MINUTES
8th NCI-JSPS JOINT STEERING COMMITTEE MEETING
Hotel New Otani
Tokyo, Japan, June 27-28, 1985

The meeting was called to order by Mr. Koichi Igarashi at 9 a.m. He welcomed the participants and asked for approval to serve temporarily as the Chairman until a Co-chairman could be duly elected for this meeting.
Mr. Igarashi introduced Dr. Hiroshi Kida, recently appointed Director General of JSPS, who replaced Dr. Sogo Okamura. Dr. Kida served as Vice Minister of Education, Science, and Culture in 1976-1978. He thanked the United States for its contribution to this joint program. Through this cooperation, close ties developed, leading to considerable scientific advancements. The US-Japan bilateral agreement played the role of a pioneer in this type of endeavor. Dr. Kida said he appreciated the rapid pace of scientific advances in this area.
Dr. Richard Adamson expressed his delight to be back in Japan. He announced the retirement of Dr. Robert Omata. Dr. Ihor Masnyk agreed to serve as the Executive Secretary for this meeting and as a stand-in for Dr. Richard Hodes, who could not attend. The US-Japan Cooperative Cancer Research Program has proven to be the best of the bilateral programs. This success is due to the excellent collaboration in the four program areas. The NCI appreciates the interest and contribution of their Japanese colleagues and especially the new initiatives promulgated under the Nakasone Program. Mr. Igarashi next addressed administrative aspects of the meeting. The agenda was compressed to fit a one-day meeting: program reports would be handled in the morning and plans for FY 1985-86 in the afternoon. The agenda was accepted. The 1984 Annual Report format was distributed; Dr. Masnyk will assemble the material for the report.
Dr. Adamson was pleased to see representatives at this meeting. On behalf of the U.S. delegation he wished for the speedy recovery of Dr. Sugimura from his illness. Dr. Shozo Takayama acted for Dr. Sugimura as coordinator of the Etiology Area.
Dr. Haruo Sugano introduced Dr. Makoto Ogawa, who replaced Dr. Sakurai (retired). Dr. Ogawa was happy to join this group. He is from the same institute as Dr. Sakurai. In the past he has been involved in a joint project with Dr. Michael Friedman.
Dr. Adamson was the first to report. The Etiology Program consists of four areas: Epidemiology, Chemical Carcinogenesis, Viral Oncology, and Genetics. During the last reporting period, two seminars were held in the United States. One seminar concerned new approaches to immunodiagnosis and immunotherapy of gastrointestinal tract cancers; the second seminar focused on molecular mechanisms underlying the, development of cancer, with the primary goal of exchange of information on the role of oncogenes in carcinogenesis. These two seminars were especially timely and beneficial to scientists of the United States and Japan because of the rapid progress in the use of tumor-associated antigens of digestive organs for diagnosis and because of progress in the use of monoclonal antibodies for both therapy and in studies on the molecular mechanisms underlying the development of cancer.
Five scientists came to the United States from Japan as exchange scientists: three conducting collaborative research in the area of viral oncology and two in the area of chemical carcinogenesis. Three scientists came to Japan from the United States as exchange scientists and carried out collaborative research in the areas of viral oncology and chemical carcinogenesis. Although the exchange visits were relatively short, this program was effective in sup-porting research of mutual interest and helped to initiate new collaborative research which will further promote future exchanges. Dr. Adamson then gave a more detailed description of the two seminars.
The seminar on "Analysis of Tumor-Associated Antigens of Digestive Organs with Monoclonal Antibodies and Their Clinical Application" was held on February 21-23, 1985 at the La Jolla Village Inn in La Jolla, California. The organizers were Dr. Ralph A. Reisfeld, Scripps Clinic and Research Foundation, La Jolla, California, and Dr. Akira Yachi, Department of Internal Medicine, Sapporo Medical College, Sapporo, Japan. There were seven participants each from the United States and Japan.
Dr. Miller opened the discussion by noting that there was no overview in the report of this conference. He asked what were the leading observations. Dr. Adamson responded that this seminar was held because of rapid advances in the field of monoclonal antibodies applied to diagnosis and therapy against digestive tract tumors. In Japan this was especially important because of the prevalence of stomach tumors. In addition, both countries are highly interested in pancreatic cancer. It appears that monoclonals could be used to diagnose tumors with substantial leadtime. Dr. Friedman remarked that many investigators share enthusiasm in this new diagnostic use of monoclonals, but much of the work is based on anecdotal reports. What is needed are a few well-planned studies. Dr. Adamson agreed that the need exists for basic scientists to meet with clinicians to design good studies with adequate follow-up and evaluation. Dr. Miller wondered if monoclonals depended on various subtypes. Dr. Sugano stated that some have wide applications and others have more narrow use. For the purpose of detection, a wide spectrum of sensitivity is needed. Then one needs a narrowly defined specificity. Therefore, many monoclonals are needed. He asked whether there are any registeries kept on monoclonals in the United States. Dr. Friedman noted that there were attempts to develop such a library. Dr. Adamson suggested that it could be very useful to create such libraries and to exchange information. Dr. Masnyk cautioned that one problem with such libraries may be the question of verification of the data. A central facility would be necessary. He reported on the efforts of the Breast Cancer Serum Bank devoted to this issue. He wondered what exactly was the issue raised by Dr. Miller. Did he suggest that a summary of findings be developed for each meeting? Dr. Adamson said that once a meeting was decided upon, the organizers should be made aware that a summary of their findings would comprise a part of the report. Other participants were in agreement.
Dr. Adamson then reported on the seminar on "Oncogenes and Experimental Carcinogenesis" that was held March 12-14, 1985 at the East-West Center of the University of Hawaii in Honolulu, Hawaii. The organizers were Dr. Masaaki Terada, National Cancer Center Research Institute, Tokyo, and Dr. Stuart Aaronson, National Cancer Institute, Bethesda, Maryland. There were seven participants each from Japan and the United States.
In the discussion, Dr. Sugano stated that this was an exciting meeting in an exciting area. The number of oncogenes is growing; the question may be raised-how many can be expected ultimately?
Dr. Adamson believed that there are a limited number of oncogenes and a need for a new system to detect them. At this moment, it is difficult to predict, but probably there should be less than 50 oncogenes. Dr. Miller wondered if there might possibly be international differences in the distribution of oncogenes. Dr. Adamson speculated that various injuries may induce different oncogenes and thus may be geographically related.
Dr. Takayama then reported on the exchange of scientists and their studies in both countries.
In the area of the Biology and Diagnosis Program, three seminars were held during the reporting period. Dr. Yamamura discussed the seminar on "Altered Regulatory Mechanisms of Growth and Phenotypes in Neoplastic Cells" held at the East-West Center, University of Hawaii on January 14-16, 1985.
In light of the absence of Dr. Hodes and unavailability of a written report on the seminar on "Molecular Mechanisms of Cell-Cell Interactions Involved in Tumor Immunity " the next report covered the seminar on "Tumor Markers and Their Genes" held January 14-16, 1985 at the NIH.
During the discussion of this report, it was again mentioned that such reports should present more than just a compilation of abstracts. Discussions, a very important component of such meetings, should also be reflected. In organizing seminars, Dr. Friedman felt that enough time should be allocated for discussions and the exchanges should be reported.
Another issue discussed was the lack of representatives from the Steering Committee at some meetings. It was felt that such representation is desirable.
Dr. Yamamura reported on the activity in the exchange area. The United States sent Dr. A. Schultz as an exchange scientist in late August to the Laboratory of Molecular Oncology, the Institute of Physical and Chemical Research (RIDEN), where he stayed for one week. He contributed to the research work on molecular structure of gag gene products and protease in BLV.
Dr. S. Orozlan, FCRF, Frederick, Maryland, joined Dr. Schultz on the last day of his visit at RIKEN and exchanged N' terminal amino acid sequences of protease in BLV with its DNA sequences. These were analyzed by Dr. N. Sagata, RIKEN.
Dr. H. Amanuma, Chief, Laboratory of Gene Technology and Safety, RIKEN, was sent to the United States from February 4-24, 1985. He visited Dr. A. Khan, NIAID, NIH, Dr. B. Chesebro at the Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, and Dr. D. Kabat at the Oregon Health Sciences University. He exchanged the latest research data and information on structure and leukemogenic activity of a modified env gene or gp55 gene in Friend and Rauscher spleen focus-forming viruses. He also discussed the possible origin of the unique genes.
Dr. Tadatsugu Taniguchi from Osaka University visited Prof. Jan Vilcek at the New York University Medical Center (March 20-31, 1985) with whom he started a collaborative project studying genes whose expressions are induced in inter-leukin-2. He also visited Drs. Gallo and Paul at NCI and Dr. Tjian at the University of California, Berkeley.
The reports from the Treatment area were given by Drs. Friedman and Ogawa. There were three seminars held during the reporting period. Four Japanese investigators visited various institutions in the United States relating to their research projects.
During May 2-4, 1984, a seminar on "Advances and New Techniques in Radiation Oncology Research" was held in Seattle, Washington.
Dr. Adamson brought up an interesting possibility of encapsulating radiation sensitizers in the heat-sensitive lymphosomes; this could lead to radiotherapy coupled with hyperthermia.
Dr. Sugano wondered how one would evaluate bone marrow transplantation in therapy. In answer to Dr. Miller's question on the differences between Japan and the United States in radiation oncology, Dr. Ogawa noted that the United States has more neutron generators. In the area of computers, Japan is behind, while the United States is approaching artificial intelligence with the fifth generation computers. Dr. Friedman pointed out that in the United States combined modalities are used more often. Dr. Adamson asked about possible effects of neutron therapy on secondary cancers but, according to Drs. Friedman and Ogawa, there are no definitive comparative studies on conventional and neutron therapies.
To answer Dr. Yamamura's question, Dr. Friedman explained that cyclosporin's use in bone marrow transplantation is increasing, but its renal toxicity appears to be the limiting factor.
The seminar on "Biochemical Modulation of Chemotherapy and Immunotherapy" was held on November 19-20, 1984, in Tokyo. Although biochemical modulation is an attractive investigational direction, there are many problems that remain unsolved. These include the evaluation criterion; the difficulty in performing confirmatory studies, i.e., doses, schedules, sequence, etc.; and the clarification of interaction of each drug with others. Thus, biochemical modulation has no established clinical role currently. This seminar concerned the present status of biochemical modulation, chemoendocrine therapy for breast cancer, drug resistance, and immunotherapy, including interferons and interferon inducers.
A third seminar was devoted to "Drug Development and Clinical Results of New Antitumor Agents." It was held on February 25-26, 1985, in Oahu, Hawaii. The seminar focused on both general topics of methodology of drug development and clinical results of specific new agents.
Dr. Ogawa added that it appears that we might have to change the screening system, because the current one is not very productive. Should human cell lines be used or, more specifically, the gastric instead of lung carcinoma cell lines? Finally, he wondered: "Are we entering cis-platinum era of chemotherapy?" Dr. Adamson stated that, when looking for activity of various metals, one should study their potential accumulation, both for treatment strategy and for potential toxicity. Dr. Friedman noted that at this seminar a new presentation technique was carried out--hard copies of all slides were distributed to the participants ahead of the seminar, which proved to be very useful. This might be a helpful addition for other seminars.
Concerning the scientist exchange activity, four Japanese investigators visited U.S. laboratories:
1. Dr. Takashi Tsuruo stayed 13 months (April 23, 1984 - May 31, 1985) in Dr. R. F. Ozols' section, DCT, NCI, in order to study basic research for overcoming anthracycline resistance.
2. Dr. Toshitada Takahashi visited the Memorial Sloan-Kettering Cancer Center in New York (October 8-23, 1984) in order to discuss the current research status of monoclonal antibody with Dr. H. F. Oettgen and Dr. L. J. Old. He then visited the Virginia Mason Research Center to meet Dr. M. A. Bean in order to discuss applications of monoclonal antibody in an autologous bone marrow transplantation setting.
3. Dr. Tohru Masaoka visited Dr. E. D. Thomas at the Fred Hutchinson Cancer Research Center in Seattle (February 3-17, 1985) in order to discuss current problems with bone marrow transplantation.
4. Dr. Taketo Mukaiyama stayed in Dr. Housman's laboratory in Massachusetts Institute of Technology in Boston (November 6, 1984 - February 5, 1985) in order to study the mechanism of drug resistance and thereafter visited Dr. D. D. Von Hoff, University of Texas at San Antonio to discuss human tumor assay.
The last report was given by Dr. Miller on the area of interdisciplinary studies.
The Interdisciplinary Program continues to stimulate ideas through its workshops by focusing on areas in which the two countries differ greatly--disease frequency or in approaches to research.
A series of workshops on the role of pathologists in cancer etiology was extended during the past year by a meeting on the etiologic importance of studying cancer by subtypes. The workshop was held on October 16-17, 1984, at the East-West Center in Honolulu.
Even when cancers were classified grossly by location within an organ, important differences were noted between U.S. Caucasian and Japanese patients. Differences also were marked when other ways of subclassifying cancer were used--by tissue patterns, cytohistology, histochemistry, antigenic response, cell surface markers, etc. Epidemiologically, cancer can be subclassified by demographic or ethnic characteristics or excessive occurrence in high-risk groups.
The workshop had three components. One concerned the organ affected, the second concerned clinical and epidemiologic aspects, and the third component concerned tumor markers through which subtypes can be recognized.
Dr. Miller stated that criteria for pathological readings are changing, creating problems in retrospective and prospective studies. Dr. Sugano noticed that it is easier to classify Japanese lung cancer than the United States--the former is "classical" in presentation, the latter is "mixed" and "heterogeneous."
A workshop on adult-type cancers in patients under 30 years of age was held in Tokyo on March 11-13, 1985. The purpose was to seek new understanding of the etiology or pathogenesis of cancer through studying its occurrence at an earlier age than usual. When the workshop was first proposed, it was judged to be of special interest to the Nakasone Program, which provided funding for additional participants from both countries.
Prior to the workshop, participants from both countries prepared data from a variety of sources. A key source on the U.S. side was the Surveillance, Epidemiology and End-Results (SEER) Program of the NCI. The SEER data were remarkably filled with clusters that invite further study. The epidemic of Kaposi's sarcoma in the United States was detectable in 1981-82 in San Francisco, and DES-induced cancers of the lower female genital tract were apparently discernible in the data for this site. These observations lead to the belief that other clusters under age 30 within the data system also may be etiologically informative and may, in some instances, be due to the intrauterine exposure. From the Japanese side came the information that there are on the average about 550 deaths annually from stomach cancer in patients under age 30--eleven times the number of new cases diagnosed among whites in the United States according to the SEER data. The subtype of the cases in Japan is diffuse rather than intestinal, a surprising observation because the diffuse type was thought to have a constant rate worldwide.
The Tumor Tissue Registries at the Radiation Effects Research Foundation (RERF) in Hiroshima and Nagasaki provided data which may improve in the future when ascertainment is more complete and duplications have been excluded.
The existence of a thyroid cancer registry in Japan, unknown to the U.S. participants, led them to realize that identifying information for atomic bomb survivors could be matched against that for persons listed in the registry and thus improve estimates of the risk of thyroid cancer from radiation exposure.
The following Japanese scientists visited U.S. laboratories:
1. Dr. Naoto Aoki from Tokyo University, Department of Pathology, visited Dr. W. S. Robinson at Stanford University, Department of Medicine; Dr. Peters at USC Liver Unit; and Dr. Mason at Fox Chase Cancer Center. Dr. Aoki developed a collaborative program with Dr. DeTolla.
2. Dr. Kazuhiro Sogawa from the Cancer Institute spent April 1985 in the United States attending a workshop of P-450 genes and their regulations and then visited McArdle Laboratory scientists.
3. Dr. Yoshinori Urano, the University of Tokyo, spent two weeks with Prof. G. N. Stemmermann at the Kuakini Medical Center in Honolulu, Hawaii.

FUTURE PLANS
Twelve future seminars or symposia were envisioned: five in Japan and seven in the United States. Eighteen scientists will be involved in exchange visits; fifteen from Japan to the United States and three from the United States to Japan. A limited exchange of materials is being planned.
Planned Seminars in Etiology
1. "Oxidizing Agents in Relation to Chemical Carcinogenesis, " December 16-19, 1985, in Hawaii.
2. "Modifying Factors in GI Carcinogenesis," January or March 1986 (3 days), Tokyo, Japan.
3. "Risk Analysis of Carcinogenesis Factors," January or March 1986 (2 days), Hawaii.
4. "Oncogenes in Chemical Carcinogenesis", March 1986 (3 days), Hawaii.

Planned Seminars in Biology and Diagnosis
1. "Analysis of Host's Antitumor Immune Responses Responsible for Tumor Protection In Vivo, " November 10-12, 1985, Kyoto.
2. "Cell Surface Markers" January 31 - February 3, 1986, Sapporo.
3. "Topics in Gene Expression Related to Cancer," February 1986 (2 days), Hawaii.

Planned Seminars in Treatment
1. "Recent Development of Combined Modality Treatment, October 11-12, 1985," Tokyo (symposium)
2. "Clinical Trials Methodology: Chemotherapy and BRMP, " January 1986 (32 days), Hawaii.
3. "New Drug Development and Regional Chemotherapy, " March 1986 (3 days), Bethesda, Maryland.

Planned Seminars in Interdisciplinary Area
1. "Epidemiological Studies of Cancer in Southeast Asia Countries, " December 12-13, 1985, Hawaii.
2. "Bladder Tumors, " March 1986 (2 days), Nagoya.

Proposed Exchange of Scientists

Tasks were assigned next for the editing and publishing of the Annual Report.
Drs. Omata and Sakurai left this program. Their contribution to the program was great and should be noted in the report.
The date and site of the next meeting was selected. It was agreed to meet in Anchorage, Alaska during the dates listed in descending order of priority:
June 26-27, 1986 (top priority)
June 19-20, 1986
June 12-13, 1986
The meeting was adjourned at 4 p.m.