IV. INTERDISCIPLINARY PROGRAM AND COORDINATION AREA

1. SUMMARY OF ACTIVITIES

We use a formula that has worked well for our binational meetings. We select for discussion a neglected disease that we know or suspect has a dissimilar frequency of occurrence in the two countries. We choose participants who know well some aspect of the subject but who often do not know one another, and we compile in advance a book containing abstracts and relevant reprints from each of the participants. As a result, presentations are shorter and discussions are longer than usual.

Seminars and Workshops:
In March 1981 we had such a meeting on differences between the two countries in lymphocytic diseases. It led to the realization that the high frequency of certain lymphoproliferative diseases in the United States as compared with Japan and the low frequency of lupus erythematosus and certain other autoimmune diseases in the U.S. as compared with Japan may be due to differences in the function of a subset of lymphocytes that protect against lymphomas but predispose to autoimmune diseases (Miller RW, Gilman PA and Sugano H: JNCI 67:739, 1981).
During the meeting, adult T-cell leukemia/lymphoma (ATL), which occurs in clusters in Kyushu and Okinawa, was discussed. During the following year, Dr. Yorio Hinuma of Kyoto University and Dr. Robert C. Gallo of NCI (RCG did not attend the meeting) made important independent advances in identifying a virus associated with ATL. Problems had arisen concerning the work each had done, and to seek a resolution, a special meeting was held in Seattle under the Interdisciplinary Program on March 11-12, 1982. Dr. Myron Essex has prepared a summary of the meeting.
The regularly scheduled meeting of a new topic under the Interdisciplinary Program was held in Honolulu on March 1-2, 1982. The subject was neural crest tumors. Is it biologically informative to know that certain syndromes associated with tumors or familial neoplasia are derived from the neural crest? Are there differences between the two countries in the frequencies of these tumors? These were the two questions to be addressed by the conference.
A special feature of the meeting was the participation, the first time ever at a scientific meeting, by Prince Masahito, the Emperor's younger son. He spoke on pigmented tumors of giant goldfish, among which the neoplasms increase with age, and of melanomas that occur spontaneously in croakers (nibe), especially off the Kii Peninsula. In this area the waters are less polluted than elsewhere along the east coast of Japan, where the frequency of melanomas among corakers is 0-10 percent. (We later learned that a cluster of amyotrophic lateral sclerosis was known among the people living on the peninsula.) The human counterpart of the pigmented tumors in fish is melanoma. Other neural crest tumors in man include pheochromocytoma; medullary carcinoma of the thyroid as in multiple endocrine neoplasia syndromes types II and III; neurofibromatosis; neuroblastoma and meningioma. In the last 90 minutes of the meeting, the group synthesized the information it had generated and developed a hypothesis as to how, during embryogenesis, gene action can affect the neural crest in a way that explains the various syndromes and familial cancers. A gene acting early in the development of the neural crest would affect the "trunk line," producing cafe-au-lait spots, neurofibromas, pheochromocytomas and meningiomas, among other disorders. A gene acting later in the development of the neural crest would produce MEN type III (medullary carcinoma of the thyroid, pheochromocytomas and neuromas of the mucosa - the blubbery lip syndrome). Acting later in development would be the gene for MEN type II (the same as MEN type III, but without neuromas of the mucosa). Acting still later would be the gene that is responsible for familial pheochromocytoma with none of the other elements of the syndromes described above.
The group thought melanomas would be the best measure of a neural crest tumor to determine if there is a difference in frequency in the two countries. This neoplasm, because it so often affects the skin, is well ascertained in both countries. The tumor registries in Hiroshima and Nagasaki can provide population-based data for the tumor in Japan for comparison with that in the U.S., as determined in the Third National Cancer Survey. A request has been made through the RERF to make this determination.
The hypothesis on gene action and neural crest tumors, as summarized above will be prepared for publication as a collaborative endeavor by several of the conferees.
The seminar on "T-bell leukemia/lymphoma - Role of Human Type C Retroviruses" was held in Seattle, Washington, on March 10 and 11, 1982.
It was concluded that
a) Human T-cell leukemia virus (HTLV) and adult T cell leukemia virus (ATLV) are newly identified human retroviruses. These two isolates seems to be identical or very similar to each other.
b) The viruses are endemic in the southwestern part of Japan and certain Caribbean islands. syndrome and adult T-cell leukemia, which belong to the category of differentiated T cell lymphoma and leukemia.
c) The viruses are endemic in the southwestern part of Japan and certain Caribbean islands.
d) The pathogenicity of these viruses seems to be low. In most cases with lymphoma or leukemia, a latent period is very long.
The details of the seminar appear later.
Under the exchange scientist program, two Japanese scientists, Dr. Naoyoshi Mori and Dr. Kohji Ezaki visited the U.S. The aim of Dr. Mori's visit was to find morphological and immunological differences of malignant lymphoma in the U.S. and Japan. He reviewed numerous pathological slides of malignant lymphoma and related diseases at leading laboratories in this field, and obtained the results that B cell lymphoma and follicular lymphoma are much more common in Americans than in Japanese. He was impressed that host responses to lymphoma cells in Americans are different from those in Japanese. As described above in Exchange Material, he brought materials from hairy cell leukemia back to Japan and proved that some of this type of leukemia are of B cell origin. He emphasized the introduction of new techniques such as electronmicroscopical immunohistochemistry, monoclonal antibody into the area of studies on lymphocytic diseases, and wishes to continue the collaborative study on lymphoma with Dr. Marshall E. Kadin in Seattle.
Dr. Kohji Ezaki has been engaged in a work on the cytotoxic lymphocyte system. The purpose of his visit was to be familiar with techniques of in vitro generation of anti-tumor lymphocyte by auto- and allosensitization which has been developed at Dr. Fritz H. Bach's laboratory. He examined three different methods on generation and learned that both cytotoxic T cells and NK-like cells seemed to be generated in in vitro sensitization. Using monoclonal anti-human T cell antibodies, it became clear that lysis of autologous tumor cells is mediated by cytotoxic T cells rather than NK-like cells. Further steps in his study will be cloning of cytotoxic cells and propagation of these cells in use of TCGF. Finally these cells will be applied for adoptive immunotherapy of malignant tumors. He wishes to continue his studies in collaboration with Dr. Bach.