FIRST JOINT MEETING FOR THE U.S.-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM

AGENDA

MAY 14-15, 1974
QUEEN KAPIOLANI HOTEL
HONOLULU, HAWAII

PARTICIPANTS

MAY 14-15, 1974 HONOLULU, HAWAII

MINUTES

MAY 14-15, 1974
HONOLULU, HAWAII

The first joint meeting of the Japanese and the American Scientific Advisory Groups for the U.S.-Japan Cooperative Cancer Research Program was convened at the Queen Kapiolani Hotel in Honolulu, Hawaii. The meeting was opened at 9:15 AM, May 14, 1974, with an informal ceremony for the signing of the Agreement for Cooperation in Cancer Research by Mr. Kiyoshi Okano, Executive Director, Japan Society for the Promotion of Science (JSPS) and Dr. Guy R. Newell, Deputy Director, National Cancer Institute, representing their respective governments and sponsoring organizations.
The business session was called to order at 9:30 AM by Dr. Newell, Acting Chairman for the first day of the meeting. Dr. Gregory T. O’Conor provided information to the participants on the administrative and staff support for the assistance of all participants during the meeting.
Dr. Newell welcomed the members of the Japanese delegation, the American delegation and also the observers: Dr. Richard C. K. Lee, University of Hawaii; Dr. Grant Stimmerman, and Dr. Hirohata of the University of Hawaii Cancer Research Center. Dr. Newell then read a letter from Dr. Frank J. Rauscher, Jr., Director, National Cancer Program, National Cancer Institute, and then presented the letter to Dr. Haruo Sugano, Director, Cancer Institute, Chairman of the Japanese delegation. Dr. Rauscher expressed his regret and disappointment in being unable to participate at this first meeting due to his important duties in appearing before the Senate Appropriation Subcommittee to testify on behalf of the National Cancer Program. He also wished the group a successful meeting.
Dr. Newell extended his personal welcome to Japanese delegation as well as to the American group. He expressed his deep interest in the commencement of the U.S.-Japan Cooperative Cancer Research Program to formalize and to strengthen the tradition of cooperation in cancer research which has been in effect for many years on an informal basis. He expressed his hopes and wishes that the future would bring about an extensive, period of cooperation and collaboration in a medical field important to the world and all of mankind.
Dr. Sugano responded by expressing his thanks for the meeting arrangements and welcomed the opportunity to participate at an auspicious occasion to formalize the Cooperative Cancer Research Program. He stated that all the Japanese scientists have high hopes for the future of the Program. He gave a brief report on the evaluation of the Program which began with informal discussions among Japanese and American cancer researchers. He expressed special recognition and thanks to Dr. O’Conor and Dr. Yoji Ikawa, Secretary, JSPS Scientific Group, for their individual efforts in initial discussion of the program in 1972 and the signing of the Memorandum of Understanding in September 1973.
Dr. Sugano introduced the members of the Japanese delegations. He was then followed by Dr. Newell in introducing the NCI delegation and other participants and observers.
Dr. O’Conor provided background information leading to the signing of the Agreement, which is a more formal document but included all the substantive portions of the original Memorandum of Understanding. The Agreement calls for the mutual exchange for a 5 year program of scientific information, materials and personnel, related to cancer research. The Agreement would strengthen and enhance the on-going collaboration and add new program areas for future cooperation.
Dr. Sugano made a brief presentation on the cancer effort in Japan. There have been discussions for many years to formulate a National Cancer Program in Japan and he expressed the Japanese interest in the U.S. National Cancer Program. The greatest portion of cancer research in Japan is supported by the Ministry of Education and the Ministry of Health and Welfare. He then turned the detailed discussion to Mr. Okano and Mr. Genkichi Hara of the JSPS, who were formerly with the Ministry of Education.
Mr. Genkichi Hara of JSPS, former Science Adviser of the Ministry of Education of Japan explained the Japanese national systems to encourage cancer research. The support of cancer research has been an organized entity since 1958, when Dr. Tomizo Yoshida and other prominent cancer researchers recommended that special grants program be supported by the Ministry of Education. The Ministry of Health and Welfare has joined in the support since 1966. In order to eliminate duplication of support, there was general agreement between the two Ministries that the Ministry of Education (Mombusho) would be responsible for the support of basic cancer research, eg. carcinogenesis, virology, etc. by means of research project grants to groups of scientists and individual scientists. The special cancer research grants programs were primarily for cooperative group grants and inter-institutional grants, which provided larger sums of monies for group or cooperative research. All of these types of grants were investigator initiated and reviewed by special peer groups before awarding by the Ministry of Education. There were 80 group or cooperative cancer grants in 1973, covering pathology, biochemistry, carcinogenesis, immunology, virology and chemotherapy. These grants involve approximately 1,000 individual scientists. Dr. Ikawa further explained that approximately $3.6 million (U.S.) was available for the grants supported by the Ministry of Education. The grants do not provide any salary support and funds may be used only for equipment, supplies and other direct costs, which are added to the ordinary support from the host institution to encourage a scientist of a certain project area. It is estimated that the Japanese Cancer Association has over 4,000 members, including 1,000 senior scientists and approximately 3,000 junior scientists. It was stated that about 60% of the senior scientists and many of the younger scientists have had research experience in the United States.
The Ministry of Health and Welfare (Koseisho) provided approximately $3 million (U.S.) in 1973 to support 34 programmed grants. These grants are based on specific program interests of the Ministry and are usually in clinical and applied cancer research, i.e. patient or treatment oriented projects, ranging from cancer chemotherapy, diagnostics and environmental factors causing cancer.
Dr. Newell presented a brief explanation and background of the NCI National Cancer Program of 1971, which by legislation provides for the intensification, promotion and coordination of national effort for the conquest of cancer. At the present time, the National Cancer Act is undergoing revision and amendment of the original Cancer Act of 1971. He stated that the U.S. Congress has a deep awareness of the National Cancer Program and has provided a mandate to expand international programs in cancer research, ostensibly for the sharing and exchange of information and knowledge for the conquest of cancer. The National Cancer Plan calls for the support of research, cancer control, and rehabilitation and the 1974 revision will further expand the scope of the general plan to cover research and development in the cancer fields and the application of the developed information for treatment, control and prevention. The purpose of the Program is to support the above mentioned broad areas related to cancer and has provided for flexibility to plan for changes in future years as new leads and ideas evolve. Therefore the Program provides for a dynamic strategy and not a rigid program which may stifle research. He also provided some information on the support of cancer research outside of the governmental agencies, such as the American Cancer Society and other private and public charitable organizations. The total NCI Program calls for $600 million for FY 1974 and $700 million for FY 1975. It is estimated that the private and public sector provided between $140 to $180 million for cancer in 1973.
The general organization of the National Cancer Institute has been organized on a programmatic basis to meet the general research objectives: Cause and Prevention; Detection and Diagnosis; Treatment and Cancer Control (Rehabilitation). Under these general objectives concerted efforts have been placed on research in environmental factors, nutritional factors, epidemiology; immunology, viral oncology, cancer therapy, prevention or treatment, and rehabilitation.
Dr. Arthur C. Upton, who recently served on a special NCI Committee to revise the strategic plan, stated that there are no major changes, but placed emphasis on new approaches and objectives and on the elimination of unproductive avenues of research. He stated that there will be need for continuing review and evaluation and felt that program progress review should be made every 18 months for optimum results. The special committee reiterated the importance of an adequate NCI training program for producing research scientists.
Dr. O’Conor gave a brief presentation on the NCI international activities, reporting on the bilateral programs, i.e.: US-USSR Program, the new US-Japan Program, the pending agreements with Poland, Argentina and The Netherlands. He also reported on the NCI activities in the international organization, namely World Health Organization, International Union Against Cancer, and the International Agency for Cancer Research. A brief description of the International Cancer Research Data Bank was given and the prospective expansion of its activities with contracts for the compilation of international data on cancer research.
Dr. J. Palmer Saunders, presented a brief history background of the NIH grants programs and the peer review system which were developed after World War II. The NIH and NCI grants programs, which are investigator initiated, were reviewed and awarded on the basis of scientific quality of project, capabilities of the investigator and relevance to the mission of the National Institutes of Health. During FY 1974, approximately $285 million will be obligated in NCI grants programs. This amount may be subdivided in the following categories:

1. Research Projects Grants. $219 million, including traditional research project grants, clinical trials, centers grants, planning grants, organ sites programs and foreign research grants, totaling $ 1.5 million.
   
2. Construction Grants. $36 million
   
3. Manpower Programs. $23.6 million
   
4. Control Programs. $7.0 million

Dr. James A. Peters gave a short presentation on the program interests of the Division of Cancer Cause and Prevention, including carcinogenesis, epidemiology, viral oncology and others. He provided some statistics on the incidence of various types of cancer and projections on the increase of certain types of cancer. He also discussed the contract programs of the Division and the interagency programs on cancer research, involving NCI and other Federal Agencies, such as the Food and Drug Administration and the Veterans Administration.
Dr. Nathaniel I. Berlin, Director, Division of Cancer Biology and Diagnosis, discussed the research programs of the Division, particularly cancer pathology, cancer diagnosis and cancer immunology. He stated that a number of foreign scientists were actively engaged in cancer research with senior NCI investigators under the NCI Visiting Program and that there are possibilities for young Japanese scientists to study as Visiting Fellows.
The Chairman adjourned the meeting at 1:00 PM for luncheon and reconvened at 3:00 PM

An open discussion was continued with Drs. Peters, Robert Miller, and Rulon Rawson, providing information on program interests in chemical carcinogenesis, environmental carcinogens, viral oncology, and epidemiological field studies.
The areas of cancer biology and diagnosis were briefly discussed by Drs. Berlin, William Terry and Palmer Saunders; while the areas of cancer treatment were discussed by Drs. Oleg Selawry and George Bryan.
Dr. Takashi Sugimura presented a resume of the interests of Japanese scientists in chemical carcinogenesis and the research being conducted in Japan. The areas discussed were research in carcinogenesis in human and experimental animals; food additives, such as the nitroso-compounds as possible carcinogens; the study of clinical models for tumor formation ; and chemotherapy. Considerable effort has been made in the study of cell transformation and the identification of tumor cells.
An area of great interest is the possibility of agents blocking tumorgenesis. Drs. Bryan and Sugimura presented information on their collaborative efforts on the nitroso compounds as carcinogens, with several joint publications resulting from the collaboration.
Drs. Yohei Ito and Yoji Ikawa spoke on the current research activities in viral oncology. Dr. Ito has been the principal investigator on an NCI contract and has been collaborating with Drs. John Moloney and Paul Levine for several years.
Dr. Takeshi Hirayama expressed Japanese interests in comparative demography and the incidence of different types of cancers. He mentioned the Japan-Hawaii Program and the need for more studies in migrant groups. He stated that the Japanese population was approaching the U.S. pattern of cancer types and incidence. He pointed out a collaborative effort was being carried out in comparative analytical epidemiology with exchange of findings on all types of cancer, including childhood cancer, Leukemia and other malignancies. He also pointed out some differences in the incidence of lung cancer between the two population groups.
Dr. Robert Miller reported on studies of high-risk families, developing diagnostic methods for laboratory findings which portend high-risk populations, extension of family studies on Japanese population, and detection methods for viruses, physiological abnormalities and finding new syndromes for different cancer types.
Dr. Rulon Rawson discussed the opportunities for studies in high and low risk populations and the need for more comparative studies on diets, gut flora, and other factors, particularly in view of recent findings of correlation between beef consumption and colon cancer. He also expressed his interest in therapy programs, cooperative epidemiologic studies on transplacental factors, and the study of the metabolism of hormones, particularly steroids, estrogens and prolactin.
Dr. Berlin further discussed the program interests of the Division of Cancer Biology and Diagnosis and the opportunities for guest workers, visiting scientists and cooperative research in the various branches which include the basic sciences groups and the clinical research groups. He reported on the intramural research activities and contracts supporting the Breast Cancer Task Force, which includes epidemiology, biology diagnosis and treatment. Considerable effort is being placed on cancer diagnosis, including immunology, biochemistry and cytology. He expressed particular interest in automated instrumentation for scanning cytologic specimens. He mentioned the use of fiberoptics in cooperation with Dr. Ikeda of the National Cancer Center and other Japanese, who have developed specialized fiber optic techniques. He would encourage more cooperation in developing diagnostic methods for the Organ Sites Programs.
Dr. Yuichi Yamamura discussed the interests of Japanese workers in immunotherapy. He briefly mentioned the investigations of Dr. Hirai at Hokkaido University on alpha-feto-proteins. He also alluded to the high incidence of liver cancer in Japan and the need for reliable diagnostic methods. He also mentioned the investigations in radioimmunoassay techniques and the need for obtaining purified antigens for these studies. Enzymatic studies were being made for diagnostic markers. In immunology, considerable effort is being placed on the study of immuno-potentiation of lipoproteins in BCG and thymus cells in cancer immunology. At the end of May, a conference in cancer immunotherapy was being held in Hokkaido.
Dr. William Terry stated that NCI was making special efforts in immunobiology, immunodiagnosis and immunotherapy. The following areas are being investigated by the NCI staff and other American scientists:

1. Tumor associated antigens-cell surface studies-the nature of response to tumor cells and the nature of tumor antibodies.
   
2. Genetics of tumor cells.
   
3. Nature of immune mechanisms.
   
4. Immunotherapy-effects of BCG and adjuvants.
   
5. Immunogenicity of tumor cells, modification of tumor cell surfaces and study of soluble factors for cell transformation.

Dr. Terry mentioned his concern regarding other Japanese scientists who are potential collaborators in immunology and may not be represented in the existing research groups. He encouraged the seeking out of active researchers.
Dr. Tadashi Yamamoto expressed considerable interest in anti-tumor antigens and he welcomed the opportunity for cooperation in the exchange and the standardization of sera from cancer patients. Dr. Miller mentioned the existing registry for immuno-deficient diseases which is available for use.
Dr. Haruo Sato spoke on the activities of his research group and others, who are investigating the mechanisms of metastases. His group has been particularly interested in the rep4ir of cells of the primary sites, lodgement of tumor cells, animal model systems and tumor immunology. He stated that time is rapidly approaching for a conference and would like to propose a milieu for the exchange of information and materials on experimental tumors such as strains of metastatic cells. He stated that tumor immunologists are becoming more interested in metastasis and its immunologic aspects.
Dr. Ikawa briefly spoke on the low incidence of breast cancer in Japan and that there are 15,000 registered cases in the Japan Mammary Cancer Society. This society is made up of pathologists and surgeons who have developed an extensive registry and an excellent manual for diagnostics and treatment. Dr. Grant Stimmerman, Observer from the University of Hawaii, briefly mentioned the Japan-Hawaii studies on breast cancer, a cooperative study with Japanese scientists on endocrinological investigation on steroids, and protein hormones.
Dr. Berlin mentioned the NCI Program on Therapy of Breast Cancer, using single and multiple agents studies for treatment, using steroid and estrogenic hormones and antibiotics as well as surgery and radiation. He expressed the need for comparative studies on breast cancer among American and Japanese women. These studies provide opportunities to approach the problems from many disciplines. He welcomed the Japanese scientists to attend the Breast Cancer Task Force conferences held several times a year. The next conference will be held in February 1975 with an emphasis on the virus studies in breast cancer.
Dr. J. Palmer Saunders expressed the developing interest in the Research Grant Programs on Radiation Therapy. He mentioned that the English groups at Hammersmith Hospital and the Medical Research Council have done some studies on the effectiveness of therapy with fast neutrons. The U.S. Atomic Energy Commission and others at Chicago, Cleveland and New Mexico have been doing some preliminary radiation therapy studies. He stated that cooperation was needed in obtaining sufficient numbers of cases for trial studies. It is anticipated that economical equipment and methods may be developed with input from Japanese and American nuclear physicists and engineers.
Dr. Yamamoto mentioned that there has been very little activity in Japan in high energy radiation therapy; however, there are three major institutions where high energy radiation systems have been installed. The scientists in those institutes have high interest in radiation therapy and radiation hazards. It is desirable that a high energy radiation program be developed in the future.
Dr. Arthur C. Upton reported that Dr. Takahashi has reported on the cure vs. risk studies on radiation exposure in treatment of stomach cancer. Dr. Hirayama felt that cure-risk studies might be initiated. Dr. Selawry mentioned reports on thymic radiation causing chromosomal damages.
Dr. Selawry then reported on the activities of the Division of Cancer Treatment, NCI, in the area of Cancer Chemotherapy, and the cooperative activities with the Cancer Chemotherapy Center in Japan. The current interests in cancer treatment are centered on drug screening, comparative clinical studies and combined modality studies. At present combinations of surgery, radiation, immunotherapy and chemical therapy are being studied in the treatment of breast and lung cancer.
Dr. Yoshio Sakurai expressed considerable interest in cooperative studies in drug testing, experimental therapeutic trials and standardized drug testing for comparative studies. At the present time, there are four research groups screening new anti-tumor drugs, including some 600 synthetic compounds and antibiotics from fermentation products. The present testing is done on mouse leukemia and Yoshida sarcoma and ascites hepatoma system. Also, derivatives of nitroso compounds with strong activities are being tested. There is need for comparative clinical trials and quantitative evaluation studies. There is a great need on an international scale, for Phase I and 11 studies, cooperative evaluation studies, comparative clinical standards, and information exchange.
Dr. George Bryan mentioned the increased activities and interests in Organ Sites Programs, such as the prostatic gland, colon and large bowel and bladder. He has been deeply involved in the National Bladder Cancer Program in the development of comprehensive studies on detection, prevention, therapy and rehabilitation. There are presently 35 institutions collaborating in the Program. The Japanese have begun a clinical studies group on bladder cancer and have contacted Dr. Bryan’s group for information and for exploring possibilities for cooperation. Dr. Bryan stated that the NCI supported group would like to develop better relationships with the Japanese group and possibly invite them to attend the annual meeting of program directors.
Dr. Miller stated that bladder cancer studies would be a very good project area for the study of environmental and occupational factors. Although bladder cancer is rare in Japan, there is an excellent opportunity for comparative epidemiologic investigations.
Dr. Upton stated that the foregoing discussion brought out many areas of mutual interest and areas of potential interest. He believes that the biggest problem would be in selecting appropriate areas for cooperation.
Dr. Newell requested that Drs. O’Conor and Ikawa have an evening session to discuss some of the program areas which should be brought up for further discussion at the morning session.
The meeting was adjourned at 6:00 PM by the Chairman.
A dinner party for the Japanese participants was hosted by the NCI Scientific Group in the Peacock Room, Queen Kapiolani Hotel at 7:30 PM.

The meeting was called to order by Dr. Sugano at 9:00 AM, May 15, 1974, for the continuation of discussion and the selection of program areas for cooperation.
Dr. O’Conor reported on the meeting with Dr. Ikawa on the project areas of mutual interest. A list of 11 program areas was presented to the group for further discussion. It was pointed out that although a larger number of areas was being presented, it is anticipated that some areas would be very active while others may take longer to develop after further discussion and exchange of information.
Dr. Newell stated that the original intent was to make a decision on at least 5 and no more than 10 areas for cooperation. A larger number could create many difficulties and may cause very superficial coverage in program content.
A discussion ensued on the manner by which personnel exchanges and resources and materials exchange would be implemented as separate items or as part of the program areas. The Japanese Group expressed their views that personnel exchange was a very important part of their program, particularly the exchange of senior investigators on short-term basis and young scientist on long-term basis. The sharing of research experience in different laboratories would be a very stimulating experience as well as medium of exchange of information. Several of the American participants endorsed the activity of personnel exchange and would encourage American scientists to study in Japanese laboratories to acquire new ideas and perspectives, particularly senior investigators.
The NCI has the NIH Visiting Program available for young investigators or fellows; however, appointments at the senior levels would be limited and restricted due to personnel ceiling, but senior scientists could be invited as guest workers at NCI, with support from other sources. Dr. Upton stated that it would be somewhat difficult for American universities and institutions to invite and support visiting professors due to lack of funds and positions; and therefore, they would have to seek supplemental funding from non-institutional sources. There was a general consensus that some mechanism for funding should be available, particularly for the American scientists. The JSPS will have some funds available for the support of Japanese scientists this year.
Drs. Newell and O’Conor encouraged the group to promote the use of seminars and exchange of information initially in order to implement the cooperation.
Dr. Berlin commented on the language problems among the Japanese visiting scientists at NIH. Dr. Ikawa explained that Mr. Hara will be coordinator for the exchange of personnel, and will check the ability of speaking, reading, and writing English of the Japanese scientists to be sent to the U.S. under this program, and that Dr. Yamamoto will be coordinator for the exchange of materials to work cooperatively with the coordinator of each project area for joint activity to endorse the arrangement of exchange of materials.
Dr. Terry presented his views on the inclusion of scientists from other nations at some of the U.S.-Japan meetings for a more productive exchange of information. He also feels that there are many scientists who are not members of any organized groups who should be invited to participate in the cooperative programs.
Dr. Ikawa expressed his feeling that a language barrier might well exist between the program coordinators and that he would like to ask for forebearance and patience on the part of the coordinators.
Dr. Newell reviewed Section 2 of the Agreement to call attention to the role of the members to define program areas and to nominate and select the program coordinators. He recommended that the matter of personnel and resources exchanges be the responsibility of the program coordinators and these items should not be separated but be included as means of implementing programs for each of the project areas. There was general agreement and endorsement by all of the participants that personnel and resources exchange should not be fragmented and separated from the specific project areas. Mechanisms for the exchange programs would be further explored and made available.
The list of Program Areas was brought up for discussion by Dr. O’Conor. Subsequently, Drs. Sugano and Newell nominated the respective coordinators for the Program Areas.

1. Chemical Carcinogenesis - Dr. Takashi Sugimura and Dr. Arthur C. Upton. Program area to include: development and standardization of screening methods, studies on specific compounds, mechanism of carcinogenesis, and large animal model studies.
   
2. Cancer Virology - Dr. Yohei Ito and Dr. Charles A. Evans. Program area to include: mechanisms of viral carcinogenesis and human cancer virus studies.
   
3. Cancer Immunology - Dr. Yuichi Yamamura and Dr. William Terry. Program area to include: diagnostic methods, immunotherapy and immunobiology.
   
4. Cancer Therapy - Dr. Yoshio Sakurai and Dr. Stephen K. Carter. Program area to include development of new drugs and Phase I and II studies.
   
5. Analytical Epidemiology - Dr. Takeshi Hirayama and Dr. Robert W. Miller. Program area to include: metabolic studies, high risk group studies, multiple case families, and occupational groups.
   
6. Breast Cancer - Dr. Haruo Sugano and Dr. Nathaniel I. Berlin. Program area: multidisciplinary studies.
   
7. Lung Cancer - Dr. Takeshi Hirayama and Dr. Oleg S. Selawry Program area: multidisciplinary studies.
   
8. Urinary Bladder Cancer - Dr. Osamu Yoshida and Dr. George T. Bryan. Program area to include: comparative morphology -human and animal models, clinical study groups, and occupational risks.
   
9. High Energy Radiation - Dr. Takashi Sugimura and Dr. Frederick W. George Program area to include: equipment development, biological effects and pilot clinical trials.
   
10. Cytology - Dr. Haruo Sugano and Dr. Chester J. Herman Program area to include: exchange of information and automated instrumentation.
    
11. Metastases - Cancer Biology - Dr. Haruo Sato and Dr. Philip G. Stansly Program area to include: exchange of information and materials.
    

During the discussion it was brought out by several of the participants that active collaboration and the exchange of information and material have been going on informally for many years and that this Program would greatly assist in increasing the flow of information and promote more cooperation among the scientists of the two countries. The formal invitation to the key coordinators would be forwarded to the nominees in the near future.
It was generally agreed the first review and evaluation meeting for the Joint Scientific Group would be tentatively scheduled for October 23 and 24, 1975 in San Francisco, California. At that time joint reports would be submitted by the program coordinators to the Joint Scientific Group to assess the activities of each of the program areas for the period. It would be appropriate to discuss other areas of mutual interest for inclusion in the cooperative program in the future.
Drs. Sugano and Newell expressed their appreciation to the participants for their advice, ideas, and recommendations to launch the Program. They expressed their hopes for fruitful and productive cooperation in the future. The meeting was adjourned at 1 1:30 AM, May 15, 1974.
A Luncheon for the U.S. and Japanese participants was hosted by JSPS at the Windjammer Restaurant of the Holiday Inn Waikiki.