MINUTES OF THE FOURTH ANNUAL JOINT MEETING

UNITED STATES-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM

Sponsored by the Japan Society for the Promotion of Science and the National Cancer Institute National Institutes of Health, Bethesda, Maryland October 31 and November 1. 1977

The meeting was called to order at 9:00 a.m., October 31, 1977, by Dr. Guy R. Newell, Deputy Director, NCI, and Co-Chairman of the Joint NCI-JSPS Scientific Group.

Opening Session:

In his opening remarks, Dr. Newell warmly welcomed the Japanese and American participants. He thanked the Japanese delegation for the warm reception and hospitality extended to the NCI Scientific Group at the Third Joint Annual Meeting held last year in Kyoto, Japan. He stated that he was particularly proud to be associated with this highly successful and productive program. This meeting denotes a landmark year, since the Program will enter into the fifth year of the Program. The Joint Scientific Group will have to reevaluate the total Program to continue improving the cooperation in the coming year. He extended wishes that the Japanese delegation have a very enjoyable visit in Bethesda and the Capitol Area.
Dr. Haruo Sugano, Director, Cancer Institute, and Co-Chairman of the Joint NCI-JSPS Scientific Group, expressed the appreciation and gratitude of the Japanese delegation for the warm hospitality extended to them. On behalf of the Japanese delegation, he extended to Dr. Arthur C. Upton, Director, NCI, heartiest congratulations on his appointment as the new Director. He stated that Dr. Upton has been the U.S. Program Coordinator for the Chemical Carcinogenesis Program Area since the inception of the Program in May 1974. He also thanked Dr. Upton for his very able management of the Program Area during the past three and one-half years and complimented him for his excellent presentation at the Scientific Session on Carcinogenesis in Kyoto last year.
Dr. Sugano has had great personal satisfaction from the progress of the Program, particularly from the standpoint of supporting excellent joint scientific meetings and the high quality of scientists from both of the countries involved in the exchange of scientists. He has been particularly pleased with the visits made by scientists prior to and after the planned meetings to present additional lectures and seminars at various laboratories. He has been impressed by the collaborations being continued by the Exchange Scientists after their visits to their respective countries. There have been a number of cooperative research projects and joint publications of scientific articles and monographs resulting from the visits and meetings. He hoped that the next year would be as productive as the past years.
He expressed his appreciation to Mr. Kichimasa Soda and Dr. Robert R. Omata for their efforts and contributions towards the administration of the Program.
Dr. Newell acknowledged the appointment of Mr. Soda as Chief, Science Department, JSPS, and expressed his gratitude for the excellent cooperation rendered by the JSPS staff in implementing the Program.
Dr. Newell presented Dr. Arthur C. Upton to the Joint Meeting.
Dr. Upton expressed his appreciation for the warm reception from the joint delegation and for the excellent cooperation he has received from all of the Japanese and American scientists who have been involved with the Program. He expressed his desire that the Program will continue to flourish and to succeed in meeting the objectives of the Program. He particularly acknowledged the many contributions and collaborations resulting from the Program. He pledged his firm support for the continuation of the successful Program. In conclusion, he extended his best wishes to the scientists for a successful meeting. He also expressed his hope that the Japanese delegation would have a most enjoyable visit to the National Institutes of Health (NIH) and the Washington area. In spite of his extremely busy schedule, he hoped that he would be able to attend the first day of the meeting.
Dr. Newell stated that since Dr. Upton has a prior commitment, the Agenda would be rearranged to have Dr. Upton and Dr. Sugimura present the Chemical Carcinogenesis Annual Report at 11:00 a.m.
Dr. Omata announced the reception and dinner honoring the Japanese delegation at 7:00 p.m. on October 31st and the tour of the White House on November 2nd. The following observers were introduced: Dr. Hayashi and Dr. Schmale from the Environmental Protection Agency; Dr. Takayama from the Cancer Institute, Tokyo; Dr. Saul Schepartz and Dr. Abraham Goldin, Division of Cancer Treatment, NCI; Mr. Nakajima and Mr. Sawamura from the Embassy of Japan; and Drs. Kakunaga and Kakefuda, Division of Cancer Cause and Prevention, NCI.

Breast Cancer Program Area:
Coordinators: Dr. Haruo Sugano and Dr. Nathaniel I. Berlin.

Dr. Yoji Ikawa was asked to present the Annual Report for the Breast Cancer Program Area, since Dr. Nathaniel I. Berlin was unable to attend the meeting.
Dr. Ikawa presented a resume of the activities for the current year outlining the highlights in the Program Area. He specifically mentioned: (1) the meeting on Breast Cancer Epidemiology and Diet which was held at the Fred Hutchinson Cancer Center in Seattle, Washington, on March 14-15, 1977, organized by Dr. Takeshi Hirayama and Dr. Guy R. Newell; (2) Dr. William Hartmann, Vanderbilt University, visited Japan as an Exchange Scientist; in addition Dr. Goi Sakamoto is spending six months with Dr. Hartmann as an Exchange Scientist to engage in collaborative activities on the comparison of the histopathology of breast cancer in Japan and in the U.S.
A future meeting on the Hormone Receptors in Breast Cancer is being planned to be held in Hawaii in March 1978. The meeting is being organized by Dr. Haruo Sugano, Dr. Keishi Matsumoto, and Dr. William McGuire.
Dr. Hirayama stated that as a result of the meeting on Epidemiology and Diet in Seattle, several of the papers presented at the meeting will be published in Preventive Medicine at the urging of Dr. Ernst Wynder.
There was discussion on the comparative histopathology on borderline cases and the mass screening of early stages of mammary cancer in the United States. There is considerable controversy in the U.S. regarding the use of mammography, the problem of risk-benefit, and the potential hazards involved in breast cancer detection. It would be advantageous to develop some nonhazardous methods for the detection of cancer, either biochemical tests, ultrasonics, or other new technology. There is a great need for precise diagnostic methodology for detecting cancerous, minimal cancers, and precancerous lesions. It was brought out that mammography is not widely used in Japan. Extensive discussion ensued on hazards of radiation dosage for mass screening, for instance, for gastric cancer, of a large number of the population. This is an area of considerable interest in the U.S. and other parts of the world because of the medical and legal problems associated with diagnosis, detection, and treatment of borderline cases and early cancers.

Cancer Therapy Program Area:
Coordinators: Dr. Yoshio Sakurai, Dr. Stephen K. Carter, and Dr. Franco Muggia.

Dr. Stephen K. Carter began the discussion by stating that this past year had been particularly active in view of the long-standing relationship between Japanese and American clinical oncologists. The Japanese had developed two very effective drugs, Mitomycin C and Bleomycin, which are being used quite extensively both in Japan and in the U.S. There has been a resurgence of interest in intermittent dosage and combination drug treatment with Mitomycin C in the U.S. for use in the treatment of gastric cancer, pancreatic cancer, and adenocarcinomas of the lung. Bleomycin has been used in the treatment of testicular cancer with very high cure rates in Japan. Other new drugs developed in Japan, namely Neocarzinostatin, Macromomycin, and Aclacinomycin are now being tested in both countries. The Cancer Therapy Program Area will continue to be a very exciting and productive area for continuing cooperation.
During the past year, a Symposium on Antitumor Antibiotics, organized by Drs. Sakurai, Umezawa, Carter, and John Douros, was held in San Francisco in May. It was a successful meeting reviewing the status of various antitumor antibiotics. Discussions were held on the preclinical testing and early clinical studies on Bleomycin, Anthocyclines, Mitomycin, and other antibiotics being used in both countries. Papers from this symposium will be published by Academic Press.
Another aspect of the current year’s activities is the establishment of the Joint Clinical Studies on the treatment of gastric cancer by the Northern California Oncology Group of the Northern California Cancer Program (NCCP) and several Japanese cancer centers, and just recently joint protocols have been drawn up to initiate the studies using different combinations of drugs for treatment, such as the Adriamycin, CCNU, and Ftorafur (U.S. side) and the combination of Adriamycin, Ftorafur, and Mitomycin C (Japanese side). Other areas of cooperation in treatment will be developed in the future. This cooperation was initiated by an earlier exchange of U.S. scientists under this Program for the survey of treatment of gastric cancer in Japan. Since then, the Japanese scientists have been involved in the U.S. Gastrointestinal Tumor Study Group because of great mutual interest. This collaboration should be advantageous in comparing the similarities in types of gastric cancer and treatment. The cooperation is being supported from the general NCCP funds partially funded by the NCI. On the Japanese side, domestic funds will support their clinical studies.
There was discussion on the activity of various analogues of the better known drugs and antibiotics as to their toxicity. Some time was spent on the mechanisms of action of some of the drugs. Dr. Carter brought out the problem of secondary tumors associated with the long-term use of antitumor drugs. This problem needs to be closely studied in the future. New methodologies will need to be developed.
A group of American scientists, including Dr. Carter and Dr. Abraham Goldin, NCI, have been invited to the Eighth International Symposium on Cancer Chemotherapy, sponsored by the Princess Takamatsu Cancer Research Foundation, to be held in Japan in November 1977.
A future meeting for Program review and a review of the Phase I new drugs studies in Japan and the U.S. will be held in Japan in late spring of 1978.

Chemical Carcinogenesis Program Area:
Coordinators: Dr. Takashi Sugimura, Dr. Arthur C. Upton, and Dr. I. Bernard Weinstein.

Dr. Upton stated that the Program Area had a very productive year and thanked Dr. Sugimura for his excellent leadership in program planning. The highlight of the year was the Conference on Polycyclic HydrQcarbons organized by Drs. Harry Gelboin of NCI, Paul Ts’o of Johns Hopkins University, and C. Nagata of the National Cancer Center Research Institute, Tokyo. The meeting was held in New Orleans in January 1977.
The purpose of the conference was to discuss the various aspects related to the carcinogenic effects of the polycyclic hydrocarbons. Main emphasis was placed on the benzopyrene as well as on the multidisciplinary approach to the study of the effects of polycyclic hydrocarbons. This conference clearly indicated the existence of a great wealth of information about polycyclic hydrocarbon carcinogenesis. In fact, of the extensive research on all of the known carcinogens, the research on polycyclic hydrocarbons is probably the most extensive and thorough. In addition, momentum appears to be gathering in the research on this area, which will result in even greater progress. The research on polycyclic hydrocarbons can become the model for research on other carcinogens.
Continued surveillance should be made in uncovering unknown carcinogens in the environment. Also, additional efforts should be made to solve or reduce the problems created by the known carcinogens. In view of the acute energy crisis and the close relationship of polycyclic hydrocarbon carcinogenesis to energy consumption and production, the research on hydrocarbon carcinogenesis may provide vital information needed to make proper decisions on energy.
It was reported that the presentations at this conference will be published in the near future by the Academic Press.
The activities of the several Exchange Scientists were reviewed. During the past year, personnel exchanges were complementary and quite productive. Long-term visits are always important for yielding fruitful results; however, previous arrangements between visitors and sponsors are crucial for success and productivity. Short-term visits to several laboratories by individuals were not recommended.
The exchange of valuable and interesting antiprotease inhibitors, supplied by Dr. H. Umezawa, has initiated a new and promising area of research in studying cell mutation, tumor initiation, and cellular enzymology.
Dr. Sugimura stated that from the standpoint of the Japanese participants at the Polycyclic Hydrocarbons Conference, it was a great success. A meeting is being held on the DNA Repair and Misrepair in Carcinogenesis by Chemicals and Radiation in December 1977, in Kyoto, Japan.
After the formal presentation of the Annual Report, there was an active discussion on cell mutation, DNA damage and repair, and cell transformation in the course of events initiating carcinogenesis, and on the possible effect of some of the antiproteases on the events occurring in cell mutation.

Cancer Virology Program Area:
Coordinators: Dr. Yohei Ito and Dr. Robert M. McAllister.

Dr. Ito began the discussion with a resume of the year’s activities in the Program Area. He presented a brief summary of the Symposium on the Origin and Function of Oncogenic Sequences in RNA Tumor Viruses, which was organized by Drs. Ito and McAllister and held in Pasadena, California, in May 1977. The meeting was an assembly of several of the leading cancer virologists from Japan and the United States to discuss the rapidly developing information on the molecular biology and genetics of the RNA tumor viruses in animals. The meeting was successful in provoking active discussion on the latest developments in the field. It also made it possible to continue collaborative research on viral oncology.
Dr. Ito also briefly discussed the activities of the Exchange Scientists, making it possible for several highly regarded scientists from both countries to visit other laboratories and present seminars and lectures. In addition, several Japanese virologists attended the Cold Springs Harbor Symposium, in conjunction with the Pasadena meeting. Related to this Program Area, several American scientists were invited to Japan by members of the Japanese working group to participate at the Conference on Epstein-Barr virus and a meeting on Friend leukemia virus, organized by Dr. Ikawa. The interaction between Japanese and American scientists has been greatly enhanced through the efforts of the Cancer Virology Program Area.
Dr. McAllister began a discussion on the role of type C viruses in the avian system and other animal tumor systems. The next area to be discussed at a future meeting will be the DNA viruses and the gene products. It will probably be held in May 1978, in Hawaii.
Dr. Newell called for a recess for luncheon and announced that the group would reconvene at 2:00 p.m.

High LET Radiation Therapy Program Area:
Coordinators: Dr. Akira Tsuya and Dr. Glenn E. Sheline.

Dr. Sheline, in the absence of Dr. Tsuya, led the discussion on the current year’s activities for the Program Area. The High LET Radiation Therapy Program has been particularly active with the exchange of six American radiobiologists to collaborate with the Japanese scientists to make some intercomparison on radiation dosimetry between the facilities in the U.S. and Japan. This phase of the program was very successful and thus led to the Workshop on High LET Radiation Therapy in September 1977 to discuss the results of the collaborative efforts and prepare for cooperative clinical studies. It was generally agreed that the equipment in both countries was comparable and that mutually agreeable clinical protocols should be drawn up for cooperative clinical studies. It was brought out that approximately 10,000 patients will need to be treated with high energy neutron radiation to accumulate meaningful data for comparative studies on effectiveness of treatment.
In addition, Dr. Sheline explained many of the complexities and high cost of the high energy equipment associated with clinical studies. Several questions were brought up by others for explanation. Since the essential groundwork has been laid for the intercomparison studies and establishing the treatment protocols, the collaboration on neutron treatment will be a continuing activity.
In the future, there are two areas which the Japanese and American scientists would like to explore: (1) radiation therapies, other than the high LET radiation therapy, and (2) the possibility of using the new group of radiosensitizing compounds for therapeutic use. There are a number of these compounds, but they are highly toxic. The problem of dosage and toxicity may be modified with the development and use of new analogues of the radiosensitizers.
A joint U.S.-Japan meeting is being planned to be held in the U.S. in June 1978, to continue the discussions on collaborative activities and to explore new areas of mutual interest.

Lung Cancer Program Area:
Coordinators: Dr. Yuichi Yamamura and Dr. Oleg S. Selawry.

Dr. Selawry briefly outlined the year's activities as presented in the Annual Report. He discussed the purpose and results of the Third Joint Seminar on Lung Cancer which was held in Beverly Hills, California in March 1977. At the seminar, six Japanese lung cancer specialists joined eleven Americans and two invited guests to discuss the multidisciplinary approach to the treatment of lung cancer. In the first session, the up-to-date morphologic classification of lung cancer was discussed as well as the reliability of cytologic diagnosis by cell type.
The remainder of the two-day meeting was devoted to immunotherapy with BCG cell-wall skeleton, tumor-associated antigens, immunoprognosis and therapy, as well as the treatment of small-cell carcinoma with radiotherapy and surgery. The open discussion on the multidisciplinary treatment was very lively. The problem of treatment of carcinomas of different cell types is a big topic among experts in the field of lung cancer. As a result of these discussions, a future meeting on multidisciplinary treatment and the current status of anticarcinogens will be organized in Hawaii in February 1978.
Dr. Selawry reported that the incidence of lung cancer is increasing worldwide at a rapid rate. Lung cancer leads with 24 percent of all types of cancer and it is estimated that within 20 years lung cancer will reach 51 percent of all cancers.
Dr. Yamamura reported that there has been an agreement among pathologists on the cytological classification of lung cancer types based on the WHO classification. He also reported that joint studies in treatment to prolong the life of patients with small-cell lung carcinomas have been initiated. Small-cell carcinoma is the most malignant type and treatment data would be most valuable. Immunotherapy from present information depends on the method of administration. This phase is being pursued by several Japanese oncological groups. The use of anticancer drugs will be an interesting area for study among high-risk groups, such as former workers in poison gas manufacturing, and these studies will be initiated.
Dr. Selawry stated that the use of retinoid compounds, derivatives of Vitamin A, is under trial but there are some toxic effects from administration. There are several retinoid analogues, such as 13-cis-retinoic acid, which show some promise. There was further discussion of randomized treatment studies and the problems associated with randomized studies.
It was noted that in May 1977, Dr. Yamamura, Dr. S. Ishikawa, and Dr. T. Naruke were invited to participate at the International Workshop on Treatment of Lung Cancer, sponsored by NCI, at the Airlie House in Virginia.

Cytology Program Area:
Coordinators: Dr. Kiyoji Kimura and Dr. Chester A. Herman.

Dr. Herman, in the absence of Dr. Kimura, presented the report for the Cytology Program. He stated that several positive results have transpired during this past year with the exchange of scientists under this Program. Dr. Tadashi Sugishita spent three months at the Los Alamos Scientific Laboratory to do some collaborative work in comparing specimens with the flow microfluorometric technique and the static slide scanning instrumentation. Later Dr. Phillip Dean spent two and one-half weeks in Japan to learn more about the tape transport method and the fiberoptic scanning of cells as developed by Japanese researchers. As a result, the new Japanese technique is currently under investigation in conjunction with the Livermore Laboratory flow system. Dr. Herman visited Kanazawa University to observe the CYBEST system developed by the Toshiba Company and made preliminary arrangements for the use of the specimen preparation technique developed by Drs. Weid and Bahr of Chicago and further refined by the Ames Company. The Ames technique will be tested in the CYBEST screener in the future.
The Joint Seminar on Automated Cytology, held in Hakone, Japan, in April 1977, resulted in the extensive exchange of up-to-date information on the development of cytology automation in Japan and the U.S. It has become obvious that the series of meetings and exchange of information and personnel during the past three and one-half years of the Program are now bearing fruit in the form of collaborative and cooperative protocols for development and testing that would have been impossible for either country alone. During the coming year, the collaborations will be continued and new efforts will be fostered.
A meeting in late 1978 will be planned to discuss the recent advances.

Scientific Session on Automated Cytology:
Dr. Herman presented a brief history of the development of automated cytology, beginning in 1968. Even at that time there were many similarities in the concept of automation. In Japan, efforts were targeted toward the image-processing and slide scanning system, while in the U.S., the cell-flow system was being developed. Since then, both systems were applied to specimens from cervical cancer, sputum, urine, and other body fluids and easily accessible specimens. Much effort was made toward using cervical squamous cell specimens since the histology for cervical cells had to be fully accepted by the medical specialists.
He further discussed pros and cons of the slide scanning image processing system and the cell-flow system in respect to the parameters and criteria used to distinguish cancerous, precancerous, and normal cells and the accuracy rate. It has become evident that the Japanese system and the U.S. system are merging and future collaboration will probably focus on merging the image processing and the flow systems.
The meeting was reconvened at 2:00 p.m. for the Scientific Session on Cancer Immunology (see page 94).
After the session, several groups of scientists were taken on a tour to observe the automated instrumentation and to observe several demonstrations conducted by Dr. Herman, Dr. Nishiya (Exchange Scientist, U.S.-Japan Program), and Dr. Alabaster.
The meeting was reconvened by Dr. Newell and Dr. Sugano at 9:10 a.m., November 1, 1977.

Bladder Cancer Program Area:
Coordinators: Dr. Osamu Yoshida and Dr. George T. Bryan.

Dr. Yoshida was asked to present the report for the Bladder Cancer Program. He stated that in September 1976 a very successful meeting on the Etiology of Bladder Cancer was held in Kyoto. The meeting was multidisciplinary with several clinicians, urologists, pathologists, epidemiologists, and molecular biologists coming together to discuss and exchange information and ideas. The purpose and goals of the meeting were defined: (1) to discuss and demonstrate knowledge and concepts concerning the etiology of human bladder cancer; (2) to attempt to evolve strategies for prevention or amelioration of carcinogenic influences; and (3) to explore opportunities for joint collaborative projects for future mutual development. The discussions during and after the presentations were vigorous and informative.
The subject of carcinogens in bracken fern as an etiologic factor in animal and human bladder cancer was one of the main topics for intensive and extensive discussion. A considerable amount of research on bracken fern is being conducted in Japan and several other countries. Other areas discussed were the genetic factors and bladder cancer; tryptophane metabolism and bladder cancer; and comparative histopathology on human cases in Japan and the U.S.
Dr. Bryan reported that the long-term scientist exchange of Dr. Samuel Cohen has been one of the highlights of the year’s activities, since he was very actively engaged in collaborative cancer research. It has been an extremely positive experience in cultural exchange as well as scientific productivity. Dr. M. Mochizuki’s visit to the Veterans Administration (VA) Hospital in Memphis, Tennessee, was also extremely productive and it will result in continuing collaboration.
Dr. Bryan discussed some of the problems encountered by Dr. Cohen during his stay in Japan. However, the reception by the Japanese scientists and the populous was very good. This long-term visit could serve as a model for young American scientists to gain experience in Japanese laboratories.
Dr. Bryan stated that many of the presentations given at the Kyoto meeting will be published as individual publications. In the future, meeting proceedings may be published as a monograph.
Plans are being made to organize a meeting on the integrated multidisciplinary treatment of bladder cancer.
As the result of the last meeting, several new collaborative bilateral efforts are being planned and are moving forward. The Bladder Cancer Program has been particularly gratifying to those who have participated, particularly to Drs. Yoshida and Bryan who have had the responsibility for organizing the Program. The results thus far have been very fruitful.
After the formal presentation there was virgorous discussion on the histopathology of bladder cancer, a bladder cancer in man and cattle caused by consumption of bracken fern, and a study of high-risk population, particularly industrial workers and heavy smokers in both countries. Dr. Bryan also reported on future studies on high-risk populations in Egypt, Turkey, and other countries.

Metastasis Program Area:
Coordinators: Dr. Haruo Sato and Dr. Philip G. Stansly.

Dr. Stansly reported on the year’s activities of the Metastasis Program. He stated that as an outgrowth of the U.S.-Japan Program, Dr. Sato, Dr. Eiro Tsubura, and Dr. Shigeru Tsukagoshi were invited to participate at the International Workshop on Cancer Invasion and Metastasis, Biologic Mechanisms and Therapy, which took place at the Rockefeller University, New York, in November 1977. The Workshop was sponsored by the Memorial Sloan-Kettering Cancer Center, Mario Negii Institute of Italy, and the National Cancer Institute. The proceedings will be published in the series on “Progress in Cancer Research and Therapy,” by Raven Press.
He also announced the publication of the Proceedings of the Workshop on Metastasis, sponsored by the U.S.-Japan Cancer Program, which took place in Hawaii in May 1976, as a monograph of GANN, published by the University of Tokyo Press. Copies were provided by JSPS and distributed to the members of the NCI-JSPS Scientific Group.
Dr. Stansly reported that the year’s program emphasis was placed on the exchange of scientists. Dr. Noritaka Kimura spent seven months with Dr. Joseph Leighton, Medical College of Pennsylvania, to collaborate and develop a model of in vitro metastasis.
A particularly notable event was the visit of Dr. Isaiah Fidler and Dr. George Poste to eight cancer research centers in Japan under the auspices of the U.S.-Japan Program. They visited the Cancer Chemotherapy Center in Tokyo, National Cancer Center Hospital, Kyushu University, Tokushima University, Kyoto Prefectural University Medical School, Akita University, Hokkaido University, and Tohoku University to participate as a team in seminars and workshops, and give formal lectures on cancer biology and metastasis.
As a result of the past meetings and exhange of scientists, it has been possible to strengthen the ties between Japanese and American investigators. In the future, the exhange of scientists will be encouraged and a meeting on the study of model systems and treatment of metastatic diseases is being planned for 1978.
Dr. Sato reported that there has been increased activity in investigation of the blood circulation in tumor and tumor sites. Model systems in animals are being used to study the blood flow and flow regulation in normal tissue and tumor tissues. Data may be of considerable interest in the treatment of cancer and metastasis in experimental animals.
During the discussion period there were several questions brought up regarding model systems for metastasis and metastasis treatment research.

Analytical Epidemiology Program Area:
Coordinators: Dr. Takeshi Hirayama and Dr. Robert W. Miller.

Dr. Miller reported briefly on the results of the Workshop on Cancer Epidemiology held in Tokyo, October 1976. The participants were from various areas of cancer research, epidemiology, and statistics. As a result of the exchange of morbidity and mortality tables and charts, Dr. Hirayama edited a monograph on “Comparative Epidemiology of Cancer in the U.S. and Japan: Mortality.”
Topics that were discussed at the Workshop were the review of recent developments in the etiology of childhood cancer, with special reference to mortality rates by type in Japan; discussion on the contrast in origins of leukemia; bladder cancer, and uterine cervical cancer. The discussion on the contrast of the etiologies of these cancers revealed different modes of origin, and new approaches were suggested for laboratory, chemical, and epidemiologic research in the future. Participation of researchers from several disciplines added greatly to the open discussions.
Dr. Hirayama reported that data received from the NCI will be further analyzed and a monograph on the morbidity rates, a comparison of American and Japanese data, will be published during the coming year. He stated that there are some differences in the incidence pattern of sites of cancer between Japan and the U.S. These differences may be due to environmental factors, Iife style, genetic factors, and nutritional patterns. There was a lively discussion on the possible etiologic factors and site of cancer.
The exchange of selected scientists has been particularly productive.
The Analytical Epidemiology Program is sponsoring a meeting on Biostatistics in the Study of Human Cancer in Hiroshima, Japan, in May 1978.

Cancer Immunology Program Area:
Coordinators: Dr. Yuichi Yamamura and Dr. William Terry.

Dr. Terry began the discussion by stating that his two-week visit to Japan in September-October 1976 was most informative and provided him the opportunity to visit with several of the leading cancer immunologists in Japan. He presented several seminars and exchanged scientific information with the Japanese investigators. In addition, Dr. Tsuyoshi Igarashi, an Exchange Scientist from Osaka University, is spending one year in the Laboratory of Cell Biology, NCI. He reported that in the fall of 1976 Dr. Charles Boone spent two months at Hokkaido University and the visit resulted in a very productive collaboration with Professor Hiroshi Kobayashi and his group.
The exchange of resources and material resulted in Dr. Terry's laboratory receiving BCG cell-wall skeleton and Nocardia cell-wall skeleton preparations from Osaka University for experimental work. Also, two pairs of breeding stock of strain-2 guinea pigs were received from the National Cancer Center Research Institute in Tokyo.
Dr. Terry then gave a brief report at the seminar on Immunotherapy of Cancer and Its Fundamental Basis which was held in Osaka, Japan, on September 16 and 17, 1977. He stated that this meeting as well as the two previous meetings sponsored by the Program Area were extremely informative and brought the investigators from both countries closer together with increasing informality and frankness in discussing scientific information. At the last meeting the following topics were openly discussed: (1) recent studies on tumor antigens, (2) the mechanism of induction and manifestation of immune response against tumor-specific antigens, (3) properties of immunopotentiators having anticancer activity and their mechanism of action, (4) immunotherapy of cancer of the lung, pleura, and breast, (5) immunotherapy of digestive organ cancers, (6) immunotherapy of melanoma and sarcoma, and (7) immunotherapy of leukemia. In total there were 17 Japanese and 8 American participants at this meeting. After the meeting, three American scientists visited several laboratories in Japan to present seminars and lectures.
The other major accomplishments during the year were the parallel but independent clinical trials in immunotherapy with BCG, BCG cell-wall skeleton and other adjuvants; and exchange of information on planning and implementation of clinical trials in both countries and collaboration on evaluating the comparative efficiency of BCG cell-wall skeleton and whole BCG vaccines in the guinea pig hepatoma model.
A future meeting is being planned in September 1978 to maintain a continuing dialogue on basic immunology and immunotherapy of cancer.
Dr. Yamamura reported that the past year's activities and discussions have been focused mainly on immunotherapy of tumors. He further stated that clinical investigations in immunotherapy are reaching a critical point and that there is a great need for study and discussions on the immunological basis of tumor immunology as well as a need for greater effort in research in basic immunology.
Most of the discussion on cancer immunology was postponed until the Scientific Session on Cancer Immunology.
There was some discussion on the exchange of scientists and it was the general opinion that junior or younger scientists should be encouraged to spend 12 to 18 months or up to 24 months in a laboratory, particularly for the Japanese scientists, because of the cultural and language differences. Longer periods of time would provide more productive and meaningful experiences. However, there should be flexibility in the length of time an Exchange Scientist should spend in a laboratory, based on the needs of the individual and the hosting laboratory, since some experiments or investigations can be accomplished on very short-term visits, particularly for the experienced or established investigators. There is need for both short-term and long-term exchanges based on the purpose and needs of the individuals and the program areas to meet program objectives. Scientific “tourisms” should be discouraged unless highly warranted. Good planning between the visitor and the sponsor and hosting laboratory should be encouraged and selections should be of the highest quality. Each program area should exercise great care to maximize time and funds for the exchange of scientists.
Drs. Newell and Sugano called for a recess for luncheon at 11:45 a.m., since Drs. Robert Miller and William Terry had a press conference at 12 noon to speak on their recent visit to the People’s Republic of China.
The meeting was reconvened at 2:00 p.m. for the Scientific Session on Cancer Immunology (see page 94).
Dr. Terry presented introductory remarks by reviewing the basic mechanisms of immunologic response and relation to cancer immunology. There are many problems in basic immunology, such as tumor antigens, mechanisms of the induction of immune response, cell-mediated immunity, cell-specific and nonspecific immune response, and cytotoxic activity of immune response.
Dr. Yamamura reported that tumor immunotherapy was one of the main topics of U.S.-Japan cooperative activities. He presented an in-depth review of BCG vaccine as an immunotherapeutic agent for the treatment of tumors. Recent joint U.S.-Japan cooperative investigations have shown that the cell-wall skeleton of BCG strain of tubercle bacilli has the greatest immunopotentiating effect on tumor immune response.
Dr. Yamamura and his research group have made great strides in the fundamental investigation on the fractionation and testing of the BCG cell-wall skeleton (BCG-CWS). The crude BCG-CWS preparation was treated with organic solvent extraction. There were three major components obtained, namely: (1) mycolic acid, high molecular weight fatty acid, containing 80 carbon atoms, (2) alpha-galactan polymer, containing d-arabinose and d-galactose, (3) mucopeptide, containing n-acetyl-glucosamine, glyconeuraminic acid, d-N-alanine, fumaric acid and glutamic acid. The mucopeptide is a very important immunopotentiating factor in BCG-CWS.
Cell-wall skeleton material has been used as an oil-in-water suspension for immunological investigation. BCG-CWS has been quite effective in treating several types of animal tumors. Experimental studies on animal lung cancer models have shown that treatment with BCG-CWS was effective in diminishing the size of the lung tumor and in lengthening the survival time. Clinical trials have been done on human subjects with intravenous inoculations of BCG-CWS with encouraging results.
In explaining the possible mechanism of action, BCG-CWS has a very potent activity of enhancing antibody production with the stimulating effect on cell-mediated immunity. Subsequent experiments showed cell-mediated cytotoxic activity was greatly increased. It has been shown that Corynebacterium diptheriae and Nocardia rubra cell-wall skeleton preparations have similar immunopotentiating activity. As a result of these experimental results in animal models, bacterial cell-wall skeleton preparations could be used to treat human patients suffering from lung cancer, melanoma, myeloblastic leukemia, uterine cancer, and gastric cancer.
Since 1964 approximately 500 lung cancer patients have been treated with BCG-CWS preparations and clinical results have been most encouraging. Several reports have already been published. Clinical trials have been started at Kyushu Cancer Center. Thus far stage III and IV lung cancer patients have been treated and show significant prolongation of survival time. Clinical trials on adenocarcinomas have also been encouraging.
Studies on the use of BCG-CWS for treatment of metastasis have been initiated. Studies on in situ injection in lung cancer cases have shown considerable regression of the tumor.
Analysis of clinical trials of 455 cases with cancer of the lung show that BCG-CWS treated patients had significantly longer survival time than those patients treated by the more conventional methods of treatment.
Side effects from BCG-CWS administration were not serious compared to other forms of treatment including BCG treatment. The side effects were confined to increased body temperature for two to three days and swelling at the site of injection.
Investigations are continuing on other cell-wall skeleton preparations such as Nocardia rubra CWS, which appears to be a very potent immunotherapeutic agent in animal model systems and in preliminary trials in human patients with lung or pleural cancer. The Nocardia CWS is nonpathogenic and had less toxic side effects than BCG-CWS and BCG, as well as being a more effective agent for immunotherapy.
Studies are being conducted in Japan on synthetic adjuvants and antitumor active materials. Cell-wall skeleton preparations from Nocardia and BCG are being used to make several synthetic analogues to enhance the antitumor and immunopotentiating activities.
Dr. Newell warmly complimented Dr. Yamamura for his lucid presentation.
Dr. Terry continued the discussion on some of the currently used and promising immunotherapeutic techniques and agents such as intratumor inoculation, regional and systemic treatment, particularly in melanoma and adenomas. Clinical studies with BCG are being conducted at the NCI and other cancer centers in the U.S. Further investigations are being conducted on the basic aspects of the mechanism of tumor immunology and immunopotentiation.
The presentations provoked further discussion on the mechanism of action of immunotherapeutic agents and immunologic activity in human and animal systems.

Business Session:
After a brief recess, Dr. Newell reconvened the meeting for the business and administrative matters.
First, the schedule for the next joint meeting was discussed. It was agreed that October 31 and November 1, 1978 would be the most appropriate dates for the next meeting to be held in Japan. The locale of the meeting will be decided later by the JSPS, depending upon the availability of adequate accommodations and meeting facilities.
Dr. Omata stated that a Joint Drafting Committee composed of Dr. Ikawa and Dr. Hirayama, Mrs. Furukawa, Drs. Sheline, Herman, and Omata will write up the material for the second Progress Report of the U.S.-Japan Cooperative Cancer Research Program, covering the activities for 1976 and 1977. The final draft will be submitted to the Joint Steering Committee for approval and planning for 1978 and 1979. The Steering Committee will also consider the continuation of the Program for the second five-year term.
The Program Coordinators were advised to provide a review and evaluation of their respective Program Areas to cover the period between 1974 and 1978 and to include evaluation based on the following questions:

1. Were the cooperative research subjects appropriate in terms of the present status of knowledge, need, timing, and competency?
   
2. Were the research areas or activities well organized to achieve the expected objectives?
   
3. How efficiently were the research areas or plans implemented, and to what extent were the aims of the cooperative research or plan achieved during the first five-year period?
   
4. To what extent and in what way did the cooperative activities make an impact on the respective countries with particular reference to the following:
   1. Merits which the respective countries received from cooperative research.
      
   2. Any subsequent developments from cooperative research in the respective countries.

The review and evaluation should be provided sometime early in 1978 and presented at the 1978 Annual Joint Meeting for the purpose of including them in the five-year evaluation to be written at the end of 1978.
Drs. Sugano and Ikawa and Mr. Soda stated that the JSPS would need the evaluation to obtain approval and funds from the Ministry of Education to continue the Program. Everyone’s cooperation was requested.
Dr. Newell briefly reported on the meeting of the Joint Steering Committee held in August 1977. He stated that the aim is not to disrupt this extremely productive and successful cooperative program, but the intent is to give the Program greater flexibility to cover certain research areas which are not presently covered under the current structure with 11 circumscribed Program Areas. He requested that each Program Coordinator peruse the minutes of the meeting and think about the recommendations for discussion at the next Joint Meeting.
Dr. Omata encouraged the Program Coordinators to continue their plans and objectives in their activities for the coming year.
Dr. Newell stated that the recommended plan is not to hold annual joint meetings of the present magnitude, but to hold the large meeting on a biennial basis since most of the Program Areas are already sponsoring annual meetings. In this way, financial resources can be conserved to support scientific meetings and exchanges instead of using the limited resources for business and administrative meetings.
Dr. Newell stated that the recommended restructuring of the Program Areas, if approved fully, would take place over the second five-year period after discussing the proposal next year. Dr. O’Conor stated that the implementation of the recommended plan would depend on how each side wishes to operate in their own environment; that is, the Japanese side could establish their own “working group” while the U.S. side may operate somewhat differently.
Dr. Newell reemphasized the fact that the proposed plan is not to disrupt a very successful program but to make the Program a better and more flexible one to meet current and future needs. The meeting was adjourned at 4:40 p.m. with thanks expressed by all of the attendees.

Respectfully submitted,

Robert R. Omata, Ph.D.
Executive Secretary
U.S.-Japan Cooperative
Cancer Research Program

Summary of Scientific Session on Cytology

The Cytology Program Area of the U.S.-Japan Cooperative Cancer Research Program has focused primarily on cytology automation. This mutual U.S.-Japan interest in automation was the reason the Cytology Program Area was originally included in the Cooperative Program and both the United States and Japan are supporting major national research and development efforts in cytology automation.
Both the U.S. and Japanese automation efforts were begun in the late 1960s. Many of the fundamental decisions made independently by the originators of the two automation programs were identical. The goal of both programs was the same: the automation of the screening function of cytopathology. In practice, this restricts automation to the screening of cell samples from the vagina and cervix for squamous cell carcinoma of the uterine cervix and its precursor lesions, dysplasia, and carcinoma in situ. Cytopathologic examination is applied as a diagnostic technique to cell samples from a number of other sites such as sputum, urine, body fluids, etc. However, the only accepted screening application of cytopathology is in cervical cancer where regular Pap testing asymptomatic women is accepted as contributing to lowered morbidity and mortality rates from this disease.
Similar functional requirements for an automated cytology screening system were defined by both the U.S. and Japanese programs. The false negative rate (truly positive samples called negative by the system) must be in the 1 to 5 percent range. This error rate appears to agree with the estimated screening error rate of manual cytology screening. The false positive rate (truly negative samples called positive by the system) would have to be no higher than 20 to 30 percent in order for an automated screening system to be economic. In addition, the Japanese defined the minimum number of samples examined as 10 samples per hour.
Any attempt to automate screening of cytology specimens is limited by the machine-sensible parameters which are related to malignant transformation of epithelial cells. These parameters are the size and shape of nucleus and cytoplasm, the DNA, RNA, and protein content of nucleus and cytoplasm and, possibly the most informative single parameter, the ratio of nuclear to cytoplasmic volume. Thus the choice of a subset of these parameters constrains and determines the final configuration of a machine for automated screening.
Typical examples of U.S. and Japanese approaches to automated screening include the CYBEST, built by Toshiba under the supervision of Dr. Noboru Tanaka and his associates, and the Los Alamos Scientific Laboratory flow microfluorometer at the National Cancer Institute (NCI). These two instruments are discussed since they are the only instruments which have at the present time been used in true clinical trials.
The Toshiba CYBEST is a slide-based image processing system which analyzes cells fixed on glass slides and stained by the traditional Papanicolaou technique. Optical density measurements at 4^µ and 1^µ resolution are mapped for each cell on the slide and integrated nuclear optical density, nuclear size and shape, and nuclear/cytoplasmic ratio are determined. From these parameters, cell analyses are made. The number of abnormal cells and degree of abnormality of each cell determine whether a specimen is called normal or abnormal.
The NCI flow microfluorometer analyzes cells in suspension stained with propidium iodide for nucleic acid and fluorescein isothiocyanate for protein. Analysis of the fluorescence of each cell allows determination of nuclear and cytoplasmic size and nuclear/cytoplasmic ratio. The distribution of these parameters determines whether a specimen is called normal or abnormal.
The development of both these systems followed similar courses. After the parameters to be measured were chosen, these parameters were evaluated qualitatively and quantitatively. Their usefulness as markers of abnormal cells was evaluated with model cell systems and with carefully analyzed clinical specimens. The ultimate criterion for performance of each marker or set of markers is its correlation with “true” cellular and specimen classification as determined by manual cytopathologic evaluation. Finally both instruments have been used to screen a large number of clinical samples. These clinical trials have revealed similar problems in both systems, namely sample preparation and specimen analytic logic.
Both systems require good single cell preparations with a minimum of cellular debris and cell clumping. In addition, both systems require further work on the specimen decision logic. Once the measurements are made and analyzed on each cell, this information must be effectively dealt with to determine the normality or abnormality of the whole specimen. Both of these problems are currently the subjects of intensive work by both Japanese and U.S. investigators and are principal areas of bilateral cooperation and exchange.
It appears that the cellular and specimen changes which distinguish premalignant specimens from normal specimens are being sensed by automated instrumentation. The problem of extracting all the information available from the raw machine data is presently a major challenge. However, this problem is also the most exciting and potentially most rewarding aspect of cytology automation. Manual cytopathologic examination is qualitative and subjective. Automated cytologic techniques are quantitative and rigorously reproducible. Therefore the process of developing automated cytology screening systems is really the attempt to define malignant transformation in rigorous quantitative biochemical terms. This biochemical definition would certainly include that part of the premalignant cellular spectrum which precedes the development of morphologic changes recognizable by the cytopathologist. In addition, the availability of reproducible numerical data will inevitably lead to a quantitative indicator of cellular normality or abnormality which can more precisely define each individual patient's prognosis as well as diagnosis.
Following the formal discussion, the coordinators visited the Quantitative Cytology Section at the National Cancer Institute. Demonstrations of applications of quantitative cytology techniques to cancer screening, evaluation of tumor cell response to chemotherapy, and research on cytochemistry of malignant transformation were presented.

Summary of Scientific Session on Cancer Immunology

Dr. William Terry presented introductory remarks by reviewing the basic mechanisms of immunologic response and relation to cancer immunology. There are many problems in basic immunology, such as tumor antigens, mechanisms of the induction of immune response, cell-mediated immunity, cell-specific and nonspecific immune response, and cytotoxic activity of immune response.
Dr. Yamamura reported that tumor immunotherapy was one of the main topics of U.S.-Japan cooperative activities. He presented an in-depth review of BCG vaccine as an immunotherapeutic agent for the treatment of tumor. Recent joint U.S.-Japan cooperative investigations have shown that the cell-wall skeleton of BCG strain of tubercle bacilli has the greatest immunopotentiating effect on tumor immune response.
Dr. Yamamura and his research group have made great strides in the fundamental investigation on the fractionation and testing of the BCG cell-wall skeleton (BCG-CWS). The crude BCG-CWS preparation was treated with organic solvent extraction. There were three major components obtained: (1) mycolic acid, high molecular weight fatty acid, containing 80 carbon atoms; (2) alpha-galactan polymer, containing d-arabinose and d-galactose; and (3) mucopeptide, containing n-acetyl-glucosamine, glyconeuraminic acid, d-N-alanine, fumaric acid and glutamic acid. The mucopeptide is a very important immunopotentiating factor in BCG-CWS.
Cell-wall skeleton material has been used as an oil-in-water suspension for immunological investigation. BCG-CWS has been quite effective in treating several types of animal tumors. Experimental studies on animal lung cancer models have shown that treatment with BCG-CWS was effective in diminishing the size of the lung tumor and lengthened the survival time. Clinical trials have been done on human subjects with intravenous inoculations of BCG-CWS with encouraging results.
In explaining the possible mechanism of action, BCG-CWS has a very potent activity in enhancing antibody production with the stimulating effect on cell-mediated immunity. Subsequent experiments showed cell-mediated cytoxic activity was greatly increased. It has been shown that Corynebacterium diptheriae and Nocardia rubra cell-wall skeleton preparations have similar immunopotentiating activity. As a result of these experimental results in animal models, bacterial cell-wall skeleton preparations could be used to treat human patients suffering from lung cancer, melanoma, myeloblastic leukemia, uterine cancer, and gastric cancer.
Since 1964, approximately 500 lung cancer patients have been treated with BCG-CWS preparations and clinical results have been most encouraging. Several reports have already been published. Clinical trials have been started at Kyushu Cancer Center. Thus far stage III and IV lung cancer patients have been treated and show significant prolongation of survival time. Clinical trials on adenocarcinomas have also been encouraging.
Studies on the use of BCG-CWS for treatment of metastasis have been initiated. Studies on in situ injection in lung cancer cases have shown considerable regression of the tumor.
Analysis of clinical trials of 455 cases with cancer of the lung show that BCG-CWS treated patients had significantly longer survival time than those patients treated by the more conventional methods of treatment.
Side effects from BCG-CWS administration were not serious compared to other forms of treatment including BCG treatment. The side effects were confined to increased body temperature for two to three days and swelling at the site of injection.
Investigations are continuing on other cell-wall skeleton preparations such as Nocardia rubra-CWS, which appears to be a very potent immunotherapeutic agent in animal model systems and in preliminary trials in human patients with lung or pleural cancer. The Nocardia CWS is non-pathogenic and had less toxic side effects than BCG-CWS and BCG, as well as being a more effective agent for immunotherapy.
Studies are being conducted in Japan on synthetic adjuvants and antitumor active materials. Cell-wall skeleton preparations from Nocardia and BCG are being used to make several synthetic analogues to enhance the antitumor and immunopotentiating activities.
Dr. Terry continued the discussion on some of the currently used and promising immunotherapeutic techniques and agents such as intratumor inoculation, regional and systemic treatment, particularly in melanoma and adenomas. Clinical studies with BCG are being conducted at the NCI and other cancer centers in the United States. Further investigations are being conducted on the basic aspects of the mechanism of tumor immunology and immunopotentiation.
The presentations provoked further discussion on the mechanism of action of immunotherapeutic agents and immunologic activity in human and animal systems.

FOURTH ANNUAL JOINT MEETING UNITED STATES-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM

National Institutes of Health
Bethesda, Maryland
October 31 and November 1, 1977

AGENDA

PARTICIPANTS

JAPAN

Dr. Haruo Sugano
Director, Cancer Institute

Dr. Takeshi Hirayama
Head, Division of Epidemiology,National Cancer Center Research Institute

Dr. Yoji Ikawa
Head, Laboratory of Viral Oncology, Cancer Institute

Dr. Yohei Ito
Professor, Department of Microbiology, School of Medicine, Kyoto University

Dr. Yoshio Sakurai
Director, Cancer Chemotherapy Center

Dr. Haruo Sato
Professor, Research Institute for Tuberculosis, Leprosy and Cancer
Tohoku University

Dr. Takashi Sugimura
Director, National Cancer Center
Research Institute

Dr. Tadashi Yamamoto
Professor, Institute of Medical Science, The University of Tokyo

Dr. Yuichi Yamamura
Professor, Department of Internal Medicine, School of Medicine Osaka University

Dr. Osamu Yoshida
Professor, Department of Urology School of Medicine, Kyoto University

Dr. Fujiro Otani
Councillor for Science and Technology, Minister’s Secretariat, Ministry of Health and Welfare

Mr. Akira Tezuka
Deputy Director-General, Science and International Affair’s Bureau Ministry of Education, Science and Culture


JSPS Members

Mr. Kichimasa Soda
Head, Program Department

Mr. Nagahide Onozawa
Head, Research Cooperation Division, Program Department


UNITED STATES

Dr. Guy R. Newell, Chairman
Deputy Director
National Cancer Institute

Dr. I. Bernard Weinstein
Institute for Cancer Research
Columbia-Presbyterian Medical Center, Columbia University

Dr. Robert M. McAllister
Childrens Hospital of Los Angeles
Los Angeles, California

Dr. William Terry
Associate Director for Immunology
Division of Cancer Biology and Diagnosis
National Cancer Institute

Dr. Stephen K. Carter
Director, Northern California
Cancer Programs Palo Alto, California

Dr. Robert W. Miller
Chief, Epidemiology Branch, DCCP
National Cancer Institute

Dr. Oleg S. Selawry
Deputy Director for Intramural Affairs
Comprehensive Cancer Center of Greater Miami
University of Miami School of Medicine

Dr. George T. Bryan
Professor, Clinical Oncology and Surgery
University of Wisconsin Madison, Wisconsin

Dr. Glenn E. Sheline
Professor, Division of Radiation Oncology
University of California, San Francisco
San Francisco, California

Dr. Chester Herman
Laboratory of Pathology
Division of Cancer Biology and Diagnosis
National Cancer Institute

Dr. Philip G. Stansly
Program Director for Viral Oncology
Division of Cancer Research Resources and Centers
National Cancer Institute


Ex Officio Members

Dr. Arthur C. Upton
Director
National Cancer Institute

Dr. Gregory T. O’Conor
Associate Director for International Affairs
National Cancer Institute

Dr. Robert R. Omata
Executive Secretary
U.S.-Japan Cooperative Cancer Research Program
National Cancer Institute