SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Noriyuki Sato
Department of Pathology
Sapporo Medical University
School of Medicine

SPONSOR AND HOST INSTITUTION:
Dr. Franco Marincola
Dr. Steven Rosenberg
Dr. Paul Robbins
Dr. Mark Dudley
Surgery Branch
National Cancer Institute
Dates of Visit: February 15-21, 1998

SUMMARY OF ACTIVITIES:
In Surgery Branch, NCI
In NCI, we discussed 1) characteristics of antigenic peptides and proteins of melanoma, 2) identification of colon cancer antigens, 3) clinical protocol and trials and 4) identification of gastric tumor antigens.
In NCI, currently clinical trials using four melanoma peptides composed of two gp100, one MART-1 and one tyrosinase with IL-2 are underway. Surprisingly, preliminary study indicates that this immunotherapy protocol gives them with 45-50% efficacy for HLA-A2 (+) melanoma patients. Dr. Marincola also just began this clinical trial in conjunction with dendritic cells.
Dr. Robbins’s group identified a new melanoma HLA-A2-restricted antigen gene. Dr. Dudley’s group has attempted to establish colon tumor line and its cytotoxic T lymphocytes (CTL). From these studies NCI group may isolate new powerful cadidates of antigenic peptides for the future immunotherapy of tumors.
In my talk as to “Identification of HLA-A31-restricted gastric tumor antigen recognized by CTL”, I had nice comments from several scientists in NCI. I began to cooperate with NCI group by sharing tumor lines, primers for HLA DNA typing and technical knowledge and appliances.
In University of Connecticut
In Dr. Srivastava lab., we discussed heat shock proteins (HSP) as general tumor vaccines. He already published such protocol in a recent Science issue. He will apply his protocol in the clinical trials.
I also gave them my seminar entitled “HSP as the Tumor Target Molecules”. I had several important comments, and in some points I began to cooperate with Dr. Srivastava group.
Overall, present visits to two institutes in USA were so fruitful to me. Cooperations were begun with them, and our research could be proceeded more effectively. I would like to so much appreciate US-Japan Cooperate Cancer Research Program, and I sincerely hope that such chances should be extended to many scientists in our country.



(2) Chihiro Shimazaki
Kyoto Prefectural University of Medicine

SPONSOR AND HOST INSTITUTION:
Dr. Bayard Clarkson
Sloan Kettering Cancer Center (SKCC)
Dr. Richard Champlin
MD Anderson Cancer Center (MDACC)
Dr. Karl Blume
Stanford University Medical Center (SUMC)
Dr. William Bensinger
Fred Hutchinson Cancer Research Center (FHCRC)
Dates of Visit: September 4 - 21, 1997

SUMMARY OF ACTIVITIES:
The objectives of this study are to change the opinions with several US investigators about peripheral blood stem cell transplantation (PBSCT) in autologous and allogeneic setting.
I presented the data concerning PBSC mobilization by FLT3 Ligand (FL) and anti-adhesion molecule antibody. FL in combination with granulocyte colony-stimulating factor (F-CSF) could induce PBSC mobilization dramatically. While anti-VCAM1 antibody but not anti-VLA4 antibody could mobilize stem and progenitors into blood, which is in contrast to the previous report but some investigators supported our data. Then I reported and interim result of multicenter trial of PBSCT for acute myelogenous leukemia (AML) and intermediate grade non-Hodgkin’s lymphoma (IG-NHL) by Japan Blood Cell Transplantation Study Group (JBCTSG). Disease free survival of AML receiving PBSCT in first complete remission (1CR) is 63%, which prompted us to start prospective randomized study to compare PBSCT with conventional chemotherapy as intensification therapy for AML in 1CR. We also started prospective randomized study to compare PBSCT with conventional chemotherapy for high risk IG-NHL in 1 CR. They approved these trials.
I discussed with many investigators about the following issues. 1) Auto-PBSCT; Thrombopoietin (TPO) may be useful for PBSC mobilization (MDACC). Myeloma cell is sensitive to Taxol, and CY and Taxol followed by G-CSF is useful for PBSC mobilization in myeloma (FHCRC). 2) Allo-PBSCT; More than 150 patients received allo-PBSCT at MDACC and FHCRC. G-CSF at doses of 10-12â g/kg was used for PBSC mobilization. Allo-PBSCT showed that hematopoietic recovery is faster and the incidence of chronic GVHD might be higher as compared with allo-BMT, but severity of acute GVHD in allo-PBSCT is same as allo-BMT (FHCRC). Prospective randomized study is ongoing to compare allo-PBSCT with allo-BMT (MDACC, FHCRC). 3) CD34+PBSCT; Isolex 300 (Baxter) is superior to Cell Pro device as regard to the purity of CD34+cells after selection (MDACC, FHCRC). Purity of CD34+cell after selection by Isolex 300 is reported to be 90%. 4) Adoptive immunotherapy after auto-PBSCT; Many investigators agree that immunotherapy is required after PBSCT to decrease the incidence of relapse. Newer approach includes dendritic cell primed T-cell infusion (MDACC), transplantation of IL-2-treated PBSC (MDACC, FHCRC) and vaccination using idiotype protein for myeloma (SUMC). 5) Gene therapy; New approach to treat relapsed CML patients is donor lymphocyte infusion transduced with suicide gene. Clinical trials using this approach is ongoing at MDACC and FHCRC. 6) Other new approaches; Mini-transplant using fludarabin and melphalan as conditioning regimen is an unique allo-PBSCT for aged patients (<70 years-old). This regimen is not myeloablative but fludarabin is a potent immunosuppressor, which can engraft allogeneic stem cells (MDACC).
These new information obtained by the talk with US investigators stimulate me to develop new innovative approach to treat cancer patients.

ACKNOWLEDGMENT:
I thank US-Japan Cooperative Cancer Research Program for being given this opportunity to visit several institutions in US.



(3) Toshitada Takahashi
Aichi Cancer Center Research Institute

SPONSOR AND HOST INSTITUTION:
Dr. Lloyd J. Old
Ludwig Institute for Cancer Research, New York Branch
Dates of Visit: October 15 - 26, 1997

SUMMARY OF ACTIVITIES:
The purpose of my visit to the following 4 laboratories is to learn the present status of basic and clinical aspects of cancer therapy in USA for defining the future direction of my study. The following informations were obtained. (At the University of Pittsburgh, I gave a seminar with the title of “Mouse TL Antigen as a Target for Immunotherapy.”)
Dr .Deleo (University of Pittsburgh Cancer Institute) has been working on p53 gene product as a possible target for immunotherapy and has shown previously that the growth of CMS4, a chemically induced sarcoma of BALB/c mice, can be suppressed by irnmunization with the peptides derived from wild type p53 gene product. Together with Dr. Storkus, he succeeded in generating dendritic cells expressing p53 gene product by way of particle mediated gene transfer and showed that immunization with such dendritic cells suppressed the growth of CMS4. Although the gene transfer efficiency is relatively low when compared with viral vectors, this new technique is valuable, since viral vectors are highly immunogenic to the hosts, so that immune responses against tumor antigens with relatively weak immunogenecity is generally difficult to induce.
Dr. Marincola, as a staff member of Dr. Rosenberg’s group (Surgical Section, NCI), has long been involved in basic and clinical studies on cancer immunotherapy. Using a new viral vector, poxvirus, he infected human dendritic cells to express MART-1 melanoma antigen and succeeded in generating cytotoxic T cells (CTL) against MART-1 after a single stimulation in vitro with these dendritic cells. This new approach is more efficient than the previous attempt with dendritic cells preexposed to MART-1 peptides which require multiple restimulations to generate CTL.
Dr. Lloyd (Memorial Sloan-Kettering Cancer Center) has long studied carbohydrate antigens of human melanoma and ovarian cancer, and together with Dr. Livingston, he has recently started active immunization of melanoma patients with GM2 and GD2 gangliosides conjugated with keyhole limpet hemocyanin (KLH) in QS-21 ajuvant. In addition, by collaboration with Dr. Danishefsky’s group, an attempt has been made to synthesize carbohydrate tumor antigens, such Ley, with a possible use for active immunization.
At Dr. Old’s laboratory (Ludwig Institute for Cancer Research), an attempt has been made to utilize humanized monoclonal antibody for cancer treatment. Radiolabelled mouse monoclonal antibody, A33 has been shown to target metastatic colon cancer and to mediate modest anti-tumor effects in patients with advanced disease. Subsequently, a humanized A33 was produced and evaluated in a phase I study in 11 patients, showing no major toxicities, although induction of human anti-humanized A33 (HAHA) reactivity was observed. Now, a phase II trial is in progress, but no major responses were observed in the first 12 evaluable patients.
In addition, detection of human tumor antigens has been conducted. NY-ESO-I defined by the SEREX method as a esophagus cancer-associated antigen was found to be expressed in other types of tumors, such as melanoma, breast cancer and bladder cancer, although it is not expressed in normal tissues except for testis and ovary. Methods to detect T cell reactivity against this antigen are now being developed. Several other antigens have also been characterized. In several years, the SEREX method will provide us with a vanity of human tumor antigens as a target for tumor vaccination.


(4) Hirohiko Tsuji
Department of Radiation Medicine
Research Center of Heavy Particle Therapy
National Institute of Radiological Sciences

SPONSOR AND HOST INSTITUTION:
Dr. George E. Laramore
Department of Radiation Oncology
The University of Washington Medical Center
Dr. Michael J. Zelefsky
Department of Radiation Oncology
Memorial Sloan-Kettering Cancer Center
Dr. Herman D. Suite
Department of Radiation Oncology
Massachusetts General Hospital
Dates of Visit: November 30 - December 13, 1997

SUMMARY OF ACTIVITIES:
Research Background:
Clinical trials for cancer treatment with heavy ions generated by the HIMAC (Heavy Ion Medical Accelerator in Chiba) have been conducted at the National Institute of Radiological Sciences (NIRS) since 1994. The HIMAC is the first medical heavy ion accelerator complex in the world, Since heavy ions have a superior dose distribution and increased relative biological effectiveness (RBE), it should have greater efficacy for cancers that have been difficult to control by conventional radiations (X-rays, gamma-rays and electron beams). However, in order to realize the advantages of this treatment method, development of suitable high level irradiation technology is very important as well as maintaining a long-term view toward future prospects. Surveys into other leading-edge treatment methods, comparative investigations, discussions and cooperative research with specialists in other fields, as well as other activities may help us achieve this long-term view. With this in mind, the overseas survey research conducted at this time presented a great opportunity. Installation of new particle beam treatment centers in Japan has been approved at the National Cancer Center East, the Hyogo Particle Bean Treatment Center, Proton Medical Research Center of the Tsukuba University (a new plan), the Wakasa-Bay Energy Research Center, the Shizuoka Prefectural Cancer Center. Several other locations also have a plan to have a hospital-based proton center. In the next few years, particle beam treatment can be expected in at least 6 locations including the NRS. Under these circumstances, we need to consider the future of particle beam treatment, for which it is desirable to study the current state of leading-edge radiation treatment techniques overseas.
The visit research was done in the following institutions.

(1) Department of Radiation Oncology, University of Washington Medical Center (WUMC), Seattle, WA (Chairman: George E. Laramore)
The University of Washington Medical Center (WUMC) is famous for their results obtained by fast neutron treatment. Although the dose distribution characteristics of fast neutrons are similar to conventional radiation, they possess high linear energy transfer (LET) and their relative biological effectiveness (RBE) is higher than photon beams. Since heavy ions, which also possess high LET radiations, have many similarities with neutrons in terms of potential efficacy in cancer therapy, the visit to WUMC was very useful in considering the future of the heavy particle treatment project at the NIRS. During the 2 day visit, we observed treatment procedures with fast neutrons, gave lectures on the results of heavy ion treatment conducted at the NIRS, and had mutual discussions.
In the United States, with support from NCI, fast neutron treatment began in the 1970’s at 4 hospitals; WUMC, MD Anderson Hospital, UCLA Medical Center-Wadsworth VA Hospital, and Fox Chase Hospital. The first 3 hospitals performed clinical research using a reaction (Pü¿Be) caused by a cyclotron, while Fox Chase Hospital completed their research after treating only several people using the dT-reaction. Since then, several other facilities have participated in fast neutron treatment in the States, but many of research centers have stopped clinical research since the mid-1980’s. Currently, there are only 3 operating facilities; WUMC (50MeV Pü¿Be), Fermi Laboratory (66MeV Pü¿Be), and the Harper-Grace Hospital in Detroit (48MeV Pü¿Be). The reason for this decrease is the relatively small number of patients with applicable conditions such as salivary gland tumors, prostate cancers, and bone and soft tissue cancers. In other type of tumors, the biological advantages of fast neutrons are negated by the disadvantages associated with the inferior dose distribution. Accordingly, all research funding from the NCI has been stopped. The currently operating facilities must now operate under independent funding. Of note, patients eligible for treatment at WUMC have salivary gland tumors, prostate cancer, bone and soft tissue cancers, or those tumors for which photons are assumed to be biologically ineffective. Nearly all of these treatments are covered under insurance systems.
The fast neutron accelerator at WUMC is a cyclotron with a rotating gantry (Scanditronics Co.). The same machine is also used in Korea and Arabia. In general, the research at WUMC involves primarily treatment of salivary gland tumors, prostate cancer, and bone/soft tissue cancers. Management and maintenance of the machine is done by 4 internal operators. According to J. L. Schwarz, the operator in charge, about 10 patients per day are treated with fast neutrons. This is less than the number treated previously. The facility, however, has a very complete environment as a radiation treatment center because, in addition to fast neutron machine, it has 4 linacs and 2 remotely afterloading machines (high and low dose rates).
The problems with fast neutrons include a penumbra that is broader than X-rays and possibility of higher skin reactions since, even though the dose distribution depth is about the same as 6~8 MeV X-rays, the surface dose is almost 70%. The irradiation room of WUMC was built about 20 years ago and has had almost no remodeling. The treatment table and floor are made completely of wood to avoid radioactivation. The gantry can rotate 360üKand contains bending magnets for 50MeV proton beams, a beryllium target for generating neutrons, 3 types of ridge filters (30üK, 45üK and 60üK), an X-ray tube for confirmation of patient positioning, a multi-leaf collimator, and other equipments. This gantry is therefore fairly large compared to the lineac gantry. However, the movement is only slightly slower than the lineac gantry, fine angle adjustment is relatively easy, and 3D-irradiation is also easy to perform. There is a large space below the floor directly under the table and the gantry is directed there by opening and closing the wooden floor in time with gantry rotation. The treatment beam contains 10% gamma-rays but measuring only neutrons is difficult with current technology. The neutron and gamma-rays are measured in a hollow chamber (IC-17) and the gamma-rays are measured by a GM-dosimeter. The neutron dose is then determined from the difference in the values of the two.
The most representative candidate for fast neutron treatment are patients with salivary gland tumors. The RBE value of fast neutron beam is 3~3.5 for late effects of the musculo-connective tissues in fractionated RT, whereas the value is thought to be about 8.0 for a salivary gland tumor. At WUMC, the head and neck tumors are irradiated 4 days per week at a dosage of 1.2Gynr per fraction. Treatment is given over 4 weeks for a total dose of 19.2Gynr in 16 fractions. This corresponds to 60~70Gy for normal tissue, but for salivary gland tumors it could be as high as 160Gy. As a result, the therapeutic gain factor in this type of tumor becomes 2.3~2.6. At WUMC, an effort has been placed on improvement of dose distribution in order to reduce side-effects. However, since high-LET radiation has a higher RBE for the central nervous system, great consideration is given to keeping the radiation dose below tolerable levels. In carbon ion treatment at the NIRS, the tolerable dose in treatment of head and neck tumors would be 57.6~62.0GyE for 16 fractions of 3.6~4.0GyE given 4 times per week for 4 weeks. This is nearly the same as the dose used in the fast neutron treatment (equivalent to a physical dose of 20Gynr). When the skin reaction is used as an endpoint, our estimation of the carbon ion RBE being 3.0 at the distal part of the SOBP is justified.
Recently, a new method has been proposed to increase the effect of fast neutron beams by combining the effects of neutron capture treatment (BNCT) with fast neutron irradiation. In order to improve dose distribution in fast neutron treatment, the contamination of the low energy neutron component must be suppressed as much as possible, for which a material such as Cu is placed just below the Be target. In the proposed method using the BNCT, thermal and epitheramal neutrons are included as much as possible during fast neutron beam irradiation. BNCT is then done between these neutrons and the previously administered 10B compound, With this method, a 10~15% increase in effectiveness is possible compared to the fast neutron beam alone. Irradiation experiments are currently underway using animals.

(2) Memorial Sloan Kettering Cancer Center (MSKCC)
New York, NY (Chairman: Michael Zelfsky)
This center has a long history as a radiation treatment facility. In the field of brachytherapy in particular, Dr. Henscnke, one of the first researchers who developed a remotely afterloading system (RALS), worked here and his legacy continues to this day. The facilities are complete with radiation treatment equipment including 9 Lineac units, I cobalt unit, 2 RALS units (GammaMed), 3 simulators (including one CT simulator), and one diagnostic CT unit. The staff includes 12 radiotherapists, 11 residents, 2 research fellows, and 20 medical physicists. There are also many staff personnel, called dosimetrists, dedicated specifically to treatment planning. On this scale, the center performs external irradiation treatment for 250~300 patients every day.
MSKCC is well-known for implementing the 3-D dynamic irradiation method using CT. This method is called Intensity Modulated Radiotherapy (IMR) which is based on the proposals by Spirou et al. in 1994. The method became possible through the use of a multi-leaf collimator (MLC), developed in Japan. The principle involves varying radiation dose during irradiation from any given direction by continuously opening and closing the MLC. The procedure is really a multiple field, dynamic irradiation method and is primarily used in the treatment of prostate cancer. The patients receive a fixed daily dose of 1.8Gy and a dose escalation study was done with the total dose being increased to 66Gy, 70Gy, 76Gy, 81Gy and 86.4Gy. Valuable data regarding side-effects and control rate were obtained. Five or 6 fields were used in the prostate cancer treatment and the safety margin of the targets, including the prostate gland and the seminal vesicle, was 1.0cm on the lateral and bladder side and 0.6cm on the rectal side. The field size was 7~8cm (horizontal) by 12~14cm (vertical). Although 75Gy was the upper limit in the standard treatment, it was possible to irradiate up to the 81 Gy level through the use of IMR. It has been shown that, based on physiological observation and PSA values obtained 3 years after irradiation, the control rate clearly improved with increased radiation dose.
The dose distribution of IMR is intended to keep the rectal dose less than 75Gy whenever the target dose is given a planned tumor dose. The dose gradient must be made as calculated from the distribution of each field. The method involves changing the irradiation dose through continuous variation of the irradiation field shape created by MLC and not through a compensation filter. Using this method, a similar distribution as in charged particle beams can be obtained with photon beams if a tumor is 3cm or smaller. When a tumor has an irregular shape or is relatively large, the charged particle beams may be superior to photon beams. This must be clarified by comparative clinical trials. With heavy ions, since a high RBE is expected because of containing high LET components, the potential candidate will probably be different from IMR and proton beam treatment. In any case, IMR is not yet complete but will stand out as a major accomplishment among specifically targeted irradiation methods developed in the latter half of the 20th century. IMR will certainly have an important place in history in the next century.
The Brachytherapy division belongs to the medical physics section and supports the radiation oncology section. The annual number of patients is 400~500, of which nearly half are treated with low dose-rate RT. The remainder are treated with high dose-rate RT. In addition to uterine cancer, bronchial lung cancer, and esophageal cancer, the 2 GammaMed units also treat pelvic and digestive tract cancers. For a long time, the 1251 was used for permanent implantation in the tissue for the relatively large number of prostate cancer patients, but this has recently changed to IMR. For digestive tract cancers, an 192Ir source has been used in intra-operative radiotherapy (IORT). In this method thin catheters, in which 192Ir sources are inserted, are placed at lcm intervals on the surface of a lcm thick silicon plate. The plate is then cut to an appropriate length and used. In some tumor sites, 103Pd is also used but supply tends to be delayed. Recently, the trend has been to decrease the number of brachytherapy patients, which is probably related to the advance of IMR.

(3) Department of Radiation Oncology
Massachusetts General Hospital (MGH), Boston, MA
(Chairman: Herman D. Suit)
MGH has the most extensive record in basic and clinical research related to proton therapy. The effectiveness of proton therapy on choroidal melanoma or skull base sarcoma was established at MGH. It is no overstatement to say that nearly all the 17 proton therapy facilities in the world received technical support from MGH. A new North-East Proton Therapy Center (NPTC), located in the same campus, is nearly complete. The accelerator at the new facility is the same cyclotron from the IBA Company of Belgium used at the East Hospital of the National Cancer Center. The facility has therefore gained great attention in Japan as well. Last year, Dr. Loeffler was named director of NPTC. Dr. Suit, however, remains the chairman of the clinical, physical and biological departments. In addition to observing actual proton treatment at the Harvard Cyclotron Laboratory during the visit, I also gave lectures on the results of heavy ion therapy conducted at the NIRS. Dr. Suit also arranged for meetings with a number of related personnel after I expressed interest in the research system, medical expense problems, and other areas from the standpoint of radiation therapy. Although the expression may not be appropriate, there was a deep feeling that principles of competition are supported in the States even in the area of medical treatment.

Medical Expenses:
A major problem facing the medical treatment in America is the balance between cost and benefit. In radiation therapy for prostate cancer for example, although PSA measurement and biopsy are effective in determining treatment effects, not all patients should undergo biopsy from an economics standpoint due to the low rate of positive results actually obtained (15~20%). As a result, in the protocol recently approved by NCI (PROG-95-09), only patients with PSA values of 1.0 or more undergo biopsy 2~2.5 years after treatment (approximately 30%). As a recent trend in the American medical treatment system, not only must a new therapy show disease or QOL improvement to be recognized, but the new therapy must be approved for MediCare through the AMA (American Medical Association) in order that certain patients can be covered for the cost of therapy. Only then will payment for the treatment be made by private insurance companies. Although results for over 20,000 people have already been obtained for proton therapy, the only codes given for insured treatment in America are for patients with pituitary grand tumors, choriodal melanoma, and AVM. Although treatment of skull base tumors (approximately 1 month) costs $60,000~$80,000, this is only the lower limit. When biopsies and other examinations are included, the cost is estimated at $100,000. For treatments based on the protocol, however, the treatment costs must be paid from research expenses. The research expenses that can be obtained from NCI therefore become the determining factor for research content. While the expenses of research activities are covered from a number of sources, the largest source is the support by NIH. Staff salaries, including that of the Chairman, come from the funding provided.

Clinical Research:
C. C. Wang is known as the first researcher to use a hyperfrationation therapy for cranial tumors and has received a gold medal from ASTRO for his success and contributions to education and research. At MGH, the irradiation method for head and neck cancers, other than T1 tumors, involves 2 fractionated irradiations in a single day. In this method, 1.6Gy is administered twice in 1 day and a total dose of 73.6Gy is given over 46 treatments over 5~6 weeks. When a severe reaction is observed, a rest period may be given during the treatment period. An important point is that even long rest periods do not exceed 2 weeks and the complete treatment is finished within 6 weeks.
According to C. C. Wang, 6 hours is not required between the 2 fractions given in a single day. Rather, 4 hours is a sufficient interval. His long clinical experience is detailed in the book, “Radiation Therapy for Head and Neck Neoplasrns,” and I was fortunate enough to obtain a signed copy of the 3rd version from him. Currently, although the hyperfractionation method is highly regarded, many feel that a randomized trial is required to scientifically verify its superiority to the conventional divided method. However, C. C. Wang feels there is no need for a randomized trial since the effectiveness of this method is sufficiently shown in the data obtained to date. However, increasingly the recent trend is not to recognize new methods until a randomized trial is conducted. This method is no exception and currently the effectiveness is being studied in a randomized trial being conducted in cooperation with a number of facilities through RTOG.
The hyperfractionation method at MGH includes a number of points that should be considered. While dividing treatment into 2 fractions in a single day, the interval between 1.6Gy doses is only 4 hours. This means that a fairly large total dose of 3.2Gy is given in a day. Although the mucous membrane reaction is stronger with larger daily doses, a longer treatment period or remarkably improved dose distribution are required to make the radiation endurable. At MGH, the patients are given a rest when the reaction is strong and great efforts are made to concentrate the dose on the tumor area only. I believe that the excellent results obtained by the MGH method are largely a result of the large daily dosage and dramatically improved dose distribution, but the effect of the hyperfractionation may be minimal. At any rate, I obtained a lot of valuable information that can be applied at the NIRS from the treatment conducted routinely at MGH.

Basic Research:
A great disparity is often pointed out between America and Japan in funding provided for basic research. The disparity can also be seen at MGH. Dr. Suit, the Chairman, was originally specialized in radiation biology and had already created an excellent research environment in the 1970’s. Here, research animals (primarily mice) are all bred on site and animal research can be done using instruments brought into the facilities with strict contamination prevention measures. Generally, the removal and placement of animals in the animal experiment breeding room is restricted to prevent contamination. This restriction has an influence on the conduct of experiments. With the MGH method, there is almost no worry of contamination. Even in America, MGH may be the only facility of this type. Realization of this environment is another success of Dr. Suit. Using apoptosis, radiation sensitivity amplifier agents and protection agents, and mouse ventral vessel chambers, strong efforts in tumor blood vessel research are progressing through the direction of Dr. Held, Dr. Jain and Dr. Powell.