Attachment 3 Cancer Board Meeting, 4/23/52 Please note on calendar I will "illegible" this at the next meeting. NEXT MEETING: WEDNESDAY, MAY 21, 1952 CANCER BOARD MEETING Wednesday, April 23, 1952 Members Present: D. H.G. Bell Dr. E.B. Boldrey Dr. D.M. Greenberg Dr. H.B. Jones Dr. J.F. Rinehart Dr. M.B. Shimkin Dr. R.S. Stone (Chairman) Dr. D.A. Wood Members Absent: Dr. B.V.A.Low-Beer Dr. H.B. Jones Dr. F.S. Smyth Dr. W.M. Stanley 1) Approval of Minutes: It was moved by Dr. Bell, seconded by Dr. Greenberg, and carried by the Board that the minutes of the meeting of Wednesday, March 19 be approved as circulated. 2) Protocol for Procedures at Laboratory of Experimental Oncology: a) Biochemical and Metabolic Characteristics of the Portal Venous System. Dr. Shimkin commented that this was merely a request for formal approval as this procedure was already being done at the Laboratory. Dr. Stone pointed out that procedures should be approved in advance as the Laboratory is part of the Cancer Research Institute and thus of the School of Medicine, and approval must be given by the Board as representative members of the School of Medicine. As regards this particular procedure, Dr. Bell said that he did not approve of blind procedures and felt that this should be done at surgery. He stated that as long as this was already being done, the Laboratory might as well be allowed to complete the study. It was moved by Dr. Bell, seconded by Dr. Boldrey, and carried by the Board that this procedure be approved. b) Transplantation of Malignant Melanoma. Dr. Shimkin reported that in undertaking this procedure patients would be most carefully selected and would understand clearly what was being done. Dr. Stone stated that he felt such a procedure was not in line with the basic principles governing human experimentation outlined at the War Crimes Tribunal at Nuremberg or the code of ethics regarding human experimentation adopted by the American Medical Association. In particular, the investigator Reproduction from Special Collections, The Library, University of California, San Francisco. No portion of this material may be quoted, copied, or reproduced in any fashion without written permission from the copyright holder. 1 could not terminate the experiment and it would not seem to serve any purpose to benefit humanity. Dr. Rinehart suggested preliminary studies in selected cases with cutaneous metastases. Dr. Greenberg commented that the board would be subject to censure if approval were given to such a procedure, and that even a patient with untreatable cancer should not be subjected to another malignancy. Experimental procedures are offered to patients in hope of some possible cure, and the suggested transplantation of malignant melanoma does not offer any such hope. Dr. Greenberg suggested that this application for approval be withdrawn. Dr. Shimkin suggested that it be tabled. This was placed as a motion by Dr. Bell, seconded by Dr. Rinehart, and carried by the Board. c) To place stress upon the removal mechanism by temporarily destroying the hematopoietic productivity. Dr. Shimkin pointed out that this would be a hazardous procedure and mortality is expected, but the aim is therapeutic. Dr. Stone said that as long as he is Chairman of the Division of Radiology, this will not be done with x-ray at the University of California. Dr. Rinehart reported that there is still much to be done in animal experimentation in this regard. Dr. Jones briefly reported what progress had ben made with such experiments in animals, and agreed that this is still a matter for animal experiments. Dr. Greenberg moved that this application be tabled without prejudice. This was seconded by Dr. Jones and carried by the Board. d) Study of the effect of hepatic artery ligation in cases of advanced neoplastic disease with hepatic metastasis: It was moved by Dr. Boldrey, seconded by Dr. Greenberg, and carried by the Board that this procedure be approved, including support of hospitalization of patients from the ACS Institution Grant Bed Fund. e) Fetal adrenocortical transplantation in childhood leukemia: It was moved by Dr. Jones, seconded by Dr. Bell, and carried by the Board that this procedure be approved, including support of hospitalization of patients from the ACS Institutional Grant Bed Fund. 3) Applications for Funds: a) Dr. W.R. Lyons: It was moved by Dr. Shimkin, seconded by Dr. Bell, and carried by the Board that the application of Dr. Lyons for support of the project "Further Studies on the Effect of Pituitary ACTH and STH on the Growth of Translatable Adenocarcinoma in C3H Mice", in the sum of $600., be approved. b) Dr. E. B. Boldrey, Dr. Gale Clark: The Chairman asked the wishes of the Board in regard to this application, which was received too late for circulation to the members. In view of the fact that Dr. Clark is a resident and will be at the Hospital a limited time, it was moved by Dr. Rinehart, seconded by Dr. Jones, and carried by the Board that the Reproduction from Special Collections, The Library, University of California, San Francisco. No portion of this material may be quoted, copied, or reproduced in any fashion without written permission from the copyright holder. 2 application be considered. It was moved by Dr. Shimkin, seconded by Dr. Bell,and carried by the Board that the sum of $"illegible", be granted to Drs. Boldrey and Clark for study of the project "Transplantation of Glioblastoma Multiforme from the Human Brain to the Dog Brain". Approval is to include hospitalization of patients on the Bed Fund of the American Cancer Society Institutional Grant if and when funds are needed for this purpose. 4) New Business Catheter Technique Fund: Dr. Wood reported an oral request from Dr. Bierman and Dr. Byron to utilize this fund to cover costs incident to publication of a manual on the catheter procedure. Dr. Shimkin said that this work had been done at the Laboratory, but planned publication of such a manual had not been brought to his attention. It was emphasized that this work was being supported by the Cancer Research Institute and the National Cancer Institute, and any publication such a is planned must be cleared with Dr. Wood and Dr. Shimkin prior to submission to any journal or agency, or before plans are made for local publication. Dr. Bell suggested that the entire proposal be cleared through proper channels. Dr. Stone reviewed the history of the Catheter Technique Fund, and from this it is clear that these funds were contributed to the Cancer Research Institute, and therefore expenditure of such funds must have approval of the Director of the Institute and the Cancer Board. It was moved by Dr. Jones, seconded by Dr. Bell, and carried by the Board that the matter be tabled pending recommendation regarding publication of such a manual from Dr. Shimkin and Dr. Wood. The meeting was adjourned. Reproduction from Special Collections, The Library, University of California, San Francisco. No portion of this material may be quoted, copied, or reproduced in any fashion without written permission from the copyright holder. 3 No. 2 19 October 1951 PROTOCOL TRANSPLANTATION OF MALIGNANT MELANOMA Aim: To ascertain in man the minimum number of homologous cells of malignant melanoma to take successfully and to study the growth, degeneration phenomena and characteristics of the transplants under various physiological conditions. Purpose: To determine the fundamental requirements of metastases of malignant melanoma and how they may be influenced by environmental conditions. Introduction: It has been shown in mice that a definite minimal number of homologous tumor cells are required in a transplant to take hold and develop successfully. Below this critical number of cells, failure to take will result. This critical number of cells will vary with different tumors and hosts. Malignant melanoma in man spreads widely but the growth of these metastases is frequently unpredictable. Various physiological alternations will influence tumor growth in both animals and man but there is no data available to indicate if such physiological conditions could determine the success or failure of a given number of cells to take once implantation had occurred. If one assumes that the critical number of cells necessary to achieve a successful take or metastasis of X15, it might be determined that a specific alteration in the blood supply of the transplanted area could change this critical number of X150 or, perchance, X1.5. Such data might support further experimentation to develop a new approach which might eventually lead to material prevention or slowing metastatic spread. Procedure: Rt. Lt. A A B B C C D D Patients with advanced metastic neoplastic disease to be employed. Transplant subcutaneously large (A) to progressively smaller (D) amounts of 10X increments of sterile homologous tumor in both upper and lower extremities. Remove sites when larger transplants show evidence of growth. The initial number of cells in the transplant would be determined by direct count (Chalkley- Earle). 1 After the critical minimal number of cells to achieve a successful take has been ascertained, the environment of one extremity is to be altered physiologically by venous or arterial route by combined compression, sympathetically, inter-arterial infusion of glucose, lactic acid, vitamins, metabolic antagonists, mitotic inhibitors, steroids, and various other chemotherapeutic substances. Therefore, the direct effect of such agents upon isolated neoplastic lesions can be determined under controlled conditions in man. In addition, the evaluation of the effectiveness of these substances inter-arterially upon such tumors would be determined by direct histological study. Since the transplants will be observed daily and under continuous visual control, it is not contemplated that such studies in this group of patients with advanced neoplastic disease would in any serious manner jeopardize or impair the remaining duration of the course of the disease. Reproduction from Special Collections, The Library, University of California, San Francisco. No portion of this material may be quoted, copied, or reproduced in any fashion without written permission from the copyright holder. 2 ETHICS OF THE USE OF HUMAN SUBJECTS IN MEDICAL EXPERIMENTS as set up for the WAR CRIMES TRIBUNAL AT NUREMBERG* "The great weight of the evidence before us is to the effect that certain types of medical experiments on human beings, when kept within reasonably well-defined bounds, conform to the ethics of the medical profession generally. The protagonists of the practice of human experimentation justify their views on the basis that such experiments yield results for the good of society that are unprocurable by other methods or means of study. All agree, however, that certain basic principles must be observed in order to satisfy moral, ethical and legal concepts: "1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other form of ulterior constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possible come from his participation in the experiment. "The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. "2 The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. "3. The experimental should be so designated and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problems under study that the anticipated results will justify the performance of the experiment. *An excerpt from "Doctors of Infamy", by Alexander Mitscherlich, M.D., translated by Heinz Norden. 1 Reproduction from Special Collections, The Library, University of California, San Francisco. No portion of this material may be quoted, copied, or reproduced in any fashion without written permission from the copyright holder. "4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. "5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. "6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. "7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. "8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stage of the experiment of those who conduct or engage in the experiment. "9. During the course of the experiment, the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him impossible. "10. During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage if he has probable cause to believe, in the exercise of good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject." Reproduction from Special Collections, The Library, University of California, San Francisco. No portion of this material may be quoted, copied, or reproduced in any fashion without written permission from the copyright holder. 2 No. 5 5 June 1952 PROTOCOL 1. Aim: To place stress upon the removal mechanism by temporarily destroying the hematopoietic productivity. 2. Purpose: To determine the relative importance of delivery of white cells versus the removal in the non-leukemid and leukemic patient. 3. Introduction and Procedure: Many competent hematologists feel that leukemia is strongly entrenched in the bone marrow, which they feel is the basic origin of the disease. These men also are of the firm conviction that one could cure leukemia if the bone marrow and other hematopoietic sites could be destroyed, but they are aware of the dangers of such a result and feel that it limits the usefulness of therapy employing excessive hematopoietic destruction. No one has established the validity of this opinion, and it should be challenged. Recently, Lorenz has reported cures in mice with lymphosarcoma treated by excessive and often lethal doses of irradiation and protected by bone marrow introduction after the irradiation. Admittedly, the lymphosarcoma Lorenz employed may be localized. Nevertheless, it has never been cured by local irradiation. (1) The development of the cross-circulation technique and the survival of x-irradiated animals (L. Donovon) (2) both large and small with cross-circulation makes such an experiment feasible. It is proposed: (1) To give a patient with leukemia who has a short prognosis an excessive dose of either nitrogen mustard or some radioactive substance and then to cross-transfuse this patient with one or two short-time prognosis cancer patients and attempt to keep the leukemia patient alive for the necessary time to study the effect on the leukemia, bone marrow, and removal mechanism. While this study sounds perhaps experimental beyond the usual ethical standards, it has some vital conclusions which may be learned. 1. Does leukemia indeed reside in the hematopoietic tissues that can be depressed or destroyed by irradiation or HML? 2. If so, is it possible to cure leukemia by destroying these hematopoietic tissues provide the patient can survive? 1