University of California Medical Center
San Francisco, California, June 25-26, 1984

The meeting was called to order by Dr. Richard Adamson, Co-chairman. He welcomed the members of the Joint Steering Committee to San Francisco. Dr. Adamson reported that the past year was very active and productive, culminating the last of the second five-year period of the cooperation in cancer research between the Japanese and American scientists. He stated that the seminar on heterocyclic amines, which he attended in Hawaii, was an excellent and successful meeting. The caliber of exchange scientists was excellent and the exchange of research materials, such as tumor promoters, would contribute greatly towards the progress of research. Dr. Adamson expressed his appreciation to the committee members for their active and devoted participation in this very successful bilateral activity.
Dr. Takashi Sugimura, co-chairman, responded by thanking the committee members for their contributions to the program and said that he and the JSPS Steering Committee were looking forward to the next five years for a more active and productive period of cooperation. He also added a personal note that San Francisco was a nostalgic locale for this meeting, since he spent his first night here upon arriving in the United States for the first time in 1957, before traveling to the National Cancer Institute to take a position as a Visiting Scientist.
Dr. Fuminori Sakai, Executive Director, JSPS, stated that he was personally pleased to see all the committee members again and reported that the special meeting in February in Tokyo was very successful. He was pleased that the Joint Steering Committee discussed quite extensively the new Japanese 10-Year Comprehensive Cancer Control Program. Dr. Sakai asked the committee to assist in developing the new program.
Dr. Robert Omata announced that the NCI Steering Committee was hosting the JSPS Steering Committee at a dinner on Monday evening at Alioto’s Restaurant on the Fisherman’s Wharf. Mr. Nagahide Onozawa invited the NCI committee to a luncheon on Tuesday at the Kiku Restaurant in the Hilton Hotel.
The chairmen requested that Drs. Richard Hodes and Yuichi Yamamura present the annual report for the Biology and Diagnosis Program Area. Dr. Hodes reported that the past year was a very active one in two major areas of research - cellular and molecular biology and tumor immunology. This year, scientific exchange in automated cytology was not supported as agreed upon at the last Steering Committee Meeting.
A meeting on “Oncogene Products and Neoplastic Cell Growth” was held in Washington, D.C., on October 17-19, 1983. This meeting was organized by Drs. Benoit de Crombrugghe and Yoji Ikawa. Discussions were held on viral oncogenes and their structural requirement for oncogenicity; activation of cellular oncogenes; and the structure of hormone receptors and their potential use in drug targeting. (See annual report for details.)
A meeting on “Immunogenetic Analysis of the Expression of Tumor Antigens and Responses to Tumors” was held in La Jolla. California, October 31 through November 2, 1983. Three primary areas were extensively discussed by the participants; namely, the immunology and molecular biology of tumor antigens; the biology of host-tumor immune interactions; and the preclinical approaches to tumor immunotherapy.
Drs. Yamamura and Hodes stated that there has been considerable transition in the merging of immunology and molecular biology of tumor antigens. The immunologists are involved in the immunogenetic analysis of the immune system and the identification and characterization of tumor antibodies. There is considerable research going on in exploring monoclonal antibodies for diagnostic methodologies. There has been recent interest in the targeting of monoclonal antibodies for cancer treatment. Discussions ensued on the experimental approach to targeting monoclonal antibodies which are conjugated with cytotoxins for tumor cells.
Dr. Robert Miller asked what main developments are anticipated in immunology during the next five years. Dr. Hodes said that research on nonspecific adjuvant immunotherapy has been generally disappointing. Future research will be focused on monoclonal antibodies as diagnostic tools and this technology will be applied to diagnose and to follow malignancies. Currently, isotope-labeled antibodies are being used for diagnosis. Preclinical therapeutic research has progressed in several areas. Ricin toxins coupled to tumor specific antibodies are being tested in phase I studies to tumor therapy. Studies of T-cell mediated antitumor responses have been applied to experimental therapy in animal tumor models employing presensitization with haptens or PPD as “helper” determinants.
There has been a recent close relationship between molecular biology and tumor immunology. Research on transplantation antigens as an approach to study immunotherapy has been enhanced by studies of the genetic regulation of expression of tumor and transplantation antigens. Recent studies of immunoglobulin gene regulation have given interesting results relevant to oncogene regulation.
Dr. Yoshio Sakurai reported that recent studies show that tumor cells release tumor antigens after chemotherapy treatment, thus creating a multitude of problems. It is known that malignant cells can shed soluble tumor antigens. Dr. Haruo Sugano asked if lymphokines have immunological functions. Dr. Hodes stated that the studies on the identification and structure of lymphokines have been very frustating thus far. New studies are just beginning. Research on function, structure, and receptor sites of antigens, antibodies, and lymphokines are going on now. These will be exciting areas in the future.
Dr. Yamamura stated that the next large symposium will be held on the “Molecular Analysis of Monoclonal Antibodies, Receptors, and Lymphokines.” There are very important subjects and research on these entities are just beginning. The clinicians are very much interested in studies on lymphokines.
The chairmen thanked Drs. Yamamura and Hodes for their presentations and in leading the discussions.
After the coffee break, Drs. Robert Miller and Haruo Sugano were asked to present the report for the Interdisciplinary Programs Area. They reported that extra benefits have been realized from previous seminars which were sponsored under the Interdisciplinary Programs Area. The bilateral interest in the comparison of lymphatic diseases in Japan and the U.S. still draws attention from scientists on both sides. Also, it was reported that a senior epidemiologist from the National Institute of Environmental Health Sciences in North Carolina is spending two years at the Radiation Effects Research Foundation (RERF) in Hiroshima. These benefits were results of previous interactions during the U.S.-Japan seminars and workshops.
A workshop on “Statistical Methods in Cancer Epidemiology” was convened at the Radiation Effects Research Foundation (RERF) in Hiroshima in March 1984. This meeting was primarily held to encourage the merging of biostatistics and epidemiology in Japan with the participation and strengthening of the interests of biostatisticians, physicians, and biologists in conducting epidemiological studies on cancer.
The workshop on the “Role of Pathologists in Cancer Epidemiology” was held in San Francisco just prior to the annual meeting of the International Academy of Pathology in March 1984. Several of the participants stayed in San Francisco to attend the meetings of the Academy. The topics discussed at the meeting included the difference in the incidence of various types of cancer and lymphatic diseases in Japan and the United States. Recent time-trend data indicate that cancer incidence in Japan generally tends to become “westernized,” particularly in the cases of lung cancer and breast cancer. It was also reported that an etiologic agent of adult T-cell lymphoma (ATL) in Japan is closely related to or identical to the retroviruses, human T-cell lymphoma virus (HTLV) found in the U.S., the Caribbean Islands, and other tropical countries. It was reported that there exists a close relationship between epidemiology and pathology, but they are also related to nutritional, metabolic, and biochemical studies. The importance of histologic subtypes in epidemiologic research was pointed out.
During the past year, the exchanges of scientists involved several investigators who collaboratively studied the relationship between the viral agents, ATLV and HTLV. These exchanges and meetings helped to allay much of the controversy concerning the identification and establishment of the similarity between the two viruses. It is generally accepted that the ATLV is identical or very similar to HTLV-I.
Considerable discussion was held on the differences in the incidence of various types of cancer in the two countries. Also, the relationship between ATLV and HTLV were discussed. As a result of previous workshops on lymphatic disease, Dr. Sugano reported that the Annual Princess Takamatsu Symposium in Tokyo, which is bringing together scientists from Japan, the United States, France, and other nations, will focus on the types of human T-cell lymphoma virus research. This should be a very exciting and interesting symposium.
The meeting was recessed for luncheon.
The co-chairmen reconvened the meeting at 1:30 p.m. and asked Drs. Yoshio Sakurai and Michael Friedman to present the annual report for the Treatment Program Area.
Dr. Friedman thanked the chair and reported that it was a great pleasure to be present for his first meeting with the Joint Steering Committee as program area coordinator. He stated that he had been deeply involved in the cooperative study on the treatment of advanced gastric cancer, which was carried out by a group of Japanese oncologists and the Northern California Oncology Group. The collaborative effort had been a very successful endeavor to familiarize oncologists from both sides with terminology. methodology, and clinical protocols used in the joint study. This project will be used as a model for future clinical studies. Dr. Friedman also said that the annual report was prepared by Dr. Sakurai and Dr. Saul Schepartz, formerly the Deputy Director, Division of Cancer Treatment, National Cancer Institute, who recently retired from government service to take a position at the New Jersey College of Medicine and Dentistry.
Drs. Sakurai and Friedman reported that the past year had been an active one with two very successful meetings which were supported under the Treatment Program Area. The workshop on the “Resistance to Anticancer Drug” was organized by Drs. Sakurai and John Driscoll and held in Honolulu, Hawaii, in May-June 1983. The discussions were held on the phenomenon of drug resistance and the approaches to overcoming drug resistance.
In February 1984, the Annual Program Review of the Cancer Treatment Program was held in Tokyo, Japan. Sessions were held on the review of selected drug screening methods using in vivo systems and human tumor colony forming assay for selected drugs; preclinical and clinical data on fluorouracil analogs and derivatives; new experimental data on biological response modifiers; and new anticancer drugs, such as a mitomycin C analogue and an adriamycin derivative.
Dr. Sakurai reported that a team of senior American investigators visited cancer centers in Tokyo and Nagoya and participated in a series of joint seminars on treatment of three curable cancers: small-cell lung, testicular, and ovarian cancers. These seminars were very well attended by Japanese clinicians and information on various clinical studies being conducted in both countries was exchanged.
In addition, a staff member of the Cancer Chemotherapy Center, Tokyo, has been a regular participant at the periodic meetings sponsored by the NCI phase I and II drug studies group.
In the ensuing discussion, Dr. Adamson asked about the latest theory on drug resistance. Dr. Friedman stated that the resistance may be a pleotrophic biochemical resistance to drugs. It is a serious clinical problem. There are new theories; however, recent investigations are going on to study certain types of drugs. Currently, calcium blockers are being tested in the U.S. Drug resistance is quite clear in certain situation, such as the anthracyclines and antifolates and may be due to membrane resistance or gene amplification.
The Chair thanked Drs. Sakurai and Friedman for their presentations. Then Drs. Sugimura and Adamson presented the report for the Etiology Program. During the year, two excellent seminars were sponsored. The seminar on the “Carcinogenicity, Mutagenicity, and Metabolism of Heterocyclic Amines” was held in Honolulu in February 1984, and was organized by Drs. Shigeaki Sato and Snorri Thorgeirsson. The other seminar was on the “Eukaryotic DNA Replication and Repair” held at Stanford University in California in March 1984.
At the seminar on heterocyclic amines, data were presented on the identification of mutagenic and carcinogenic heterocyclic amines from cooked beef. Heterocylic amines have been found in various processed foods, including mutagens in coffee. Studies on the activation mechanisms of the heterocyclic amines in target organs and the actual risk estimation of those compounds were discussed as future problems for cooperative studies. Much of the early research on the mutagenic heterocyclic amines was initiated by Japanese investigators.
The seminar on “Eukaryotic DNA Replication and Repair” was organized by Drs. Katsuro Koike, David Korn, and E. Friedburg. The speakers addressed the mechanisms of eukaryotic DNA replication and the DNA of SV40 virus, the adenoviruses, and mitochondria. Also, presentations were given on the fidelity of DNA polymerases; temperature-sensitive DNA synthesis in mutant mouse cells, cloning of part of the human gene for terminal deoxynucleotidyl transferase, cloning of yeast DNA repair genes, and other topics.
During the year, seven Japanese scientists studied in the U.S. and conducted collaborative research in the areas of viral oncology and chemical carcinogenesis. Three American scientists were invited to Japanese laboratories to present seminars and workshops on viral oncology and molecular biology. The program has been effective in supporting research of mutual interest and has helped the initiation of new collaborative research.
Dr. Sugano asked if the U.S. has a national policy on risk assessment on environmental factors. Dr. Adamson responded by explaining that the principles on chemical carcinogenesis have been discussed, under the auspices of the Office of Science and Technology, by various research and regulatory agencies. These principles might be used as a guideline for performing risk assessment by the regulatory agencies. Dr. Adamson also stated that the National Cancer Advisory Board had issued a report on quantitative risk assessment.
Dr. Adamson went on to state that in risk assessment there are two phases, hazard evaluation and exposure assessment. The first phase relies on epidemiological analyses; animal bioassays; in vitro, metabolism, structure activity, and numerous other studies, including the use of human epithelial cells and tissue explants. The second phase relies on exposure assessment takes into account routes of exposure, different concentrations, human activity, chemical reactions, environmental transport mechanisms, and limitations in analytical techniques. When both hazard evaluation and exposure assessment are completed, then quantitative risk assessment can be performed. He stressed that many uncertainties are apparent at each stage of the process and need to be clearly stated to assist in the management of the risk. Dr. Adamson also stated that it may be a good idea to think about a large U.S.-Japan Conference on Biochemical Epidemiology to be held in 1986.
After a brief recess, the Joint Steering Committee discussed the program plans for 1984-85.
Drs. Sugano and Miller proposed the following activities for the Interdisciplinary Programs Area for the coming year:
1) Workshop on “The Prognostic and Etiologic Importance of Subtypes of Cancer,” Hawaii, October 1984. Organizers: Drs. Sugano and Miller
2) Workshop on “Adult-type Cancers under 30 Years of Age: U.S. Compared with Japan,” Tokyo, March 1985. Organizers: Drs. Kunio Aoki, Sugano, and Miller
3) Scientist Exchanges:
a) Dr. Motoharu Shimizu, molecular biologist, Cancer Insitute, Tokyo, to study microinjection techniques with Dr. Kazuhiro Ogawa, Jackson Memorial Laboratory, Maine.
b) Dr. Yoshifumi Urano, pathologist, Tokyo University, to consult about autopsy registration with Drs. Grant Stemmerman and Abraham Nomura, Kaukini Hospital. Honolulu, Hawaii, and Dr. C.R. Key, Albuquerque, New Mexico.
c) Dr. Naoto Aoki. pathologist, Tokyo University, to study the relationship between hepatitis B virus (HBV) and hepatocellular carcinoma, using the wookchuck model with Dr. W.S. Maison, Philadelphia, Pennsylvania.
d) A prospective Japanese scientist interested in Leukemia is being considered.
The Joint Steering Committee voted for tentative approval of the proposed workshops and the exchange of scientists.
Dr. Miller reported that during the last workshop on the “Role of Pathologists in Cancer Epidemiology” there was some discussion of the Nakasone Cancer Program, which has mentioned interest in cancers in young adults. Also, there is some interest in the incidence data which has been produced under the SEER Program. Discussions were also held on the tissue registries of cancers of the stomach, pancreas, liver, and nasopharynx in Japan.
It is anticipated that two American scientists will be invited by JSPS to participate at the workshop on cancer in young adults.
Drs. Yamamura and Hodes discussed the proposed future activities of the Biology and Diagnosis Program Area:
1) Seminar on “Tumor Markers and Oncogenes: Application for Diagnosis,” Washington, D.C., November 1984. Organizers: Drs. T. Kishimoto, Osaka University; K. Higashino, Hyogo Medical College; and S. Korsmeyer, NCI
2) Seminar on “Altered Regulatory Mechanisms of Growth and Phenotypes on Neoplastic Cells,” Hawaii, January 1985. Organizers: Drs. H. Sugano and I. Pastan
3) Conference on “Molecular Analysis of Tumor Immunology,” Honolulu, November 25-28, 1984. Two American investigators will be invited as participants by JSPS.
4) Scientist Exchanges:
a) Dr. Koreaki Taniguchi, Osaka University, to visit NCI.
b) Dr. Toshio Hirano, Osaka University, to study with Dr. William Paul, NIH.
c) Dr. Allan Schultz, Frederick Cancer Research Facility, Frederick, Mary-land, to study the molecular biology of bovine leukemia virus with Dr. Yoji Ikawa, Institute for Physical and Chemical Research, Saitama, Japan.
The Joint Steering Committee tentatively approved seminars, conference, and the exchange of scientists.
Drs. Sakurai and Friedman presented the future activities of the Treatment Program Area:
1) Meeting on “Advances and New Techniques in Radiation Oncology Research,” Seattle, Washington, May 1-4, 1985.
Organizers: Dr. M. Abe, Kyoto University, and Dr. Glenn Sheline, University of California, San Francisco.
This meeting was held in May 1984 and it was a very successful meeting on fast neutron, use of computers for staging and radiotherapy, intraoperative radiotherapy, and total body radiation.
2) Seminar on “Biochemical Modulation of Antitumor Effect,” Tokyo, November 1984.
Organizers: Drs. Y. Sakurai and M. Friedman
This meeting will have presentations on biochemical pharmacology and preclinical and clinical drug studies.
3) Seminar on “New Anticancer Agents, Biological Response Modifiers, and Cytokines in Progress of Cancer Treatment.” The 10th Annual Program Review Meeting, Honolulu, March 1985.
Organizers: Drs. Sakurai and Friedman
The new platinum compounds with low toxicity will be discussed; also, data on the clinical trials with interferon and the latest research information on treatment with monoclonal antibodies will be presented.
4) Scientist Exchanges:
a) Dr. Takashi Tsuruo, Cancer Chemotherapy Center, Tokyo, is currently studying drug resistance and calcium blockers with Dr. R. F. Ozols at NCI and he will be at NCI for 12 months.
b) Dr. Toshitada Takahashi, Aichi Cancer Center, Nagoya, plans to discuss monoclonal antibody research with Dr. Lloyd J. Old at Memorial Sloan-Kettering Cancer Center, New York.
c) Dr. Tohru Masaoka, Center for Adult Diseases, Osaka, plans to discuss bone marrow transplantation with Dr. E. D. Thomas at the Fred Hutchinson Cancer Center, Seattle.
d) Dr. Richard Simon, NCI, will visit with Dr. Y. Sakurai and his colleagues at the Cancer Chemotherapy Center in Tokyo to discuss clinical trials and statistical studies on chemotherapy trials.
e) Dr. Susan Ellenberg, NCI, will join Dr. Simon on the above visit to discuss statistical methodology.
The Joint Steering Committee tentatively approved the projected activities of the Treatment Program Area.
Dr. Friedman reported that plans are being made for a future collaborative effort to share clinical information on certain types of cancer. Also, data on phase II studies in Japan are to be exchanged. There is considerable interest in Japan on lymphomas and viral leukemia studies (adult T-cell leukemia). Joint collaborations will be encouraged.
Dr. Glenn Sheline attended as an observer and discussed the radiation oncology meeting recently held in Seattle. The Japanese are in the developmental stage of large equipment to heavy particles and there is currently one such machine in the U.S. There has been previous meetings to discuss recent advances in radiation oncology. Recently a radiologist from Kyoto University arrived at the University of California at San Francisco to spend two years collaborating on hyperthermia research. Dr. Sheline would like to organize a meeting on radiation oncology in the fall 1985.
Dr. Miller stated that a spin-off of the meeting on lymphatic diseases in 1982 resulted in the publication of new data on the adult T-cell leukemia virus (ATLV) and the human T-cell leukemia virus (HTLV).
Dr. Sugimura and Adamson presented the future activities for the Etiology Program Area
1) Seminar on “Analyses of Tumor-associated Antigens of Digestive Organs with Monoclonal Antibodies and Their Clinical Application,” Lake Arrowhead, California. February 22-24, 1985.
Organizers: Drs. Ralph Reisfeld, Scripps Clinic and Research Foundation, and Akira Yachi, Sapporo Medical College. The material to be presented will be related to the seminar held on stomach dysphasia and gastric cancer.
2) Seminar on “Oncogenes and Experimental Carcinogenesis,” Honolulu, Hawaii, March 12-14, 1985.
Organizers: Drs. Stuart Aaronson, NCI, and Masaaki Terada, National Cancer Center Research Institute, Tokyo
3) Scientist Exchanges:
a) Dr. Kunitada Shimotono, National Cancer Center Research Institute, Tokyo, will exchange information on HTLV-II with Dr. D. W. Golde University of California, Los Angeles.
b) Dr. Yoshinari Onishi, Tokushima University, Tokushima, to collaborate on nitroarenes studies with Dr. F. A. Beland, National Center for Toxicology Research, Arkansas.
c) Dr. Ikuo Abe, Tohoku University, Sendai, to visit with Dr. G. A. Boorman, National Institute of Environmental Health Sciences, North Carolina, to discuss risk assessment.
d) Dr. Kazuo Yanagi, Tsukuba University, Tsukuba, to study herpes simplex virus with Dr. B. Roizman, University of Chicago.
e) Dr. Yoichi Taya, National Cancer Center Research Institute, Tokyo, to collaborate on gene amplification in human giant cell lung carcinoma with Dr. F. Tamanoi, Cold Spring Harbor Laboratory, New York.
f) Dr. William Haseltine, Dana-Farber Cancer Institute, Boston, Massachusetts, has proposed to study HTLV and ATLV with Dr. Yohei Ito at Kyoto University.
g) Two other American scientists will be considered as Exchange Scientists.
The proposed activities for the Etiology Program Area were tentatively approved by the Joint Steering Committee.
The Chair brought up the discussion of the Joint Steering Committee for 1985. It was unanimously agreed that the next meeting will be held in or near Tokyo on June 27-28, 1985.
The meeting was adjourned by the Chairmen, after thanking the Committee members for their contributions to a stimulating meeting.

Respectfully submitted,

Robert R. Omata, Ph. D.

San Francisco, California June 25-26, 1984


Monday, June 25
9:00 a.m. Welcoming Remarks Dr. Adamson and Dr. Sugimura
Announcements Dr. Omata
Annual Report for the Biology and Diagnosis Program Area Dr. Hodes and Dr. Yamamura
Coffee Break
Annual Report for the Treatment Program Area Dr. Friedman and Dr. Sakurai
2:00 p.m. Annual Report for the Etiology Program Area Dr. Sugimura and Dr. Adamson
Annual Report for the Interdisciplinary Program Area Dr. Sugano and Dr. Miller

Tuesday, June 26
9:00 a.m. Program Plans for 1984-85
Etiology Program Area Dr. Sugimura and Dr. Adamson
Biology and Diagnosis Program Area Dr. Yamamura and Dr. Hodes
Coffee Break
Treatment Program Area Dr. Sakurai and Dr. Friedman
Interdisciplinary Program Area Dr. Sugano and Dr. Miller
Closing Remarks Dr. Sugimura and Dr. Adamson