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NATIONAL CANCER INSTITUTE

ANNUAL REPORT

July 1, 1976 through September 30, 1977

Part I

OFFICE OF THE DIRECTOR

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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

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

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 (Cancer Literature) , 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 Projects), 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 Protocols) , 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.

"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.

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.

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

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

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

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.

TABLE 1 - ICRETT APPLICATIONS AND AWARDS— 1976

CANCER DISCIPLINE APPLICATIONS AWARDS

1. Behavioral and Social Sciences 0 0

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 0

6. Controlled Therapeutic Trials 1 1

7. Detection and Diagnosis 2 1

8. Environmental Factors and

Prevention 2 0

y. Epidemiology, Biostatistics,

Registries 0 0

10. Experimental Chemotherapy 6 6

11. Experimental Pathology 6 4

12. Immunology 7 4

13. Radiobiology and Radiotherapy 5 5

14. Surgery 0 0

15. Viral Carcinogenesis 9 5

51 33

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. "

FIGURE 3: ICRETT AWARDEES AND THEIR
SCiENTIFIC INTERACTION

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l-rance

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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.

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."

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

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

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

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

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

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.

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.

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.

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

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.

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

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

FROM THE USA

TO THE USA

Individuals

Delegations

Individuals

Delegations

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

1
1

1
1
1
2
2

TOTAL

NCI-INSERM:
Clinical Trials
Hormone Regulation
Virology

TOTAL

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

1 (4)
1 (5)

3 (14)

2 (9)

NCI-GERMANY:

Automated Cytology 1 (7)

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

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.

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

2
5

Western Europe

Eastern Europe

South America

Africa

Asia

Australia

(a)

13
2
2
2
2

1
2

1
3

Alien Residents

(b)
TOTAL

134

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.

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

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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.

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

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.

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.

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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.

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.

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 RESEARCH

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:

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

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.

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 Cancer in
April lb»76.

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.

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.

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.

SIGNIFICANCE 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

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

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

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

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

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.

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.

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.

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

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.

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).

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.

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

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

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,

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

Non-
Custom

861

Publications
Distributed

39,617

WATS Line
Calls

1,542

266

818

955

32,783

293

761

1,432

32,301

359

980

1,834

39,014

414

721

1,102

34,903

435

934

1,033

48,529

457

730

2,701

70,283

742

1,456

2,173

102,585

785

1,329

3,078

78,970

670

1,622

2,298

145,149

678

1,503

3,495

166,242

642

1,500

3,000

150,000

675

1,500

3,000

150,000

675

1,500

3,000

150,000

675

1,500

3,000

150,000

675

18,396

547

32,962

1,390,376

8,441

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.

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.

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.

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.

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.

SAMPLE COPY

RESEARCH PROJECTS

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.

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

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. CONTROL 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

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

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 0 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

•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 FLUIDS OF AMIHALS POLLOMIMG PIFFEBEBT BODES OF
ADHImSTBATIOH '

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

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

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 CUEHICAL AHD BI01.QCICH. HATESHLS FOB

iaiioiionoDiii.tTOBi acthiii

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

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

distehpeb 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 BUO 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

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| ,

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 PBOTEIl IHLHOTBITIOil OB TBE ImniE
1E5P0IISE 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

>B0

GBESS:

Our i

!rel

.iai

nari

f dal

ta show

are supp

ressor

cells

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

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 AMD 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.

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

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
SEPARATE 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

• 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, GLTC05PHING0LIPID COHPOSITIOH OP PLASHA HEHBRAWES
raOH HORHAL BAT LIVER CELLS AND HEPAT0I1A CELLS
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

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 tohob

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

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,

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:

with 991

.Tc dlst

:anni

stabilized wit)

1 C.

APPROACH:

indicatf

=d bone

seal

labeled

HEDP conta:

sodlua i

iscorbal

:e.

Proctor

and Gamble

17-U511 i

ipplies

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

FeLV,

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

This Cancergram is a service of the INTERNATIONAL CANCER RESEARCH DATA BANK (ICRDB)
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SCIENCE INFORMATION SERVICES

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20TH AND RACE STREETS
PHILADELPHIA, PA 19103

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)

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)

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)

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)

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

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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
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PB-265 085

.researchL.

SPECIAL LISTING

mmm zhiizm research

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
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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
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maries called "CANCERPROJ."

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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

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 SIGNIFICANCE
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 0 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 TECHNIgOES
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

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 . COBPABISOS 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

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

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 LEUKEMIA - 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. tBDLTIPLE 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. 0 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

are su]

ppressed

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ire a

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supply

oi L-asi

paragine in v:

itro.

;nsitive mouse

leulcen.

cells,

to 1

nsan

isitive

do not

contain

the enzyme L-

-aspa

raqi

.ne synthetase

The dri

IS SU]

pplied as ste;

die.

iyc

iphilized

pouder

fresh

solutions in

ster

lie

are

prepar.

every

day.

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 SUBSEQUENT 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 FOR

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 ADRIAWYCIH IN ADVAilCED LEUKEMIAS.
lIHPHOnAS AND OTIJEH 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 CHBONIC

GBANOLOCYTIC LEUKEHIA

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 IRKAD-
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 CHEMOTHERAPY OF ACUTE
LEUKEHIA - 5YSTEI1ATIC EXA'mINAT ICN OF NEW D°')r
COHBINATION HITH EXISTING THERAPY
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. THIOGUANINE. CYTOSINE ARABINOSIDE, DAOSOHTCIN
It LYMPHATIC LEUKEMIA

Puerto Rico, School of

Velez, E., Uni

Medicine, P.O.
00936

167. THERAPY OF PBEVIOOSLY
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. SEQUEHTIAL 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 IRRAD-
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. DETERMINATION, IN PEDIATRICS, OF 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 LYMPHC
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 0
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. COWPARISOH 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 CHEMOTHERAPY

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

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.

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 TUBOR 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

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 GRAFTS
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 GRANULOCYTE

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

ariou;

lly, .e

are

ictive

uqs

1 the eff

ect

rophil's

.coccus 01

■riments

,n prevent

, help

lysis of

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

fUTIEHIS

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~-tfanover, 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'JMODIAGNOSIS 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 STiinv - 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. PERCUTANEOUS 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

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,

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253, 266, 278
Bhitson, B. E., 11
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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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