 30 
Bovassaghi, H,, 3i1 
Buidal, S., 27 
Bullereberhard, 0., 393 
Burphy, B. J.. 38 
Burphy, B. L., 119 
Hurphy, S., 20, 318, 357 
Buss. B. B., 387, 106 
Nachaan, B. L. , 005 
Xakazaaa, S., 93 
Nasciaento, t. , 226 
Nathan. D. G. , 90. 328 
Kayak, N., 357 
Kecheles. T. F.. 10, 100 
Neely, c. L.. 153 
Nesbit. B. . 305 
llesbit. B. E. . 171 
Neuratb, P. V,. 10 
Beaton, v. A.. 012 
Bickson, J. J., 268 
Hlitsu, Y. , 233 
Bowell, P. C, 31 
Nyhan, B. L., 393 



189 



Oconnor, T. B^, 53, 225 
Oettgen, H. F. , 1«9, 351 
Ogawa, n., 156 
Obtsuka, S., 233 
Old, L. J., 1H9 
Oldham, F. B., 113, 1114, 

117, lie, 119, 1142, 

1147, 152, 15U, 2140, 

2141, 256, 263, 2614, 

286, 2914, 296, 297, 

307, 306, 1428, 14314, 

14 35 
Oleinick, S. R., 24 
Oliver, B. I., 35, 52, 

103, 219 
Onmaya, A. K. , 67 
Onura, G., 16 
Onura, G. A., 168, 169, 

173, 176, 185 
Osieka, R. , 258 
Ossorio, R. C, 195 
Ota, K., 158 
Papendieck, C, 280 
Papendieck, C. «. , 206 
ParkBan, E. , 914, 326 
Pasnantier, H. , UOS 
Pataki, J., 359 
Patterson, E. B. , 202, 

387, 1406 
Paulsen, M. A., 190 
Pauly, J. L., 19 
Pavlovsky, S., 260 
Pearson, H. A., 162, 165, 

1156 
Penchasky, L., 260 
Penington, D, , 293 
Penland, w. z., 33i4 
Penan, v., 345 
Peters, v., ^268 
Piazza, R. , 227 
Pierre, E. v., 13, 32 
Pindar, A., 223 
Pinkel, D. , 81 
Pinkus, G. , 229 
Pitner, S. E., 191 
Pitney, V. K. , 293 
Pomeroy, 7. C, 334 
Poplack, D. G., 67 
Powazek, n., 190, 191 
Pratt, C, 76, 95 
Presant, c, 264 
Price, R., 192 
Prosnitz, L., 247, 269, 

300 
Prosnitz, L. R., 214 
Quagliana, J. M. , 179, 

313 
Bahin, n. A., 140 
Baich, P., 411 
Eaeanan, S. v., 394 
Bao, P. N., 28 
Bappaport, H., 268 
Bappeport, J,, 326 
Beddi, I., 394 
Bedo, S. F., 415 
Reed, R., 122 
Reich, 354 
Reich, S. D., 306 
Beid, J. C. , 12 
Bice, n. S., 60 
Richards, F., 352, 387, 

406 
Bichnan, C, 356 
Bicks, J. E., 441 
Eicd, H., 79 
Bifkind, R. A., 395 
Bilke, F., 227 
Rillll, A., 81 



Rivera, G. , 76 
Robert, F., 18 
Rotinson, A., 30 
Robinson. W. A., 365 
Bodriguez, v., 197, 262, 

370 
Boot, R., 357 
Rosen, F., 94 
Rosenberg, S. A., 246, 

268 
Euhl, U., 159 
Sachs, D. H., 441 
SackJnann, F., 260 
Saiki, J., 145 
Salk, L., 415 
Sallan, S., S2 
sallan, S. E., 73 
Salmon, S., 265 
Salmon, S. E., 444 
Saiaha, R., 392 
Santos, G. v., 335 
Sassetti, P. J., 408 
Sato, T., 205 
Sauerbrunn, B. J., 209 
Sanitsky, A., 385 
Schacter, B. Z., 335 
Scbaefer, U. «., 132, 326, 

327, 342 
Scher, C, 94 
Schiffer, C, 295 
Schiffer, C. A., 306 
Schilling, R. F., 411 
Schimpff, S., 295 
Schimpff, S. C, 376 
Schmidt, C. G., 132, 135, 

326, 327, 342 
Schrier, S., 50 
Schrier, S. L., 9, 136 
Schur, P. B., 229 
Schvartzman, E., 280 
Schyving, J., 190 
Seeber, S., 258 
Seibert, D. J., 398 
Sen, L., 38 

Sensenbrenner, L. L. , 335 
Sergis, E., 415 
Shah, P. n., 239 
Shalek, E. J., 266 
Shamoto, M., 205 
Shapiro, N., 25, 44 
Shapiro, W. H., 125 
Shattuck, L., 400 
Shan, ». T., 460 
Sheehan, R. G., 298 
Shreiber, A., 357 
Shullenberger, C. C, 242, 

243, 282, 283, 287 
Siddigui, F. A., 41 
Sieger, 1., 413 
Sigel, II. , 447 
Silver, R. T., 405, 424 
Silverstein, B. N., 316 
Silvestrini, E., 227 
Simone, J., 72 
Singer, J. A., 217 
Sinkovics, J. G., 282, 

283, 287 
Sinks, I. F., 93 
Skeel, E. T., 110 
Ekvaril, F. , 439 
Slavin, R. E., 335 
Slauson. R. A., 216, 24S, 

446 
Sledge, C. , 442 
Siichter, S. J., 347 
Smets, L. A., 1, 16, 17 
Smith, B. J., 52 
Smith, J., 380 



Slith, K., 2711 

Smyth, A. C. 136, 148 

Sokal, J. E.. 19, 120, 

316 
Solidoro, A., 116, 145, 

236, 285 
Somers, B. , 222, 249, 250, 

252, 275 
Soule, E. H., 399 
Spinelli, P., 212 
Spitzer, 105, 332 
Splinter, T., 222 
Spurr, C. L., 352, 387, 

406 
Stlvastava, B. I., 41 
Stathakis, N. E. , 346 
Stephens, E. J., 293 
Sterchi, J. «., 367, 406 
Stickney, D. R., 160 
Storb, E., 337 
Storb, E. F., 347 
Storts, R. C, 398 
Stossel, I., 94 



Str 



20 



Stutzman, L. , 396 
Suchi, T., 205 
Sullivan, M. P., 79, 303 
Sumer, T., 93 
Sutcliffe, S. B. , 213, 

219, 253, 266 
Sutherland, J., 217 
Sutow, U. v., 79, 303 
Suzuki, E. , 205 
lagnon, H., 371 
Tallal, L. , 149 
Ian, C, 127, 139, 146, 

149 
Tan, c. T., 305 
Tankersley, M. , 374 
Taub, B. N., 108 
lauro, G. P., 46, 59 
Teixeira, J. A., 226 
Tekinalp. C 254 
Tekuzman, G., 141, 304 
Terry, B. D. , 441 
Testa, N. G., 15 
Thatcher, L. G. , 61 
Theologides, A., 403 
Thomas, E. D. , 321, 322, 

323, 324, 325, 329, 

330, 331, 337, 340, 

343, 347, 356 
Thompson, E., 20 
Thompson, J. E., 445 
Thomson, A. E., 53, 54, 

225, 231 
lierie, A. H., 249, 250, 

275 
Tilbury, 218 
loogood, I. E., 60 
lourtellotte, U., 195 
Iraggis, D., 73, 82 
Trapani, R. J., 355 
Tretter, P., 395 
Trobaugh, F. E., 408 
Trubowitz, S., 234 
Trujillo, J. M., 33 
Tubergen, D. G., 70 
lullob, B. E., 398 
Turner, J. E., 368 
Tyndall, R., 374 
Dkita, B., 440 
arushizaki, I., 3, 233 
Uslenghi, C, 237 
?alle, B. J., 268 
Vallejos, C, 116, 145, 

236, 285 
Vacbeek, B. P., 1 



Vandermeme, .A. B., 384 
Vandervaaij, D., 369 
Vandyk, J. J., 364 
Vaneden, E. B., 384 
Tanunnik, J. A., 222, 249, 

2 50, 27 5 
Vaughansmith, S., 54, 231 
Velez, E., 156, 166, 167, 

175, 181, 188, 248, 

310, 311, 430, 431 
Verzosa, B., 72 
Viamonte, B., 268 
Vianna, N. J., 207 
Vietti, T. J., 80, 257 
Vila, J., 108 
Vincent, P. C, 48, 129 
Vodopick, H., 194 
Vodopick, H. A., 155, 333 
Vogler, B. E., 360 
Vonessen, C, 393 
Vosika, G. J., 403 
Haddell, B. R., 161 
Balker, B. D., 126 
Balker, R. D. , 368 
Baiters, I., 458 
Basserman, L., 418 
Basserman, L. R. , 389 
Baters, K. D., 49, 56, 57 
Beiden, P. L., 337 
Beil, B., 391 
Bernstein, G. D., 447 
Beiss, B. B., 394 
Beitsler, B., 405 
Besterman, B. P., 408 
Betherleymein, G., 53, 54, 

225, 231 
Bheelock, E. F., 378 
White, D. B., 387, 406 
Bhite, J. 3., 345 
Bhitehouse, J. B. , 37, 

128, 213, 223, 224, 

253, 266, 278 
Bhitson, B. E., 11 
Wiernik, P. H., 126, 136, 

143, 144, 146, 151, 

216, 217, 228, 245, 

255, 261, 295, 306, 

376, 448 
Wilkinson, p. H. , 208 
Billiams, A., 35 
Wilson, B., 382 
Bilson, P. E., 229 
Binton, E. r. , 360 
Bong, H. K., 270 
Bood, A., 72 
Boodard, 218 
Woods, R. , 443 
workman, J., 206 
Wust, C. J., 11 
yagoda. A., 433 
Yam, L. T. , 33, 115, 150, 

259, 299, 429 
Yankee, R. A., 356 
Young, C. W., 305, 433 
Young, V. n., 375, 376 
Zacharski, I. E., 398 
Zackheim, H. S., 449, 450, 

451 

Zaentz, S. D. , 260 
Zaharia, B., 236 
Zauadzki, Z. A., 440 
Ziegler, J. L., 67 
Zighelboim, J., 107 
Zimbler, H., 272 
Zimmerman, S. 0., 43 
Zinneman, H. H., 425 
Zucali, R., 237 



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