The Institute of Medical Science University of Tokyo
Sponsor and Host Institution: Marshall E. Kadin, University of Washington, and Richard E. Slavin, University of Texas at Galveston
Dates of Visit: February 6 to February 26, 1984

Summary of Activities:
1. Immunohistologic identification of surface markers on malignant lymphomas of T-cell origin:
I was given a chance to review data of such studies performed at the University of Washington in the last few years. I also practiced such tests on my specimens (Japanese T-cell lymphomas). In comparing the results of the T-cell lymphomas in Japan and the U.S., we concluded that in terms of tumor cell-surface markers studied to date, there seems to be no difference between them regardless of anti-adult T-cell leukemia/lymphoma antigen (anti-ATLA) positivity: both are positive with Leu 4 and Leu 3a, and most, or a large part of them are DR and Tac antigen positive.
2. Morphologic Study of Malignant Lymphomas in Areas along the Gulf of Mexico:
Sixty-two cases of malignant lymphoma were studied at the University of Texas at Galveston. It was found that the incidence of T-cell lymphomas of the peripheral type was not high: there was only one case of typical pleomorphic type (the type commonly seen in ATL). Six additional cases which might belong to ATL were also noted: all belonged to the category of cutaneous T-cell malignant lymphoma or mycosis fungoides. As none of these cases were tested with regard to the serum anti-ATLA titer, it was suggested that the patients’ sera be sent to a laboratory with funds for such studies.
3. Lectures:
Two lecutres were given to the Department of Pathology, University of Texas, concerning 1) the pathology of HNK-1 cells in lymph nodes, and 2) recent progress in ATL studies in Japan.
4. Technical Discussions:
My series of discussions with the personnel at the University of Washington concerning immunohistologic methods in lymphoma studies brought me new knowledge and understanding of sophisticated techniques.
5. Other:
(a) A monoclonal antibody, anti-THP, produced by Dr. Oodo of Tokyo University Hospital was studied for its usefulness in the diagnosis of malignant lymphoma. Recently we found that this antibody can react with only part of perpheral lymphocytes, blood vessels and lympth vessels. In the present study we could not identify what kind of lymphocyte this positive cell was. However, we could confirm that the antigen detected in this antibody is a unique molecule, different from Factor VIII. This antibody can be used in the diagnostic pathology of lymph nodes and other organs to clearly demonstrate endothelium.
(b) I visited the Fred Hutchinson Memorial Institute, Seattle, following the advice of the Host Scientist, Professor M. Kadin. There I could hear an information-Iaden lecture from Professor Hackman about transplantation immunology and the prospect of bone-marrow transplantation for patients with malignant lymphoma.
1. This program greatly enriched my research program on hematopathology in general, particularly in the areas of malignant lymphoma research and immunopathological training.
2. Understanding of ATL is becoming popular. However, the basic understanding among pathologists might be insufficient, and in this regard there may exist a further need for communication. We are keeping in contact after my return to Japan by exchanging information on cases, pathology specimens and patients’ sera.

Cancer Institute, Department of Viral Oncology, Tokyo
Sponsor and Host Institution: Dr. Robert C. Gallo Laboratory of Tumor Cell Biology, NCI
Dates of Visit: May 22 to June 10, 1983

Summary of Activities:
The purpose of this visit was to exchange and discuss recent information on human adult T-cell leukemia (ATL) and the human retrovirus (ATLV or HTLV) associated with ATL, on which I am working. Especially in the field of molecular biology of these viruses, we have quite advanced information on ATLV, which is endemic in Kyushu and Shikoku in Japan. Therefore, comparison of our data with those of Dr. R. C. Gallo in NCI, on HTLV, which is endemic in the Caribbean and in Africa, was expected to be very helpful in discussions of the possible mechanisms of leukemogenesis by these viruses. The discussion should also reduce any conflict between Japan and the U.S., and enhance future collaboration between the two countries in this area of research.
From May 30 to June 3, I visited Dr. Gallo’s laboratory at NCI and discussed recent data on ATLV and HTLV. It appeared that the Japanese ATLV and the HTLV of the U.S. are very similar with regard to information so far available. It was suggested that these viruses are the same. Since we have DNA probes to detect each part of the viral genome, we decided to compare these viruses directly. Dr. Gallo agreed to supply his cell line, HUT 102, which contains HTLV provirus genome. Experiments on this line are now in progress in our laboratory. Furthermore, Dr. Gallo and I agreed to unify the name of the viruses into HTLV if the Japanese ATLV is the same as the U.S. HTLV, since HTLV was isolated earlier than ATLV. I think this agreement on the nomenclature of the virus isolates resolves one of the conflicts between the U.S. and Japan in this field of research.
On the integration sites of ATLV and HTLV proviruses in leukemic cell, our result was contradictory to that of Dr. Gallo; that is, he claimed a specific integration site for HTLV but we proposed non-specific integration for ATLV. We both agreed that the specificity of the provirus integration is very important for understanding the mechanisms of ATL leukemogenesis, but the problem was left for further studies.
At NCI, I realized that Dr. Gallo is working together with so many people covering the various fields of cancer research that I could not find any possibility for our small group to compete with his research group. I felt that effective collaboration of Japanese groups is most important to survive in the top level of this leukemia research.
In a RNA tumor virus meeting at Cold Spring Harbor, held from May 25 to 29, many retroviruses, including some of human origin, were discussed. Our presentation on the total nucleotide sequence of ATLV was highly regarded since it was the first such determination. Many presentations on the functions of onc genes, on differences between viral onc and cellular proto-onc, and on structural information on cellular proto-onc were very suggestive for our future programs on ATLV research.
I also visited Dr. P. K. Vogt of the University of Southern California, Dr. R. A. Weinberg of Massachusetts Institute of Technology, and Dr. Hanafusa of the Rockefeller University, and discussed the possible mechanisms of ATL development induced by ATLV or HTLV, the specificity of viral replication and also the possible onc gene which may be involved in ATL leukemogenesis. These three scientists who are leading our field made various invaluable suggestions on ATL research and influenced my attitude as a scientist. These discussions and suggestions by top scientists will help and encourage me in my future research.
I am very grateful to the U.S.-Japan Cooperative Cancer Research Program for supporting such a wonderful and useful visit to the USA.

Aichi Cancer Center Hospital
81-1159 Kanokoden, Tashiro-Cho, Chikusa-ku, Nagoya, Japan
Sponsor and Host Institution: Henry Rappaport, M.D., Pathology Panel for Lymphoma Clinical Studies City of Hope National Medical Center, Duarte, California
Dates of Visit: September 11 to October 2, 1983

Summary of Activities:
I. Lectures
1. “The histopathology of T-cell lymphomas in Japan” at the 1983 annual meeting of the Lymphoma Pathology Panel on September 12 & 13 in Chicago, Illinois. A primary purpose of my visit was to give this lecture by invitation. The objective was to demonstrate and explain the features and the range of the histopathological spectrum displayed by the ATLV-induced T-cell lymphomas endemically occurring in Japan, together with their immunological character and clinical behavior. The lecture also concerned the specific features of nuclear morphology in virus-induced lymphomas, and my tentative scheme of T-cell lymphoma classification.
2. “Adult T-cell Leukemia-Lymphomas” at a hematology conference at NCI in Bethesda, Maryland, on September 23.
3. “Pathology of Adult T-cell Leukemia-Lymphoma” at a pathology conference at Stanford University Medical Center, Palo Alto, California, on September 30.
II. Studies and Exchange of Information
1. Comparative studies on virus-positive and virus-negative T-cell lymphomas between the United States and Japan. There were some differences between the two countries in the histological appearance of the virus-positive lymphomas. The pleomorphic configurations of the nuclei and irregularity in size are more pronounced in the Japanese cases, which may be worth further investigation.
2. Histopathological study of lymph node lesions in the AIDS patients.
3. The problems of differential diagnostic criteria between Hodgkin’s disease and T-cell lymphomas. These studies were made possible by visiting scientists listed:
1) Nancy Harris, M.D., Hematopathology Section, Massachusetts General Hospital, Boston, Mass.
2) Geraldine Pinkuss, M.D., Hematopathology Section, Brigham and Women’s Hospital, Boston, Mass.
3) Elaine Jaffe, M.D., Hematopathology Section, NCI Clinical Center, Bethesda, Maryland.
4) Henry Rappaport, M.D. and Bharat Nathwani, M.D., Department of Anatomic Pathology, City of Hope National Medical Center, Duarte, California.
5) Robert J. Lukes, M.D., Department of Pathology, University of Southern California, Los Angeles, California.
6) Ronald Dorfman, Pathology Section, Stanford University School of Medicine, Palo Alto, California.
I believe my lectures contributed to understanding by U.S. lymphoma pathologists of the variegated histopathological picture and special features of the virus-induced T-cell lymphomas as well as their immunological character and clinical behavior. I gained greatly by this visit by being given opportunities to study T-cell lymphoma cases in the U.S., and by exchanging views with expert lymphoma researchers in the U.S.

First Department of Medicine, Faculty of Medicine University of Tokyo
Sponsor and Host Institution: Robert L. Peters, University of Southern California at Downey
E. Alpert, Baylor College of Medicine, Houston
S. Galli, Harvard Medical School and Beth Israel Hospital, Boston
F. Schaffner, Mount Sinai Hospital, New York
Dates of Visit: March 27 to April 1 8, 1984

Summary of Activities:
l) Analysis of autopsy cases.
To compare the clinicopathological features of hepatoma in U.S. with those in Japan, autopsy records and clinical documents of hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) were analyzed at the USC Medical Center, Rancho Los Amigos Hospital and John Wesley Hospital.
The number of autopsy cases during 10 years (from 1974 to 1983) were 90 cases of HCC and 10 cases of CCC.
The following are the summary of the analyses of HCC.

a) age distribution:
- 40 yrs: 9 cases
41-50yrs: 10 cases
51-60yrs: 21 cases
61-70yrs: 30 cases
71 -: 20 cases
The youngest was a 21-year-old HBsAg positive Negro male and the oldest was a 95-year-old Mexican female.
b) racial distribution:
Mexican: 32
Caucasian: 32
Negro: 16
Oriental: 10
c) positive rate of HBsAg: 20.3%
a higher positive rate of HBsAg was observed in Orientals (66.7%) than in Mexicans or Caucasians.
in patients younger than 40, 5/7 (71%) were HBsAg positive.
d) positive rate of AFP:
Mexican: 58.8%
Caucasian: 35.3%
Negro: 40%
Oriental: 85.7%
e) mean age at death:
HCC with positive HBsAg: 48.9yrs
HCC with negative HBsAg: 58.6yrs
f) analysis of etiologic background:
HCC with LC: 72
with hepatitis: 9
without LC. CH: 9
Among HCC with LC:
with alcoholic cirrhosis: 50
with non-alcoholic cirrhosis: 22
HCC with alcoholic etiology was dominant in Mexicans (21 cases) and Caucasians (19 cases). On the other hand, HBV-related HCC was dominant in Orientals.
2) I gave a lecture at a meeting of the Liver Unit of the University of Southern California (Chairman: Prof. Reynolds) on the following subject:
“Lectin binding analysis of AFP as a diagnostic tool in differentiating HCC from other diseases”
3) Dr. Alpert and I discussed AFP genes and hepatoma oncogenes.
4) I gave some information to the staff of Dr. Galli on the tissue culture system of hepatoma cells of our laboratory at Tokyo University.

Center for Cancer Research
Massachusetts Institute of Technology
Sponsor and Host Institution: Mitsuaki Yoshida, Cancer Institute, Tokyo
Kumao Toyoshima, 2lst Japan Medical Congress, Osaka, and a special lecutre in Tokyo.
Yorio Hinuma, Kyoto University
Masakazu Hatanaka, Kyoto University
Shiro Kato, Osaka University

Summary of Activities:
Lectures were given at each of the above-listed places. Individual symposia and lectures were sponsored by the Otsuka Company, Takeda Chemical and the Yakult Company. Discussions were held with some of Japan’s top molecular biologists, and lectures were given to almost a thousand scientists.