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Biennial Report JULY 1, 1955-JUNE 30, 1957 SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH Restarcle Uait of MEMORIAL CENTER FOR CANCER AND ALLIED DISEASES Division of CORNELL UNIVERSITY MEDICAL COLLEGE 410 EAST 68TH STREET, N EW YORK 21, N. Y.

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I Contents Officers and Trustees ............................................................................ 5 Board Committees, Scientific Consultants, and Administrative Staff .................................................................... 6 Introduction .......................................................................................... 7 Report of the Administrator .............................................................. 13 Report of the Director Summary ...................................................................................... 15 Scientific Report .......................................................................... 17 Educational Report .................................................................... 69 Balance Sheet ........................................................................................ 73 Source and Application of Funds .................................................... 74 Conclusion .....................................................:...................................... 75 Professional Staff ................................................................................ 76 Supporting Staff .................................................................................. 78 Staff Publications .....:.......................................................................... 80 3

SlonrrA-ettering Institute for Canur Researrh, opened in 1995, stands as a yart o) a morlnn snediral center, A1enr- oria! Center for Canter and Allied Diseases. In 19.50, the role of tearhing u'as added to re"eareh, evith the estab- lisiuneat of the Sloa i-A'ettering Division of Cornell Uniuersit} Medical College. The activities of the Institute are eloselJ' Jnter4('oT'en U'Ith the hoSrltal anu ont0atlent ser4'lfes of the Center. niher nn/ts of the Cente!' inelu/le Alennorial llospital, James F.ioing Jlospital of the Cit) of Neu York, and Sbang Canrer I'rerention Clinic.

S1.,OAN-I:f+:7 1'ERING FOR CANCER RESEARCH ALFRED P. SL0.4N, JR. Chairman of the Board FRANK A. HOWARD President EDWARD C. DELAFIELD Secretary OFFICERS ELL\IORE C. PATTERSON Treasurer HARRISON V. SMITH Assistant Treasurer H. LAWRENCE HESS Assistant Secretary BOARD RoGER ADAMS, Ph.I). Research Professor, University of Illinois, Department of Chemistry and Chemical Engineering ALBERT BRADLEY Chairman of the Board, General t11 otors Corporation DETLEV W. BRONK, Ph.I). President, Rockefeller Institute for .lledical Research REGINALDG.COOnIBE Senior 1'ice President, The Hanorer Bank EDWARD C. DELAFIELD Senior Partner, Delafreld and Delafield JOSEPH C. HINSEY, Ph.D. Director, The Neu York Hospital- Cornell .1lydical Center FRANK A. HOWARD Research Consultant, Standard Oil Company (N.J.) CHARLES F. KETTERING Research Consultant, Grneral Jlofors Corporation EUGENE W. KETTERING Assistant Chief Engineer, Electro-JI otioe Division, General,llotors Corporation DEANE W. NIALOTT P/esfdenf, Cornell Uniivrsity OF TRUSTEES W. ALBERT NOYES, JR., Ph.D. Chairman, Department of Chemistry, University of Rochester ELL1fORE C. PATTERSON Yice President, J. P..llorgan & Cornpany'.Inc. JOHN L. PRATT Engineer and Philanthropist C. P. RHOADS, M.D. Director, Sloan-Kettering Institute Scientific Director. Alemorial Center for Cancer and Allied Diseases LAURANCE S. ROCKEFELLER Rockefeller Brothers, Inc. ALFRED P. SLOAN, JR. Honorary Chairman of the Board, GeneralAlotors Corporation LEWIS L. STRAUSS Chairnean, U. S. Btonrie Energy Commission ROBERT E. STRAWBRIDGE, JR. Director, Strau-bridge & Clothier WARREN LVEAVER, Ph.D. T'ice President for fhe Natural and .1ledicol Sciences, Rockefeller Foundation GEORGE WHITNEY Director J. P- dlorgan & Couepanj.Ine. THEODORE P. WRIGHT, D.Sc. 1 irc President for Research, Cornell University EXECUTIVE CO\IdiI'i"I'EE , FRANK A. HOWARD Chairman REGINALD G. COO.IBE C. P. RHOADS, M.D. EDWARD C. DELAF/ELD LAURANCE S. ROCKEFELLER ELL\IORE C. PATTERSON ALFRED P. SLOAN, JR. JOHNL. PRATT WARREN WEAVER, Ph.D. GEORGE WHITNEY

CO\lAtITTEE ON SCIEN'1'1F1C 1'OLICY WARREN WEAVER, Ph.I). Chairmmn RIIGER AD.4MS, Ph.I). C11.4RLES F. KETTERING JOSEPH C. HINSEY, Ph.D. W. ALBERT NOYES, JR., Ph.I). FRANK A. HOWARD C. P. RHOADS, M.D. 1NVESTMEhT COXIAiITTEE ALFRED P. SLOAN, JR. Chairman ELLMORE C. PATTERSON LAVRANCE S. ROCKEFELLER SCIENTIFIC WARREN H. COLE, M.D. Head, Department of Surgtry, Univrrsity of Illinois College of 9ledicinr ARTHUR CLAY COPE, Ph.D. Chairman, Department of Chemistry, Alassachusetts Institute of Technology LAWRENCE R. HAFSTAD, Ph.D. Vice President, Research Staff, General tllotors Corporation JOHN R. HELLER, M.D. Director, National Cancer Institute, Department of Health, Education and Welfare - HOWARD ALBERT TANNER, Ph.D., ex officio Director of Research, Charles F. Kettering Foundation CONSULTANTS PEYTON Rous, M.D. Alember Emeritus, Rockefeller lnstitute for aledical Research RICHARD E. SHOPE, M.D. .1lember, Rockefeller Institute for .1ledical Research J. WALTER WILSON, Ph.D. Chairman, Department of Biology, Brown University JOHN E. DEITRICK, :II.D., ex officio Dean, Cornell University Medical College HOWARD EARL SKIPPER, Ph.D., ex officio Assistant Director, Southern Research Institute DIRECTOR C. P. RHoADs, M.D. ASSOCIATE DIRECTOR HENRY T. RANDALL, M.D. DEPUTY DIRECTOR A. R. T. DENUES, Ph.D. ASSOCIATE DIRECTOR C. CHESTERSTOCI:, Ph.D. BERNHARD L. MECKE Administrator HENRY E. MELENEY, JR. Assistant Administrator H. W. RIENOw Personnel Officer dt o1 Octobtr 1, 1957 BERNARD J. PALUMBO Fiscal O fjirtr HARRIET C. HUGHES dssistant ddministrator l;ENJA]IIN W. ERICKSON Assistant Personnel Officer

V b .0 S1.UAN-AETTERING 1RSTITVTE FOR CANCER RESEARCH Introduction When the Sloan-Kettering Institute was founded in 1945, it had a clear and simply defined objective, the better control of cancer in man. lt was felt by the founders - and the events of the last decade have proved them right- that the time had come, the total scientific pictu re was adequately clear, for a major attack on the cancer problem. Furthermore, many realized that the public was demanding, and justi- fiably so, that there be exerted a vigorous and orderly scientific effort to stem the growing threat of this most dreaded disease. The real life and spirit of the Institute resides in the basic con- cepts on which it was established, the vision that brought it into being, and, most of all, the devoted and skilled creative effort of its scientists. To make the intangibles functional, however, required a 14-story laboratory building, completed in 1948. Progress required expansion in 1952 by the addition of the Andre and Bella Meyer Physiology Laboratory and Kress Betatron Unit. Prior to the establishment of the Institute, the research of Mem- orial Center, then Memorial Hospital, was conducted in a few crowded rooms on a back corridor of the original structure. Two of these were devoted to what was then considered a curious and imprac- tical project, the search for chemicals against cancer. By the time the Institute opened its doors, it was clear to those associated with it that this search must be a major effort, as offering the most direct approach to our goal of cancer control. At that time, however, only a rare indi- vidual shared our point of view and cancer chemotherapy was the choice of few investigators. Despite skepticism in many quarters, however, the program grew rapidly. The idea of chemicals for cancer control took heart from the mounting triumph of chemicals in the cure of infectious disease. In our laboratories and others, the effectiveness of certain compounds against some types of animal cancer was clearly demonstrated - the concept that cancer cells could be destroyed with- out fatal injury to the host cells became credible. Chemical 'agents exerting some useful though transient effects against cancer in man began to capture public and scientific attention. Though their benefits were weak and brief, some did relieve suffering, some prolonged life, and all offered strong evidence that more effective measures were a reasonable possibility. 6 f r- A ITG i 3:, . E 4.1 E~:i~1:1s--~

8 SLOAIK-i:ET7ERING INSTITUTE FOR CANCER RESEARCH Today cancer chemotherapy has become a major activity of medi- cal research laboratories throughout the country, a principal interest of the philanthropic agencies supporting cancer research and of the Federal Government. Similarly, pressures from the developments of our own program, and by the public and the agencies that support our work, force an expansion of our own efforts in this field. As a result of this need for an accelerated program - and the fact that present space limitations are preventing normal expansion of research efforts -Sloan-Kettering is now entering a period in which it again faces the need for structure. Two temporary steps toward meeting our need for physical ex- pansion have been made. One has been the lease and occupancy of the Polak Laboratory, in Brooklyn. This now houses the activities relating to the culture of molds yielding antibiotics for anti-cancer tests, the large scale growth of human cancers in laboratory animals, and the study of cancer which has become resistant to chemical con- trol, all important facets of the experimental chemotherapy program. In addition, a four-story brownstone on East 65th Street has been con- verted into laboratories for furthering research toward removal of carcinogens from tobacco tar. Space has been purchased at Woodside in Queens, for an animal depot, to provide ideal holding accommo- dations for laboratory animals. Two major and permanent steps are now under consideration. The Institute has made a search for a suburban site for the expansion of our chemotherapy program. At this time, there seems to be a good possibility that a suitable location for a new laboratory has been found in nearby Westchester County. Also, the Health Service Facilities of the National Institutes of Health have already made available funds for half the cost of new research laboratory space in a proposed new building of Memorial Center on the north side of 68th Street, facing the present buildings. It is the belief of the trustees that construction of these new facilities will be rapidly justified by the increase in yield of the research efTort- a yield that can be measured only in terms of human lives. Clinical Research by the Sloan•Kettering Institute Another major area in the txpanding chemotherapy program, as well as in the total activities of the Institute, is the work with patients. From its inception and throughout the development of the pro- gram, the Sloan-Kettering Institute research has extended from labo- ratory bench to bedside. Treatment of patients (clinical investigation)

9 SLOAN-KETTERING INSTITVTE !OR CANCRR RESEARCH is the crucial area in which the results of laboratory science are brought to final test; it is the front line of the research effort, the final trial by which a new procedure becomes established or discarded. The clinical cancer chemotherapy investigation is pursued by the research physicians of the Sloan-Kettering Institute functioning also as members of the medical staffs of the two associated hospitals. Most of this work is in the special research facilities provided by the James Ewing Hospital of the City of New York. The research wards serve as testing and training centers, perform pioneer work in developing better methods of treatment by studies in man, and train medical specialists to carry forward cancer chemotherapy in other institutions. The Institute's units in the Ewing Hospital were the first such full-scale facilities recognized for study and training in this field, and continue to represent outstanding examples. The extensive facilities for clinical investigation required for this work represent a major financial obligation, properly met, in sub- stantial part, by research funds. The Sloan-Kettering Institute invests annually a total of $619,000 directly in the work with patients. This includes (1) $102,000 for special research nursing in the James Ewing Hospital, where 60 research beds are available; (2) $36,000 toward hospitalization costs of patients in the James Ewing Hospital receiv- ing research therapy; (3) $56,000 toward the cost of ward care in the Memorial Hospital of suitable indigent research patients; (4) $30,000 toward such care in the research outpatient clinics of Memorial Hos- pital; and (S) $395,000 in salaries to the 48 physicians of the Sloan- Kettering Institute research staff who work on the staffs of the Mem- orial and James Ewing Hospitals. Organizational Changes Board of Trustees The Board of Trustees, which now has 21 members, guides the policies of the Institute, administers its finances, and aids and advises in its program. During the past biennium, Mr. Robert E. Straw- bridge, Jr., a long-time friend, joined the Board, replacing Mr. Raymond P. Sloan. Mr. Ellmore C. Patterson and Drs. C. P. Rhoads and Warren Weaver ioined the Executive Committee during the period under report. Mr. Lewis L. Strauss (Chairman of the Atomic Energy Com- mission) resigned from the Executive Committee, although he re- mains a member of the Board.

10 SLOAN-KETTERINGINSTITVTE FOR CANCER RESEARCH Scientific Consultants Five new Scientific Consultants have been appointed. The Con- sultants, who represent an impartial cross-section of the nation's lead- ing scientists, meet quarterly with the Director, the Division Chiefs, and the investigators to review the programs and to recommend policy. New Members of the Board of Scientific Consultants are Drs. Peyton Rous and Richard Shope, of the Rockefeller Institute for Medical Research; J. Walter Wilson of Brown University; Warren H. Cole of the University of Illinois College of Medicine; Lawrence R. Hafstad of the General Motors Corporation; and John E. Deitrick, the newly appointed Dean of Cornell University Medical College. We record with sorrow the death on March 4, 1957 of Dr. Evarts A. Graham who served with marked distinction as a Scientific Con- sultant of the Institute. Dr. Graham contributed greatly to the cure of cancer through his leadership in surgery, teaching, and research and gave unstintingly of his time and counsel to our research program. Sta$ To meet the increasing administrative pressures brought about by expansion and acceleration of the program, changes have been made in the executive staff of the Institute. Drs. H. T. Randall and C. C. Stock have been appointed Associate Directors, and Dr. A. R. T. Denues has become Deputy Director of the Institute. Dr. Randall will assume responsibility for certain aspects of the Institute's pro- gram which bear on the special aspects of the work with patients. Dr. Stock's appointment is in recognition of the growing administra- tive problem associated with the growth of the chemotherapy research program. A new research division has been created, the Division of Metab- olism and Enzyme Studies, with Dr. Oscar Bodansky as its Chief. This has come about in recognition both of Dr. Bodansky's great personal contributions in the field of biochemistry and of the growing importance and productivity of this phase of the program. There are now twelve major research divisions of the Institute.

SLOAN-KETTERING INSTITVTE FOR CANCER RESEARCH Sloan Awards In May 1957, the Alfred P. Sloan Award in Cancer Research for Recognition of Meritorious Contribution from the Institute to tb e Rdvancement of 1Lnowl edge was again presented. This intramural award was given to the Division of Clinical Investigation in recogni- tion of two outstanding programs. One was represented by the report, Hypophysectomy in the Treatment of Advanced Cancer, by Drs. Olof H Pearson, Bronson S. Ray, Charles C. Harrold, Charles D. West, Min-Chiu Li, John P. Maclean, and Mortimer B. Lipsett; and the other by Studies on Transaminase Activity in Blood, a series of reports authored by Drs. Felix Wroblewski, John S. LaDue, Irwin Nydick, Charlotte Friend, David Molander, and Arthur Karmen. Both of these distinguished studies represent contributions not only to our fundamental knowledge but also to the ability to care for patients. In Acknowledgment The work described in this fourth biennial report has been pos- sible only because of the generous contributions of many individuals and organizations. Among these are the Alfred P. Sloan Foundation, the American Cancer Society, the Andre and Bela Meyer Founda- tion, the Black-Stevenson Fund, the Damon Runyon Memorial Fund for Cancer Research, the Fannie E. Rippel Foundation, the Max C. Fleischmann Foundation, the Samuel H. Kress Foundation, the United States Atomic Energy Commission, and the United States Public Health Service. No less important to the very existence of the Center is the support of hundreds of groups, corporations, and indi- vidual donors whose aggregate gifts make possible a substantial por- tion of the Institute's work. To all of these, as well as to the men and women who work in the laboratories, the Trustees wish to express their profound gratitude.

n SLOAN-KETTERING INSTITUTE'S LABORATORY OPERATIONS ® MEMORIAL HOSPITAL JAMES EWING HOSPITAL PROPOSED BBTH ST. LAB. CENTRAL LABORATORY 377 E. 65TH ST. POLAK BLDG. WOODSIDE PROPOSED SUBURBAN LABORATORY F

i 13 SLOAIt-KETTERING INSTITUTE FOR CANCER RESEARCH Report of the Administrator The continuous drive of the Institute to find better means of cancer control has led to further expansion of work in the scientific areas already proved to be useful. The encouragement received for our program from the Congress and the general public, supported_ by financial aid from governmental agencies and private foundations, has made it abundantly clear that additional quarters would have to be sought for an expanded effort, particularly in cancer chemotherapy. We were fortunate in finding a building owned by and immediately adjoining Long Island College Hospital in Brooklyn. A cooperative agreement was made with Long Island College Hospital, in the fall of 1956, and three laboratory groups from the Institute moved into the Polak Laboratory, a five-story building of approximately 14,000 gross square feet. The laboratories are serving their purpose admi- rably and probably will continue to do so until more permanent quarters can be found. Our animal residence area, in Woodside, Queens, has also been expanded. Because of the usefulness of this area for dog and cat quarantine, as well as long-term maintenance of animals, approxi- matelyone-third o€-the former-1y -rentedgropertywas-purchased:-This area, approximately 200 by 125 feet, allows for considerable increase of the dog, cat, chicken, and goat colony with a possibility of further expansion if we should wish to breed our own rodents for laboratory purposes. Personnel Office The Sloan-Kettering Institute had 607 employees on its payroll as of June 30, 1957, not including a considerable number of individuals actively connected with the organization who receive stipends from other sources. It became evident that a personnel office must become an integral part of the administrative organization. One was opened in March 1957 in renovated quarters adjacent to the main lobby and reception room on the first floor. An experienced personnel officer, Mr. H. N'1'. Hienow, heads the staff. Numerous functions were assigned to the new office. Among the most important are: (1) recruiting, interviewing, and inducting pro- fessional as well as non-professional personnel; (2) centralizing the personnel records of all employees of the Institute; (3) coordinating wage and salary administration; (4) promoting desirable employee U 0 W N J 0 W F

14 SLOAN-KETTERINO INSTITUTE FOR CANCER RESEARCH relations; and (5) developing effective communications within the organization. Significant progress has been made in all these areas, and definite improvement has been reported in the filling of staff vacancies. The Institute works constantly to attract and retain the services of the best qualified men and women in all parts of the organization. The increasing number of scientific research organizations competing for the limited number of science graduates makes it necessary to keep pace with the latest developments in research personnel admin- istration and to provide leadership in that area. Improvement in Procedures The unusual complexity of Sloan-Kettering lnstitute's account- ing system, due to the need for accounting on the expenditure of many special funds, made it desirable to establish still better fiscal control. An assistant administrator has been employed, whose task it is to establish better control over expenditures. We are indeed fortunate to have been able to work out with the National Cancer Institute of the U.S. Public Health Service a system of submitting applications and receiving grant awards from them on a divisional organization basis. This replaces in some part awards to individual investigators and permits a much needed flexibility for the division chiefs in assigning funds to the various laboratory sec- tions within the division. Four divisional applications were sub- mitted in 1956 and awarded in 1957. The remainder of the divisions submitted applications to the National Cancer Institute this year, and we expect to have essentially all grants-in-aid from that source awarded on a divisional basis in 1958. We are also in the early stages of negotiating with the National Cancer Institute the terms and details of several research contracts - - t roug the ancer Chemotherapy National Service Center. This is a new type of support offered by the National Cancer Institute and we are watching this development with great interest in order to determine its potential effect on the future support of Sloan-Kettering Institute. We continue to enjoy most pleasant relations with the many offices of the federal agencies as well as with such organizations as the American Cancer Society and the Damon Runyon Memorial Fund. Bernhard L. Mecke Administrator

15 SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH Report of the Director SUMMARY I. Cancer Prevention 6y Defrnition and Rernoval of Cause A. INTERNAL CAUSES 1. Hormones in cause and control of cancer a) Steroid hormones (1) Hormonal influences on blood components b) Pituitary hormones 2. Natural resistance to cancer and its enhancement a) Immunochemical studies (1) Analysis of immunological components b) Resistance to implanted cancer in man c) Resistance to transplanted cancer in animals (1) Zymosan studies d) Virus studies (1) Vaccination (2) Fluorescent antibody studies B. ENVIRONMENTAL CAUSES 1. Lung cancer and cigarette smoking a) Cigarette filters b) Reduction of burning temperatures of cigarettes c) Treatment of tobacco d) Identification and removal of cancer-causing agents 2. Other studies of environmental cancer induction II. Crrre of Cancer A. LOCALIZED CANCER 1. Early diagnosis a) Enzymes in diagnosis (1) Detection of precancerous change

s 16 SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH 2. Treatment a) Improvement of surgical supportive techniques b) Improvement of radiation techniques B. DISSEMINATED CANCER 1. Analysis a) Nucleic acids (1) Uptake studies b) Biophysical analytical techniques (1) Spectrometer (2) Analysis of trace substances in tissues (a) X-ray fluorescence (b) Radio-autography 2. Synthesis 3. Trial a) Laboratory trials (1) Improvement of test methods (a) Transplanted human cancer: in the labo- ratory animal and in the fertilized egg (b) Spontaneous cancer: in the mouse and in the hamster (c) Resistant cancer (d) Combination chemotherapy (2) New agents in laboratory trial b) Clinical trials (1) Improvement of methods (a) Technique for measurement of response (b) Natural history of cancer (2) New agents in clinical trial (a) Disseminated cancer (b) Acute leukemia in children (c) Acute leukemia in adults (d) Breast cancer c) Special studies (1) Viruses (2) Melanoma studies (3) Effects of hormone alteration

SLOAN•KETTERINO INSTITVTE POR CANCER RESEARCH SCIENTIFIC PROGRAM I. Cancer Prevention hy Dcfrvitio» and Removal of Cause One phase of the Institute's program is directed toward definition and removal of the causes of cancer, with the ultimate goal of cancer prevention. There are two approaches to this objective. First, we try to define and control specific internal chemical functions of our own bodies which cause cancer or determine whether or not a partic- ular individual is susceptible or resistant to the disease. Second, we seek the identification and removal of external, environmental factors which cause or predispose toward certain kinds of cancer. Progress has been and is being made in both these areas of research. INTERNAL CAUSES Hormones in Cause and Control of Cancer All living tissue is built up of an orderly honeycomb of living cells, each type with its own special abilities and functions. Some cells, such as those of the sex and adrenal glands, have the particularly important task of making hormones-those peculiar chemicals a hich control sex, size, and many other characteristics. This function, like all others of the cell, is governed by the cell's genes, minute struc- tures passed on from parent to offspring. They contain special ar- rangements .of unique chemicals, functioning as codes, which spell out in detail the development, structure, and function of all living things. Recent evidence shows that inherited defects in the genes result in errors in the coded messages sent out by these master control boards. The garbled instructions may result in the production of hormones abnormal either in quality or quantity. There is evidence that such abnormalities may cause a number of disorders, including cancer. Steroid Hormones At the Sloan-Kettering Institute, new methods of defining and measuring the details of hormone production in man have been devel- oped by laborious research. The steroid hormones produced by the sex and adrenal glands have been studied with particular care. Many different hormonal products excreted by patients with congenital dis- orders of the adrenal gland have been isolated and identified chemi- cally. Some contain the same imperfection. It is as if an automobile assembly line turned out car after car, differing in style and color,

SLOA\-KETTERI\C I\STITVTE. FOR CAN' CER RESEARCH but each one missing a vital part, owing to a flaw in the master template. In the human body, this template is the gene. Similar studies have been made of a group of women suffering from a peculiar body abnormality, hirsutism, a common and often distressing condition which appears to be hereditary in nature. This also seems to be linked to abnormal hormone production; in this case the error is a quantitative one, a difference in the amounts of hormone produced. It is as if the master plan for hormone produc- tion contained one tiny error, resulting in the overproduction of one small but specially important group of steroid hormones. Its remote and extreme consequence manifests itself in a physical deformity as, for example, the bearded lady of the old-time carnival. Much evidence has been accumulated linking to cancer devel- opment the body's hormones, particularly the steroids. Cancer tends to develop in hormone-dependent tissues, such as the breast, ovary, uterus, and prostate gland. It occurs somewhat more frequently at puberty and at the menopause, when hormone production and utiliza- tion are undergoing basic changes. Certain varieties of cancer in man can be controlled temporarily by the administration of sex or adrenal hormones, or conversely, by removal or neutralization of hormone sources. Hormone administration has been demonstrated to cause a wide variety of cancer types in animals. Most of the Institute's work with hormones over the past twelve years has been devoted to the development of techniques by which the production and action of the steroids can be studied. This has involved the evolution of new methods of chemical separation and analysis, including the use of radioactive tracers and new syntheses of related compounds. Today most of the hormones formed by the adrenals and testes have been identified, and their normal breakdown products defined. Similar studies of the hormones formed by the ovaries are going forward. Each step forward not only brings new insight, but also takes us deeper into this complex field of study and turns up important applications to the other fields of disease. It is increasingly certain that there exist in the body, hormones of even greater potency; perhaps undreamed-of activity, and that their discover awaits only further technical development. As this program goes forward, we should be able to reconstruct in increasing detail the gene's master blueprint of hormone production and to recognize in it the defects which, if not corrected, may lead to many serious disorders, including cancer.

19 SLOAN-KETTERING INSTITVTE FOR CANCER RESEARCH HOk\IONAL INFLUENCES ON BLOOD COMPONENTS Studies of certain types of lipoproteins, fatty particles isolated from one blood fraction, have given further evidence of a hormonal imbalance underlying at least one form of cancer. Women with in- operable breast cancer weie discovered to have lower levels of one lipoprotein (alpha) and higher levels of another (beta) than healthy women of the same age. More detailed studies of a larger series showed that statistically significant differences in the lipopro- teins could be found among women with (1) normal breasts, (2) benign breast disease, (3) early operable breast cancer, (4) breast cancer spread to soft tissues, and (5) breast cancer spread to bone. Since there is overlap among the groups, the differences are not yet of diagnostic usefulness. What they do reveal, however, is some com- mon underlying problem; the tiny lesion associated even with benign breast disease or early operable cancer must be not the cause but the reflection, in the lipoprotein pattern in the blood, of some constitu- tional change. Lipoproteins are known to be influenced by the hormones of sex and adrenal glands. Women normally have higher alpha lipoproteins than men and lower beta lipoproteins. These differences are thought to account for the higher inctdence among men of arteriosclerosis and consequent heart disorders. Administration of estrogen to men results in a lowering of the beta level. Studies were made of lipoprotein levels in women with breast cancer before and after the ovaries (the source of estrogen) were removed. A change in levels toward normal resulted. Apparently the levels of these blood constituents reflect some complex imbalance of hormones that was partially righted by removal of the ovaries. Conceivably the imbalance is the cause of the cancer, a possibility long suspected. Pituitary Hormones During the past year in our laboratories, a new principle has been discovered which may make it possible to alter specifically the individual components in the body s hormone pattern. This new ability may become the key to future prevention as well as cure of many presently uncontrollable diseases due to defective body chem- istry. The hormone used in this pilot study is TSH (thyroid-stimulat- ing hormone), one of five or more produced by the pituitary, the minute "master gland" at the base of the brain. TSH has two char- acteristic properties: it localizes in the thyroid gland and, once ~ 0 W N v O A Cf O

20 SLOAN-KETTERING IA'STITUTE FOR CATCER RESEARCH attached, it stimulates the gland to produce, in turn, its peculiar hormone, thyroxin, a wholly different substance. In order to study TSH, our investigators extracted this complex protein-substance from animal pituitaries and attached to it a radioactive atom as a tag, which would indicate where in the body the hormone traveled and localized. In order to add the radioactive atoms, a minor change had to be made in the chemical structure of the TSH. The TSH, thus changed, was administered to laboratory animals. The treated ones showed none of the usual effects of thyroid stimulation, but when their thyroid glands were examined, it was found that the modified and radioactive material had localized as well as ever. The two characteristic abilities of TSH, to localize and to stimulate, had been separated. When normal untreated TSH was given to the animals which had previously received and held the changed hormone, still no evidence of thyroid stimulation could be found. The localization of the altered material in the thyroid had left no room for the normal thyroid-stimulating hormone (TSH). Hence, the force normally driving the thyroid was removed, and the gland began to decrease its output. When altered TSH was given to animals over a period of time, their thyroids grew small and thyroid deficiency resulted. A most encouraging fact is that in preliminary trials in man, the altered TSH has also blocked off from the thyroid the normal TSH. Consequently, our changed hormone may have value in the treatment of thyroid disorders in man, including thyroid cancer. At the very least, an important new principle has been established, capable of extension. Our new technique, using altered,TSH, is the first known way to destroy accurately the function of a hormone without surgical removal of the gland that manufacturers it. Now it has been clearly demonstrated for the first time that the two outstanding properties of hormones, localization and stimulation, are not inseparable, as was previously thought. The path has been opened for attempts at simi- lar control of the other hormones of the body. ENVIRONMENTAL CAUSES Many causes of cancer are already well known and some can be eliminated with consequent cancer prevention. There is nothing new about the facts, although they seem to be forgotten frequently. Not- able examples of environmental causes of cancer are at hand in the pitiful group of women, watch-dial painters, who died of bone cancer from ingesting radium by.moistening their radium-covered I

21 SLOA\-KETT£RINC INSTITUTE FOR CANCER RESEARCH brushes with the tips of their tongues; dye industry workers who developed bladder cancer due to exposure to certain chemicals, the early students of x-rays and radium, including Madame Curie, who nearly all by now have fallen victim to the slow and silent develop- ment of skin cancers or leukemia. These andd other environmental factors have forced the adoption of practical safety measures and demand further search for cancer-inducing agents in our daily activi- ties and contacts. To establish a cause-and-effect relationship between exposure to a rare chemical and an unusual type of cancer and to take swift steps toward prevention is comparatively simple when the individuals involved are few and the exposure unusual. It is much more difficult, however, to identify and eliminate those factors to which a broad segment of the population is exposed, which are almost imperceptible and entrenched parts of our lives, and which increase the risk of cancer to thousands of individuals rather than to a com- parative handful. It is to this task that we now direct our attention. Lung Cancer and Cigarette Smoking One of the most urgent and accessible immediate problems in practical cancer preverition is that of cancer of the lung. This disease, rare twenty years ago, is now one of the most common causes of death among American males. Each year, furthermore, it increases in prevalence to a degree which actually nullifies all of our improved abilities to cure and prevent cancer of other types. Eighteen separate studies from seven different countries are in agreement that the risk of developing lung cancer increases in direct ratio to the duration of smoking and quantity of cigarette smoke inhaled. Therefore, the practical problem which remains to be solved -one of great impor- tance, since cigarette smoking continues - is to devolop a safer cigarette, preferably a wholly innocuous one. Recent research at the Institute has been directed largely toward this goal, and seems to be productive. This is encouraging indeed, since lung cancer now kills 25,000 persons a year in this country. Cigarette Filters Our evidence indicates that the greater the amount of tar inhaled in the form of tobacco smoke, the greater the chances of developing lung cancer. Therefore, if a significant amount of tar were to be removed simply by mechanical filtration, the cancer risk would be reduced. Surveys of presently-available filtered cigarettes revealed an un- U

SLOA\-KETTERiNO IIaSTITUTE FOR CANCER RESEARCH expected and disturbing fact, however. Smokers of most brands, but not all, are inhaling as much, and in sonie cases more, tar than smokers of regular unfiltered cigarettes. This is due to the fact that the type and cut of the tobacco have been altered in response to public demands for increased "flavor," so that the smoker is exposed to more tar, despite the filter. It is now possible to produce a commercially acceptable filter which will remove 40 per cent of the tar from the smoke. If all other factors -type of tobacco, size of cigarette, cigarette consumption per person - remain equal, use of this filter should, according to our evidence, significantly reduce the toll of lung cancer. Reduction of Brn-ning Teruperatures of Cigarettes Our tests show that virtually no cancer-causing substances are present in the tar of the smoke when tobacco is burned at 620°C. or less (present cigarette burning temperature is about 880°C.). Even a reduction of 50° decreases greatly the ability of the tar to cause can- cer in animals. A safer cigarette, therefore, might be produced by adding chemicals oi by changing the cut of the tobacco so that it would burn at a lower temperature. Promising results are already at hand. Treatment of Tobacco The waxy outer coating of the tobacco leaf contains much of the substances shown to be the source of cancer-causing agents in the tar of cigarette smoke. "Dry-cleaning" the leaf with a solvent appar- ently removes a substantial part of these waxes. Laboratory experi- ments testing the cancer-causing ability of tar from the treated tobacco are now in progress and appear promising. Identification and Removal of Cancer-Causing Agents A fraction has been isolated, representing 1.5 per cent of the total tar, which appears to contain most of the cancer-causing activity of the total. It is made up of several components. If the combination which produces cancer in animals can be identified; reduction or elimination by chemical procedures or by specific filtration might be achieved. Progress is being made in this area. Other Studies of Environmental Cancer Induction Studies have been carried out on cancer of mouth, vocal cords, and related structures. The results indicate that smoking also plays

23 SI.nAX -FETTFRIX G IN" STITVTE FOR CA\CER RESEARCH a considerable role in their cause. The factors differ, however, from those previously established for lung cancer, in that cigar and pipe smoking were found to be more important than the inhalation of cigarette smoke. It also appears that heavy alcohol consumption is a contributing factor in the development of cancer of the mouth and nearby structures, but not in cancer of the lung. Interviews with patients have been completed in a study of fac- tors possibly related to the cause of cancer of the breast. The work was conducted with investigators in lndia, Japan, and England, as well as elsewhere in this country. The frequency of breast cancer varies materially in different locations, a fact which may be an important clue to the origin of the disease. Other work currently in progress includes studies of environ- mental factors in cancer of the stomach, colon, rectum, esophagus, prostate, and bladder. Particularly ivorthy of mention is an active program in cooperation with Dr. Niels Dungal of the University of Iceland. The incidence of stomach cancer in Iceland is about three times that in the United States. A difference as great as this should be a source of significant leads to cancer cause, Natural Resistance to Cancer and Its Enhancement The question of the existence of a natural defense against the induction and growth of cancer has been one of the most debated subjects of research. Recent work at the Institute indicates that a defense does in fact exist; has revealed suggestions about its nature, source, and the way it works; and offers the hope that it may be used eventually to achieve better control of cancer in man. Immunochemical Studies When an invader -bacteria, virus, foreign tissue implant - enters the body, the body responds by forming antibodies. These are large protein molecules shaped specifically to fasten themselves to a particular invader (antigen), just as two pieces of a jig saw puzzle fit together. Antibody formation is important for several reasons. First, antibodies are the means by which the body fights off infection. When penicillin is used to cure bacterial infection, actually it serves to reduce the number of infecting organisms to a point at which these potent defense mechanisms of the body can take over. If equally strong resistant mechanisms could be evoked in the case of cancer, certain forms of the disease, for instance, acute leukemia, could be cured today with the help of available agents.

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30 SLO:1N -KE7TERIKC IN STITATE FOR CaNCER RESF.:IRC}1 Active immunity to an infection, such as measles, is conferred by the continuing presence in the blood stream of specific antibodies against the measles virus; these stand by ready to stave off any second invasion. Killed or slightly altered versions of the disease-causing organism can evoke the formation of similar protective antibodies: the formalin-killed polio virus particles serve to protect against polio; cow pox virus vaccination induces the formation of antibodies which give immunity to small pox; and typhus rickettsia virus, changed slightly by repeated cultivation in the chick embryo, Avards off typhus. Recent studies of Sloan-Kettering stir the hope that a vaccine against some types of cancer may someday be available. The biochemist can also make important use of antibodies. Be- cause of the high specificity of the antibody-antigen reaction, it can be used as a swift sure means of chemical identification. For instance, in the crime laboratory, whether or not a blood stain is of human origin is readily determined by testing it.vith appropriate antibodies. Antibodies are similarly used in cancer research in an effort to detect points of chemical difference between cancer and normal cells and to gain new leads to the selective destruction of cancer. Immunology also plays a major role in disease detection. The Wassermann test for syphilis, one of the most specific and effective of diagnostic tests, depends on the detection in the blood stream of the specific antibody against the spirochete of syphilis, a clear signal that the disease is present. Use of antibodies is now aiding in the diagnosis of one rare type of cancer, and further leads to a more widely useful diagnostic test are being explored intensively. Immun- ology is one of the most exciting fields opening in the path of cancer research. .aXA[J'SIS OF I\I\IU\OLOGICAt. COMPONENTS One of the most important investigations in this area is the immunological search for the specific point of difference, either quantitative or qualitative, between normal and cancer cells. Finding this point is important. It would serve as a basis for the study of the body's ability to form antibodies against cancer. It would provide the starting point for studies of possible diagnostic tests. It could offer ncw leads to cancer treatment. The individual cell is a complex mixture of components that can serve as antigens, that is, provoke the formation of different antibodies. Most of these are proteins and accordingly esceptionally diflicult to purify. The first step was to select a more suitable component for V c W N J

31 SLOAN-R'.ETTERL\G I\STITIITE FOR CANCER RESEARCFi study. Different fractions of rat ( ancer cells were tested and then dif- ferent components of the fractions, until a strong antigenic material was found associated with a group of substances known as lipids. Then, by use of the extremely sensitive «'assermann technique, many differ- ent types of tissues were tested for the presence of this rat cancer lipid antigen. It was first found to be species specific, that is, present only in rat tissues. A more exciting finding, however, was that this partic- ular lipid component was absent from many of the normal rat tissues tested and present in all of eight different rat cancers. This is an indi- cation that im1minol0gically n:easurable differences between cancer and normal cells may exist. The next step ..~as to redo the work in terms of human cancers. Thi, wa> far more difficult because of the biological variability among humans and the scarcity of tumor specimens of adequate size. Partic- ulate fractions .rere removed from these tissues and injected into rabbits where antibodies then were formed. Some reacted with our lipid component. The rabbit-produced anti-lipid antibodies were then used to test for the presence of the lipid substance or substances in other tissues. Results were not uniform, and it was obvious that mix- tures of substances were present, but there were again the sought-for differences between normal and cancer cells, for instance a thirty- fold difference between lung cancer and normal lung tissue. 'l'he next question was ho;v to obtain the material in a pure form, both c) standardize the testing procedures and to identify this only vaguely defined compound. Since the material under study represents only a tiny fraction of cellular components, large, uniform amounts of tissue specimens are necessary to obtain any useful amount of material. Human cancers grown in the laboratory animal offered a ready solu- tion; the problem was, however, that these cancers, once growth is established, become surrounded bv connective tissue of the rat, and, when injected into the rabbit, antibodies which react with lipid com- ponents are formed only against rat antigens rather than human. Then awav around this problem was found. It was discovered that, although rat-grown human cancers could not be used to produce antibodies, antibodies produced in the rabbit against human cancer taken directly from patients would react with the rat-grown cancers; that is, the anti-lipid antibodies would seek out and combine with the material from the human cancer cells. This finding lent strength to our belief that we had perhaps found a component common to cancer cells and also gave a method by..•hich it could be obtained for stlldy. Tust as this report is being written, a small quantity of the lipid antigen from human cancer tissue has been obtained in pure form. By the

32 1 1.I-A ~ -At"r'1lRlS C IN S7ITUTE FOR l'A\l'r.R RF:S r:\RC'tl technique, developed, it can be detected in quantities of less than 1 1000 of a microgram (less than one ten thousandth of thc weight of a grain of sugar). Now that this material is available, it will be possible to determine definitely whether or not we have found what we have been so intensively seeking, an immunological point of differ- ence between cancer and normal tissuef l f this has been found, it would provide the starting point for major investigations in cancer diagnosis and treatment. Sf:IRCtI FOR A llI.1CXOSTIC TEST Using another method, a second group at the Institute has been engaged in studying the differences in composition between normal and cancerous tissues. Antisera (blood seruni containing antibodies) were prepared in rabbits by injecting them with tissue or tumor extracts. These antisera, which form precipitates with specific tissue protein components (antigens), were then studied by a new method in which tissue extract and antiserum diffuse towards each other in an agar gel. «'hite precipitin lines are formed wherever an antigen and its antibody meet. By this method, some common antigens were found to be present in almost all tissues analyzed; some were found in the tissues of sume individuals but not in others. I twas also found that all cancers were not alike in all their antigenic properties. Of great im- portance, however, was the demonstration that antigens are present in cancer tissues which could not be detected in the surrounding normal tissue of the same organ from the same patients. That cancer cells may indeed produce specific components has m>xv been established for two relatirelv rare forms of cancer; multiple m}•eloma and macroglobulinemia, A%-hich involve cells of the bone marrow and the lymphatic tissues respectively. In the blood of pa- tients who sufl'er from these two diseases, antigens can be found which are absent from the blood of normal persons, and these two diseases can be distinguished from each other because each is characterized by a different antigen. This finding has resulted in a simple test using immunological technique for these diseases which is now being used diagnostically on blood samples sent here from maity parts of the worl d . An interesting sidelight of this .vork has been the observation that.%hen multiple mveloma responds to urcthane treatment, a chem- ical that effects transient relief, the abnormal antigen may at times disappear. This change in the antigen pattern ma' y be useful when objective criteria will be needed in the evaluation of other chemo- therapeutic agents for this disease. u+ C N a 0 F J w

33 S L fl .i N - I: E T"I E R I\ C FN' S T I T l." T E F1l R C AX l' E R R E S E A R C H Rcsistance to Infpln,ncd Ca,rccr in :'llan The first step of this crucial study involved patient-volunteers with advanced cancer. Cancer cells removed from other patients, and long in artificial cultivation in test tubes, were implanted under the skin of the patient-volunteers' forearms. To our amazement the implants grew until they' %vere removed surgically. The result of this esperimentwas unexpected and revolutionary, since it contravenes a principle of biol,igy that tissue from one animal will not grow if trans- plantc I to another unless the recipient be the identical twin of the donor. I t.vas necessary to know then whether the human cancer trans- plants had grown merely because the cancer patient-volunteers, all of whom were in advan:ed stages, lacked some natural defense mechanism. Perhaps the growth of their own cancer also was due to this lack. To settle this point, certain of the patient-volunteers were then inoculatr,l with viruses of types not harmful to man. Others received impl.rnts of normal human tissue. Both treatments evoked the usual bodN defense reactions. The cancer tissue, however, grew unchecked. Only a%o possible explanations could exist. Either the cancer tissue had abnormal ability to grow, and so contradicted the estab- lished rules governing tissue transplantability, or the patients lacked a normal resistance to the growth of cancer cells specifically, one not operative to the same degree against other foreign cells, such as viruses, bacteria, or normal human tissue. This raised a further ques- tion. Clarification could be h;rd only by an answer to the question, •'Would transplanted human cancer cells grow in normal human bei ngs?" For over half a century, scientists have been trying to inoculate themselves with cancer. Not one has been successful. These attempts, however, have been isolated and sporadic. Their results did not offer real scientific proof. Valid evidence cc-.rld be derived only from con- trolled experiments using.eell human beings.vho would volunteer to receive injections of uniform cultured human cancer capable of growing in animals and cancer patient volunteers. We then appealed to the Ohio State Penitentiary, where there .vas a strong tradition of aid to medical research. A notice was placed bv the inmates in their prison newspaper: "«'anted, Volunteers for Cancer Research." Fourteen men were needed for the first experi- ment; over a hundred volunteered. Those selected were implanted with the same types of cultivated human cancer cells used in the

34 SLOAK-1:ETTERI\G.INSTITCTE FOR CANCER RESEARCH study with the cancer patients. In all fourteen, there was a vigorous local inflammatory defense reaction to the cancer implant; it could not grow; implants that were not surgically removed for study under the microscope disappeared entirely within four weeks. There were no recurrences. For the first time, the normal human body was shown to possess some natural resistance to growth of cancer transplanted from other human beings; a resistance not possessed to the same degree by patients with advanced cancer. In the second step of the study at the Ohio Penitentiary, the members of the first group of volunteers were reinjected, each with the same type of cultivated cancer cells he had received previously. The cells inoculated were destroyed more rapidly in this study than after the original implantation, indicating that the defense mech- anism had been enhanced in some way by the original inoculation. This is similar to what happcns when a person is attacked for the second time by a virus or bacterium; it is the principle upon which vaccination is based. In the third part of the study, completed only recently, inmate- volunteers who already had been implanted with one type of cancer cell received implants of a second, different type. These cells also were destroyed more rapidly than those given initially, hut less efficiently than a second implant of the same cells. Control patients injected with normal human cells did not show this reaction although further studies are required. There may exist a real natural defense against cancer, a general reaction possessed to varying degrees by normal persons and either lost by or initially lacking in the cancer patient. Blood studies.vere next made in cancer patients and well volun- teers to define the factors involved in this reaction. Although they lacked defense against implanted cancer cells from others, the can- cer patients apparently were not deficient in circulating lymphocytes (white blood cells which are associated with immunity), or in the ability to produce an immune (inflammatory) response to irritants or bacterial infections. They also were adequate in their ability to produce antibodies to viruses. The best lead to the nature of the natural defense against trans- planted cancer appears, from our evidence, to be afforded by a sub- stance called properdin, a natural defense chemical present in the blood. It appears to be the only factor associated with immunity in which cancer patients are demonstrably deficient as compared with well persons. Furthermore, the levels of properdin in both our well 0 w N J O C ~ V

~ SI.i1 A \-F: ETTlRI\ l: 1\ ST/T t• T F. F0 R C'A N C-F R R r S F. A RC 11 and cancer groups vary directly with the ability to reject the implants of cultivated cancer cells. In addition to the general defense response against cancer pos- sessed by .ti•ell people and which may involve properdin, there appears to be an additional and specific defense mechanism against implanted cancer from others as shown by the well volunteers' more vigorous reactions to the second and third injections. To date, no blood serum antibodies to the implanted cancers have been regularly found, but these studies have not yet approached completion. The next studies now planned will involve the injection of well persons with killed cancer cells and certain chemical components of them. Rcsistnnre to Trwnsplantcd Cnnrrr in .4nunJals The growth in our laboratories of transplanted human cancer in suitably treated animals has been described previously. Now sub- stances have been found in the blood and tissues of these animals which will destroy the human cancer cells in thce test tube. The ability to produce, detect, and test for cancer-destroying substances may facilitate studies of inoculations against human can- cer and is considered encouraging to, the entire field of immunity. 7.1'\IOSAX STUDIES In another laboratory of the Institute, there has been uncovered, in animals, exciting evidence corollary to the findings in the Ohio volunteers. Zymosan, a yeast product, has been shown to affect the levels of properdin. Large amounts of zymosan lower the levels of properdin in the blood. Small doses, on the other hand, raise them. A single small dose of zymosan was given to mice bearing transplanted cancer. Three weeks later the cancers ulcerated through the skin, decreased in size, and finally disappeared. The studies described suggest that the normal body does indeed possess means for defending itself against cancer and that these means are wanting in patients with advanced disease. Once more, we see the analogy between in.•asion by cancer cells and invasion by other types of organisms causing disease. These similarities suggest that cancer control may be susceptible to attain- ment bt means already known in principle.

36 SLnA\-AETTERIIO 1NSTITCT E FOR CANCE. R RE.SEARCA VN'U.r .StHtflt'S 1'ACCIXATIOX An aspect of virus study concerns the isolation and definition of viruses as causes of cancer and their use to produce a vaccine for cancer prevention. The theory that viruses cause cancer has intrigued scientists for fifty years. The first evidence came in 1911, when I)r. Yevton Rous removed a growth from a hen, ground it up, and passed the material through a filter so fine that no cells could possibly get through. \\'hen the filtrate was injected into other foxvIs, an identi- cal cancer.ras caused in a few days, even if the fluid had been dried or frozen and stored for many months. Since that time, a few other types of cancer have been shown to be caused by viruses in fowls, mice, rabbits, and occasionally in frog: and dogs. There have been sporadic attempts to generalize, of course, and prove that all cancers are virus-caused, but these have foundered in researchers' repeated inability to demonstrate virus in most forms of cancer in animals. There has been no evidence, despite many efforts, to show that viruses play any role in the development of human cancer. The study of cancer-causing viruses has suffered from a num- ber of impediments. First, we are unable to define a virus very exactly. They are invisible, except under the electron microscope. They can be defined as particles which will pass through a very small filter and which can live and divide only within the proper living cell. Viruses can change, vanish, or lie dormant for years. This makes them particularly elusive subjects of research. Furthermore, the effects of viruses depend not only on the virus itself, but on many host factors, including age, sex, hormones, and genetic constitution. With all the mammalian cancer viruses discovered until very recently, there was also a long latent period of cancer development. Both the mouse breast cancer virus and the mouse leukemia virus have to be given to newborn animals. The virus then literally disappears and there are no signs of it until cancer appears a year or so later. This has made study slow and difficult indeed. About a year ago, some of these problems were lessened. An investigator at Sloan-Kettering discovered a new virus'in mouse cancer. It produced leukemia in almost all of the animals inoculated; all ages and both sexes xvere susceptible to the infection; and the first signs of leukemia appeared within two to three weeks.

UNJ (Jrosyril,osrrrnrlrir nrid), a unique rhrurierd forrrrd in the cell uur/ews, is kno¢ru to nnutmil drrnlitm7 rdor- nrtrri.elirs. Thrrr is alronp rtielrvrrr tGat in rrllr'rnNon in UNd rnttsrs a rnurrr re•ll lo !r prorlurrrl nnrl t1m111ir frurltt /)\'d is trnrrsniittrrl /ronr prrrruJ rnurrr cell, to dnugGlrr rrurrrr rr!lx. 7Yrir wodrl of tlir DXd rrn.lrrulr uws ron- strurlyd on tbr (nsis ol prr.vrul irJorvrmtion al.on( 1/unrolr- rulr's sbvrrturr from iuirrlr/erNorrr li!Gr .llydirnl /:r- rrarrd C:oauril, Riophisirs Rrsrrrrrh ['ui1, A'inri, Collrgr. /.oudou, nnrl ils ro!(n/walr.r.r nt Slarn-Kr7trriu;l l nsliNrtr. /br/oar) I)\"d ira, nrlrr~rtrd Ir~.m u/u1, I/oorl rrll.r of a hnlirnt with <'hronirlrrnflmlir lrnkrrnin, 7 he prnr mulrr-in, is uoaa undnstudr Gp srvrrnl diflrrrnt Irrlruiqurs.

38 SLOAN-K ETTERIRG 1\ STITI'TE FoR CA \ C F.R RES E ARC N Because of the comparative ease with which the new virus could be handled, we were able to undertake this crucial study in the cancer-virus field, one which had been long contemplated and had been previously attempted, but never successfully carried through. We set out to see if a vaccine could be prepared against the cancer virus. We began with mice which had been injected with the leukemia virus, but had survived. Of these, 90 per cent were immune to rein- jection of the virus. We had to find out whether this resistance was innate or whether it had been built up as a result of the original injection and could thus, perhaps, be induced in other animals. Rabbits were inoculated with the virus and blood samples later collected. Rabbits are, of course, immune to mouse leukemia, but their bodies would build up defenses to a virus injection. The treated rabbit blood was then mixed with the leukcmia virus in the test tube and the mixture injected into healthy mice. Only 5 per cent of the mice, instead of the usual 80 to 90 per cent, developed leukemia. Antibodies against the virus, clearly, had been formed in rabbits, had combined with the virus, and had rendered it harmless. The leukemia virus was next mixed with formalin (this is the way the Salk vaccine is prepared). The virus is killed, so that it cannot induce disease, but it may retain enough of its original char- acteristics so that protective antibodies are produced against it. Mice were injected with the treated material and then, after an interval, they were given the live virus. They were protected. We had pre- pared the first effective vaccine against a mammalian cancer. Subsequent experiments have shown that this vaccine is entirely specific; it does not give mice immunity to any other form of cancer. Not only are the mice protected against the virus which causes the leukemia; they are protected also against the leukemic cells them- selves. Injection of these cells regularly causes leukemia in unvacci- nated mice; it is without effect in nearly all of those vaccinated. '%A'c believe this to be an indication-the first real indication-that it may be possible to prepare a vaccine against other types of animal cancer, and perhaps sonie day even against sonie forms of human cancer. FLUORESCENT ANTIBODY STUDIES Fluorescent antibodies have been used as an analytical tool for study of the role of viruses in the cause and development of cancer. U 0 W

39 SLn AI<-KETTERING 1N STIT V TE FOR CA \ CE R R ESEARCH Antibodies are made fluorescent by tagging them with a special dye that glows apple-grecn under a special microscope. The dye is incorporated directly into the large antibody molecule, just as a radioactive atom may be tagged on a compound for tracer purposes, and serves as a ready means for detecting in tissue slices the localiza- tion of the antibody. By this method Sloan-Kettering investigators have now suc- ceeded in demonstrating,-bp the presence of antibodies, viruses in two types of cancer in animals. This affords a unique opportunity to correlate the presence of a cancer-causing agent with the trans- formation from normal to cancer cells and to observe the cellular changes step by step. Intensive work with one type of cancer has thrown new light on the mode of action of a virus as a cause of cancer. Viruses are made up of nucleic acid encapsulated in protein. Antibodies form only against the protein portion. When tissue sections of the cancer are esamined under the microscope, antibodies, although present in sonie of the cancer cells, cannot be found in those which are dividing most rapidly. It seems clear that cancer-causing viruses exist in two stages, one as an antibody-evoking complete (nucleic acid plus pro- tein) virus, which would be the form in which it is passed from one host to another, and secondly, as an incomplete virus, a pure nucleic acid hidden within the cell. This brings close together two main schools of thought on cancer cause, the one believing that can- cer is caused by an invading extrinsic agent, and the other holding that cancer represents a mutation which involves, of course, a change in the cell's nucleic acid. If a virus functions as pure, intracellular nucleic acid, the dividing line is slight indeed.

S L „AN _I . I r:RI\f_I W STITL'TE Ft1R ('A V C'F.R R FSE AR(' H U f6lJ!!C'fl' LOCALIZED CA\C'ER Early' Diagnosis 7'he :6'1t' rIf cancer today hinges on its early and accurate diag• nosis. It •,stiniated that with better methods alone, capable of detecting ~tnt still localized cancer, almost one half of all cancer victims ;,•,'.•1 be cured today by surgery and s-ray's. A major effort of the ln< iut(' is the search for such methods of early detection. \lu:!• %(ork has been devoted to the search for a blood test for cancer, as •mple and accurate as the Wassermann test for syphilis, one whic'• ~,ould reveal any kind of cancer anywhere in the body. At least ar"•' ~~ly reports appear of the discovery of such a test ; to date there is n.' ~did general test. j:n.,Ynr,: ': 1)ingltosis Thc,. .:1r many different factors in the blood which may be studied :r s',•>`ible test systems. We have chosen enzymes for one. These su! 't"ces are the body's chemical workers. No cell in the body can r• torm a single chemical function without calling into use a spc: •'• enzyme which exists only for that task. Enzyme; are like the iN•' ` in a great mass-production factory, each responsible for slipp;-':: •~ particular bolt or cog into place. Because different cells haxc •'-tlerent functions (sonie make hormones, sonie act as filters, so.- •{if;est food), they have different production staffs of enzvme,l .:. (~ •'rk for them. Under certain conditions of damage to . the cell, t1•: •`,ftrent enzymes may be released into the body's blood stream. two facts-the enzyme specificity of cells and the release ot :'%nies into the blood stream-fonn the basis of this work. The !'."'•.tn body contains enzymes in uncounted numbers. As a start, wr x:,:;t('d for study one called GO-T (glutamic oxalacetic transamin.:<• '•+ince we had reason to believe that it might be involved , • 'w growth of cancer. Froir '111al studies, we learned that heart tissue contained far more (' I' than any other tissue of the body. Blrn,d tests %vere made in : 't'` of patient: who had suf/cred a heart attack, a dammin" ,~ b\ a blood clot of one of the coronary arteries. The first samh ;''t. f'fy-f • taken immediately after the attacks, ~~~ere normal. *1'-•" 'n `amples taken a few hours later, tve began to see V c w N J O F N ..,

41 S1.i1 .\\-1: F:l'TF.R 1\l: I\ S9' ITl'T r 1: 11R t'A\ (' F R R E:S! A R('!1 a steady rise in the GO-T; 24 to 48 hnurs later the amount of enz~~me in the blood was 2 to I i times greater than normal. ~1'e took repeatcd small samples during the recovery periods in 4 to 7 days; GO-T was down to normal again. What had happened was simple. When the heart muscle cells began to die from stoppage of their blood supply, GO-T escaped into the blood stream. As scar tissue formed and repair set in, the levels decreased to normal. As the detailed data were amassed and correlated with other findings, we found that GO-T accurately reflected the severity of the heart attack, could reveal approximately when it occurred, and could indicate any relapse during the recovery phase. These measure- ments, which can be made readily in a laboratory or doctor's office, could help distinguish between a true heart attack and conditions which may simulate it. Thus, this first study gave us not only .vhat we had originally sought - a good working example of how enzymes can be used to diagnose disease -but also an unexpectedly valuable new tool for guiding treatment of patients with heart attacks. The test is now in use throughout the world. Called the most important development since the electrocardiogram, it is a significant by-produet of cancer research. The tissue which, second to heart muscle, contains the largest concentration of this GO-T enzyme is liver. We set to work to see what happened to its levels in the most common of liver diseases, viral hepatitis, the plague of our army in World War I I. In a nearby institution, three of the inmates developed the disease, exposing the other persons ..•ho shared their building. As expected, GO-T levels were markedly elevated in these patients, but there was an unexpected finding. As in most virus-caused disorders, there is a long incubation period between ezposure to the disease and the time when the first symptoms develop. The standard tests showed no hint of the impend- ing infection during this period. However, weeks before a patient became ill, and when all other tests were negative, GO-T levels began to rise. As a result of this finding, it is now possible, for the first time, to predict who is developing hepatitis, to isolate the individual so he does not infect others, and begin his treatment even before his actual illness is apparent. Also, if the enzyme level begins to rise in a patient presumably on the road to recovery, we know that a relapse of the disease is in progress and active treatmentcan begin again, even though the patient appears .vell and all other tests are normal. This gave us a new concept in the "enzyme diagnosis" of dis- U O W N v 0 r N N

.ta S L fl A\- y; E T T E R 1Nl: 1X S T 1 T l' T F. r 0 R l' .\ \ l' k R R F, 5 E A R c n ease; it is not necessary perhaps for cells actually to be destroti'ed before their enzyme patterns change. The tell-tale enzymes begin to appear in the blood when the cell is first injured. By studies of GO-T and other enzymes, we found also that we could distinguish many types of liver disorders, such as cirrhosis, poisoning, and various types of jaundice. Furthermore, liver damage can be distinguished f rom heart damage by the pattern of enzyme rise. Of particular importance to our primary problem, GO-T mea- surements have been shown to reveal hidden liver cancer. In a substantial proportion of patients studied by all known tests, the characteristic GO-T rise was the only indication that cancer had spread to the liver. Such knowledge is, of course, of great importance in patients being considered for major surgery. Thus, in the second stage of our enzyme study, we had another useful tool and further new information: that enzymes could predict a disease, could reflect abnormalities in a cell rather than just its destruction, and, by the varying sensitive patterns, could be used for differential diagnosis in the same type of cell. These new data held important implications for the cancer problem. Can enzymes be used to reveal the presence of canccr% That is, of course, one key question motivating our group. Cancer cells and normal cells were grown in test tubes in the same media and under the same conditions. The fluid in.vhich they were growing was studied for enzyme activity. It was found that an enzyme, LD (lactic de- hydrogenasej was present in much greater amounts in the fluid sur- rounding cancer cells. The production of LD was apparently a by- product of the abnormal growth. Sometimes, in man, when there is disease in the lung or abdom- inal contents, fluid collects in these areas as a result of the inflamma- tion of the tissues. This fluid may or may not be due to cancer. Samples of this sort of fluid in a series of patients, sonie with cancer, some with other disorders, revealed that, just as in the test tube experiments, the fluids that came into contact with the cancer cells were consistently higher in LD. We found, similarly, that the pres- ence of these enzymes in spinal fluid could reveal cancer deposits in the brain, often extremely difficult to diagnose. This was not only an exciting confirmation of our laboratory studies, but offered a practical and efficient test to aid in the treatment of these patient+. IIETF.C:TIO\ OF PkECAXC[:ROC'S C11:1XG1•: In the mice,.chich developed leukemia a few weeks after injection with a virus, blood samples were tested for lactic dehydrogenase. In

43 S1.O\\-K F'1'TFRI \C 1\ STITC'TF. FI. R C'R \CF R RF.SF.ARC 11 all case: the enzyme was present in increased amounts in the ]cu- kemic mice and the increase was proportional to the extent of dis- ease. Here we made another exciting finding. Between the time that the virus injection is given to the animals and evidence of leukemia appears, there is a quiet, incubation stage, similar to that preceding viral hepatitis. No traces of cancer cells or impending cancer can be found by regular tests. Yet in each case, there was an increase in the LI) in the mouse's blood before any signs of leukemia appeared. Possibly cells that are turning to cancer show an abnormal chem- ical behavior, a different pattern of enzyme manufacture, before the cancer is manifest. This interesting concept seems to be the only expla- nation in this experiment. We hope to translate it to the problem of human cancer, so that we might have a means for detecting impend- ing disease even before the first full-blown cancer cell appears any- ,,%fiere in the body. Blood tests for LI) and other enzymes are now being made on cancer patients. In many instances, the characteristic elevation of enzyme content has been found. It seems roughly proportional to the extent of disease; when the patient improves under treatment, the L..D concentration drops, to rise again if the disease becomes reacti- vated. We do not know whether LI) activity ever appears in patients before there are actual signs of cancer; this .vill entail a large-scale and enormously complex study. We do not know why the enzyme is present in the blood of some cancer patients and not in that of others. This may be due to difficulties of techniques, to the different locations of the cancers studied, or to the different types of the dis- ease. We do not know yet just where this group of studies will lead and what the limits of this new concept of disease diagnosis may be; the body contains enzyme systems still completely unstudied, many even still unknown. We do know, however, that this is a promising field of research. Treatment Improz,cnrcnt of Srrrgicnl StrpportiVe Tcchrriqires Studies have continued of methods by which surgery, the most effective means for cancer control now available, may be made safer and more regularly curative. Ammonia poisoning due to poor excre- tion, often found in patients with liver damage from cancer, can be a serious problem. Its cause has been defined and useful treatment developed. O W N v O C N t

44 SLOA\-i;ET]'FR1NG I V ST17eTF F0 R Ca\ ('F.R R FS F..A RC tl Work has continued on the artificial kidney, a mechanical device serving as a temporary substitute for nonmal kidney function in filtering waste, potential poisons, from the blood. It has been found to have a definite place in the treatment of cancer patients during acute kidney failure following massive surgery and other p roced u res. Studies in patients who have had their stomachs removed for cancer indicate that male hormones may be beneficial in reversing the nutritional deficiency that sometimes occurs as a result of this operation. In anesthesiology, new drugs have been tested and widely useful new mechanical and electronic devices have been developed to improve and control the administration of the agents employed. A component (enzyme) isolated from human blood has been studied for its ability to dissolve clots in the veins and arteries of experimental animals. It also has been useful in the treatment of some patients.vho form clots after surgery. Since clots in the arteries of the heart (coronary thrombosis) are the major cause of death from heart failure, the potential value of this agent is immense. Efforts are now under.vay to purify it and free it from contaminants which cause side reactions. 1»iproq,enrerlt of Radiation Techniques A new method to measure precisely the radiation dose in tissue- like material has been developed. Although the energy so deposited is microscopically small, our exceedingly sensitive technique is able to define the absorbed amount very exactly. It is now being applied to different materials exposed to different qualities of radiation from a variety of sources. A report on the work was given at the request of the United Nations Scientific Committee at the Atoms for Peace Conference held in Geneva. The direct measurement of the radiation dose received by the ovaries, testes, bone marrow, and other special tissues of patients who receive either diagnostic or therapeutic x-rays has been initiated. It has been made possible by the construction of a "phantom" man. A complete human skeleton is contained in this phantom, with the other special tissues such as bone marrotv and lungs, simulated with sufficient accuracy for radiation measurement by a chamber of special design constructed of conducting polystyrene. 'J'hese determinations of bone marrow dose provide new and much needed data, particularly in view of the recent recognition that small amounts of radiation can cause leukemia or bone cancer and that even minute amounts may contribute importantly to the injury. These measurements are being made for

L P. Rhoads, M D. D-cior Bernhard E Mecke Henry E. Meleney, Jr. s A. R. 1. Denues, Ph.D. Depurr D~recro. Harriet (. Hughes Adm;nle4oro. Ass;s onr Admfn;shoro. Ass;sronr Adminlsr.aror -4 Henry 1. Randall, M.D. Asrodeie Dl.ecro. C (hester Stock, Ph.D. Assoc;ore D-cio. ' . ~ ~ " ~~. ilN~h - Bernard J. Polumbo h:<ul OiGce. H. W. Rienow Benjamin W. Erickson Pe.r.-r oq<e, Ass smnr Pe,so-r oR<er John J. Biesele, Ph.D. Oscar Bodan>ky, M.D. George B. Brown, Ph.D. Joseph H. Burchenal, M.D. Emerson Day, M.D. Thomas F. Gatlagher, Ph.D. Memb" Member Membe: Membe. Member Membe. David A. Karnofsky, M.D. John S Eaughlin, Ph.D. James J. Nickson, M.D. Frederick S. Philips, Ph.D. Memb<r Member Membe. Member r" I ~~,~.~ [7~l' a"..alfi Fr / f ~ . Rulon W. Rawson, M.D. Fred W. Stewart, M.D. George W. Woolley, Pn.D. Member Member M-ber M_ Barcloy, Ph.D. R. K. Bmday, Ph.D. 1. W. Bellville, A' D. A. Bendich, Ph,D. R. Benuo, M..D. J. Berg, M.D. M. Bermon, E.E o{ v\ ~~~' ~ il"artl 1f~1 !~8 1 ~i M. Bord, Ph.D. N. Barr, Ph.D. J. W. Beottie, B.S. ' ij.. I. Bieber, M.D. A. Boeticher, Pir D. ( P. Boyan, M D.

a 7 ~n Nr..i i'::,.Itft = M /T / R. R. Eltison, M.D. H. Endo, B.S. 6( Escher, M.D. M. Fork, M D. Y Y J. H. Fryer, M. D D k. Fukushima, Ph.D. P. Garcia, M D j }-/ '; ., =I [AW 16 Fortner, M.D. J Gnspor, M.D. A&M IF."Aa'i Mt M J. F. (odington, Ph.D. H. S. (ollins, M.D. t F. (raver, M.D. ~ . _ .c~'IS ~.} ~'® ~ ..c [ . /%f1 ® A. S. Glicksmon, M.D A. GinerSorolla, Pharm.D. 71 A. H. Freiman, M.D. M. Friedman, D.V.M. l. Gross, M.D. 1. Nall, Ph.D. l D. Hamltton, D.M. A. Han,pton, Ph.D. J.1. Harris, Ph.D. R. E. L Hert:, M,D. E. Holmberg, M.D. R. W. Houde, M.D. W. S. Howlond, M.D. 1. J. Hudock, M.D. M. G, Drellich, M.D. Ih R. Gotbey, M.D (. ( Hmrold, M.D. ra . D.1. Hutchison, Ph.D. H. l Bradlow, Ph.D. W. i. Brodner, Ph.D. R. D. BrasBeld, M.D. 1, l. C Brener, M.D. A. Brockunier, M.D. I. D.l. Bross, Ph.D. B. Brown, Ph.D. :rs [:J J. C Coppuchino, Ph.D. l. F. (ovolieri, Ph.D. G. W. Chongus, M D, D. A. (larke, Ph.D. a. ~ _l~ >~'"1 I eR r!G`1 t S.l~ . A, - i ( P. Dogg, Pn D. W.W. Daniel, M.D. M. Dan:ker, M.A. M. R. Deddish, M D RI de Milies, M.D. 1 ~.~ Imhft~ ` D. Dunn, Ph.D. M. l EidinoR, Ph.D. J Fmkbeiner, M.D. 1 Fishman, Ph.D. C Friend, Ph D. E. Focht, B.A. F. W. Foote, Jr., M.D. h. D. Diamond, M.D. G Di Mayorco, M.D. i W G. Cahon, M D.

~~~. P V P. Hurrer, M D J. A. Jacquer, M D. W. D. Johnson, M D. D. J. Joly, M D. R. N. lones, Ph.D. M. J. Jordan, M.D # ;T'M lit "'% B I Kinsetla, Jr., M D. l. D. Klauher, M D. G. H. Klingon, M.D. L Korngold, Ph.D. I .... w ..r i+~.. ! ! ffi~'i M ( lo, M.D. I 1 S LoDue, M D. W. Lawrence, M D. R. Leeper, MD. l. lI lencioni, M.D. ® tM i I Ps'1 Iii= ~ ~{iIIIIIIIIIIIII llllll~ ~ i: Wl'::SM C, F. Mon,o, M.D. K. Mayer, M D. 6 M:Neer, M.D. (, J. McPeak, M.D. R. C Mellors, M.D. P. ( Merker, Ph.D. D. Miller, M.D i. Miller, M.D R I. Mitchell, M.D. D. Molonder, M.D ~~ ~, - , L_ . ,/~r' ~i it 4ci -7A ' . ~ r~ adlP ~ ~ 1'. Murphr, M C W. P. L Myers, M D W. F. Noyes, III, Pn D. I. Nydick, M D W. E 0 Donnelt, M D. M. Okoda, Phorm.D. M l Crigenes, M.D L G Orlego, M D. PA 4A .:4 1 . rww jJ~~~~ T= =~ 1,R ~ ~' ~V&~~~~~ W. L Money, Ph.D. A. E. Moore, M.D. F. Morotes, M.D. J S. Munroe, M.D. M. L. Murphy, M.D. !! } n e l. G. Koss, M.D. B. J. Koren, M.D. S, levin, Ph.D. A. B ley, M D. M. C. li, M.D. l liegner, M.D. • J Palm, Ph.D. M. Paredes, M D. 0. H. Pearson, M.D. G. Perri, M.D. M L Petermonn, Ph.D. J. l. Pool, M.D. J. W. Poppell, M.D. G. Prout, M.D. &Z~M &A Ift I. Pullman, Ph.D. M. M. Ropporl, Ph.D. H C. Reilly, Ph.D. M. Rich, Ph.D. V. i. Riley G F. RoEhins, M.D. G. Roberts, Ph.D. R. S. Rosenfeld, Ph.D. ,r 21, l. Kaplan, Ph.D. R.1 Kaufman, M.D.

M. Rosofl, Ph.D. P. Ruegsegger, M.D. M. A Schwartz, Ph.D. r .3 V. Skips., Ph.D. R K. Snydermon, M.D, q-1 1< .. xs M.. W. S'eorns, Jr., M.D. G. Stecher, M.D. S G 1LOUbe, M.D. (') Treves, A1.D N F S. F Waxenberg, Ph.D. W F. Whitmore, Jr., M.D. M. Sonenberg. M.D. A- Sopchok, Ph.D. ( M. Southam, M.D. S S Sternberg, M.D. M A. Stevens, Ph.D T. T. lomlyn, M.D. C 1. (. Ion, M D. A.+. +. / I. I. Solomon, Ph,D. 1. kholler, Ph.D, M.. Schon, Ph.D. F. Schwarlr, M D. if y.. Sugiura, D.Sc R D. Sullivan, M D A. M. Sutherland, M.D. G. S lornowski, M.D. Y 1 A Urbnn, M.D . P. Van,nne M.D ~ Ad l. Venel, M.D. l. M. Walker, A!D S Y/allenstrln, M.S. F. H. Shipkey, Ph.D. F. M Sirotnak, Ph D. ( "-s "~ , W. C. Wilkerson, M.D. C Winkler, M D, S, Wolfsan, M D. H.0 Woodard, Ph D. F. Wroblewskl, M.D. K. Yamoda, M.D. S. H. Ying, M.D. C 1 lerwick, M.D. T. limmer, M D. M. B 2ucker, Ph D. B Iumafl, M.D.

49 C 1. 0 AN - K F T T E R t Nl; 1\ S T 1 T C' T F F0 R C A\ e E R R E S F A R e n all types of radiation used in the Institute and Memorial C'enter. The use of chemical reactions for the measurement of radiation effects has been initiated. \lethods of sensitizing the reactions are being developed in order to increase their usefulness in controlling the amounts of radiation given to patients and employed in chemical reactions. Radium, cobalt-60, iridium-192 and various energies of x-rays have all been included in the study to compare the activities in terms translatable to cancer treatment and research. The complex energy distribution spectrum of the atomic par- ticles released in tissue by irradiation has also been theoretically studied. Different qualities of radiation release different energies of electrons. This study has made it possible to plot the actual and complete distribution of these energies to be found in tissue from x-rays from different sources. The electron beam, providing a special type of irradiation, has been successfully brought out of the betatron and is now used routinely for both clinical and research purposes. This is the only one in this energy range routinely available for research and clinical appli- cation with this degree of control and stability. A number of comparisons have been made between the biological actions of high energy electrons and conventional energy x-rays. The response of patient skin to different doses of radiation adniinistered during therapy is also being studied. A possible synergistic action of radiation and certain chemical compounds has been found and may open a new area of cancer treatment. DISSEAIIrATED CANCER Analysis Nurleir Acids Cancer is the ability of bodily components to grow, divide, and invade without regard to ordinary restraints. This is a property of the individual cells concerned and one which is hereditary, being passed from parent cell to offspring. These inherited cellular prop- erties are known to derive largely from the nuclear material of the cell---the stuff that genes are made of --complex and mysterious chemicals knomn as nucleic acids (I)\9 and its relative, RNA). In recent vears there has been a revolution in the way scientists think about these substances which are essential to cellular repro- duction. For years it was believed that they..~ere fixed and unchange- able. Then Sloan-hettering scientists and others, using radioactively 0 r W 0

SO Sl.1,n~ /:F.7'FFRI\t: I\STIT't'l'F Ft)R C\% t IR RFSF..4RC11 labclcd chemicals, showed that the nucleic acids, like other corn- ponents of the cell, are dynamic, with the individual chemical parts changing constantly, wearing out and being replaced. This was an impurtant contribution to the theory (and soon, alst,, to the practice) of cancer control. If the nucleic acids are rebuilding and repairing, constantly using up new materials as they discard old ones, then there is a chance that we might destroy cancer by interfering with this vital supply line. '1'he next established belief to be shattered was that nucleic acids regardless of their source are of the same conipositiun. This old con- cept diti not really make sense. Cells differ enormously in their abilitics; the waste-filtering kidney cell, the hormonc-making thyroid ccll, the disease-causing bacterial cell - all differ in form and func- tiun. It (lid not seem possible that obviously diverse activities could all be controlled by identical machinery. Ordinary chemical methods, however, were too crude for the analysis and comparison of nucleic acids from different cell types. 11sing atomically labeled materials, however, Sloan-Kettering scien- tists were able to show that different types of cells have different requirements for the materials needed to build new nucleic acids. 1)iffcrent needs must mean different compositions. This could be the key to cancer control: cancer cells must differ from normal ones in having different nucleic acids, which in turn have different requirements for their replacement and repair. It should be possible therefore to alter, and so make useless, the repair chemicals needed by the cancer cells without seriously interfering with the economy of normal cells. '1'his concept %vas confirmed by test tube expe•riments. Our scien- tists and others constructed in a slightly altered form a chemical needed for nucleic acid reproduction. This altered, counterfeit chemical was put into a test tube culture of certain cancer and nor- mal cells growing at the same rate. The cancer cells died and the m,nnal cells were virtually unharmed. A classic observation had been made. The cancer cells, mistaking the counterfeit for a chem- ical they require regularly, accepted it and incorporated it in their nucleic acid. But it was like putting the wrong key in a lock; the kev fitted but it would not turn, nor could the corrcct key be inserted. '1'he cancer cells' machinery collapsed and the cells were destroyed, without harm to the normal ones offered the counterfeit. ]n the meanwhile, scientists at Kings College, London, set out to determine the three-dimensional structure of I)NA, the nucleic acid in the gene. It is a gigantic molecule, among the largest in nature.

51 ti 1. 0 A\- IC F. 'r 7! R 1N C IN S T 1 T l' T F. F n R C A\ C E R R E S E.a R C FI It cuils around and around in a spiral staircase of atoms in different orders and configurations, invisible even under the electron micro- scope. No%-,• we begin to understand that I)\ A is like a tape recording, containing and transmitting an infinite variety of messages. Some of them spell out "blue eyes", others say "utilize chemical s," or one complex group may say "make hormone z." And when cells divide, this tape miraculously duplicates itself-this order is contained in the tape recording, too-so each daughter cell has an exact copy of the original. By use of a sensitive x-ray diffraction technique, the English workers and their collaborators, co-ordinating knowledge of the small building blocks of DNA and of previous physical chemical deter- minations on DNA, were able to put together a general model of basic DNA structure. As they learn to fill in the details of this model, we may learn the deadly combination that spells out "cancer." Then came another revolution. just as scientists were beginning to accept the idea that I)NA might differ from cell to cell, another Sloan-Kettering group reported that cells contained not one, but a mixture of DNA's, each with different properties and each perhaps spelling a different message. This was proved by a very ingenious method. First, and all important, new chemical procedures were devel- oped for defining the composition of the complex DNA molecule and even of separate segments, fractions of the long chain. DNA was isolated from a number of different sources and studied. The prepa- rations from special types of cells vvere found to be mixtures, but there .vere indications that every type probably contains a charac- teristic mixture. Even IllNA's taken from different organs of the same species were found to differ from each other. DNA's recovered from the cancer cells of patients -with two different types of the disease were shown to differ. Furthermore, -when the patient im- proved under chemical treatment, the DNA was found to be changed slightly. These findings raise important questions. I)o different DNA's carry and transmit different messages conferring different properties and abilities? Properties of DNA controlling blue eyes or cancer, for example, are impossiblc to measure in the laboratory. A simple working model had to be devised, to forward the solution of the problem. So such a system was chosen, that of the pneumococcus, the microbe causing pneumunia. Diflercnt families of pneumococci vary; for instance, one mav be resistant to the antibiotic streptomycin, another sensitive to it. These qualities can be readily measured by seeing whether or not the bacteria will grow in the presence of strep- U 0 W N J O C W N

52 S1.11AI -K Fl7 F.R I\C 1\ STIT l-T F'. F'0 R (':\ \ c F: R R F: S F: A R(-1l tomycin. If the nucleic acid is removed from streptomycin-resistant pneumococci and streptomycin-sensitive pneunwcocci are grown in its presence, the sensitive pneumococci will acquire the ability to resist streptomycin and will pass this ability on to their offspring as an hereditary property. A strain of pneumococcus .vas chosen that had three such measurable properties: streptomycin resistance, penicillin resistance, and the ability to utilize a certain type of sugar. Then the DNA of this talented pneumococcus was taken apart by an ingenious method, and the different fractions tested for these three different properties. It became clear that the different fractions conferring different func- tions on the bacteria do vary in their chemical properties. \'l'e now know for the first time that a given cell contains a large number of different types of I)NA and that these different molecules are asso- ciated with different inherited capacities of the cells containing them and controlled thereby. For a brief period, it looked as if our job were clear enough. Perhaps one DNA variety characterizes one gene and that, in turn, controls one inherited characteristic. Unfortunately, this proved not to be quite true. The DNA was removed from a streptomycin- resistant pneumococcus and separated out into a number of fractions. Sonie fractions contained no ability to confer streptomycin-resistance, but most contained some, varying fifty-fold from one to another. Thus, on the basis of our present knowledge, it appears that each I)NA molecule contains a number of messages, each giving the cell special properties, and that these messages recur from molecule to molecule, perhaps varying in detail, certainly in intensitp. This arrangement may be part of nature's vital and mysterious machinery for preservation of the species. If only one gene con- tained an important message, it might be lost forever by a chance mutation or exposure to any one of a number of agents, atomic energy, for instance, which causes destruction of nucleic acid. From the point of view of cancer control, the full meaning of our discovery is not yet clear. Perhaps cancer, an abnormal, acquired cellular property, may be contained in a message that occurs only once, in just one DNA molecule. Perhaps, and this seems more likely-, the same atomic configuration repeated within different DNA molecules spells out the same command, for example, cancer, eeery time. If so, kno%vledge of the composition of this portion of the molecule might give us the nieans for chemically destroying it no matter how often it occurs. Before these questions can be answered, we need to know more about the characteristics of the complex DNA molecule

53 S 1. n A\-}: r. T T E R ING IX S T I T U T E F O R C AN C E R R E S E A R C}t and ho.v to gauge and measure its manifold properties. Wurk tn do so is being pushed intensively. 1?PTA1:E STUUIES In a special laboratory, comparisons are being made between the amounts of the chemicals with which cancer and normal cells build their key nucleic acids. In another, we learn how chemical agents can interfere specifically with various phases of this essential and complex process of reproduction. One aspect of this study, a particularly important one, involves human cancer transplants, since clearly the compounds which will kill mouse and rat cancer cells are not very useful in man. A common building block of all nucleic acids, for instance, A, is labeled with a radioactive isotope and given to the e.perimental animal. A is used by the cell to make AB, an important component of nucleic acid needed for the cell's repro- duction. The presence of the tell-tale radioactive atoms reveals how much of A the cancer cell has used in its AB. Then another chemical, C, is injected into the animal, one restraining animal can- cer, or one that because of its structure might do so. Again the uptake of the labeled building block A is studied. It may be found that this particular agent, C, for instance, has prevented the cancer cell but not the normal one from converting the A into the essential AB. Then we have a potential anti-cancer agent. This way, step by step, we are learning about the infinitely complex chetnistry- of the cancer cell and how we can cut off its vital supply lines. In a complementary study, human cancer cells are being grown in the test tube in a chemical medium of almost completely known composition. This in itself is an achievement: test tube growth of cells, especially human cells, in anything but a natural and hence only partly defined medium, such as blood, is very difficult indeed. 7'his advance enables us to test the direct effects on cell growth of a variety of agents, and to learn how and at what point in the cell's manufacturing process they act. For instance, a very small amount of compound I) completely inhibits the growth of one human cancer in a test tube. If, however, an equally small amnunt of E is given tn the cell, growth is resumed again at a normal rate. Thus we know that the first compound I) is acting very apecifically tu stop the cell from making F., and that I•: is essential to that particular cell t' v pe. The persistent studc of these actions and counteractions on the cell's supply lines provides vital clues to ne%c chemicals and combina-

Ne.< informalion aGout nutritional diflrrenres Letween eaneer tells and nonnal ones rrorides a Lasi, for the sj nthrsis of chemicals for srlectia e destruction of cancer tells.

55 S 1. ti A\- K E T T E R I N C 1\ S T I T l' T E F f1 R C A W C E R A E S E A R C H tions of chemicals that may cause specific destruction of certain cell lines like cancer without generally injuring the entire body. Biophysirn! Analytical Techniques SPECTROMETER A high sensitivity paramagnetic resonance spectrometer is being designed and built. Paramagnetic resonance is the only method that can measure directly free radicals in solutions or solids. This appa- ratus should make feasible studies of the existence, identity, and life- time of certain chemical entities created in biologically important compounds by the action of chemical agents and radiation. It may provide important leads to new means of cancer treat- ment. AX:11.1"S1S OF TRACE Sl'BSTAXCES IN TISSUES A search is underway for substances which are present in cancer and not in other tissues. If cancer cells could be shown to be the only ones which require element z or compound x, for instance, these materials might be made radioactive, poisonous, or otherwise injurious and so provide a means for the selective ciestru'ction of cancer cells. Two methods are being employed in this search, x-ray fluorescence and radioautography. A--Rny Fluoresrence A special x-ray tube has been developed for the detection and measurement of trace elements in tissue samples by means of x-ray fluorescence. Operating procedure has been developed and early work has confirmed that the method is reliable and non-destructive to tissue. The degree of sensitivity is not yet known. The developnient of the x-ray fluorescence apparatus has been sufficient to permit initiation of studies of trace metal content of living tissue. This is being done particularly with respect to the con- centration of zinc-65 in the prostate gland in the hope that a new means for treating cancer of that organ will result. ]\QlllrinUlor/raji{!}' Radioautography is a delicate analytic method by which radio~- active substances are made to take their own photographs, showing their presence, exact localization, and concentration in tissue sam- ples. Radioactive elements or radioactively labeled compounds are

36 SLOA\-);ETTFRIKG I"' STITCTF. P11R CAVCt.R RFSFARCIt being studied in a-t.•ide variety of biological systems, including bac- teria, blood cells, mouse leukemia cells, and human tissues remoced at autopsy. The autoradiographic laboratory has continued to provide unique information for a number of studies employing different radioactive isotopes. The site of localization of zinc-65 in the pros- tate has been demonstrated. The localization of iodine-131 in thyroid cancer has also been established. Synthesis Scientists from Sloan-Kettering Institute and cooperating lab- oratories have been engaged in the synthesis of compounds closely related to those found in the nucleic acids, and presumably needed for cell reproduction. The principle involved here is a simple one. For example, bacteria take up sulfa because it closely resembles PABA, a chemical needed for their growth. Sulfa differs slightly, however, from PABA. Sulfa is, therefore, the original biological key that will not turn in the lock, the machinery janu, the bacterial cell is blocked from nourishment and so is destroyed. Body cells, which do not need PABA and so are not interested in sulfa, are unharmed. Similar counterfeits to jam the vital machinery of the cancer cell are being sought. Some partially efiective ones have been found. Nucleic acids are made up of special chemical units. Seven of them are found in nature, combined with a particular sort of sugar. Hundreds of counterfeits have been made by the Sloan-Kettering chemists. Many of them have shown restraining, and some, curative effects against transplanted animal cancer. A very few exert transient beneficial action against cancer in man. The most notable of these is 6-MP, a close copy of a mitural nucleic acid component. It is now in regular clinical use all over the world in the treatment of acute leukemia. A particular object of Sloan-Kettering has been to prepare artificially the nucleic acid components functioning as building blocks in cellular reproduction in combination with the special sugar required. 7'his is done to make a suhstance capable of acting as specifically as p(issible in injuring that part of the b,dc's cellular DNA that spells cancer. The larger the I)\A fragment sy-nthesized, the more specific it should be----small pieces, like bricks and boards, can fit in almost anywhere, but a whole prefabricated corner must go only in a certain type of structure. U 0 W N J

57 S 1, 0 AN - 1: F T T F R IN l: 1\ S T t T e T E F I1 R C A"' e F R R F S F A R(' /1 Recently this has been achieved. G-\11' with its sugar has been s_%nthesi-r.ed, and the method devised is generally applicable to other cumpounds of this type. Now that this has been accomplished, the ,.vay is open for the preparation of a whole series of related com- pounds of potential usefulness. One of the most important steady gains from this program is our increasing knowledge of relationships between the molecular structure and the function of nucleic acid components. We have learned a great deal about the sort of changes that can be made in them that will transform them from nutrients to poisons. Usually only single, subtle changes at certain points in the structure of the chemical will work, otherwise the cell will reject the counterfeit immediately. 1,r16oratory Trinl s Trial 1A1PRUA'CAIEXT OF TEST AIET1tc1DS One of the most difficult problems in cancer research has been to find more precise ways to test potential anti-cancer agcnts. A num- ber of assay systems are in use, but all have sonie drawbacks. At Sloan-K;ttering, nearly all chemicals and materials of natural origin received, either from our own laboratories or from the scores of university and pharmaceutical organizations that supply us with materials, are tested for their ability to restrain a standard fast-grow- ing mouse cancer. Almost 20,000 pure chemicals and an equal num- ber of antibiotics and other natural crude materials have now been tested against this cancer ; about 3,000 chemicals in the last two years. .'1laterials of special interest are also tested against an assortment of 25 different types of animal cancers growing in the rat, mouse, and hanister; against a group of mouse leukemias; and against animal cancer types growing in the fertilized egg and in test tube cultures. In general, chemicals that have shown estremely good results in these test systems have also proved to have sonie useful though not curative effect in the treatment of man, usually in the leukemias, lymphomas, and other varieties of cancer of the blood-fonning tissues. Fexv agents have been found, however, which act against the most common types of cancer in human beings. We know that cancer cells vary widely from type to type and from species to species; human cancers are not the same as th,,sc of laboratorv anintals. We do not know .r hether or not transplanted cancers, most easily and generally employed, are the equivalent for test purposes of cancers ~ c W N J O C W OC

58 SL-A\-i: ETTF.RI\(: IN ST17e'Tr. FOR CA NCER RESEARCH that arise spontaneously. In short, we are constantly faced .vith the disturbing question of whether or not, in our test procedures, we are missing agents that would be of value to man. Hence, we are con- stantly engaged in a search for new test systems that will augment in usefulness or replace those now employed. Transplanted Human Cancer IN THE LABORATORY AN1NlA1.. A method -.cas discovered in the Sloan- Kettering laboratories for transplanting and maintaining the growth of human cancers of many types in laboratory animals. This accom- plishment, achieved by pre-treatment of the an imalswith d rugs and; br x-ray, opened the possibility of using these transplanted human cancers as a test system for potential anti-human-cancer agents. Dur- ing the past two years, this possibility has been intensively explored. Before a new type of cancer is useful as a large-scale test object, it has to fulfill certain rigid criteria. The transplants have to "take" most of the time; they should grow rapidly but uniformly (since size of the transplanted cancer is the usual standard of evaluation of an agent's activity) ; host mortality should be low; the cancers should be neither too sensitive nor too resistant to the effects of chemotherapeutic agents; and they should not change their character- istics over a period of time. Considering the natural variability of all things biological, these are difficult standards to meet. Two of our 18 types of human cancer in cultivation have been adequately studied in relation to these criterii. The number of successful takes.vas high. Both grow rapidly, and variations in their rates are not too great for test purposes. Host mortality has been reduced to a low level. Both are capable of response to chemotherapeutic compounds active in man. Their sensitivity to chemical control has remained virtually unchanged for a year. This work establishes as feasible in chemotherapy studies the use of transplantable human cancers in laboratory animals. We be- lieve that it will help us in the search for more effective agents against cancer in man. IN THE FERTILIZED Ecc. Certain types of human cancer will grow when planted on the membrane of the fertilized fowl egg. An advan- tage to this method is that no special treatment is required to make the transplant `'take." and hence the evaluation of anti-cancer agents is more exact. Of particular interest is the fact that if the eggs bearing the human cancer are permitted to hatch, chicks with widespread human cancers may be produced. Anti-cancer agents are being tested against human cancer both in the egg and the hatched chick.

59 S1.0 A\-F:lTI'F RI \(: 1\ ST1T C; TF. FI1 R CAN' CF. R R F. S F. A R C H Sr07f111Heoffs CAHCeJ' F. rne .musr.. \\'e have obtained from another laboratory a sup- ply of mice with spontaneous cancer of the breast. Use of these animals has lead to detection of the anti-cancer activity of certain antibiotics that are without effect against the standard transplanted mouse cancer at doses tolerable to the animals. It appears also that this spontaneous mouse cancer may be sensitive to certain hormones and other agents effective against human breast cancer but which would not demonstrate perceptible effects against transplanted mouse cancers. IN '1rle FL..\ISreR. Studies of the hamster have revealed heretofore undescribed tendencies in these animals to develop cancers, particu- Lrrly in the adrenal and sex glands and in the gastrointestinal tract. '1 he last type is of particular interest because it rarely, if ever, occurs in the usual laboratory animals, rats and mice. The large intestine of the hanister is also commonly involved by polyps, the common mushroom-shaped growths of the kind that may become cancer in man. These hanister polyps are very similar to those seen in humans and should open new fields for productive investigation of both the cause and treatment of polyps in patients. A large number of inel- anomas of human type (the type of cancer arising in moles) have also been found in hanisters and are under study. Melanoma in man is a particularly difficult kind of cancer to treat. Hence, the avail- ability for the first time of an experimental likeness may be of great importance. Kesislrir:l Cnnrers Acute leukemia in children, a regularly fatal disease, probably could be cured today if it were not for the problem of the cancer cells becoming resistant to agents which transiently control their growth. In manv of the children, following treatment with already available compounds, the disease becomes virtually undetectable by any means. Eventually, however, cancer cells that have withstood the effects of the drug begin to emerge, resistant to the therapy, and the disease process once more takes over. The problem of how these cells become resistant and, more important, of how, once resistant they can be destroved, is a crucial point in cancer research. This problem is now under intensive study in an expanded r,n)- gram in our laboratories using bacteria as well as mouse and huluan cancer cells. Studies with bacteria have guided the.vork because they are easy to handle and require for their growth most of the same O O O

60 S 1. u A\- 1C F 7'r F. R 1\ C 1 N S T 1 T C 7E F 0 R C.a S C F R R F. S k.1 R C 1f materials required by cancer cells in man and :rnimals. Therefore, bacteria also may be injured by agents that interfere with the supply of these nutrients to cancer cells and so control cancer for a time. If a colony of bacteria is treated by one of these agents, it can be seen that the individual cells exhibit varying degrees of sensitivity. A few of the bacteria in the supposedly homogeneous colony are killed by minute doses of the drug; the majority .vill die from a larger dose; and a small number are resistant to much greater concentrations. Furthermore these resistant cells differ. Sonie are resistant to one agent and not another, some to both, some need one type of nutrient while others have different patterns of requirements. A correspond- ing range of difference probably exists in the resistant colony of human cancer cells, since we know that their pattcrn~ of sensitivity and resistance vary also. Now we are beginning to translate these tindings to animal leukemia, bringing us one step closer to the human disease that is the actual enemy. A standard strain of leukemic cells has been passed from animal to animal while constantly under treatment with a selected agent. One, for example, will be treated with a transiently effective compound until the cancer is out of control and the animal is about to die. Then the leukemia cells from this animal are injected into another similarlv treated. The procedure is repeated until the animals receiving the treatment die at the same time as animals receiving no treatment--proof that a complete resistance has devel- oped on the part of the cancer cell. By this method, ten apparently different lines of leukemia cells have been develuped, presumably like the cells which kill children. These cell lines are now in use both for studies of the mechanism of resistance - to ascertain what alternate supply lines they possess which compensate for those blocked by the agent--and, particularly, in a broad screening pro- gram, to detect what compounds will be active against resistant lines of cancer cells, both in the laboratory and in the clinic. Combinalion Che»lonceFnry Studies are being made of the use of two agents simultaneously to strike the cancer cells a double blo%N and perhaps, by attacking on two or more fronts, knock out the two different types of cells, either one of .chich niav be resistant to a single compound. AIso wc seek combinations of chemicals that, together, will exert a greater effect than can be achieved by increasing the amount of either alone. Thus if there are two supply lines for the production of compound a, blockading both of them will have a far greater effect on the cell N O l./ N J O C R

61 SLOA\-KETTERIaG 1NSTITVTE FOR CANCER RESEARCH than shutting uff one and leaving the alternate route open. Often onc of the drugs useful in combination treatment is not in itself active at all. An agent has been found, for example, which, though it does not affect the test mouse cancer when used alone, strongly enhances the efi•ectf of another agent when used in combination with it. A variety of combinations active against animal cancers are no.v under further study and clinical trial. NEW AGEXTS IN t.:\BORATORY TR1:U, A variety of chemicals have been shown to possess some anti- cancer activity in the laboratory test systems described. Of a large series of one group of antibiotics, three Avere found to restrain spon- taneous mouse breast cancer. Normally, these are exceedingly refrac- tory to treatment. In collaboration with another laboratOrt', studies have been made of a particular mushroom, the common "puff-ball," which in some preparations shows a definite inhibiting effect against animal cancers. \tethods are being sought for its culture and for preparation of the extract that will increase and standardize the anti- cancer effect. Two other antibiotics have been under study, both of which inhibit the growth of mouse cancer and are effective against mouse leukemias. The agent I)O\, previously reported, is still under study because of its activity in animal tests although it has only negligible usefulness against cancer in man. It seems almost inlpos- sible to develop strains of mouse leukemia resistant to this compound although strains resistant to other agents develop rapidly. In tissue culture, a number of compounds closely related to a vitamin have been shown to damage mouse cancer selecti.•eh• and also to inhibit growth of human cancer cells. All of these clues, and many similar ones, provide leads for further stud). in the laboratory and in man. Clinical Trials 1\IPRO\'E\tEXT OF VF:THOIIS 7'rrhniques fi.r Jlensun•rlnrnt of Re.cnonse A search is still under way for delicate techniques that will re\eal slight effects of agents under test on cancer growth in man. I•:crn if a compoun 1 is not sufficiently potent to produce an obvious i liniral effect, it is e-,tremel\- important ul discern even slight activity. (lnce demonstrated, the effect may often be enhanced by various nleans. Furthermore, knowledge of a feebly active chemical may lead to the development of similar but more effective ones.

62 SL.1 A]-I:F.7TtRISt. 1\SIIICTE FIiR CA\CrR RFSEARCfI One of the most useful of these delicate methods is the calcium excretion test. Bone is a common site of cancer spread. When a spreading cancer erodes bone, calcium, the main constitutent of bone. is excreted, mostly in the urine,.vhere it can be measured very accu- rately. Thus, fluctuations in the amount of calcium excreted provide a sensitive index of the effectiveness of a chemotherapeutic agent in slowing or stopping cancer growth. Work during the last two years has established the validity of this method and made it avaluable clinical tool. Natural Nialory of Cancer 1)uring the past few years, there has been a tremendous upsurge of interest in cancer chemotherapy. Standards and guidelines for researchers treating cancer patients with new agents are urgenth- needed. One of the most ambitious undertakings in this area has been the studv of the natural history of cancer, now going fonward in the Sloan-Kettering Division of Clinical Chemotherapy. Complete and estremelv detailed data have been amassed. Life historv charts sum- niarizing the evolution of cancer in the patient have been prepared. From these we are developing for the first time reliable patterns of the course of cancer, so that patients A.-ith disseminated disease can be classified and their probable clinical behavior predicted. The histor}- of individual patients has been thought to have little significance because of the known variability in the course of cancer. From our recent study, howe.•er, it becomes clear that common patterns of cancer progression are applicable to the majority of patients. Through the development of reliable pattern: of cancer behavior, patients can be classified and their clinical behavior at any particular stage in their illness can be predicted on the basis of age, sex, type of cancer, and the details of its previous course. This will ultimately allow much more accurate evaluation of the effects of a potential chemotherapeatic agent and simplify analysis and comparisons with the results of others. NEW AGENTS IN C'LIXICAt. Tkl.-11. ])uring the past two years, many new compounds have been tricd on patients with disseminated cancer. The majority of these were agent, which had demonstrated activitN in the Sloan-Kettering laboratory ~creening program; some were reported as usclul by in- vestigators from other laboratories. A thorough objective e%aluation of a new agent is time-consuming. The first stage consists of determi- nation of the effective route of administration and of the safe dosage U 0 W N J O C F W

63 I 1."AN -F: FT'f F.R1\ l: 1\ cT1T'L'TE FC1R C.a \ C F. R R FS F A RC 11 in nlan. The scconli sta-c consi+th of the cvaluation nf the drug for usefulness in restraining various forms of ceuncer. If the drug appears to have any regular effect, the third stage is a full clinical study of its usefulness in comparison to other methods of treatment. Since there are many types of cancer, each varying in its susceptibility to different agents, and since the natural course of cancer in a given individual often may be erratic, it is necessary to test each drug in many patients. Disseminated Cancer T,.vo new agents related to those already in use have been shown to have some clinical effects and are being subjected to more extensive trial. One, I)0N, an agent of marked activity against transplanted cancen in the laboratory animal, has been tried in over 100 patients with disseminated cancer. Only slight evidence of cancer regression has been seen. This agent in combination v%-ith another, also of border- line activity in acfult:, has been administered to over 50 adult patients. titudies are still in progress. fleute Leukemia in Children This type of cancer is one of the most responsive to chemother- apy. The majority of leukemic children now can be maintained in apparent good health until the disease recurs in a resistant form, as it always does eventually. T.~ o new antibiotics are being tried in children resistant to other forms of therapy. There has been a questionable response. Eleven institutions have cooperated with Sloan-hettering in a comparative evaluation of one agent alone versus a combination of two in the treatment of over 150 cases of acute leukemia in children. Triple combination therap) is also under study. acnfe Leukemia in .9dulfs Acute leukemia in adults is far more refractorv to treatment than is the disease in children. One of our compounds was the first agent discovered to e.Nert a regular although transient effect in adults with this di~ease. Studies are now under way comparing its usefulness to that of :. more recently prepared but cluselv related compound. The u~e of still another chemical in adult: Nvith acute leukemia has bcen further studied. When used initialh', it induce~ remissions in only I I pei cent of patients; however,.chen it is employed in patients %\ ho have responded and then become resistant to other agents, it is effective in three times as many. This finding not only increases our

6-! s L fl :\ \- I. i: T 7 F: R 1\(: 1\ S 7 1 T V I F F0 R C:\ \ C r: R R F. S L:1 R C n abilitc Uo help the patients, even though transiently, but it supports our hnpe, based upon experiments in animals, that the development of resistance to one agent by cancer cells should increase their vulner- ability to others. A compound, first used by a group in Germany, has been adrnin- istered to a large number of children vvith widespread cancer. It is highly toxic but has shown sonie very slight and irregular useful effects in children with certain rare types of cancer. Breasl Cancer Work has continued on the screening of new hormones and other chemicals in patients with breast cancer in the search for substances Avith better actiritv and fe%cer undesirable side effects. Seventeen agents and combinations are currently under study. Comparisons are made among these and with other forms of breast cancer treatment, such as ovary removal, hypophysectomy, and radiation therapy. Une new hormone appears to have caused improvement in sonie patients with less side effect than those in common use. A group of hormones related to cortisone have been shown to produce a response in sonie patients no longer aided by the commonly employed male and fernale hormones. This group seems to be particularly useful in relieving patients who are suffering from an excess of calciurn in the blood stream owing to the breakdovm of bone tissue by spreading cancer. These preliminary results are being evaluated further. Spccinl Strtdics \'lkl'St:S Some years ago at Sloan-Kettering it was discovered that certain viruses %eill localize in sonie types of anitnal cancer and, when grown constantly in these cancers, can be trained to destroy them without harm to the animal host. Since that time, means have been sought to employ viruses as selective destructive agents to restrain or cure cancer in man. Thirtcen different viruses no%-,- have been tested for their efIr, ts a-ain.st human cancer cells growins; in test tubes, in the fom•1 cgg. nnd in rat~. Most have been found capable of growing on human cancer cells, and eight are able completely to ~ destroy human cancer in the egg. ln the rat, two destroy cancer completely .vithout harm to the animals; one destroys the cancer but many- of the animals become paral\ zed; four exert a moderate inhibitory effect, and six are inert. v 0 W N v O r v

65 5 I. i, :\ % - 1: F'1T}. It I\ (: I\ ti 7 I l l~ 7 E. E„ R (' .\ \(' E R R ES E.\ R C}I Clinical Shur1i1•.a Studies in man are going forward using the viruses specified and „thers shown to be active in laboratory tests. As yet, %%c are un- able to state whether or not tissue culture cultivation of these viruses in human cancer cells has increased their activity against cancer in man One such virus frequently has been found to be concentrated in hurr~.m cancer tissue, however, which encourages us to believe, on the basis of animal studies, that it -%vill be possible to augment its injurious effect on human cancer. Use of the fluorescent antibody technique has demonstrated that one of our viruses not only localizes on but actually within the cancer cell.'I'his new knowledge that cancer cell and potentially destructive virus can coexist without cell injury opens a possibility of a new approach to the problem of achieving cancer destruction by viruses. \lany-of these minute agents are almost constantly present in suscep- tible cells but do not attack the cells unless something happens--an injury for instance-that upsets the body economy and makes the cell more susceptible. This suggests that means may be found to activate the virus within the cell and unleash its destructive abilities. \[rL:1\(1\fA STCnIES Melanoma is one of the most vicious and fast growing cancers known to man. It is extremely resistant both to radiation and to any known chemical agents. Recent studies at Sloan-Kettering have led to 1) a possible diagnostic test for melanoma that has begun to spread, 2) a new chenwtherapeutic attack of apparent value in laboratory animals, 3) a new system for testing speiificity of action of anti- cancer agents, and 4) perhaps most important, a new general ration- ale of attack on the problem of finding chemicals to control cancer in man. One of the chief characteristics of melanoma ("black cancer") i- its dark color. Studies in the past have shown that this results from an abnormal utilization of a particular chemical naturally present. In the melanoma cell, however, it is made into an unusual substance known as DOYA, v.•hich, in turn, goes on to make the tell-tale dark pigment of melanoma. A Sloan-Kettering researcher set out to see if he could capitalize on this known idiosVncrasv of the melanoma cell. He discovered that if DOPA is combined in the test tube %\ ith another chemical, 1'Pl.)A, a vigorous reaction takes place xvhich can be readily measured. He then tested the blood and urine of patients with known melanomas. In e\en- case. DOPA or a 1)OP-a-like chemical could be detected. U C W N J O G t O

SLOAN-BETTERING INSTITUTE ORGANIZATION CHART LEGEND ~ LINE OF AOTNON/TV ---- GENERAL PGLICY LINE -.••• ADVISGRY LINE rw RMUrw roalm an e..Afe.w~ A'ADC DEAN, GSM.S ICOMC/ rtslAlc. FISG/IL DAN:ER lI WUMO 'n. M[/M_LLqY YM -f ~ -' L.~~ _- ASST FISCAL OFEILiR I~fr[[m~r.tot~ [FY{\y!. ` Ed1CAT10M AND 5u-DIV ..6Ra.M. ~nn0 GZ£OS ROARD OF SEES I r.i ~ L.... =eu Nw b E%EGVTIYE GOMMITTEE owwf. n~ r~. «e-.e I fAMMIT•[[ ON , ~ /EN11FI~wCOL~.T DIREGTOR, C.a RNORDS •S50CMTE dREDTOR ASSOCIATE DIRECTON CC STOCK D[COTY DMIECTON ~ T ReNpAll AFf DENUES ADVISORY GRpJPS STAFi Mq FAGILTY lOARD 0F SCIENTIFIC GONSOLTANTS AOMIMISTRATON •L~e4 NS?APNMISrRATDl1 •ERTOMNCLORIEER ASS PENSOMLL OFiKR 1 u~4 atM t~ MMLOt •I 'seoo f L I ~ •fuMr [ ~w Ow M CF rf,mf T l r- iV a.w.,.. ~ F.;R.». fN0 ` . qlR. 1 ~.~..... .,,«. ~ ~._OIfO~ CM<u u.. ~ f t 1R/NDN eqf wMlr4M [..wR. f...a..a. •SST.YDMIMISTRATOR ~N.[a ~ ,. A...w ~

67 51.oAN -K E77FRIN G 1N <717r'7F FOR C.aX C E R R EcF A R C n It is not known ho%c car}y the pre~ence of a melanoma could be detected by this method; it seems improbable that the few cells in- vrolt•ed in early cancer could produce enough DOPA to be detectable in the blood stream unless the methods were made exceedingly sen- sitive. It seems, however, that the test may help in the diagnosis of di stant deposits. Melanoma is a very rapidly growing cancer. If a tiny spot is found on the sole of the foot, many surgeons will amputate the leg at the groin to catch every one of ihe spreading cells. This test may give us a new means for determining whether or not such a spread has taken place and such a treatment is necessary. How else could this unusually- vigorous reaction be exploited? Our investigator reasoned that if the test chemical used, Pl'DA,were given to an animal xvith a tnelanoma, and if ff~ reaction took place in the melanoma cells inside the body, the cau .er cells would finci it difficult to proceed with their malignant functions. PPDA was added to the drinking water of mice with transplanted melanoma. There was a substantial inhibition of the melanoma, without injury to the animal. This %~•as achieved even when treatment.~~as not begun until a month after implantation. As is our policy, other chemicals like PPDA were also tried against the cancer. Two of them proved even better; with one, the transplanted melanoma was almost entirely destroyed. As stated, these compounds are not injurious to the host at the doses needed to inhibit the cancers. If very large amounts are given, however, the test animals die within a short period. This led to another interesting observation: if two groups of mi, e, one bearing melanoma and the other not, are challenged with a single fatal dose of PPllA, the melanoma-bearing mice will survive longer than those without a cancer. The cancer somehow uses up or detoxifies the com- pound and so protects the host. Other combinations of chemical and cancer were tested. In some of these systems, the exact opposite was seen; some chemicals were made more toxic by the cancer and the cancer-bearing mice died before the control mice. However, in each case when a lethal dose of an acutely toxic chemical .vas given to an animal b:iring a cancer known to he inhibited by that chemical. there was a decisive difference in survival times between cancer- hearing and control animals. This suggests a simple rapid scstem for estimating the effects of appropriate chemicals against different types of cancer.

bs ,\ ST1Tl'TF F(,R C:\\ CF.R R F. S F.\RC n ations of reactions between chemical and cancer that each cancer type has its individual char- : from those of normal tissue. Each cancer n biochemical fingerprint and so probably con- -es the melanoma cell, products and by-products eh' or quantitatively from other tissues. If these -r. he detected, isolated, and identified, as llOPA -noma cell, Nve would have solid groundwork for :,proach to cancer control. ~E ALTERATIONS =. ~,t 1{ ued to explore the effects of alterations in the e have ,• body on cancer in man. Our major efforts have r'e Icve: 1) the effects of removal of the pituitary gland, ,r,ecrne ;nit of the body, on the growth of human cancer; a-tcr cor ,1ts of this removal on the bodily function; and cner ,timulation caused by steroid and pituitary hor- c restra: of certain types of cancer. on the =' e study with The New York Hospital-Cornell (n a coo:.' ..,e pituitary gland has been removed from 191 :''e al C,er'- eed cancer. More than 100 patients -were operated 'nt,with " I year. The surgical technique has been further lurin}; th• ,norbidity and mortality are almost eliminated. %'"nc`i s" .~11 tolerated and many patients have been rehabil- , f,roccdcr rily able to resume a normal life. i and t`' ,,ne prepared from human pituitary glands has (,rowth - to be a grotvth-stintulating agent in the patient "" 'lc'"'on`' - been removed. In one patient with breast cancer, pituits+• „ntrolled dose, of this hormone on two occasions carefu• •,,Icium excretion, suggesting that growth hormone Pwluced a ri~' ,,- growth of her cancer. This observation lends I" stmit'1''t` our concept that pituitary growth hormone is an I"'ll,rr sup{'" n the progress and perhaps induction of human u~pnrtant f:' 1'I, '"t canti i ,nvesti~:tte•d the effect: of feniale hortnone aeimin- 11'e h, .i, ~~~hoce• pituitaries have been rcnu.,ved. In these t.uiun U, t'' `, .n doe: not stimulate the growth of thr cancer, nuliciiiual• r ' I, ,n paticnts ~.'hosc pituitarics are intact. 7~hi: :uggestc ~t u>ualh ' •„•t in combination \N ith a pituitary factor in stimu- '1'•'t c'str°gc'" " r ncd to te~t eriments are bein desi ro~cth Fx g g g p I.uinL breasl ' "" ~dhcr. ' Il,is pussihililN 1" e/-/- AW,M-0C. P. RttoAtrs, 11.I). n1rPc,or

SLnAN -R ETTER] K G IK sIITCTE FOR CANCE R RESEARCH :drrcational pngra»> From its creation in 1945, the Sloan-l:ettering Institute has em- phasized the importance of training talented young scientists. In 1930, this function was formally recognized by the creation of the Sloan- Kettering Division of the CornelLUniversity Medical College. In 1952, the University established its Graduate School of 'Medical Sciences, of which the Sloan-Kettering Division became a unit. Teaching in the Sloan-Kettering Division is conducted under the Director of the Institute, aided by the Advisory Group of the Sloan-Kettering Division faculty. It is subject to supervision by the Associate Dean of the Graduate School of Medical Sciences, who also functions as Dean of the Medical College. In the Sloan-Kettering Division activities, the Deputy Director of the Institute serves as a coordinator. Active administrative roles are taken by the chairmen of two internal faculty committees, one for the pre-doctoral and the other for the post-doctoral students. Pre-Doctoral Training This teaching program is designed to give opportunity to prom- ising students working toward the Ph.D. degree in basic scientific disciplines aplicable to the cancer problem. It now includes sixteen degree candidates (thirteen Ph.D. candidates and three in special programs for the master's degree in radiological physics). Each student is supervised by a special committee of three faculty members, including two from the Sloan-Kettering Division faculty and one from the cooperating regular faculty of the Cornell University Medi- cal College. Of the thirteen doctorate students, six have majors in biology. five in biochemistry, and two in biophysics. Their major programs, within the context of graduate education at Cornell University, are complemented by two minor subjects, by seminars and course work, and by active participation in research under the supervision of the staff. During the past year, two doctorate degrees tivere awarded. Support for scholarship stipends for some of these doctorate stu- dcnt~ is provided, based on need, primarily by a grant from the Sloan Foundation. The Kettering Foundation has provided t,vo special schr,lar.hip~ in radiological phcsics; and funds from the National Cancer InsWute of the U. S. I'ublic Iiealth Scr.icc have also been empk \ed as supplements. 0

70 .1 L.1:\% -F:F.77FR1\C: 1\S7I'I'l"IF r11 R CA\CF:R RFS FaRI'}I Post-lloctoral Training Continuing the original training program inaugurated in 1945, a second major educational effort provides unique opportunities for young investigators of professional standing to pursue research in training with senior members of the faculty and staff of the Institute. Currently, sixty-nine research fellows are in residence including in- vestigators from foreign countries who participate under the Insti- tute's twelve operating divisions; limitations of space are a primary deterrent to this important part of our program. Special Fellowships A third continuing general area of educational activities meets special needs of groups including both senior and junior investigators, research nurses, graduate students in cooperating instituti lns, and the lay public. A program for visiting scholars, guided by a committee of the Sloan-Kettering Division faculty, provides opportunities for qualified senior investigators to study and work with the stafi of the Institute. For the period under report, we have had nine such investigators who have been with us for periods ranging from three months to several years. Support for this program is genelously provided by renewal of a substantial grant originally made in 1955 by the Sloan Foundation. A recent development includes the creation of two Albert and \f ary Lasker Foundation Special Fellowships in Medicine for quali- fied young medical investigators in the area of cancer chemotherapy. At a more junior level, it has been possible in the last two years to encourage the young people on the technical staff of the Institute to pursue studies pertinent to their research work and professional devel- opment with part tuition paid by Julius Ochs Adler Scholarships, granted in memory of the late General Adler. To date, one hundred and one individual~ have been given such support. Experience indi- cates that these scholarships contribute directly to the overall research effort. Rrscnrch 11'ur:rc brJCrnships An important unit of the educational work is the cooperative nurse internship program at the James Ewing Nospital, conductrd with the I)epartment of Nurse Education of New York t'niversity. 1'his provides special training with emphasis on cancer chemotherapy research; and is supported by grants from the Sloan Foundation. To

71 SLI' A\-F:ETTERI\G IN STITI:7E FOR CANCER R F S EARCIi date, furty-five nurse interns have enrolled and fourteen have com- pleted the one-year course. Uthcr Coopcratil,c Programs Summer work in the laboratories is also used to provide an on- the-job educational experience in the Institute. In 1957, forty-five individuals were so employed, including twelve high school science teachers in biology. On the initiative of the New York City Cancer Committee and in a cooperative effort with the New York City Board of Education, special demonstration material has been provided to supplement the high school curriculum in biology. In another co- operative effort with the Hunter College of the City of New 1'ork, the staff of the Institute provides instruction in biochemistry and in biophysical method: to Hunter College students who are working towards master's degrees. Other courses include a special one-month session in the chemotherapy of cancer for clinical investigators; and short courses to meet technical or professional needs, as in transplanta- tion techniques with human tumors (by the Division of Experimental Pathology) and in early diagnosis of cancer (by the Division of Pre- ventive Medicine). All such offerings are reviewed by special committees of the faculty and by the Dean of the Cornell Medical College. Recent symposia to meet similar needs or to provide general information to the public have included those on radiation hazards, cooperatively with Hunter College; on alkylating agents in cancer chemotherap}•; on viruses in cancer; trace metal metabolism; hypoph}•sectomy; and on the biological characteristics of certain types of cancer. These special activities all have been available to and have gained from participation of twenty-six pre-doctoral and fourteen post-doctoral individuals supported in part bv a training grant from the National Cancer Institute of the United States Public Health Service. LM 0

72 S L O A S- 1; F 77F R 1\ G I N S 71 T C T I F O R C A] C E R R F S F. .\ R C H Sumtnary The activities described represent the Institute's discharge of its obligation to attract the most talented young people to participate in its.vork and to provide them with opportunities for independent re- search. The creation of the Sloan-Kettering Division was the first formal recognition by a university of an institution dedicated to the problem of a single disease. The Institute now is pursuing its original and vigorous program with requisite academic breadth. The oppor- tunities available at the Institute for completing graduate education while participating directly in the research programs of outstanding investigators with university f aculty rank, and the advances that accrue thereby to the field, seem adequately to justify the educational program. This topic was accorded special consideration by the Institute's Committee on Scientific Policy with the Board of Scientific Consult- ants during the recent annual review of the overall program. These groups concluded that it is of the greatest importance to continue educational activities within the Sloan-Kettering Institute, noting that the current level of effort, representing not more than about ten per cent of the total is modest indeed. With this independent endorse- ment of the Institute's educational efforts, the fruits of which are very apparent at the working level,.ve plan to press for an improved and strengthened program in the future. A. R. T. DFNueS, Ph.D. Depuly Director

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Memmial e:rnrrt aat hrddine. ad.~,.r n, rhr lnaimte'c call m 6nance q,nial reerarch proinrs A, at Cln.r of Fiaal 1tar _ 1)erember 31, 1956 Aa at Cnse o/ Fi+cal 1'ear Decrmber 31, 1955_ _ $ 76R,28t.0R $ 6t6,46t.6n 517,432.50 340,607.21 61,R35.97 31 v2t1.i7 3,607,111.74 3,029,116.26 25.394.16 11,434.12 13,357.96 121,10532 5,023,407.31 4,1RI ;oSn.nR (1,136.16) 1,576.19 211,295.69 2n9,261.33 210,157.52 21o,NI7.52 $5,233,56i,R3 $4,399.997.0 $ 107,014.77 $ 1n1,4r,t.r,3 R5,031.95 7o.2a1.33 7,500.22 12•nR6.12 1,611,065.27 1,535,R55.16 3,212,795.10 2,459.792.94 5,023,407.31 4,1RtlinSn.nR 63u,n~1 21n,157.52 21n,I5'.52 214157.52 21n,R37.52 $5,M~ $3,39n,NR'.r,n aPl+raved by he Cnmminre nn Srienti6r Pnlicv, rhe nam of R17R,9tR.tt ac .r Ih-mhrr tl. 1956 and 5ir+,424.1' ac r 1Xcrmbrr 31, 1915. an addniun, Mrrmcrial ( enmt w hr.IdinR in c Receatch Cnntinaencv R-nr Accrnmr, tIrc eum cd SI N49,9i5.lln a at Ik-.ernhrr +1, 1'ISr, and 37,41 (,6Ra N( ac ar Dnrmber iI, 1955 nn rhich he Inwitute haa a c~ll ~~nl, r„ the rxrcne tha< rhe Inuiturc c OIx'r.r~nR Acmm.t fundr a1+Plhd eacred funclc rnc-l in nr (val year. i. Nuildina and equipment acx•tc mvnnf by Mrmor7al Center !nr Can,er and Alhrd nirauc and uced Fe Slrnn-Krnerina Incrirute tnr Canan Recrar.h had aaateeac cr. t r,l S ll•c~ IN, '5 a, Dt•cemher 11, 1!/Sr, atW 4/;1r.R,R4tl.p0 ac at Dnrmher 11• Idtc, c,lu.~ce „/ the land «cuvtrd Hoerheil no he In~uK w Ruiai nl crnatn aquiPtnent and rctr.nh nh /,nw vandrrrcA Irwn he Dil wn nR.

FVNDS RECEIVED SL.UAN-KI:1°I'E:RING INS'I'I'1'U'f'E FOR CANCER RESEARCH C'f)A(1'ARA'1'1VM STATEMENT OF SOURCE AND APPLICATION OF FUNDS Far the Years Ended I)cccmher 31, 19S6 and Uecrtnher 31, 195; Fiatal Year Ended Fi•ca11-ear Ended 1)ecemher 31, 1956 _ _ 1)ecember 31, 1955 Alfred P. Sloan Foundation, lnc . ........................................... ............. ....... ..... ...............__ .............. $ 400,000.00 S 436,691-W Other Contribution., Grante, LeQaeie• and Reque•ts ....................... ......_........................ ............... $4,040.191.16 $3,4 50,292.21 Leee: Included in Aceount. Receival.le and 1)eferred Charlten, January I .................... 195,31147 1,944,977.69 70,121.95 3,3R0,160.26 Tran.fert from Memorial Center fnr ('anrer and Allied Dieea.e. ............................................ :S+,n66'+I 293,292.11 Income From Royalties .................................................................................................... ...................... 17,303.43 21,970.27 Income From DmlRla. Truntr, 1tcludinK Rrcrnue From Radium Treatment. ...................... 9,3R5.06 9,033.08 Income From Cecnritiea: Operatinq Account ........................................................... ........................ 129,212.07 99 ,431.1R Im•..tment Account ............_...................... ........ .............................. ........... ... 14,521.43 133,733.50 14,543.53 113,994.71 Miecellaneou. .......................... .. . .................................................................................................. ........ 19,143.52 12,069.23 f.4,699,510.14 $4,267,159.67 FVNDC APPLIED OperatinR Rirpenaev ......................... ...... .......... ......................... ...._................. .................... ..................... $3,757,471.03 $3,421,324.35 Tran.ferred to :\ccnunt. Rrrdvahle and Deferred CharRe. .................................. 153,1109.98 $3,603,661 .t6 200,311.96 }3,2249A2.39 Refund, on Special Grantr ..............._..... .__...................... ....................................... ....................... FunNc'1'ran.ferred tu Other OrRanir»ti~rm far t~ ~-cer and Allied I•rnjen. .............................. 21,299.14 13,50n n0 46,631.10 Equipment and RuiklinR Additinn. .................................................................................................... 194,519.07 2?2,RO1.31 Mieeellanenu. ................... .........._................ .... .. .,.,......................... ..................... .................... ........... ... 5,703.66 - F.aceae of Fund. Reeeiced O- F,m& \pldied in Current \'ear (.ce nme) .... ....... ......-......... R69,756.21 77t,,733 V7 $4,699,510.11 $3,267,159.67 dmbv9uene d ht A'otv' tncluded in Fund. Receinal in earh v r ~ •uh.~a ial a n rel.re<nrinq 0 preNrment• rd c eu vann m 6nance rc h pmjean n, be undernhen in rrar. an Asmrance Fund mnnte< vhich a.e n,n a.nIahIe h.r~current eaerndin,rc hut whi,h are he,na held a. a re.er.e u. a.<ure cnnnnuuv tdwhera mear.h pn.;ram. The 6n.neial u lu.kd in hi, rcprt havr hen erenand /rnm vu me n(urniahrd hr rtu independent ditrn. " n th ba it n( the cal d r txar, which i, the riral ,rar uf the Shwn-Knrcnnc Inat , and n.w, va. the rav n he n nial Rer,,,n t- 1954 and 1955, nn he ba.ir nf he uultm,c Year. Huwever,in all other re.pca-te, he 1liennial 0.rM- enc, tneuae. he academic ve.r. SShO LZ£OS

75 N ~ - F: k: 7 T F: R 1\(: 1N S l' 1 l' t' 7 F F 0 R C A\ C F R R F S F: .\ R C' Ff GOi/l'h1.1'l01I This review is intended only to give a general picture of the rrscarch in progress, avoiding details which would not be of wide in;crest. The scope of the work of the individual scientists whose com- bined efforts arc thus reviewed, can be grasped only from the appended list of their scientific publications. The Trustees believe that the prugram as a whole is not only sound scientific research, but that it is following lines which have promise for advances in cancer treatment. Neither test in itself can be sutfiicient for this Institute. The intention and purpose is not onlv to contribute to the sum of human knowledge by sound scientific re- se.irch, but also to choose programs -,.•hich seem most likely to fulfill the urge of mankind to find relief from a disease which is unique in its slow and tragic course. For the Board of Trrt.rires A..k a. ir„w,.L aqVn~ FRA\R A. HO\1'ARU ALFRED P. SIA.a\, JR. I'resident Chairman

SLOAn-I:ETTERInG INSTITUTE FOR CANCER RESEARCH MeHlbers PROFESSIONAL STAFF fls of October 1,1957 Director C. P. RHOADS, \f.D. DeputJ' Director A. R. T. DEwEs, Ph.D. Bssociate Directors HFSRY T. RASDALL, A1.D., rfed.Sc.D. C. CHETER STOCK, Ph.D. L3ssoeiates (6oA( d) Ji)II\ J. BIEeELE, Ph.D. DORRI< J. HL1TCHiSO\, Ph.D. UscAR BoDAN>¢T, tii.D., Ph.D. Joas A. JACQrE2, M.D. GEORGE B. BI'.o)cs, Ph.D. LEOPOLD G. Foss, M.D. J05TPI1 H. BL'RCHEVAL, M.D. ALLYN B. LEr, M.D. EltFR50l DAY, M.D. ROBERT C. DIELLORS, M.D., Ph.D. A. R. 1'. DECrES, PI. D. R'¢LI3.1 L. d1o.vn', Ph.U. THOftaS F. G\LLAf;HER, Ph.D. ALICE E. MOORE, M.D. D.{t"tD A KA R\FIFSRY,. AR\FIFSRY, M.D. ~~~• P. L.\IRD (IIYERi, 11.D. JoHS S. LAVGHas, Ph.D. OLOF H. PEARSON, M.D. J.1\iEI J. NiC-)1, M.D. MARY L. PETER}IA\\, Ph.D. FREOERICR S. }'1111.IP5, Ph.D. MAURICE M. RAPPORI', Ph.D. HENRI' T. RA\DaLI., M.D., Wd.SC.D. H. CHRISTIAE REILL), I'h,I). RL'10s W. RA\Y511,, M.D. 0KATHLEEI E. ROBERTS, I/I.D. C. I'. RHD]D5, M.D. ROBERT S. ROSE]FEID, Ph.D. FRED W. STEN'ART, Ph.D„ M.D. :LIORTO\ K. SCH\t'ART2, Ph.D. ('. C1IE1TlR STOCK, Ph.I). RM1fARTIN SO\ENBERG, M.D., Ph.D. GEFIRI:F W . YA'OOLLEI, Ph.D. CHESTER ICS. SOLTFIASf, M.D. STEPHEN S. STER\BERG, 41.I1, KA \ E\I ATSL' SI:GIL'RA, D.SC. Associates ARTHL/R AL SL'THERLA\D, M.D. Af. FARI. Bius, Ph.D. RALPH K. B.IRCLA)', Ph.D, AARDS BECnIcH, Ph.I?. IRYI\(: BIEBFR, h1.1). H. LF.(,\ BR.ADLO\l', Ph.l). I.IENE F. CAYALIFRI, Ph.D. I1tl, 11.D A. CL.ARAE, Ph.D, Ir,,F.F E. CuFFFON, D1.D. 1). I)la\IO\D, T1.D. ]: )soELl. i,. EIn1NoF-1, I'h.D. (ilr1R,:1 C. EscHrR, \1,I/, l~R{\A ~~~. I(R/TF, 1R.. <I.D. CHIRil,llr D:,rm F, I rhr;Hn1A, Ph.D. 1l1FOnOR) }1A1.1., Ph.D. LFn>IRn D. IIA'InTOS, D.D1., Ph.D. LFn~ }Ir..Faa~. >LI).. !drd.ccD. II.RU~II I:. HF csc'HRe, At.l)., Ph.l1. RA1sl-n 11'. IIOrDE, ALD. IWILLIn11 S. HOtcl_A]D, II'I.D. •LLna~ of RL.nnre HELENE W. TOOLAA, Ph.C). JOHA A1. WALAER, ALD. LI ELE\ Q. «'00DARD, Ph.D. ERNEST L. N{'Y~DER, TLl). DIARJORIE BASS ZL'CAER, Ph.D. T "isitittg llssociates CHARI F. BER\I A\, \l.(l. \f It Nli E LEO FRRFR \, \1.D. }'.1l'I i l"RFT, M.D. .<4sststailts GESEC1EVF lilneR, M.D. AI+RIUS B,RCI A), I'h.l). \.aTHA\IE) BIRR, I'h.I). .9\GL's LEOPOLD B.iTCHE1.OR, I'h.D. RICH:\RD BE\L'A, hl.l). 76 Jsslstallts (Cot7t'Ef) JOH\ W. BERG, M.D. "fosES BERS1.AS, F.E., Ph.D. XVILLIA)1 T. BRAD\ER, Ph.D. P xr F. CoDING'Eoc, Ph.D. AEIEY S. COLLINS, I11.D. -CH.aRLES P. DAC:G, Ph.D. RusE-R(rTH ELLlsnc, M.D. FDa'ARD R. EPP, Ph.D. JOHN FI\RBEIICER, M.D. ELI2ABETH FOCHT, B.A. JOSEPH G. FORT\ER, M.D. MARK FRIEO}L\\, D.V.N1. ARYI\ S. GLICKS\IA\, \LD. ROBERT GOLBET, M.D. LIsELOTTE GRAF, M.D. JOH\ J. HARRIS, M.D. WILL1.151 1). JOHNSON, ]1LD. RICHRD J. Ial'F]IAA, :11.D. GERALD H. KLI\GO\, NI.I). LE0\'HARD l.OR\GOLD, Ph.D. 1RH'I\ H. F.RAROFE, A1.D. N}'ALTER LAWRENCE, 1%I.D. SA.1 LEns, Ph.D. DLtc CHtc Li, M.D. (li~iting) PHILIP C. AIERKER, Ph.D. A1. Lois I1ICRPE)', M.D. JERO?IE S. TJSSEL6AF.1, Ph.D. NCILBFR F. \OTFS, 111, Ph.D. WAI.TER E. O'DO\\FLL, M.D. Louis G. (YRTEC;a, M.D. JO)' I'.a151, I'h.11. GIL'I.10 PERRL 11.1). 1. \1'H.rlUf 1'-PF.LL, Sl,l). lR.l Pcl : \l ), , I'ii.b. VER\O\ T. RII.I l MORTO\ RaKIE/, 1'h.D. h'A~ 1. cal.aans, I'h,D, JEI \ SCHOLLFR, I'h.i). -'a.l H- aRD SEaI, \).I), RnBERT 1). Sn.1.H'Ac, \1.11. (l-isilin.a) AtARG('ERITE P. SYRES, M.D. CHARLOTTE 1'. C. 1AIS, b1.D. LP 0 w N J O L U

.IJslsiYlnis (cOnt'(f) GtORr,F S, 'I'AR\O\VSRI, M.D. INIORPI\ \. 7'ELLER, Ph,D. SYtci \ l x . 'FR al'Br, M.D. Lltr•. \CRrn',i rasrtt. ?1.D, ~ l l-H„l' \ 1 ',. M. l ). 'LH,~.1 \• zt)IfIF:R, ntD. B\R.Irs "/.c5lolt, M.D. }Zese(71'ch AssOCNitE's JOH\ W. BEATTIE, B.S. AW:CSTA BOETTCNER, Ph,D. ELLIA BORF\ERE('\D, Ph.D. JA}IES G. CAPPVCCI\O, Ph.D. GtoaGE \\'. C'HA.cUS, M.D. JACR F1stnlAn, Ph.D. ALE1rANDER HAYIP70\, Ph.D. le,cl. AAPL\" 1'h.D, 1.t0\ ICl'T.ER, I'h.D. D.Y]IEL ISIILLER, M.D. J. SPENCER ASt'NROE, M.D., Ph.D. IIIARVIN RICH, Ph.D. GLY'R ROBERTC, Ph.D. . !A7.\t'RICE F. SH1L5, SC,D. FRANCIS M. SIROT,.AR, Ph.D. \'1.\DIYf1R SFaI'SRI, Ph.D. hLdRCI', A. STEVENS, Ph.D. 7 1w\eAC T. TA.H.vs, M.D. }'\hF:FF. \'AA.A\IEE, M.D. STA\"LtY WALLE\STEI\, MLS. IRSI 111. \\'EAIPE.I*, Il1.A. Rrsrarth Fetb,ms (cont'd) Slll TO\ DA\ZXER, \1.A. DoRI> Dcr:., Ph.D, Aiskn 11. FRtura., \i.11. .InH. ]. HcDOCR, p1.1). KDUI R ~\'. 1'. I1 L'rn.R, M.D. J. JDI.', M.D. DAiTU> L. Ar.>1lLA, JR.. M.D. Ld(, 1). SI AveeB, M.D. BtR.ARn J. 1CovES, M.D. ROBFRT 1.EEPER, M.D. LFORARD LIEGXER, M.D. KI.1115 IIIAVER, M.D. h1ORTINER h1EIDLL50HN, M.D. (I isisiaD) IRN'1\ NYDICK, M.D. An.. S. PETERSOS, M.D. }'ACI. RvEGSECGER, M.D. 1114RTHA SCHOX, Ph,D, F.R\EST SCFIR-.\RT2, M.D. h1uRTU. A. SCHWARTZ, Ph,D. FREDERICK 11. SHIPXEV, (11.1). ANDREW SOPCHAR, Ph.D. ROBERT W. SPEIR, !11.D. SHELDOS F.. WAXENBFRr., 1'h.D. \YH.1,1\YI Ci. \\'l1.XtR50], N.D. SORRELI.\{'otESos, M.D. ('xlrn J. ZFRYCicR, \I.D. J'iciting Research Frttou:r MLRI A12AYt'.Y, M.D. 'F5T\EO BABA, 111.D. l'isitin~r :/ ~r Re.rearch AssociateDO~\AB'{RRT BRON\, Ph.u. O~\A A7. CH\PRWFRE, Ph.D. RoBERT T. THOaw-,, Ph.D. RoSA DE A1HaeS, A1.D. AXtmA DEVI, Ph.D. Associate Scientists B. R. BnXER, Ph.D. FIRHa. E. BEaR, Ph.D. JO)IS J. BITTI\ER, Ph.D. 1Rvcr. 1). J BRosS, Ph.D. M,1ETH C. CORRIGAN, Ph.D. ALBERT V. D.YLTOX, Ph.D. GlotccHlso FAtLLA. Sc.D. JEFI'RFT H. FRY"ER, M.D. LcDYCIR GROSS, M.D. R. NORAIAr Jo.ES, Ph.D. CHARLES \I. :)foTTLEY, Ph.D. RICH YRD H. OiBOR\ E, Ph.D. IIELSIL'T RtiSAA, M.D. DOXALD VI.i ER, Ph,I). RoBERT R. \1'tLSOiS, Ph.D. H. hL R'reaT, Ph.D. FeFlo:cs In Trniuinq RYS.arl l: F t'ltocc'I }I\RRS \. }i\\I, I'. \. i\IoRT,I. B4RIi, 1'r" u. JACOB 1., BRtsER, \l.D. Dom'A1 I, Cor-r. \1.11. IR.t,nL:g) CiIA]fPIERO DI 1\IAYORCA, M.D. }1mEO EsoD, B.S. /\IARTr\ FARX, M.D. PABIO GARClA, M.D. JORCE GASPAR, M.D. FELICE GAVOST(I, M.D. AI.sRFDO GISEvti0RO1.E4, Pharm.D. ER\E.<l GREE\BERG, M.D. FTEOL'IFL HOLAIBERC:, M.D. .qBIK)L 1eLA)11, Il1.D. SolcHl F:cmoAXA, M.D. LEO J. I,E\CIO\I, M.D. A1F1-CHIAt• L0, A1.D. CARLnS F. 61+.eo, M.D. ROBERT IA\ MITCHELL, ALD. FRA\CISCO MORALES, M.D. vEROSICA ML'RPHY, M.D. (IIlir+n.y) 7 ASL'ARI \15HIZL'RA, hI.D. AtASaSHI OEADA, Pharm.D, /l1AL"RICIO 1.. ORIGE\E5, M.D. ROSE PAPAC, >1.D. AtaRl„ PARlDES, M.D. :l1AR!I. CEC'EI.Ii S.1'ATl'LEIA, M.D. A1EH,itT R. Sts, M.D. Jl'R[- SPRA\C'.FR, 11,D, t;lsl.ta $TE.CHER, \7.1). SHO7n'P.+EAY'AaA, \1.U. (i1Sl L{ WI\RLER, M.D. KIzcNIASA 1'A>IAM, \1.1). 77 Pre-D(,.-tnrnt REsearch Fepotas JC\E LEE BIEDLFR, ALA. LEH.A DIA>losD, B.S. AIiRY JANE lIA>11LT0!S, 11 .S, ID" \l. 11 -ns, B.S. ~1\Rf:\RFT 11ERT2, SL:\. .\Rtt :\LtaeD L\rzAR1.L \1.1>. B\RBiRA }11T111 KO1}\BfRt., N1..\. 1IIxaERT Ko>LSF:RA1E, B.S. ROBE:RT J. SCHVLZ, B.S. BERTIIA\I SPECTOR, Il1.S. BER\ARD'I'AIDLER, AL.'\. RAVAIO\D TAAAER, 111 .S. :\VDREY LARACR STO\E, I(1.S, SHIRLEI' VICRF.RS, B.A. ROBERT W. N OOD, DL.q. Clinical .3proinirueni.t Clinicians ALF.XA\DER BRL'XSCH\Clr„ M.D. I.L0Y0 F. CRAV[R, M.D. ,I1C/1 (EI. R. DEDDrSN, M.D. (iEOR(:E T. 1'ACK, M.D. UL/:, SCH\\EIIER, \l.[). ROBERT S. SHER\IA\, M.D. \OR\IA\ TREVES, aLD. Wll.l ET F. 'AVEIIT)IORE, JR., M.D. Asxorinle C7micians JOSnPtr H. FARRO)c, M.D. 1)11CHAEL J. JORDA\, 4L1). JoFls S. LADtrE, M.D. GDRDO\ AICNEER, M.D. Jo/l\ L. PooL, M.D. LAiL' I S V E NET, h1.D, Assistnnt C7inicians JOHN \\', BEtI YILLE, :11.D. C. PAtiL BOTA\, M.D. RICHARD D, BRASTIELD, M.D. ALFRED BROCXC NIER, M.D. WILLIA)1 G. CAHA\, M.D. WILUAM W. DA\IEL, M.D. h1ARVIA G. DRELUCH, M.D. HOLLON W. FARR, M.D. W1LLIAYI GELLER, M.D. CHARLES C. HARROLD, M.D. RALPH L. L. HERT2, M.D. CHARLES J. HICPEAX, M.D. THEODORE AIILLER, D1.D. D.avtD \foLANoER, M.D. GEORGE PROI;T, M.D. Guv F. RoBBI-, M.D. t0A\\E SmlTt:, M.D. REt'rts R, S.)nERaA,, NLD. \\'. STf iR\5, JR., M.D. .~ f:0.Fr\I I :1. (RB {\, \l.l F. ~ ~ w N J O t T

SUPPORTING STAFF 1llt, ARRIRB,K R Mll'll.\!1. 1)A\AO :1D41.F HiYDE\' \IlR \ :\IM/\1• :(I\RI A\\ I)\\\ \FL1.\ II11.1.1\(:FR I)(I\I I \!CO :\1:(,,Tl A O )'I\IEIa IIAYIE1 S\L\'1\ II/1.\IRit'!1 ARTI/L'R I), ;\t.EAAIDER, III SO1. IIAI'SI S.INDRa ('. HE\IPHILL SAF.1.1':1LLE\ CO/ll\F hEA\ SL'SA\ HE\DER.tiO\ MAY ALISTRO)I AIIA 1)EI. MCNtO 1)O]AI.D V. HESSI.G ELLA AL.-FON Efl)(A 1)E MARTINO MAR/;ARET HERBERT HOIt'ARD S.'ALTSCHUL $ERGEI I)E\ECRO I)OI.ORES HILLAIER LORR.AIAE ARNDT HILDA 1)EAELAN JOH\ HLI\RA RABETTEARUA50\ CL.AIRE I)EUTACHER GILBERT HOL1_A\D t11ARY LoUls! ARTIS MARGARET I)E VECCHI AUra'E'EA HOLI.A\DER VIRGI\IA RiBCOCR CARL I)i FIL.LIPO MARGARET H0011 IlOI.ORES $ALOG CHARLES I)11.1. - MARTHA HOPRIa JA.\ET HA.\L SHIRI.EI F. I~OBRI~ER 1.11.1.911 II:RA VOLOF5IAR $.A\KERS IRL, I111ERR (FRSAI.IA I\TRI FERDEIAND J, BARBATSCHI MILDRED I)ONNlR F,DIIARD L. ISENBERG I\IARI RIRESCH RL'TH I)O\OHUI HAZEI. M. ISENBERG FRA\CIS BARNARD F.1\(;SLE\ A. I)L'\IO\T CONSTANCE JACNSO\ RIC'HARD BARTERS MARGARET H. F)L'\HAAI RcTH JACOBO\tTTZ M11.DRED K. I{AR\ES A\N EDIIARDS RL'TH JA\t1ORER FIlR\ARD MATE+ FSSIE FI.I.(OTT Si\IL'El. IOHNSOX ELE\IOR RE.\TE•' NVAI.TER 1. EPSTEI\ SHIRLFI IOH\STO\ ID.l FSERtt'I51. CAR19D\ 1). El'.{\5 JEROl1E JAI\CHILI. PHH.IP FILt'\t \A\C1 F.YA\> \L1R1 F. JIl\ES NIIIDRED IiOBR0Y1CFl ROBERT FECHER JOANNE KARTCHSER AGAES FEODA\SRI- F)1.{\E FELD\IA\ I'lill.l.t5 K AYA SL'SA1' IifN:ART JACpUE1.1\! FELTER JCI.IA }.Ei.\E JANICE FIOI.AFFI JEANNE F. FE\\E.R NIKITAS I). KESSARIS GEOicc:E FSOXD TINA J. FflGCROY}NY E1..41SE KI.G ELIZABETH BOOTH RALStoc R. FH,.\(DR! MAOELEmE )(INSELI.A JE\\1!. ISOREI.LI ELIZABETH Fl- MORRIS 111RSCHE\BlUM RC'TII ISoROl1sEI 1O/1A5]A F(]S I)OLPII KLEI\ MARI' BOYCE Cl'\THIA FOLRERS JOSFPH K\Ol.l. hOR15 FSRACEI' NOLA\DE FORTIN hOET51ER FSRADLF.I ET'IIEI JULIA FRANCHI IOSLPEI ).OPP . :110\.\ KRANDRII/I LEO\ARD FRA2ER GRACE F.OR\(:OLD RICHARD RRA\:,'1 JOAN FREEDfIAN I)ORIS !\l, KR FI.1\(: SARAH FSRA\\ THEL\/A F.. FREE\IA\ (FAS.\\i AItAlIC2E\IL'N M.ARI" ISRESNAHAN V1RGI\IA FRETDRERG CHEs(IIIR F.L'H, JOSEPII A. FSLfDNIN JA\IES FRIOIE hORI• F.. F.('SH\ER ARTHC'R Rl'\Dl' ELAISF V. FRrtI [ISGHASA F1URI5 Fal-OR li\RHARI B. HIIRKHOLDER F.l'1 FURRIER CORI\'\E LACO\ \IARt'.iRET RCSH\IA\ .\LICE GAI.E RE\ATE LAOCF('R I)EiPI\A CA(.ATHES FSFATRICE GALLAGFIFR FRANCES LASR16 MARI' :\\\ CA\TERBL'RS" :\SS F. GA\IBARDCLLA VIRGENE A. LEAGI'E GEt1RGE CA\Tl j\1.ART (iARBER MIRI:111 LFAI'1' SALl.1' CAREY ESTHER (:1RE1\NEL SU-HSIA LEE CO\SOLACIO\ C. CARI\O IIELORIS (.tR\IS ROSE\IARIE I). I-EHl1A\ CHRIM\E CAR\ET .j1.ICE GARt'F\ ALH'E LE\Z JUSIF. CAST'RO L/MR1!\E Gil'DE 1)OROTHI' A. LEO\(: .\\\A CARROLL JOAN GED\El- ROBERT A. LER~SFR I',I.IZABETH A~\ CARSIYELL JA\ET GEISSEISODER hOR1.5 LESKIN (iRACE CELEN7A\O FY.ADI'E GERR4RD JANICE LE111\ 'IBA ('HAARARARTI Lvl, GERYITZ M\RT1! LEl\ls \IAF F. CHAIIPE\ FLi l , (.o1.ORERG JOIC I..IYOTI 1.ORETTA Cl1EOSC. \LIRII.1'S (iOl.Dm1fITH IcnCF I.oauu I:LADI~ FI. C/IL' C11/.A CiO\Z11.E5 13\RP..{RA 1.0\G1IRETH H\Z/1 Cil('\IIF1 h11R1 (.IwI," .\E-R 4 1.1'CAS \I \\'1• (~I IRF:( 111R1\ (.-I.- \I, \ISAc \II'RR.tI COHE\ )'lIll.l/• (:rlR/ ll \ C. M\CI\'lua/ )S1R1,{R\ ('ULI WILLI, (iORT/il .\. {1, \jaHA\ \OF.1 C" \EL1.1' \1DFLLF (.(vrll ILP \l \Rl NE\ITA ISt.A F. \THFRICt Cui,lA]]'1]O FIORAC'L (iRAI 1 FIIA \l 1R510RA1.1. ('HRl'SIE M L ('OS,TAST iNOS \1RCISA C. G!'!(.ORIO FI.IZIRrIH MAS- \I. fiATlIERI\E ( OL'1.T;15 s)1.YlA (i. (iR1/AR10 F)iRRARi 'I. 1IAKHEBET 1'.ILEL\ COl'LE EL135 (iREE\! LmLA F. MArER CH \RI Ec COX \IAIX:IE GREENE CEIYIOS MCCARTHER Wll.L.I.A?f CRANK JOAN GRIFFITHS LAWRENCE MCHUGH :1LICE P. CROAI\ ESTELA GUEYARA MARY P. MCKINNET CFLIA CROUSE A\A F,. HABER JULIA MC\EELT 7 IRESITA CUAJU\CO PATRICIA HAGAN EYE S. MEDOFF F'E(YLLIS C('AKI\GHA\I I)ORIS HARRISON CHARLIE MEFKINS IDi 1)'-aGAT'A A ITRICIA HART Vll'IA\ MELTZ KEITH 0. IlA1.El' MARGARET HASSON FE,TER MEIEC.AS 78 N ~ EJ J C F (JI AD

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STAFF PUBLICATIONS • 1uly 1, 19S.5, -June 30, 1957 ARrrss, C. M.: 3.ae;uc, A A., m;•.I 1 D1. S,: farrc~ioqAr,SJ.tbfrJ.119e.'9S,lt:,,, I:d m Alysers, J. B., and Rall, 7 E.: Tl~r mrtab,Gsm of rd;ne in evebrvspinal 9uid, l. t: hr:, (:nd:.rriaol. 6 Afetab. i3;i4S', 1955, Alpen, 7• Brifueal studk~ af th. procrxs olf !h E• RClobulin b}drolr.+s, Ar:F. Ifi,•.hrm. & Gu+F 65: 5113, 1956. ASImw*eaRecefried,Fand Rruna},i,1,,,tAlrxamler• ulyi.laa~Stu~ pf gas ryctom5: an txi-.~rrrnen[al a tt r 144:328,1956. A ehanBes tladuCtili<ra ~hnorm~t ,h~ in ParFtrGOt 49, 1955.~r ra Aries-5 ella, Ja.'ier: F"nlometri:J rh-rs in thc rat, Ar:h. 1'ueh. 60::'•. 1'i55. Bader, G M e 7 K. }. . 1-. f a 7 Uav} Astlf'tI d1ci c er, u n., cer, <itr i a. a scrcenenr dr.,ce tor an Lurrat;, Drntse: A purineAisti,i:ne rrhti„n:hifl in E•cherichia eoli, l. B,ul. Chrm" 216:9, 1955" Balis, M. E., and Dancis, 7o<enh: EHeets of merbotrteric on nudrir acid arnthe~is in leuk<m;c sl.lecn breis, Cuc:rr Rrsrar:h. 15:603, 1955" Balfs, M. E.c \•an 1'raaS. L;na, ar,1 Rrown, G. B.: Studies on the r m a( human lumors. 1. I' nto;eoud ;c z.i•IM1S,n¢hr- -;n tmm~r-hrar- mp bam=ters, Cancrr R: ~-::: 15:6•3, 19,5. Balis, M. E., and Hurchs,. L. 7., Ntreptaoreus t ol,." ~f f ae :,1,:°"Bs Ft. ~ Proc. 1 iFS,r p. 135. Ba1is, 24, E., an? Hmrhi,w:ri.1,:Il,;,1e7-s: liutixation of th•pur af and Purme~, Fr.na.• n P+:- 15;214, 19;6. Bahs, bi E.: The efiea- of -rnrrat9n: Il"r tk•syn'hes - of uclc': 6,1 uf hmn tumor- an , Pr.,, i. Rrrrara: the h s•~. P ~52, 19i6. Bts, M. E.; ]tn,n4e, •l1. S.; Bro,r,, G. B., and aA:a: nik, ltoris: The uf:h>rr.i;•nrai pn es bg purin<les< n nts af :)<roh:,ctcr .,e r nes, J, £u!. Cf:rm.t219:91:, P;Si. Balls, M. L.: Van lt;n.., and Arrcn, Fra " Smd;r .n tl•• r cn,t.a;ar, , f bnman tuo,o,sll. Prnt srnudrl o tumor-Scxr;ng ra , CRr,;.'V :ca8, t s: c. -. tle r . n l-n - ]Il~l.l ..... . . .,.: 7,. r, 1...,n. n~ r , ~ ,7 - . 1' 1!~ 14 R,ne }f, 1,: Tyrr. I F 7•• -!- i.: } e e an,ie. . S3lc,' \-r.,y ~ X,rfA'r- ara.a, 3:213, 1935. Bane, H A {Ch t h u \l C C hm dt F t'r•~-h 5:468, 19il~, B.rnr.H \ tI' , ~~ \. and ..6 1 1:1; I l h 1 :•: ehanse <f its • ' , m i~. and man, lt1n. Xr.r. Yrac. 4:1.;., 1056, u Barclay, Afuion: Rau[man, R. 7.; Kid•Irr. E. D"t C'alathec Ur,fdn:,: Each<r, G C., m+d 1'eter- mann. \I. L.: Tb 1.ma lipoproleins :r, w men wfth c of Ihr 4, rast, Pror. dn,. A. f.n, re Rrsru.cA 2r:93, 1956, Sart1ay11R.LC.t Gnluh w, 7 tlus. and Srock. C. C.: kea ,idr with eysteine and orhar aulphydra conil'aunds, Fedrrnliun Pr- 1 i:2r,3, 1956. Barclay. R. K.; Garfin6d, E•thrq and Tk.ilb;•ys. Mildrel: Eftrcl, at llC/\ r nrWra:;on of prrennar, into nurleic ae;ds,hre:. ,{, Can:reRurors):2:93, 1956. BarclaJ. R, 1:., and Garfinkel. E•eher: 7h< influ- ence of \-m<tLylf~rmam;dt on fcrmatrC'• '„rporarron. 11, 1 nucleic aeid- o: tumor- bcarin6 rats, Cc,.,rr Rr.rra.cl: 1::3J;, 19_ •. Bard, Monon, and rlan ~uJ•rJ, A. ?L : kt,,c:l- ..t fc t' t .1~. Adaptzt;•n to r..-d n. 0a•r 8:6i6, 1??5, Bard, Monon: The u<r a f d,.,•en~fr,:.e i. { d:ctfnF R•chok'enic inrah,l,-n, (r.IL,r„r.. rarh~al ,astectamy, ). Arra. E 11rnt. 12::152, 1955. Bard, Mortoo, and D>:_ R B.: Thr T•cschr,- ,Icnam..r sigr,ifinnce oi bel;efs re~: 'Inv tht a Sr rf nerious rllnecs, P.•3'•'d<•an,:~: 4 4: 146, 1956, Ba d. Morton, nd \Ca<rnbrrc, S. F.: Kekniom sh:r r f t;.+rncll :rJrca! i drx •.•cs t~ Do~+- .at iurahdrt.n, 1. Chn. Pri~h... 13:151, 1957. Bellvitle, ani B,yan, C.I•.: Ca :pari:wn af the etrcrrorn. rp!.: .ph,c pat<rrna dun;ng stere,d anrV barh:tura:~'r,ar.o;is. Arir. J..lnarnhr.na 28:50, 1956. Belfvilk, J. a•: Efiect of arfona.l .. --het;c requi durinR :lnrreli,~s„ 7trav 1 7t3i ._, 1'7iC. Bellrilie. ). R•„ and Artus;o, j. 1.. 1;.: cephme6 ~' i F ther and reln~rto7 a.< ... ~-'hr:Aia, •"In;srl:rricl•py 1%:C53~ 1'~i . Bendich, Aaron; Fresca, L • ~_~ Be dich, A rn N.aer••cr,ur;t. ,- ir;_ ac„i -ai. : i t:r::r.rs ~i;~r ~ 6<, -r. ~ S SJns , 1956, p, fa. hcndlch, A,ron, ! . }I. 1~ ? p ., e. NT C1L! ~, .,:.. ! ~ ~• , . ~ ,. , ~ h-,!, i , A.,ron: 1.,! i. II !: .. c. l l: 1rFn11 t ; ~ ~1 . In .uutr. IY~:a. 1' 3 e. ~ I~\ \ 1\ . Brndich, Aaron; Glner-Sorolla, A'.fr<L•.f and Fcz, J. ].: S_s~othesis and pro{ertirs c: rur;ne- of potcnNal biotugical fnrrrast in f } i tio Ssf•ri,un on t)se CHenurrr" d H.. a f Pan':.,r•, Bo,ton, Liulc, Rrod- a d 1957, p, 3. 80 11. F".~ S,nck, C. C., tii„rhem; ,t' 1;fl•r - L,:...rn r n'7 an;J orrtahol;sm cancer crli, 1. \uclrir l p r nraT•lasn;;, fan.'c,~rr h',.~~~e:F ISSBi, m:,l 1955, Bennnt, L. 1., Jr.; Skirt<r, IL E.; Tmlan, H. \P., and tehoads, C. P.: Sa'arches far e:pbitable b<rhrmical drfferenns betwern normal and ean cells, 11. \uck:e acid purine metaboli•m " hnman tumo ,, Caw.n Resrar;h 16:26., 1956. Ben a, R: S., et a1.: Triindathyronine in the aerum ( Tmnent. trrard! w-th a•ti.,arrice irrd,ne, l. Clu:. ls.d,rnnof. f 3lrruh. 15:1367, 1955. Ber6. 1~ a"•~ F.nplucral hrrnts: , c mpliea6on of tanter chrrary, cm:.rr 8:731• i9SS, Berp J. tg'.: AnFiatiry,myosarcoma of kidneg (mah~n:mt Aamanomamuc anc.al,pomyoma) in a caa- m;th snlftarp mr anasi. from broncbo- gen:c carc;noma, C„n:nl~':.5'~, B g. Jar: The s nif:.v< of avlllary_ node Irsrl-. n thr srudy1oi hr,.,.teca+.:-ma, l.onrrr B::7r (935. Barg. J. Of,: Sinu< h;a;-ytoa:: a fal:arL•us - nf bostrr to eanc , Cm:.e+ r 9:93i,19ir:. Be man, Monn; Katl, j. E., and Hesl ,]: Some pAysicet c, i~lrrat»ns Bn,'rrn;ng tht hoicr of ntern:.ifr >admin;stered ad;oisotop<s for ther- aDy Rad:ai,yy 65: 10G, 1956. Berman, Mones, and Schoenfrld. Robert: Imar6 es it, exrcrirnemal data on hncar kinetics and Thr formrdaean af m.virts, l. AFFf. PEy.r. 2,. 1361, 19ir~. Bethei, F. H.; Crcac L. F.: ICUnofsky, D. A., and f,.Davi, F". F.: Tbr mana:ement of chronic lymphoeytu Iruke:ma, Xfood 10:10i8, 1955. Bty , H. G.; ~Surri . J., and E~dinoff, Isi. I•.: Ch3npe' ultrarioJrt ah-orprin "I Sprctr a afreY uhrasnni<~irr:.d;al;on of s,na c mMUnds lued m Ihe nud•ic aNds. ARrsra.F 3:21a, i'55. Bieseie, J. J., an' C i.!!.',La:, F•,nd: A srudy nf caoiJ:,-m,c bf iJ c •..r; . n r~s cuhure cell,. Can,rrh'rs•a.,.li:%(~% 145i,u Bi sek, C. E., anC Vottram. F. C.: Bome early eftecin nf rarcinn:•:+c h.'droenrb+ns c skm, A.:n. trw 1-n.k A:od. St. 63: 1707,U1956. Biesele, J. J.: Comment: "A note on al•pn.:~rh ru e:mcer ~hrmrther::py',' Ter.nr- Ftantatfon Fu11. 19'_6, Biesele, J. J.: Smdi,-. w;ti <ancrr ntL and ex- par "ra4 ~r. in 33: tis<ue.40 cuhur,, (:n11. .\.a 1",~.. ~ ltrd, , 14 ". B;ecele I J T-•"^ culturc e. ., er . Sr,r,:t. a,i.- I~,i:-~. 1'i:, :tr \'r C ~ pin 1 1. I r~ c. .., Hodan 1, (T :. . ' ut.l.,,,rL. Baiansky, Oscar: Cnmlari=on n- rho:;:h,nc~>~ .r fidr: ~-aruFenase actisi- m Wttic uid e n ll . 1'<Y, d tunl0r tis~ue of tnm•rr- tra nc t., Pr~r.An:, A. Cm:crr RrreareF

}IenschAc. l'. 1:.: Inn:. i:l iml.l:nu.~nr,n xitl: 7h:,,rf:n!„- tr~~r L~hr: \\'ihs \~.,ns. Inc., 1"i4, 4. 3i5. Hc schkc, 11. K. A techmc for ` nv t' . I,I:.nt:,tiun r,r r:vli„i•ow{n~s, Rndiefnyyn68:25;, 195i. Henschke, l'. K., and Monon. J. 1..: NIonaiit] of rh,+rkeyr afl<r s'ngir tut:!I In,dr Irra~ diatr+ ,r.4 n~ l. Rarntyrnoo). i7:89•i, 11+5~. HoRR. l.ex~is, Jr., and 1':rrk. C. T.: Dia nstic of hrra a:r sr: al lnt,:, otr ., al, HoRR• Lewis, Jr., rud I'ack, G. T.: 7he e era •ia1 rrla!i„n•hit~ hrtxrrn hbw,d Rrunp Anand Ra~trit rancer, C:nar,.rnr:.oi•~py 3_'::v:, 195;. Hoode, R. Vi'., aml \\':dlen-rrin. S. L.: Clinical a•I~rrt• of thc rsatu.uir,n uf ana1F<sics, Crr,~ ar,rre A:1d„ I95o, Houd . R Vi t\\'all r t , S L' C1in cal t I r• a f . 11 ~,ai,rpph nc tnmbinatwn•n rr.r,Irroli,.r. 1 r:,, 10,411/, 1956. tioude, R. Pain and the f•alient wrth eancer, 1;. (l:r,. ,rri.u ~U:/":, 14.G. Hn,rland, Vf. S.; Schx~rixrr, Olra: 71o)'an. C. P., ::I llottn, -i. C.: }'hs.iolursc altrration- with Lhv~~l rrl~lacement, S.rp. Gyne:. & , ~l~sr, sllrt :a7v 1v_ 5. !{r,x~land, Vi'. S.; Re)'an, C. P., and \\'ang. 1Cuo- r'hrn: Thr u I a sturold (Cudril) a, agent, Anesrkrskk~py 17:1, 1956~n IL x la d, V('. S.; OF•a; Royzr , C. I'. na 7r„nu. i r cnl or a,lren'r rai ri sut nnl pr„crdurs.,uJ.~.l. ., •uRi:ier:,. ilu n;: ,Irl. A. 1GU:1.71, 195Gry Hox land, ar,d \\~ang. Ru•,-Chen: A p <=hr.i:, cAr..ForC Srate J. Alyd. _ -_JJ:, 79~L. Hoxiand, \['. S.: Royan, C. P., and Schxeirer, t:..:.\-rntrirular hbrill:nMn durinC n a •is . l~ ..,, rrl'Ia+rmcnt. Am. l. $x.y, 9_:3a;.195'. Hoxland, V(". S., and Lexis. 7. S.: I•nstintubr,- ~ pran,:lonu• of the larlns, C un;rr, 9:1.al, 1956, Hoxland. \\'. S., and 1•ewis, J. S.: 3fechanism.s dc.-rl..{•ment of rnstintubation Rranulo~ ~i thr Iarcn,, Ann. Oror., R6in. 6 Laryny. t-~11(:06, 1956. Hnx-land, dunng ) sAnrgery a nd r in altL e spo tupera- tis~e 1'ericd, Gr.iarrirt 12:14„ 1957, Hutehisn , D. J,: Gro -th stimulatlon of Strepto- e ~= taecali• b. adrn e drrrrati,e=, Frdr.a- trcn`}'r, .. 15:2'9. 15:G in Hurchrson D 1 Tt : hfl 1 ta'hx_a3• tr t:,11 ,1n:..l:...-f.fa. A~ 1: <. H 1 . D J a 1r,,..l\t. 9 F 1. ar. I•v ant s 7'r•h~r.,~ fl tro 1'-~:. 1'i C F~nla. >l. 1:.: }urther a'! C,•ulra=. n r ~ A.n,fli„ I•tam,. ...a.r.~a.,:A:..IGrr19i:. Islesias, RiBObe:rn, and Slardones, Flvira: T- r` ~ of Iontanmus «ansptamable lem kemia, in A\C rats, P.ar. Am. A. anc Crr Rrrrn.d~ 2:1:1 1956. STAFF I'L'BI,ICA'I'1C)NS IElr+ix>. Riboher I \Innlar Fl,ira 1 c.n.r,rt • ~,rf nr• . { hn :,I,Ir, tm„ tr rr,l vr ul Iz rr.i sunwr inuthr IRtesas, RiR berto, and Mardune;, Flvira: Th nllu.ncr of ehr Pmn,l• rrd of t steraid h•n tl:r c xth of 1h, aln~ r and tr..n.!dantable r~~ Ium,n ,n~i\C tat•, Car„-rr A•eara.cM 1:r'56, 1956. it Islami, A. H.: F'ack, Q T.: \Hllar,d T, R.: Cawsmee., 1'arkrr, Rand:dl. IL T., an kabens, 1:. }- : f'ustul'eratirr c,runr f.,lb,xing total riaht hcpatic Iubeclumy, Saeprry 3'1:551, 1956. Islam , A. H.: Ar riptinn and u nf a ga~trit an•1 rnt.•rrn;,l 11-1- Sx.pe1y 39:~b1r, Istam', A. H.. d 1'.rk G. T.: Frrc per' +nral cr.tfts ai n,lnn urfacinR nf crc te,l,li.rr xaund., Su:,rr)~ 4ir::(,_, 1956, laao, A. J.• A!.hx-onl:. F.thet, er 1.: omt,arison of s roiJ c erti,m :mi n t,,l„lirCehrrtc f ndh.dr„ urtiwne a,iminicttrrd 6, rliticr •, J. L`lir,. F:rrd.~rrunJ. F tJrru.'. 16 a;,t,~rly,~tr. J 9 . J. A A ci` t F .t. ' r 1' ' rl ~'`r.. Ar - Chcanced Stt'irt>, 1}ISt nF, Abnr.r rr .., a1 Pnfn., 195i, p.4nC. Juh s, H. F. n ., and Lauphlin, 7 .: 7 terarGon ~ aJ,atio xitl: S manrr, i, Fime. G. Ltiati,+n Poamrr.~, T'<x 1nrk, Aca<Irv!ir I'aess, 1956, p. 49. JoM1 w,n, J. A., Jr,; Ifutchison, D. J•: Galloxa). R. P., and Skipprr, H. F..: Studi<s on tbe mrchaniims of ~irtance to lrmpo y anti- a scents. Ic 1(esistnnce to fniic tid a taMnists h'> Strrpcrt<occus fz<cal:e, F<or. phageat asins=: ev luatinn of 36-t ease~ Am. A. Canrrr hr.«arrA ::1.1, 3956, s J hnson, af'. D.: S:nr s ,, L C.: Fapanicolaou, oG. S.. and Se,l.,,h, J, F,: CS'roto.y ot < phaerai +hinF•: eraluation of 3G7 t.r r•. Can.rr 8:951, 19 Johnson, W. Fa•ranirntacu. G. N., and Serb>It. 7. F.: Cvt,.le8y of «. phagcat xashinF;; naluathon of -3r : oses, f all. An,3'n.kArad.91rd.32:386, 1r:56. )ones, R, N.; \olin. B., and Robrrn, Clyn: Snmr s{rculxtionscunrernin¢ Ihelaxfrryueney\ibr~t,ons in hc inf red sl'rctra of Cr.ketusteroid.. J. Am, CJ.ern. Sr:, ir:G331, 1935. Jones. R. IZ., and Hertin;, Friedrrik<: Studle- n s«r.,id metal.;tism. \\\. The i frare,t f rtu.rs«ruirir k lnx 1350 Cn~., J. Ar~r. tn/:rra.r$c,-. i8:115', 1956. Jones, R. N., a•,d SanJ rfy, Camftle: Tbe appl:c trnn of infrarrd a J Rnrnan aprctrometn to the elucidof mulrcular stnrrrure in N k b-oer, .i. e•L7erl:n;qnv ri (r,rra,nir Ckrn:. .r..r. Nr., York. lnrrnoenrr i'rr.qlshnrs, Inc., 1936, v. v. Jordan, M J R1. C. \f. t Ne A. Sf 1~ l.. tenJ e,..rr Irs.or ~. ( t... E c.y .r.. .. a.., . Jordan, M. J.: Ra:ea G' anl Jsn. }7m-or• . A r.rtiunnl a[`{~rn:rrh ttlnt o ara•ica: le.-,nn. ol the eer.i., .4,Obir. f-r 1956. Jordan, M. J.;_Rader, G. \f., ami JrFmerson Cer ; diaem,stic r ratinn n n ~aa«e°rrii~:< «ratmrnt (~hm u i t of the femal< Renital tract), inrrPra ~, (Jh'ari,nnf Can:rr C'nnlnrn;r, IocA, 3'hilaa dclphia, J. B. Lippincntt Company, 195,, p. 674. 84 Rappu•, Arrelluh: [..•!rin~r, h„ne.,-!, a r_' /~alla- ~I„r. 1. I . - .-n. ~ \t--I Ii ,.r..f r ;. Chr.. v....: 33 ~1~.>Y. tw>a.°u Kappas, Attallah, an•] Gailacl:er, T. F.: Sru4ies in ruid n~wL.,li-n_ \\\'1I1. The akctur~ -ir..rr :,n y~ ~ rrul Frmah~, anri Wc rra+.mr~~to Al'TH,rl. I vrvt,patrnw 34:1iGC. 1955. . KaPpas, A«allah; 1'carson, o. IL; t\'<st. C. D., nd t;:JlafLrr. 7. }~_: .i st A.f"idinparhic•• hirsuli.m: ~ tran:awn:d adren~l abnorm:rlity, J. Ch,., l. n t-.rrinnt. E}frtu!. 15:517, L15(. Kappas, Auailah: 11r.dlman, Leon; Fukusb{ma, 11. I~ : an.l G:dlacher, T. }.: Thr h~ruFCnic !Fiect of nla:hnl:,nnlnnr (Ja-h.droaetinchnlane- J. Cli,;. Lndo..in:1. f+16:945, 19iG. Kap pas, Arr Ilah: Hellman, Leun: Fuku=hima, I/. lC., r,l Ga!IaFher, T. F.: Thc p~rocenrc lirrt ofa, n!:,nnlnne, 1. Cliu. End, reinoi. & .tlrfaD. 17:451, 19i:. Karnofsky, D. A.: Thr u of thr de.eln; ing Karnofsk,r, D. A.: Cnrmn!herap> of eancer, CA 5:1t.:, l }:araofskl, D. A.: 1,iffrr nre• brtxeen r rers i nf therahtutic rcsponsts, CanrrrRraruerk 1rrrLCJ, 1r+:4. Karnofsk>, D. A.: 'I'rratrnrnt of adrancr.! lung - rrMc!:,m:.almethnf-,inAme anCancer I4r Lrrn~7ri~ax 1'ork, Karnofsk]', D. A.: Chemna:rraf'• of lune cancer, Mzi , C.1` eds. .,.I.r+ errLr.H , r, rr Prrs:, If~ 1r:. p.r3Ji,u .it. K rnofsks, D. A, r•' !~~,Ibrr. R. R.: }lesis•n fr e.>t<rimentat tl',rn~.,l:eral'ru[ic .u.l:re. I. Kar..a: Li~tory uf fs I~a~.rrtl:rruf• ir: tin,-rr,r~ rP.oc. (?1 h'aria e r: ('.,raer,•:, Li;.{~incott Com}an>, a?5. KarnMsky, D. A.; Ilas:. C. I'.; frnra::, I_. G., n~l Ikl 31A&: lle; - ir,:, [um.rs rr Rrnxm- o, the thnrioallann•:, oflLrchicAa•mbr.r., Rts,arr5 ?.__c. 195„ IGufman, R. J.: Rarcia>~, }farion: l:iddcr, F D.; Escl:er. C:. t:.. a..d ye:ern,ann. \[. 1_: }In„an pivn,a L;oPrmrins. II. Th-<ffrct of o n rtasta-e- in patrentc xitl, ad,'ance•I carcin`onia uf the br,a<I, Canree 8:843, 1955. Klauber, L D,; Fo(,pell. 7. R'.: kandall, }I, T„ ~ml R'+re, K. E.: Chan_us in tardia< ourymt duri:,.: If~e /lmmTng a.n,)rome, $urQ. FarYm, 1r-3:4, 1956, Knis,lVernnn, :nd Collir=, 11. S,: A c ur nt n th. i;r„hlcm oi dru. re e,{~hy~ 1 :.~ani. ,1-r,r 7 orl.-/~od .\,e,1. at 1 .., }snrh H J ) i~' I. F F 7I. . }. R.: S!.i:: .. N . I., : 1 ( 7 Ar, I f [ . Koch, R. J.,nJr., and Le s. S.: Hyuediprmic xfth a i,a ted o • aranm lru tlin c:ri A'ra r<Iti~rt~ Fu9)nnd J. :lird. _. i8a. 1916.

,. z~Y Y.. .

A. 5., a,•-1 \L: ~In r•I i . l ~~IIH r „h aiItlu,,l+i t. Mnrph>. TL L.. a,:.l f:,rn,~sa;l. P. .\.: Term•- e'~'nr .ti~,t n~xir rtiert• uf unlin~rlalnlnr. in thr nl, .I•rci:,l ~ferrnce u, '.-,liar'! 5-oxn- I,n„rlrn.im Il+lt\). Murph7, M. 1.. anJ K:mn,fekl. U. A,: F:Arct ul a • u n•I nther Fr~,w'th inLihitin¢ aa•rnt- ~t:Jrdc,'rtnl~n,ent of +hr rat, 19>t. Mutphl• M. L.; UacF. C. 1'., and l:arnof.k>, I r. A. l I n of lrra+n.rn ~ 1 1mr 1 t'~k emtrvn.. --lL a•i'ht n~ f~r I~uhlicatun. I'v.lorri+s l+.,Ul, 1'.;. Mlers, U~. P. L< I•rdm~,nar. ev:,'~+:,u"n nf urin- c:Jci n nea•l n l• i, Ihr ,7rtrctinn of r ~eFlrct" ofnchrmothrr:,l•eutic aVrnl-, Yn,u.+in+. A. Cen,r. Hrsru.,-4 1'1jG. bb'erx. U'. P. L.; \Cesq C. 1/.; 7'rauon. O. H.. +n~1 F:an,ofa:y, H. A.: An.lra,.rrvin,lure,l r -crha'i•,n of hrcaU cancer m<z-ure,l h. catcium -111 n( an,lra ear„Fen `r.~~ihh nn,lcrl)i,u mechat.-4•nt, l~.i. 11. A. •Itil,:tw l!%, Nlle , U. P. L.: Chn cal l.(• , uf 1~,•IMrcalaen , il. ld+,+- .\Irrlq .{+,i„ n.rnlu::~1. I9ic. hlyin. a~ j PH~:~Therhrl` r acrJanJoRr`. nir+h)iinrnumi,le im m -, Cno,rr D1.r s, VI'. P. L., and S1aFi11, G. B.: A:araGonl calci mrtahn!i.m r•1 ~ith o~rliazu-5 uhnorleueinr, Yr.•:. E 3fr,l. 93:S1J, 19i1.. Mlcn, Ut P. L.: H.7Krculcrmia tn neurlax1ic 'h-ea-e. t on;rr 9:1135, 1954. Mlors, U'. P. L, and Reydel, Ro+alin,l: A { ~ eal rtl~_.lenr~+a cttic acirl (F.117A) eth..• fur [hendnerm~nation of calcium i ur,nr an,l .rrum. ('1in. Rrs. f'ru.'. 5:'i, 195". Nirk,on. 7rraaiarnn. rar,inntr, •t and 1956. \ickaon, ana! K- 'it, ilrrn:+rJB„liothrr i,I lunu c , ,ll,,-, \la . fl. l 1L. t. 1'. 343. ~u \ickxon, J. J.; ('hA[nn, F:, 1:., anJ 5<Ih., Iirnr): 1'arc:,~,.n,a of U,r lun,. :::xa., l"i:. \olin, B., and Jones, R\. 'fhe Infrarr,l ah~nr{,- liun .I~cara of dewrr.,t<•! < ,. 1. ?1<tha e. 11. };thvl a ta+•.. iannd. I, f-/+r+n. 3Ja:r1a3+?, 1392. 1Y5L. r 1o>es, U'. F., an,7 \\'a+wn, 1'• 1:.: Ctu'fir- .n Ihe uf x cuhure,l }„ttnan rrlt-~Laen Aofrthc`Autr~rr~c~enl nntil,u,1. trit- , \met. U- F•: \i, I. I F~.a111U1 r . h 1 .,t a-r t„~ crh. 1 r- tlu tr n a, 1n~~e . U' F 1 H 1 M - \f d '.1 r/1 - ,+M1 1. k r:t I,n,(hn ..,r+an+.,, h dr,~rl<n Jr.:. \,rdick, Irwin; \\~r:~61e..,l.i. Falix. an~l Lal,ur, I. ~: }:.i.tenrc for in •e•I - n Fluramic c ataa:~. + e r(SGU.TIr at~1,1, ful- h~n,n ra,1rJ`an ardial infarcl. in doF•, iir:r,fa!F-n 1'_:1L1` 1955, S'1'AFF YU BL.,I CATIONS , +n i_ th N)dick. irwin; TanF, ,la,nr•: ~+~Ilrrnu+n. (i. Ii.: \Cn;hlrw,k,. Frhx. :mf L:,Uuc. I. c.: Tl,o inAucnca of rht'mn:,lic frxrr o +r,mm~+ nf thr < ylnmmirr+n<aLiactir Iransamin:+.c, lir:alrri~~u 1!::'+', 195-. 1\Idick, Irw~in: Kuru,ev.!rsrnrm ~FLn amia nxah Frl+.,t~.i~nvn~in~KJt~l:rr.T+x' iati,m,fn/lnw. +rxrorunrmat an•t cVui,:d a n.uAa rn•1 7-ic:rnhti.. t 1- . h'r,roY-.'.r1:1U1, Tydick, lrwin: KnrF.r:cr,. 1•ou'; \\'r~•Llaw+7.i. }rl,x, an,i 1•allur, 1. 5~ \Irchani•m of i+ •r,l • xi,x nf Ihr rnz„ne.. rlnt:,mir xr;+lareticrlran~aenina.r (\Ii/1T1• Flnlamia' ` ~c Iran.amina.r (c(il'.T) a,ol I:rl:e de~ i:-rlruFrna<r f~l.l+). foiloaxinF n«ar,lial in~ Lirr+ion in thu dn`, t'/oa Hrs. ~I'r. ~r. 4:240, luia. 1x;Fdia'k, Irwin; KurF•eu~ r, I:,ul; \\'ri•Llex>l.i. F<h. n,l l..l,u.. I. :\~a iation. i,r Flnt xalxrrti+~ v,11ru exrr.in,rn[alan,lrtinikratrnra a~r•i,~nAiaicnr}, perica„tai+. anrl pulmnrurr infarclion, (+nnfn~ ri„n 1i:3!J. 19::, O'Dunntll. U'. F., aml Fla. Lmer.,on: The lunc u~yrrr, a 1•rnhlr+n in iarmiftratim, aoa manaFrrnent. F4e+fr lslnud ]f. J. 38:319, 195±• O'Donncll, U'. E, nn,l l,a.. Fmrr.nn: F.arly Jet n -aF ,~ •+ an•1 m ~ mrntl.r.li~t ean d.ani:.i:,, itr:;l+1,a195G. O'Wnnrll. U. F., a,i,ll,ay. F,n~,e,•un: Tl,e a<arch for the e:,rl. c. Ir, \l-<r, };,IFSr, a \nd \faier, H. ('.. e'1..~ Yuln•ionnrv Car,-~,n,mu, rx~'ork. C'uiver.ia. 17ess, 1456, y. 24~. OPpenheimer, J. H.; Tata, 1. K.. :,nai Raw It, a1..rldwbFical aml fun.:ional str:~lir< of th.wid th.ur cuhurc+, F f, '~ Crl! kr.r. 11:3t.x, 1"5t•. OruRa. L. G., an•1 ~Ietlnr;, K. t~.: Antihoqv Inr:,laatinn i, i•h ic rnenx mPlF<Jrrn- ei,.n Yr... 1":SSb. 7v5c. Onrga. L. G., an•I ?[ellors, R. C.: Analysical IutfuloF), 1\~. The r Ir of loca1izr,I u il,n,fir. ' tl t I e , of hhrot„xic nrl.hrnt+ n iL,r -E.,r.Yrf}rrd 1LLI1;L19;t. O-adia, ) c9ue Ilanz[:rr. >lih'~n: Reattie. T. `\\'., ud LauFhlin. 1. S.: lonization of 9 to 1:.5~]Ira' eteclron. in a,r. FnAintir.+, Han,rr7: 3:340, 1955. Paek, G. T.: ?iiller. 1. R. ana Brn,fiutd. R. L.: Tota1 n,ht hrOmic lohrclomy for ca r of thn canhla.ldrr: rrl'on of chrec ca ,•iun. snrp 1J':L, 1955. Pack, G- T.: Thr f alroi,nr•Nn:.l C:ma<r Corn. .nlr. of thr \atfa,al .idxi-'~rr ('anrrr Coun- ~, P-\k, G T.l Add - I" - 1 11 ~--ti a„ n,t La.tn, -.,t tuuf1rrn.rl, I.n Pack, G. L, an•I RalJnin. 1. (".: TL, 7d.'.~n Iyt 1~ , of x! oul lc, x,r.lk . ra c rr 1 rt tiu y,+J iv~-7 Paek, G. T., a,1 Rr:,+6e1•1. R. 1+.: \feta,t:nir r of ihe liar: Ihr clini.:,l 7~rul•Icn, an~t it n,..naFrn,ent..a+r+. I. Jo,d. 40:7u4, 14.5. Pack• G. T.: 1'znia a~ r ~:J «aann~no nf xa'. r r, L'.i G:91, 1'JiL, 87 Pack, G. 7'., :,nO 1J.\. 11.: 'I'I.r rri(~hrnn. Pack. G. T.: > u f 14r ,,,f t.,,n,.,t,. G..n. . .-I+,.. \ury,-,n ._.,.3. 1"a. Pack, G. T.. :•1 1 k~cic Jrti. .Srrc l~nrl ,.rurr r. 31rJ. i1:3wb. 1nia.. Pxk, G. T„ a,nl ~lillar, T. R.: 7olat riFhl h<pa~ t,c loh..+om. for rhabdom)araarcon,a, •~ir:k. \nrp. i3aU/'~0, 193t. «rannrn+ Pack. G. 7., anJ l,lami. A. 1f- 1.: 11, t 1j1e l} cB ,~ i 7ra. oi i I t' t .1 tl t.- Fl .irnw ie:+nm> (:)mro.+,un r n ~,tru inn:rr ~ eralnal traen in 1'.nn. 0,lr5nnr,nn) n/rrrrtcr, 19±'., 1'I+il:r•irl7•hiu, 1. R. Lil•yi,+- autl loml•anl; IV:;. i', bll. Paek, G. T•: Cancn :n,d ea,t non sau•e (e'tiwr ial t. Ju•yrr341:33u, 1957nt Pahl, H. B.t Bdcer, 5. \L, aud Brndich, Aarnn: ('hrnmatu.rarh,c xtudie. nn rhe «an•fonnin, 1+\.1 of lmrum.x~orru• (1'nll\.i), }'rdr'~ar+un Yr.`r. IG:_'311, 1Y5:, Pa 1m, 1. E.: 7he of arn e rl•,ratlnn. for ortimum < ndi+ioviiw u,flr , for Lt lumnr trancl,lanlation in e,.l•e t,,al chrm1 aheraP~ Prngram. Yr,.r ~r•i,n. _~hn (innr Hr~ s.arrG ::138, 1956. PaP/a i: ~an 1~}aCrik.?~ Radl- t~InFic e.aloa'ion of 6reaa . relions, .iao. \r:. 7"nrk Arad. .,. 63:1y09~~1956. Ptarwn, O, H.; Kas• R ~; H;urold, C. C: 1'.f,qaml Lir+elt.f 3adrxBnr<Hld'r,l te5 srTan'a.u.~i he3~~. G&:101, 1955. an r Pr.,rson, O. H.: 1.1, M. C., and L,;~-rt, \I. B.: F:nrLn~rine of m r,tic hrra•t a+n.er, An,. Jaryv. inr2130,5 Pnrson, O. H.: Li. >L C.: \IacLran. J. 1'.: 1_~perrt, JI. R., and Ub• ,(', U.: NL n n oi r a•tatic m mm . an.rr, 1. .iaFtil.a.9. IS`'•'1"+01. 1v55. ~+ Prarson, O. H 1 l'7. u, \I. B 1.toc ~na~em<n+ n£ .-t t,r hr ' r,riara. (fir+. \, q0::0, 11'5t,. Pearsoq O. H.t Ra>, B. S: Harrotd, C. C.: \\t,t. C. H.; Li. •ll. C.; \lacl•e:+,. 1. 1'., an•I 1•ir,a•l[, \I. B.: 11)1'orhl,eclomt in + cattnent of adranctd car,nr, /. .-I. .1l. .a. lcl a:, l05' . Prarson, 0, H`: A<mmenlctof lafealohF`r{.h..r:. Aad:~nnrrr Inl. 71rd. M:'0i. 1956. can Pra O. H.: Prru tus of adrenatenomr and hsporhqsectom>~~ sta t us, the «eaunmt of ari. c<.I ofr the~ brra.~ ~~a f,~oir t slm{•o.iun~ a 1 of t} r o. tv, o cn Y, r) h r,. C C1 7'I,lalelllia, 1. 14 L,II'in..r, (+lanl r. :r.. Ptarsnn, O, H: Thc mtr o oi•1• ir anl 7} 'F1 - ~ 71 ~t F- fl }, , I 1 -( rr4 1-.: H A rh, Yr,.r. s, \ew)'or4. A, , len i 1•re•,. ]r:: ~145+, h. IJ~. Pnrwn, O. H.: Lkcn.•inn of Ur. liuc;i,:= 1•atrr "Con«ol of c nrrr.. of man h, e•l•r1 u+h,Firal merhat..' ~( unan Hrsr,:.rA 17:4- , (r O w N J O C Q

P.rr), f. A.: At. Ic.; R:m~!:.II, II. T.. ,n~l Hnh, r,•. A. }..: Fsalun of rlar 1r„I),r- an~l r,.,I funcrnn, in l.uirnt• ith y!run.hr-, Su,g. 4~S~i~i, 19i~n:n Pern. F. 11. \\'., an.l RoF-r•. i:. }:.: BI„o,l v,l,m Llaren,ent in ica1 paur, •, S. c ln,. \trr/h Anirri.a, 19±4, pu 301. Petermann, M. L.: C>wph,•ndc nncknprotrin. of rua Ilver an.t : o-dce mduced Hcer lumor, 1.:\'as. Cao.-r• In:r. ~I5:1>ul, 1ri5>. Pc,ermann, }d 1., an,l }lamihon. 1f. C,,: A t:,hilir- inc4n (ir c)wl'la.mic nucleol~ro R,ed,nn. C~'srl. 1:a49, & Pe,rrmann, M. L.: ll:m,ihon. 31. li., and l:on,~ euhl, Lennhard; \lultii~le~m)ekn,a Protrinc 11. l'hranntrifnaal an I<kctroi'horrtn analrrk of a I.aucidi*lrrer n,)rh,n,a Flobulin, Cnu;rr 9:193, 7y:4. Petermann. M. L., an~l Il.,n,ihon, \I. t~.: 1'nrif,c:,r„ n nf nuclrol~r,.trin R irnm r I Iicrr cao- t.la.n. . }'rdrrn Yr... 19: /,. Prt n. M. 1;~lirrr,. N. A., an~l 1lamih,: .i` 1: ~ Thr r,a,dacn,i. nnrlrnprntrin? nf . li.er tun,ur , Cnn:r. Fr.,arxh drr ,nr,, 1(,:4',tI ly:, . Peter -nn. t'f. L., nnd flamit «,, \7 G.: TI I,urifiration and prui-u<, of orto'~la<nsic ril, uclrol'rnte(n frorn r+a ha~rr. 1. Nn,f. ('hrn,. ~?1:7:i, 19i7. Perermann, M. L., and }lan,ihun. ]I. (i.: 1leera- latinn of il,a,uclroprot<fn fron, nt hrer. F'rdrn,tinu Pn.:. wr,::3:, 19>:. Phfliy.s F. S: Ft<nJ,erw S. F.: }familtan. 1.. lU.. an:l Cl:nl;r. 1) ,i.: };firrt. of thioeaanine In m.vum:d~,lan,-rr9alt":. Puo1.1. l.: Thr rr.uh. , f r:xlic.:,. t'neurnnnectun,) nf thr In,:_. i :\merican Cancrr .~~'n.~Pl. ~In<, Caorr, rt rtr l.ang, \rv 1'orl, PoDDell, ]~i'q Cuajunro, }'idrl, lr.; Horstq, 1. S., IS[: RamIzIL }1 T.. u,d Rnhntr. 6. E.: Reml aneriovrn:'us a , d!6rrce„ae to, a!an,t a! r ,al a ,tnrr,.luntion i n l, cidneieran.l ral.alotsic dor~, Cln,. Rr;, Pr,a.'.. i:13~,195G. .R,hrrt,, . }'_. Popp 11 1-~!'-: \'an Pzrl:r: 1: :-d R:untaA, H. 7~:<T4c eHrct of vrntilatury .nRc rn n r ' Irar) rnml'r .at,Rn• in J. L 8. E Pupc~al, 1. `'., and Rotcn.. R. H,: Renal a~_ ern rnlnian i cidosi• and alkalnsi., frdrra- r" f'ro:. IG 1101, 1957. Pr.%.. ~man, Davidd and 6ornanld.l.<onhard: f.ocal~ /'rolKnir. of amiPlacenta aerum, J. Pres,n,an, Darid, 1~. rf.a , I, of h. i,l: an1~ Proat, G R: 5,rcrl. ~Ir,!rolm: i-Fr.r:n.. F.. ti., ~! \\Ia,:.N a. \\. }.. Ir.: tl.:.,,.,:~:,eir t,a . m(,'irnt. „i,l" car.n. ... c~ t~roaata, witl, untrrzte,l h!zd~trr turmu., (nn:rr 4:551, , S. F: Cha1, T. H., nd >7<c<r. 1C. F.: Q 1're eed Ii,inF avirnlent Pta4nr aaccin<, Ba.-r. Prn;er 1954, p. :8. STAFF PUBLICATIONS li~:fi, rnlx~ .nl~jrcl• xnh fun.,i.~n:,l Rall. 1. E.: I'rarwn, (s. Sl.; l.il••rtl. \1. H., a Ra„ R. \1'.: ~Iruhr,lic eftr. thr we,ia-ari:l nalo.ur• of th)rosinr ant tri ` _l . ,nlurh.' . (1,u . t:nd:,.-.n,r~f , tl,rai. 14195 <,. Randall, H. T., and RuL,rtr, K. F.: Thr :•nffi- nd treaun<nt of acidosi• and aR.aln.i. c I4 ~mcurkical ):alVent•, . Cfu,. 1'nrrL 54, .S .1~. 315. RaPWrr, M. M., cn•I (:raf. Li+rLnte: l,nmunn- rh<mie~l noru.at an.l h) ronl•1rtn,nl~fivation~in l'oncrro.11- , Im vuion dr Bi,¢9dmie. R,:'unn:. ouuruarn,r. Rru.rlk-. loi3, P. 1]1. Rap Wrt, M. M., a J Graf. Lisebue [h,amitati<e Aetrrmin:,tion of (-.reartiee nrotein M1r comt~lr- mrnt fisation, Fnfnminn Y.,':. ls:j}s, locr. R po rr, M. M., und GraL l.i.el tte: Antirrn~r aiP,Rrrr . Iwt ,:,I an,lotun,nr tf•.nr+ d<tern.iord hywa r~,l,le fisatiun, Pnr..-ln:. .4. (~an; rr Rra::1i 1. 1o;r, RaPPOrq M. M.: >ctivatfm, of Dhn•pAohl'i 1 thr1•.;•t,n h, lrcithin, .M1'ararr I7N:~91. 1441.. R Wrq M. M., a d Graf. l.f.r4xtr- (luanitativv 'f terminat,on i crrartiv< rrotein h, ae. art 6sxHOC, y,a;, S,:. F,.rp:r. 8in1. f- l1rd. 9J:o9, ,n;(.. Rapport, M. lst., anct Atnnro. \iclwla.: ('hromatukraphic fraction.a,ion of tix.ne fl.n,l:h-arma) phn•ohotil'id•. in 1•ohiarh• (... n,l LrRrecon. Pmllnnr ,.f l.ipid! London. Ruttrr,ronh ~rxnulic I•un!ica- tim,., 19:6. la 49. RaPPOn, M. SL; sd,xarv. A. f:., and f).af. Lierlottr: l'-r<ac,iae ~.rutr ,n Icuient. follnnin4 olxration, .-fnn. urp.j11J.::i_1. 19Si, vPor+ M. M.: lnuu•:dmt of "Ecidr, ~r fur R. he Parnri',am,on \'ool f rotonin in e a l rr«.c•" hy ll. \\'. \r) Isic) and F..~". Bhau, .4nn. A'.z: 3'„rk .4rad. Sr. ei6:r,L;, R.Dporo M. Dt., anrt Franrl, R. };,; The strurmre f Pla•mab[:rns. 1. H1drol)+i, of Pho- Phatirlal rhnlint h> Ircithiria.r s\.. j. Rrof. Rz~pors, M. M.a 1, r<q Brruzrd: .ilnv., :~ lolas, and FranxL rR. }:,: Th< atn,cturr Pla:matr;fccnr. H. Cp'=tan,n< ysnrhnsp F.ati,lf a thanolamine (aertnl l~hesi,holil'ide). J. Ri,'f. C'J,rni. .1t:8±'I, 19;i. Rasmusun, L. H., nd B-den I m t: ca•trlc Vlicmfuns in tta treat,nent of h<ad an,. nrok Camnceq can:rr 8:1]85, 1955. R-n, R. ~f'.. and Rall. 1. E.: Thr r~ dr,~ ,no!o8s~ nf nen;~laair disra•r. in I'incu•. f.rr: r .ed.:Rr,nnY,c,p•:no:Ffn.n,uxrFr,ru..r \e.: 1'url:. Aca'Ien,ic p._^z7. Ravs ,R.\% Tbcr 1r;n: i,"l~~ II al•., i~'\\arrrrr~l l., l1:: 7'1,,.id, \<,. tiorL:. 1'u„I B. }Ir,rl~er. Ir,c.. lai5, {,. 400. Ra,hcCsoq R.'IP.: 1•,mitnrs tLnotror'in and Grare; arcun,ent. fn rrlalinn~Iaf'. in 1\rrrJS.~C.. erl.: Thr 1'or6. 1•a„! R. jl.,ehrr, Inr.. 1ni[.1~. 441. Aawson, R. a('.: Ratl. 1. F... and Sonrnherc. Vartin: The <hemi.trv an,l P6a-sioWer of thc 1L.roid, 11 F'mcv-. frruor). and Thiownn, 1:~ \'., <,1..: Th; i7~rrnenrr, ~<w1'urA, Ara4,v,ic )'re=s, lnc., 1953. v, 3. /'-4J3. 88 )lrfoh"r16:1J:~r~'i Ir'~4. Rawsun, R.'R~ : Thr d)rn:.l n, tL, a v tac~., --, Il„rx,:'ur' und rFr .isinp Yrr:rr~r,\rw~ 1'ork, Acadrn,ic I'rr.s, Inc, 19i(, 4~ 39. Rawson. R. R~., a,rl R:Jt. 1. F.: Carein,no:, af tbr r1,.ront 1{•an<t di.cu••ionl. .\r..)'r'k 1lyd 13:}?3, 19- i{ . R. S., an:l l'rar n. U. H.~ tl>Ir,PL).r.n'n~> RxY the 1rt:nn,rnr n/uadvanred canctr of nn. Sarp. IN:3"a, 19">4. H. C: }:Rrc, nf sr-, ,ediu,n ulon tLe drn n+trr:ro,e of a ru l~ial a a, arr ,am antiF„ne•.An~r~~ Y .oc.. RefslsearS,c . eBSghr,lnel'ennl:,.`nd Lbcic:d • J1rd ?9:io3, 1957, ar Rhoads, C. P.: Tbe rrlarion :,E lonurrit) to nro p1a.,a, JJim. nl'fi Ib:n- 10:4. Rhoads, C. P. lmolrrat-: Burchrnal. I. H.: T:arnofak). I). a.. an,l 1'r:,rsnn, Il. }7 : Chrm" 11,eraP)' in can.rr I1'anrl rlivu•.ion), 1'ork Rhwds.C. P.: Rdationi,'q. of mrcteia aid an:Jxr h.m so thr trnnnrnt af canc<r. lf. ('/'n. .1'r..rh .9n,rri:a 4O:M, 1956. Rhoads, C. P.: Ca nuackrrl (.ur-t editori:ll. C an:rr Rr.rar:l,c er 1G:373, 19?(,. Rhoads, C. P,: Summarc of informal o[ sercn,l da_, locrhr Amrnran Cancer Scwi n ml-un,: .\ r ical l'1'rai•al of thr hio chr , cal <harartrriaic.a of morl~hnln.irah_r arab!e unc<r.). I,n„rr f:-;n,;h 1r.'__, 10".. Rlsoads, C. P.: >b.drrn c pts of c ncranl zirrn}l~ ir . arch, in Ua>rr, F.dcar. Sl ed..: P M, ,a t ;inrli, e ,\ru1'ork. Co. rrr . 1•re.~~r,i Rbozds, C. P.: Tt.< :utlnolc for ca,rrr. in ]larrr. Edcar, a, f ll.vr,. H. ('.. <d.: P „' ~, ~rrs 1'urA. t'nn, Rhoads. C. P.: TLr iluhlr ;: orlr . rrol, .-Inr. Re3. Cr!!. Sar„~ _'a,a: ~~. Richerdson, H. L.c Ans. 1.. t a R.: An <valuztion of lhr ~~~ o ~ oro8ical anrl hi=toc)~toh,Flal tect.niµ,ia e ~t 1, e aupr ) 6 n of cm,crr Ir . foliatrd ~.., from variau-sources, Can;rr 8:9}8, 195.t~~ Richardsoa, H. L.: Sin,en. T. R., ana l:nss. 1. G,: An ecaluation of the cancomitan u r of and « 17 tl«k ttdmiyue• i„ the d:a¢nn.!+ cC cancrr, Rufl. A'r.. 3'ork R.-nd. l1rd. 385, 19>h. Rite)', V. T.: Senrrei,tic osid:airr rned,:mk iated .~:I f:i 4n,rn, fnrn.:,riun. %. Crll. f- Pk}:, ~ L, ar:3rJ. 1955. R,le), V. T \' Ila 11 .( k i.I I: -I r.r < atfir.:c).. la.l :I c<I. .ulnr r r,lf 1' ,Irnrn'n -. , : :.•FriimRsr~r~F~ISrd."tallul,~~~ Riles'. V. T., anP, \~alln, \C. e:nad procrdnn h~r r[hr •rftin r~ ar! hrn~am,ri~ wlcr ith,rs -ulni, d~•tri!~::rnni r ralue- -cdrrain,.- ,Y".. RileS. V. T.: ChrmnarorraPhia ah-nqnion tudir- emPloa'in=thr w-hole hel'arln4reJ f.lc,od of h<z![hv d dis>•r,l suhi<cn. Y.:". .tr,:. .i. Cunu. Rrsra•rh ::143, 1934.

Rilrs.\ T.I fl' r7 t Ifmrf,,,~:aa,,7rt. Thc I~rin.u, , r..hlr hrr:,-t RoFbim, Jarob, a„I R,11. J. F..: 9'h~roxinr- hu,.l,r nal m.,n. .!. 3leli_'4,~r1 l.u~rt ~ Robbils. lacob, an,l RiII, J. F. -: ERact: if tri „~h,. r,l ot~rr thrruxinr a vurur- ~ ti,r a rr,rrLin,iin' n hu n>rrmn.i. r r,n. ln:Jl:1},th, 1'/S Robbfns, )acob; Rdl, 7. g., and A nrw , uin-linc cnrnlc,nrnl ,n {,atirn,s witb fuuctiunrlc nf Ihr 1J:1l1;, Robbins, Jncob: Hall, I. }'.., an,l KaaIc. {\.: .1,i u ual i,,annrr t thvr,,.,ne-hin.linK L~ liunwnu- um Kamn,::e~L,lrulin. /. l'f,r.. .,n..r. F ]lrfO,. Roberts. K. E.; \'anamra, 14rLer, Hand:dl. il. T., anilri`li~lker. I. 91.:rC'mntw,nhuwrl rulr,e ah iecl f 11, I1 IL 1: h{x,` L:a.n .~ u.ar w ml h>larrtbrr,-r ~:ra,... Roheru, K. E: K:,n,l:,ll. 11. T.: H:,ne. II. \; )Ir~lwi'1. 41he t. an~l ~rhwartr, \I. "urli.- nf ,Imul.inc ..'ndrur~,. .\n• I'urk Jratr JU'\/cd~. +.._"9.. Roberts, K. I.; Punl'rll, J. N'., and Raoaall. 1<ohcrt, arnl Nau•IaH. H. T.: Eval,,..1,rn1 -1„ra,,,r> c.,ml•r,,:atum in n,<tal,ohr al'..,lo- , Roberrs, K. E.; 1'o~q,cll. T. \\'.. and K:,nd:dl. fl. 7.: Hrla,ion hetx r nal ox) am'Fen a n- nm,inn, carWn d,nxid,r~l'rulurtinn l hr'Irr. n.ecrer,un, ];a i3, ~mtw E.: nrCn=-:. 1. ]., and Randatl Rnbern, K i the fl. 1.: Flui~l an,l IccirollR ru1,!<m+ of tlie a a~<~I. Nnll. .\'Yr„)'r~rk .I/r+trra ':Ip,, 1"a. Robert,, K E.: \'anx,nee, 1'arLrr`I' ni„I11RAndail. ku, ~ ,n . .a 1. . : Hra.rn::,n. \\'. }-.I«r,rulr,e al,<'ratinn+ ' lirrr di<ea.c 1'nrn .4nirrt:,, iu:4 il. l Roberu, K. E.; H,n.lzll, 11. T.; ParLer, ian•I I'ul'I~cl'. 1. \\'.: krnal mechani•::•. involced n 6:cartwn,'r ,ti.arl.tian, llefnf,, S:JOJ, vst.. Roneru, K. F: Firm,t. Groree: 1'rwder. Totm: .~1:,,urtz.sl K., an•I Kaw.un N. St'.: }:d'cct of 11~^l•haR i h,ncin/; tLe art of trl- I~ crunine, tF nd~~: rin-'fu,u)Sg:SG f n 1956. Rober:.. K. E.: Thoml'•on, F. f.-, 111: yahpol. 1. \.., and \'ananur, I'arker: Rea'irator.- I. Laln• mt*'n n,um lox,c,t~- 1. Afff. PaJa,l. 19il Robcrf,. t:. E.: \-:ma,:~a. 1'arkrr: lar•luri. 1. .\.: La„rr:~r,-. \c,lrcr. tr_ nn,l 1',q~lrn. r. \c.: Robrrt• }:. }.; )•ntl e11, I. l1'.: 11. 1.. Roll. Y. bl.; \1'rinfcLl. }I<rlnrt; Carr„Il, Elira~ :I H 1' R. 71e u,i1,znf nn ' b ti I\ Tril•1)~ lahelrl tn ., u.leuti le~. 1. . CMru, 2_'0:4J9, a'I'.-1NN I'['IiLIC'A'1'IC)\S Roll. P M \\ f I I 11 1 t I 1 It, F'lin 1,1 \ I\L1.1 1 f 1> 1 lin. Inlr,~ t'4, u.__ 1,.,. Rosa•nfelal. R. 5., t of atrrui~l ine 1' Lrn,[ .nrt:ur-. -~ an:iut'A.~.•. ,; ~t1,.;. V RosenfeW. R, 5.; }[c11m:,n. Leon. an,l f,allacbrr. 'I'. F'.: Tran.fnrmatkn of chnk•rrrnl J,1. N't' lo rul r,-tanol: fncatio,- of d.•x,trrium i, rolno- a.uwl. Frdr,utL•n Proc. 1i:J4u. F/Se. r Rosenfeld R. 5.: Hdlmau. I.eon, m d(::Jlaeher, T. F.: 'S'hr• r n<forntat,on of rhok-:rrul 3,1 tu rul,roaannl~.f. 1., ation of deuterium in repro: t:uml. I. Hi,r. Chrru. .._':1_I. 105,.. Rosenfeld, R. S.: Teniar,r Iq~droxlt aroul' dim~ i, arrui•1 L<,uK, i Amrri<an ll,emical oJ fn.. inc,u1J1=t inc, .-R~rbmrr Pa :nlet, i >Irrt 7.,;:. v. J:./1. Roso/L Morton: Hatura.. (Imar; F'i,linoff. \t. L., ud C:d rk I.. F,: .4 an,.tr of Ihe x'rradi,- tion of d<ox}I•enro,enu~lrir ~ri•I 4,lutin,,.. Radinrtmt Rrtrurrh 5:59?, 195G. Roswi,. Bernard, nd Lanne. 1• 5~: cecondarr of the Im'a. in \farer. Edear. md ~fa li f.. 1_ 1, a't Cm:,nrmn, \rw )mk, Fms s,f> lr,' ."1•t;6 1• ao;. Rubin, A. E.: Rrarrman. p'. `;.: lh>trr, R. i..: \~:u,:,,,,rr. I'arLer. arol k.~l,ert=. R. F:.: Th,rrla, n.hil' hetwren Ila.m:r ~molalirt, a.~.! .~ntratmn in ,li+ra=r Clir:. k,•.. Pror. 4~1.'", 1o;t:. RneesegRer, Paul; \rdirk, Trwin: \CrJblewski, F bx. and Lanur. 1. S.; Ahrration• i, aaun, xluramir o laretic Iran+an,ina~r (~(:i r T,• n I:lutamir l,yru.~ic trancnmina.r `ud~ti,ctic deh,rdrocena•e n.m f.,a w; rx~ i,rnmrnta/ m ,r,hal inrarcaon, cc,in~srr. Ruegsegger, Paul: ]y,l4ck. Irwiu: Laln,c. 7. 5., nd l'lifiwn, E. F: : The in ue fl rf l.l,=min ttl'm exl'rrimental onlnw,nan- er mir,:• ,n.l tl- mm. ary inlarcec, Clin. R- Pree 4: .., 1i;6. Rush. B. F., Jr., and Cliffrnn. F.. F..: F.xprrin,rnr,t ' n n of ihe Irachra witl, 1,)a,l~{rr mn ro ,`~ur_~ '10:110;. 1 rr;r,. Ruth. B, F., Jr., and Rand,1L lt. T.: }ntra and extraretluhr chanee= of Hui•1 n a i electr.,lvle- exper rnral urrn , .Sarp.nF.+rtu'r, 195/, ":10", 19i7. Sageti, Naomi: \\'aite, 1. Ff.; 1'nptK1l. 7. t\".. and }i wtan.i. \\', G,; Cervo-n,•chanian, fu, th< reculaKon T blond p......... kr.. Snrnr. ln~ s.rumtnfs 2R:1i, 195:. Scanlon, E. F.; Morton. 1). R.; \Calkcr. 7. \I., and \\'atsan. \\', L.: The aeaina seamm~rd rction for ~upharrai ~e Snrp., rci, Gvn;;. E 06.r. 101:29t1, ty- Schlumberter, H. G., sml Hen•c1~4q L'. F.: Effen of hnal lgttl~ a~irra•ha,inn nn Ihr f Arrt. Frr: cor. F.rfrr. Fiel. F)1rd. 9J:.'rt. 19;l. Srholleq Jnan: Philip" F. 8.; S,<n:Lere. f .! R~;:n,r. 7- l.: .4 conu':va,irr +,u,l> ~ che ~,li.r~.;wn,ir 94en1: i K',ntanrOn, r :.r., of`~n n.l in v,'-.; nr ~r,.,n. cn.,~n'a1n. fyc Scholler, Jean: Gordar,. ?LI:. ~~ aml 5cernherc. C . 1 " - I -, n.lcnt- mf d„F- 1r,,. J.,. }rf, 144. f• .1/rJ. 91:121, 1••i!. 89 Sr1,oRcr, Jean: Philip. F. rrnler,•, ~ c I'ro,lnrtinn nf r,nv~hvr Il -+ . lnra I(li 1I I ' I r I ,n.l l,nl I,-icnl -uh, .) ,.. cr,ul:Ef... lt,.l f Cc/ w rtx, A. E.: Law \\'alr,~ Ir. an•' Nr,hr - K. }:.: }'.Irv oi 1•rrilrhrral 1 :~ f„Iluwini n,rul:u r.x" n, ., !. t1,,: h,:.~,nYnn„n JL n]: 1 Srhwartx, M. K.' Rwt:m~kr, ftaar, aml R:mdall. c. i. \r 11. T: Hntat.>It:m in rureical patirnt trus'en metaholicn, totally gaatrcclnmixr•I pmSem.. ll. Fat and mineral ntall.m i tne,u.ea+urrtnmi:ed rotienls. Aa,. 1. Crh;' A'ufrili,,n a:Ji, 51. I'1;1.. Sehwanx, M. K: naniel. Owen: 1-inh. S. N., rol Ral,m.kr, O.zar: EHrct of storace 'n dvrp !rr nl+m ~ r4r,K t nunar)' ac, phn<plua 1'arL. 6:511, 19.<d - Cfot. _ Schwartz, M. K.: NTrdwi,L Alhcrt: Rohrrt.. F:. E.: ~Ir,+eneer. \larein, an•1 kxm1a11, F1. T.: Fat wnd nitroeen n Mah,li.m ' ' tier. wilh m: •wnall bowel rr.a•eliun'~."trY~ 1'?i+, 6,J8+~ 056. Sehwartx, M K.: Slei~ena•er, M. H.; Pert. i. H: Rulwn.. Ramlall, H. T„ nd Alm,r, T. 1'.~ Thr Hrrt of a rluten free di<t on fat, nirr,r,rn. m i minrr.,l „etatnhsn, in n,M1rnt- wnh .prue. Gn,rrorurr.~i.•.nc 72:_37. 105,. Srhweizer, Olga: fnmf•li, arinn= u( an«ahr.i:, ,h,r- r:,lical .nreer)' th< h.:~~f en,l the n-L, -{rrrs/l:,iuf~pr 1955, Schweixer, Olga, an,l }1„n~land. \l'. C„ Thr •liaene ar~l lreatmenr of ten.sinn oneumn. thnrax~r ml~Iiratinc radnal rurpery hout the h,. r Oeck mI thorax. .inrsfA, & R„nt,,. J;:Ji j Ip.(:a Scoren, E. F„ an,l Ha•lfield. G. T.: '•Tan rrol•hic actn~ity of r tract+ of him,an uri e, a {rta-linnn , refart.xCnnrrr B;N1p- 19~;5.n Sni. S. H.: A m<thal for ro eneratinc eaP rrtl- .val,<n•kd in larcr quantitie.c of finit. l~m,;r, 4:BGC, Ig;(.. +eed. ). C.: \\'alkn.tein, c. L.: Re/1ville. I. \\'.. n:l Hnude, R. {\~.: C m.arm r< re,vir.vory drrprr,unt ffrrl• f itt,y,lr,xn~leine d 1•hine, l. 1Znrn:. N Erfrr, TLnap.a119:1cI. Iq;,. Selb, C. C.: Rierrlr. 7. I.. an•i (:r.,,.. C. E,: }:I trnn n' r cnI,e • ,iier f•cit« lumnr ~ ee1ls.:f„n.~hrs: 7'n•kt9rn,1. Sr. 6s;;Aa, 195G. Sefbl, H. M.; Shrrmnn. RZ c-, and Pn.k. C. T.: A ocntgen Imlc of bone «ae:,-e= frmn meL noma, Radiol.-p\• !',::.2i. 1?S(. Serra, Pierre, and Rrun.cb-ie. Alexandrn Freez- ',¢ f liver parrnch)~ma w~ith li9sti,l nitroern fnr hrmoaa=ic i~ e i<ional li.-er a ~er , an exprrimental atof)',xCancrr 8:12Ji,t7~+31~~ Shapiro. Gerald: Ernet, \\'. `, and Oradia. lacque+: Radiatinn doae d1=:~~hution 'n v ter fnr ~ c.tlr.-.qmak rurm~rn _ , Rndirlntrr 6r:J*i, 79ir.. Slegel, Makolm, ,nd Cifffmn. F. F..; Th, rule nf •,mnminam in thl,in h, thr hu:,t, pl- . m'n ., , ,-h+n, 7. Gn:. ao:J77, f rt fitr,n,ictic 1 rt 1 c .n~t.cnrn,-, Slmon, T. R.: Frrtoloyy. i R 7956. St.ipsk ~ P., I R t( .\i. \l.~ Panrr I r } ~{Iv of Fi,luv, .I I,te ti.-ue iel•lulin.~rJrreri- P..:, Is;:2i0, 1957.

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