·No text on this page.

·HYPOPHYSECTOMY

·Publication Number 315
AMERICAN LECTURE SERIES
A Monograph in
The BANNERSTONE DIVISION of
AMERICAN LECTURES ON TUMORS
Edited by
DAVID A KARNOFSKY MD
Associate Professor of Medicine
Comell University Medical College
New York New York
Associate attending Physician
Mem and fames Ewing ifospitals
Member Sloan-Kettering Institute for Cancer Research

·HYPOPHYSECTOMY
Edited by
OH PEARSON MDF.ACP
Associate Sloan-Kettering Institute
Associate Professor of Medicine
Cornell Unscersity Medical College
Associate Attending Physician
Medical Serpice Memorial and James Ewing Hospitals
New York City
PUBLISHER
CHARLES C THOMAS
Springfield IUINOLS
USA

·CHARLES C THOMAS PUBLISHER
BANNERSTOVE HOUSE
301-327 East Lawrence Avenue Springfield, Illinois U S.A
Published simultaneously in the British Commonu ealth of Nations by
BLACKWELL SCIEYTIFIC PUBLICATIONS LTD OTFORD ENGLAND
Published simultaneously in Canada by
TIE RYERSON PRESS TORONTO
This book is protected by copyright. No part
of it may be reproduced in any manner with
out written permission from the publisher
Copyright 1957 by CHARLES C THOMAS
PUBLISHER
Library of Congress Catalog Card Number 57 10442
Printed at Fulton Blissourt in the United States of America

·PARTICIPANTS DR FRANK AD AIR Memorial Center New York NY DR WILLIAM H BAKER Massachusetts General Hospital, Boston Alass DR DELBERT M BERGENSTAL National Cancer Institute Bethesda Md DR. NORMAN DE NOSAQUO American Medical Association Chicago III DR LEOVARD P ELIEL Oklahoma Medical Research Foun dation Oklahoma City Okla DR JOSEPH P Evans University of Chucago Medical School Chicago III DR A PATRICK MI FORREST University of Glasgow Glasgow Scotland DR HENRY HOOD The New York Hospital New York NY DR ANDREW G JESSIMAN Peter Bent Brigham Hospital Bos ton Mass DR B J KENNEDY University of Minnesota Medical School Minneapolis Minn DR MORTIMER B LIPSETT Memorial Center New York NY DR ROLF LUFT Karolinska Institutet Stockholm Sueden DR DONALD D Matsov Peter Bent Brigham Hospital Bos ton Mass DR JAMES J NICKSON Memorial Center New York NY DR OLOF H PEARSOV Memorial Center New York NY DR FREMONT PECK, JR The New York Hospital New York NY DR HENRY T RANDALL Memorial Center New York NY DR RULON W RAWSON Memorial Center New York NY DR BRONSON S Ray The New York Hospital New York NY DR CORNELIUS P RHOADS Memorial Center New York NY DR SAMUEL G TAYLOR, III Unilersity of Illinois Chicago IN V

·CHARLES C THOMAS PUBLISHER
BANNERSTONE HOUSE
301-327 East Lawrence Avenue Springfield Illinois U S.A
Published simultaneously in the British Commonu ealth of Nations by
BLACKWELL SCIENTIFIC PUBLICATIOYS LTD OTFORD ENGLAND
Published simultaneously in Canada by
THE RYERSON PRESS TORONTO
This book is protected by copynght. No part
of it may be reproduced in any manner with
out written permission from the publisher
Copyright 1957 by CHARLES C THOMAS
PUBLISHER
Library of Congress Catalog Card Number 57 10442
Printed at Fulton, Missouri in the United States of America

·FOREWORD grown stead on the growth of human neoplasms has ily during the past fifteen years The possibility that the pituitary gland might play an important role in the growth of certain neoplasms has been speculated upon for some time Although sporadic attempts had been made to re move the hypophysis in man it was not until cortisone be came available and was found to be effective replacement therapy in adrenal insufficiency that hypophy sectomy seemed to be a reasonable procedure to undertale At tempts to perform hypophysectomy in man began inde pendently in several clinics almost simultaneously Dr C P Rhoads Director of the Sloan Kettenng In stitute Memorial Center suggested that a conference of workers interested in this field might be helpful in evalu ating the potential of hypophysectomy The meetings were held on March 19 and 20 1956 at the Sloan Ketter ing Institute in New York The conference was made pos sible by generous support from the Alfred P Sloan Foun dation All of the contributors to the symposium felt that the sharing of their experiences had been very useful and that publication of the proceedings should prove helpful to others who might become interested in the effects of removal of the pituitary gland Sicere appreciation is due Mrs Helena Curtis for assistance in editing the discussions OH PEARSON MD VII

·Hypophysectomy
DR NORMAN E TREVES Memorial Center New York NY
DR CHARLES D WEST Memorial Center New York NY
DR GEORGE WV WOOLLEY Memorial Center New York NY

·CONTENTS Page V Y11 PARTICIPANTS FOREWORD Chapter I SURGICAL HYPOPITYSECTOVY IN PATIENTS WITH CANCER Dr Rolf Luft Summary of cases Completeness of hypophysectomy Laboratory findings Correlation of laboratory and clinical findings Dr Bronson Ray Operative procedure Hormonal replacement Clinical results Examples of objective remission Summary of clinical data Summary and conclusions Dr B J Kennedy Operative procedure Hormonal replacement Complications Clinical response Summary of clinical results Mortality Regression data Dr Donald D Matson Operative procedure Hormonal replacement Mortality Morbidity 3 3 3 8 9 11 14 14 15 16 18 19 23 25 26 27 27 28 30 31 31 33 33 35 35 36 IX

·No text on this page.

·Contents X1 Page 107 110 113 113 114 115 119 120 Chapter Clinical results Hormone effects Addendum July 1956 Dr Delbert M Bergenstal Development of implant procedure Animal erperiments Preliminary clinical trials Results of anatomical studies Clinical results Dr Joseph P Evans Operative procedure Mortality and morbidity Dr James J Nickson External beam irradiation Operative procedure Clinical results Dr George W Woolley Discussion BIBLIOGRAPHY 123 123 104 127 128 129 131 131 135 152 ·Hypophysectomy Chapter Page Laboratory and clinical studies 37 Clinical results 39 Dr Leonard P Eliel 41 Hormonal replacement 41 Mortality and morbidity 41 Clinical and laboratory results Dr Samuel G Taylor III 45 Climcal results 45 Dr William H Baker Discussion 49 II SURGICAL HYPOPITYSECTOMY IN DIABETIC PATIENTS 68 Dr Luft 88 Clinical results 69 Discussion 72 JIL PHYSIOLOGICAL EFFECTS OF HYPOPHYSECTORY 77 Dr Mortimer B Lipsett 77 Estrogen excretion 77 Thyroid function 77 Sodium metabobsm 78 Hormone withdrawal and replacement 79 Carbohydrate metabolism 80 Diabetes insipidus 60 Completeness of hypophysectomy 81 Dr Ele] 83 Serum glycoprotein tests 83 Glucose utilization 85 Sodium metabolism 89 Dr Kennedy 91 Endocrine function 91 Discussion 93 IV RADIATION HYPOPITYSECTOMY 106 Dr APM Forrest 106 Postoperatre course and complications 107 ·HYPOPHYSECTOWY

·No text on this page.

·I SURGICAL HYPOPHYSECTOMY IN PATIENTS WITH CANCER DR. ROLF LUFT Na recent report' we described our results in patients fore June 1954 The main part of this report will deal with the continued course of this first group of patients In the small series treated since that date however the propor tion of favorable responses has been on the whole of the same magnitude Experience with this latter group also has confirmed previous evidence that three types of pa trents are not improved by hypophy sectomy 1) patients above an approximate age limit of sixty years 2) patients with metastases to the central nervous system and 3) patients with liver enlargement due to metastases Summary of Cases To recapitulate our first series included thirty seven unselected cases of breast cancer nearly all with wide spread metastases (see Tables 1 and 2) In four patients the hypophysectomy was known to be far from complete and three patients died of other causes shortly after the operation Seven of the remaining thirty patients be longed to one of the previously mentioned unfavorable groups Thus there remained twenty three patients who could be evaluated of whom fourteen were alıve in June 1954 Of the nine who died three had shown consider able improvement for some time Up to March 1 1956 3

·No text on this page.

·Ip tlent t hypophy ectomy Wyt log PL F Dy pea ra - + + +++ ++ + +++ + ? +++ - + + + + ++ 3 + ++ . + + + ++ - 1 Indent CER OF THE BREAST SUBMITTED TO HYPOPHYSECTOMY Het stases ¢ &t Car Treatment C Sex Discovered Loatlo Date Type to d Szin, local 1943 Std C trati 1949 Right breest TP PA 1949 Lelt axula 1949 Irrad FI 1950 Ela, local 1950 Ind 1931 Bo 1951 32 1951 1950 Region. oder 1950-52 Imd. Poo 19$L kun, lai 1943 92 TP 1950 Pja, Alp 1952 Irrad Poo 1951 Pin les 1932 ТР 1952 Bnal 1992 Rerlo Dodes 1952 Remo bral met Good 1952 Ce bell m 6 1959 Region, sodel 1957 Bon 1952 Clin, local 1952 Remov Oral metas Good 1952 Retlo bodes $952 Cer bell m 8 1951 Region, Boden 1952 I rad. F1 F 1951 Co tralat. Dod 1952 Bon 1952 kir, local 1952 Let pleura 1948 Region, rodet. 1951 S TP F1 F 3951 Bone 10 1950 Region, odest 1951 52 Irrad F 1951 B ne 1952 TP 1950 Rerion odes. 1952 53 Ind Cood 1952 Riebt breast. 1932 0 TP 1952 Right unila 1952 Rmov it st+ 1952 53 Skin, local u1 12 1950 Rrion, nodes. 1952 Right axilla. Poo 1952 Co tralat. od 1952 Ir a 1952 Bone 1953 ТР 13 1947 Region. oder 1947 Rm It. ala. Good M 1951 LA EN 1931 s P Iob ca. 1952 Left supracla Estrs 1952 Irrad 14 1950 Bruta 1931 Rem braln mts Good F 1953 BOD 1951 Irrad. 1952 TP 1953 R mov mtsak 11 13 1950 Replon. odes Fur F 1932 16 1991 Rglon, Dod 1931 53 Irrad Poo F 1951 kin, local 17 1950 Region oder Good F 1953 Sk'n, local 1953 Boo 16 1952 Bone 1952 In d Fi F 1953 TP 19 1951 Region. odes. > 1953 I rad F! F 1952 Во 1953 Brain 20 1949 Region, odet. 1949-52 FU F 1951 Le maprad 1953 1952 kin, local 1953 Bone 20 1951 Bone Fair 1953 Lo 1951 Region odet. 1953 TP Poor 1952 BO 1952 Region, nodes 1953 Cast tion. Good 1953 Ski local 1933 Irrad. 1953 TP 1950 R pan, codes 1953 Irrad. Fir F 1951 Ren sodat 25 1953 Rigbt prad 195$ Imad Fats 1953 Lungs 26 1951 Let sup acta 1951 Inad FT M 1992 Lungi 1949 Region, nodas. Fai 1952 25 1947 Region. Dodes. F 1953 Babe 29 1951 Redas, rodet 1953 Innad. Good 1952 Boce 1941 Lung 30 19.50 Record sodat Poor F 1952 Pons + 1952 ++ + ++ + + Eyes + + + + + + + Tradi + + +++ + ++ + Duit + + + +++ +++ + - + + +++ ·TABLZ CLINICAL DATA IN THIRTY CASES OF METASTATIC CAN Amertorties en e Beat Asul ty per hode TeCL Beast Other t eatment Botni 1902 Breast Cancer oted 1945 Type de che Schoos 1945 1945 + Irrad. 1891 1940 1946 Left 1947 Israd Por du sol 1906 1951 Irrad Poor Gold 194% poins 1950 lymph node. 1951 breast 1950 1909 Right Reput m str 1950 t 110 Poor d: Gd 1209 4/1952 + Israd colla Regular Ataxer 1951 4/1953 1950 1903 Left Let Right 1950 1 + + Irrad. Poor : 1904 1951 3/1952 Imrad. Uoknews 1916 1951 Left Rerular menst 1951 Inad Poot CIA & 5 + doa 1288 1943 1948 Left 1948 Solid adenomaton Irrad. lela ndum Irrad 1977 Rht 19.50 1924 Rerular m austr + + + Simples 1950 1950 1913 Lett 1951 Irrad Too 4 rolid 1894 1944 3950 Left 1950 + Irrad Sotid denomatod $888 1945 Delt 1945 Imd. Unknown 1914 1952 1951 Left 1951 + Irrada Adenoca. 1902 1952 Right 1953 + Irod. TP Scirrhoo $396 1945 1950 1951 1948 Left See tear Poot dia 1859 1948 Lot 1950 Inad Poor 1903 1948 1941 Lelt 1948 + Isted Solid d som komt Solte tubular 1905 1951 Left 1951 Regular metst + Imid 1909 1949 1949 1949 + Irade austru SOD Satildadeanm tout 1905 1949 Let 1951 Irrad. Schott Inter nenet 1948 1898 1951 Richt + + + + 1951 1952 Troud. Poor our sch rbous) Poor dit koud 3510 1952 Right Imad Rerular CREU 1985 1938 Imnd. Poor dit word 1950 1955 1951 Right Richt 1950 1951 1951 1901 Solid mouth Recolar st ured. Irrad 1994 1948 Let 1948 + Adenoca. Poor de 1906 1948 Lot 1919 Intada Poor d.1 1910 Rerulat penety Rerola menstr 371950 1947 Let 1947 Ind Solla tabelar Pour dis (147 Roc) Richt 1951 1951 + In 1921 1950 Rietat 1950 Ind 1906 Podt (1) ITTE Der Reproduced by pertelsalon Cancer ? 261 1955 ·In Patients with Cancer 7 the cerebellum At yutopsy no other metastases could be demonstrated Case 11 The patient was asymptomatic for thirteen months postoperatively She died twenty six months after the operation Autopsy revealed extensive involvement of the liver Case 13 (Male) This patient was well and active up to the time of our evimination eighteen months after hypophy sectomy While in the hospital for study he acquired without known trauma, a compression of one of the thoracic vertebrae which has since kept him in bed with considerable pain He was alive thurty five months after hypophysectomy Case 15 New metastases appeared fifteen months after hypophysectomy pain recurred three months later and the patient expired twenty two months postoperatively Case 16 After the hypophy sectomy a small ulceration and infiltration of the skin above the remaining primary tumor persisted This remained unchanged for twenty three months postoperatively after which the infiltration and ulceration increased slowly The patient died thirty three months after the operation of septicemia No distant metastases could be revealed at autopsy Case 17 The patient was alive and asymptomatic thuty four months after hypophysectomy Case 21 For thirty months after hypophysectomy the patient was asymptomatic From then on moderate epı gastric distress and slow enlargement of the liver were observed She died thirty three months after hypophysec tomy with extensive metastases involving the liver Case 25 The patient showed some improvernent for eight months after the operation We have been told that she died nine months postoperatively The patient was a drug addict, and it is difficult to get reliable information about her Case 26 The patient was asymptomatic twenty eight months after hypophysectomy ·6 Hypophysectomy the following could be stated about the fourteen patients (the numbering of the cases refers to Tables 1 and 2) Case 1 The patient was asymptomatic for nineteen months following hypophysectomy then progression of soft tissue metastases was noted She was still alive fifty months post hypophysectomy Case 5 Before the hypophysectomy the only metastasis found was a solitary one in the cerebellum which was extirpated The patient died twenty three months post operatively after the extirpation of a local recurrence in TABLC 2 EXTENT OF METASTASES AND POSTOPERATIVE OBSERVATION TIME IN THIRTY CASES OF METASTATIC CANCER OF THE BREAST SUBMITTED TO HYPOPHYSECTOVY Months Age at obser Metastases oper vation Case ation Lungs no YT operative Local Skeleton pleurae Status Eyes Вга п Liver 50 28 ++++ Living 43 20 Living 40 14 ++ Living 65 14 +++ Linog 51 +++ Living ++ +++ Living post Living Living Living SonNamaNEN SOM Living Living LIVINE Living ++ Living Dead + +4+ Dead Dead Dead Dead Dead Dead Dead 59 Dead 39 50 Dead 19 48 Dead 20 + Dead 7+ Dead Dead 68 Dead The extent of the metastases locally and to the skeleton and lungs 16 denoted from + 10 ++++ Meta Dead tases to one eye 18 denoted + to both eyes ++ Metastases to the bra n are denoted irrespective of thert ertent. In all cases the I ver metastases denoted + were very exten ve and made the liver palpable before the operation Reprodu ed by permisul a Can ep 8 261 1966 ·In Patients with Cancer 9 plete elimination of the hypophysis was achieved only in a few cases and that in 30 to 40 per cent at the most the pituitary remnants contained not more than single cell layers The remuning 60 to 70 per cent dem onstrated more than a single layer of pituitary cells Only a small number had a large pituitary remnant most of these were cases in which there were complications and the operation could not be completed in the usual way Tonnis et al state that remnants of the pituitary anlage in the pharyngeal roof may regenerate after destruction of the hypophysis in humans We have not checked our material in this respect nor have we looked for pituitary remnants along the central part of the pituitary stalk The Functionally complete Hypophysectomy All this brings up another question does a hypophysectomy have to be anatomically complete in order to bring about a favorable effect or can we be content with a hypophy sectomy that is complete from a functional point of view? Furthermore what are the possibilities of defining a functional hypophysectomy? During the past four years we have exerted efforts to find the laboratory test or tests that give the best information about the degree of hypophysectomy The difficulties of solving this prob lem may be seen from the following review which is based on results obtained during the last two years all the fol lowing laboratory studies were performed at least six weeks after operation According to our experience laboratory tests performed during the first six postopera tive weeks have a very limited practical value Laboratory Findings Almost none of the patients showed the ability post operatively to respond normally to subcutaneous admin istration of ACTH or epinephrine A normal response was ·8 Hypophysectomy Case 27 The patient was asymptomatic twenty seven months after hypophysectomy Case 28 The patient was asymptomatic for twenty five months after hypophysectomy and was alive twenty six months after the operation but slight pain has re appeared Case 29 The patient was asymptomatic for fifteen months after hypophysectomy Then there was sudden progression of disease and she died eighteen months postoperatively Case 30 The patient was asymptomatic for fifteen months then pain reappeared and simultaneously the liver became palpable She expired twenty three months after hypophysectomy with extensive metastatic involve ment of the liver As to the objective findings on palpation and x ray examination of lungs and skeleton, we have found that in general the improvement obtained during the first year after hypophysectomy has remained constant dunng the asymptomatic period Further regression of the metastases has not been noted Completeness of Hypophysectomy Next I would like to discuss some questions of impor tance in connection with this procedure The Anatomically Complete Hypophysectomy The first concerns completeness of the hypophysectomy A complete hypophysectomy from an anatomical point of view, can be defined only in one way serial sectioning of the content of the sella turcica shows that no pituitary tissue is left In this respect I can give only preliminary data from twenty-Six cases studied This material includes even those cases in which we could presume that the hypophysectomy was incomplete We estimate that com ·In Patients with Cancer 11 Our work with all these and other tests of endocrine function has made clear to us the difficulty of estimating whether or not pituitary function has disappeared com pletely I leave the question open as to whether or not the thyroid gland the ganads, and the adrenal cortex of humans have an autonomous basal function after hy pophysectomy I would like to mention the following in four patients we studied the effect of an intravenous infusion of ACTH on the excretion of 17 ketosteroids and 17 ketogenic ster ods In all four the steriod excretion increased due to the stimulation of the adrenal cortex The condition of three of these patients all of whom had shown promising im provement up to the time of the control examinations deteriorated within one month after the studies This change for the worse could not be arrested and the pa trents died within a few months Correlation of Laboratory and Clinical Fındıngs We have not as yet examined our material as regards 1) the correlation between the tests of endocrine func tions and the therapeutic effect and 2) the correlation between these tests and the results of the histological examination of the sella turcica and of the peripheral en docrine glands Among the patients who responded favor ably however are some whose thyroid function was un impaired according to the radiolodine tests For example Case 16 This woman born in 1896 was hypophysec tomized in April 1953 The latest control study in No vember 1955 showed the following BMR -29 per cent thyroid clearance 20 ml per minute 24 hour uptake of I 131 30 per cent conversion rate in twenty four hours 8 per cent and in forty eight hours 46 per cent ACTH test negative calcium in urine 20 mg per day 17 keto ·10 Hypophysectomy defined as a decrease in the number of circulating eosinophils by at least 40 per cent If the patients were on cortisone the epinephrine test was usually positive The excretion of 17 Letosteroids and 17 ketogenic ster ods (according to Norymberskı") was one to two mg in at least 75 per cent of tests performed on patients who were not receiving substitution therapy but was com pletely absent only in a few tests When cortisone was given in a dose of 25 mg daily, the excretion of 17 he tosteroids increased by 1 to 3 mg Our experience with the steroid excretion during administration of prednisone or similar preparations is very limited As to thyroid function, the BMR decreased in all cases, usually to about 20 per cent to -30 per cent We have used the following criteria for complete or almost com plete depression of thyroid function Thyroid clearance of 1 131 <3 ml/min A Hour uptake of 1 131 Conversion rate of 1 131 in 24 hours Conversion rate of 1 131 in 48 hours Protein bouad I 131 in % of dose given FBI (at least 2 months after operation) 25 mg/% Sixteen out of twenty nine patients examined, or 55 per cent fulfilled these requirements of a complete or almost complete depression of thyroid function The capacity to concentrate the urine to a specific gravi ty above 1 010 was restored in practically all cases after five to six months Recent examinations have shown that antidiuretic hormone can be produced after hypophysec tomy The capacity to increase the secretion of adrenalın during insulin hypoglycemia was intact after hypophysec tomy The excretion of calcium in the urine decreased mark edly in most of the cases <03% ·In Patients with Cancer 13 sectomy to patients with metastatic breast cancer and patients with diabetes mellitus with vascular complıca tions We also have performed the operation in one case of Cushings syndrome with recurrence after subtotal adren alectomy This patient is still in complete remission six months after the operation You may also remember that almost five years ago we electrocoagulated the hypophysis of a patient with a very advanced Cushings syndrome This patient is still in remission menstruates regularly and has even become pregnant We have not continued our trials to influence prostatic cancer and malignant melanomas by hypophysectomy We cannot elucidate the important question of whether or not hypophysectomy has any therapeutic effect beyond that achieved by hormone treatment and bilateral adrenalectomy and oophorectomy We have performed hypophysectomy in four patients previously treated by adrenalectomy and oophorectomy All of the patients were of the types previously described as not being im proved by hypophysectomy ·12 Hypophysectomy steroids, 28 mg per day (while on 25 mg of cortisone per day) The patient never needed thyroid substitution Despite the obviously normal thyroid function the pa bent showed no progression of disease for twenty four months after hypophysectomy At autopsy the thyroid gland was found to be of normal size the adrenals how ever showed marked atrophic changes Case 28 This woman born in 1910 was hypophysec tomized in December 1953 The last control study in the fall of 1955 showed BMR -20 per cent thyroid clear ance 19 ml per minute 24 hour uptake of 1 131 50 per cent PBI 18 gamina per cent ACTH test positive er cretion of 17 ketosteroids 34 mg per day (while on 25 mg of cortisone per day) calesam in urine 150 mg per day There was no thyroid substitution Despite the obvious incompleteness of the hypophysectomy the pa tient was asymptomatic for twenty six months after the operation Thus it seems that a complete hypophysectomy may not be a prerequisite for a favorable response But despite this finding in a few cases we continue to demand a com plete hypophysectomy so as to be able to evaluate cor tectly the therapeutic value of the procedure In order to achieve complete hypophysectomy, we have modified our earlier method of surgical removal of the gland the mechanical evacuation has been made more effective and the dura imings of the sella have been cauterized both with IN NaOH and Zenkers fud in doing this we have not been able to avoid some damage to the right optie nerve In two cases we tried to destroy the hypophysis by injecting 10 mc of radioactive chromic phosphate into the intact gland however we were not able to make the solution remain in the sella and are therefore unable to evaluate this method On the whole we have limited the use of hypophy ·In Patients with Cancer 17 Morbidity The important complications after operation are listed in Table 4 Each of the two patients with "im portant visual loss retained some degree of useful vision and in the five with minor visual loss the defects consisted TABLE 4 Important visual loss Minor visual loss Neurological complications Intracranial clots Impaired olfaction (estimated) 2 patients 5 patients 3 patents 2 patients 40% of quadrantıc temporal impairment which was either un noticed or unimportant to the patient It is believed that although visual impairment was usually the result of acci dental trauma or excessive handling of the optic nerves TABLE 5 Criteria for Evaluating Remission Arrest (8 Cases) No progress of previous lesions Disappearance of hypercalcemia and hypercalcuna Improvement in myelophthisic anemia Regression (28 Cases) Recalcification of bone lesions Diminution in size of any lesion No new lesions No progression of old lesions there is a possibility that in some cases minute nutrient blood vessels to the nerves may have been damaged in the process of freeing the arachnoid from the nerves and pituitary stalk The neurological complications seen in three patients included transient aphasia and hemiparesis The two pa ·16 Hypophysectomy as a means of preventing bleeding when it is sectioned and also to insure destruction of any anterior lobe cells that might extend into the stall In more recent cases the stall has been divided at the diaphragm sella without co agulation and the incidence of diabetes insipidus requir ing pitressin has been significantly reduced Thyroid replacement is usually not instituted until four to eight weeks after operation since myxedema does not appear before that time Two grains of dessiccated thyroid daily adequately control the myxedema Clinical Results In the period between March 1954 and January 1 1955 seventy five hypophysectomies were performed on seven ty four female patients with advanced metastatic mam mary cancer using the present surgical technique as pre viously described The data that follow present our er perience with this series of patients It is believed that hypophysectomy was not complete in five cases but in one of these the destruction of the gland was completed by a second operation Mortality There were seven deaths in the first thirty days following operation making an operative mortality of 9 per cent However the deaths that can fairly be attributed to complications of the operation are more nearly 5 per cent (Table 3) TABLE 3 Postoperative Deaths in the First Thirty Days 3 1 Directly due to surgery Pulmonary embolism at home Advance of metastatic disease unimproved by hypophysectomy TOTAL 3 ·In Patients with Cancer 19 Case 3 A 31 year old (premenopausal) woman had a radıcal mastectomy eight months prior to the develop ment of extensive pulmonary and several skin me tastases Comparison of a roentgenogram of the chest four months after operation with a preoperative film shows the regression of intrathoracic tumor This patient is teaching school and is still in remission one year after hypophysectomy Case 4 A 40-year old woman had developed intra thoracic metastases three years following radıcal mast ectomy for cucinoma She then had an oophorectomy fol lowed by dramatic regression of the disease The remis sion ended after seven months Several months later at the time of hypophysectomy she had extensive neoplastic infiltration of both lungs pleural effusion on one side and bloody pericardial effusion with accompanying enlarge ment of the cardiac shadow on x ray Roentgenograms taken only six weeks after hypophy sectory show apparent disappearance of intrapulmonary lesions absence of pleural flund and diminution in the size of the cardiac shadow Her remission continues ten months after hypophysectomy Case 5 A 44 year old woman two years after radical mastectomy had extensive skeletal metastases with hyper calciuria and hypercalcemia Comparison of roentgeno grams of the pelvis and femur before operation with those taken six months after hypophysectomy shows improved structural appearance A lantern slide shows the subsidence of hypercalcuria and hypercalcemia within ten days after operation and a concomitant disappearance of azotemia (return to nor mal from a preoperative BUN of 45 mg per cent) Summary of Clinical Data Of the sixty seven patients who survived operation six were premenopausal thirty four were postmenopausal sixteen had been oophorectomized and eleven had had ·18 Hypophysectomy tients with intracranial clots required secondary opera tions Impairment of the sense of smell has seemed to be an unavoidable result of deliberate section of the night olfac tory nerve and the stretching of the left nerve which oc curs when the frontal lobes are displaced by retraction and drainage of spinal fluid Fortunately this is not to be regarded as a serious complication Remissions Thirty six patients (about one-half) had objective remission of their disease, and of these eight were regarded as having arrest of disease while twenty eight had regression Table 5 lists the criteria employed for determining objective remission of disease Although some patients demonstrated symptomatic improvement they were not counted as remissions unless some objec tive evidence existed Examples of Objective Remission Case 1 A 42 year old (premenopausal) woman pre sented herself with an ulcerating tumor of the right breast The lesion was raised had a granular and ne crotic surface and measured 4 cm in diameter A photograph six months after hypophysectomy shows marked contraction of the lesion with epithelialization of the surface The patient is still in remission eleven months after operation Case 2 A woman of seventy two had extensive involve ment of the left breast by carcinoma with wide spread of the tumor to adjacent regions of the left chest axılla arm supraclavicular region and even to the right side of the chest wall A photograph taken nine months after hypophysectomy shows disappearance of the lesion Shortly after this small local recurrences of tumor growth appeared but they have grown very slowly and the pabent is other wise well tventy months after hypophysectomy ·In Patients tuith Cancer 21 tients could not be determined only two of these obtained remission from hypophysectomy Table 8 shows the results of hypophy sectomy in eleven patients previously treated by oophorectomy and adrenal ectomy It is notable that hypophysectomy can add to the TABLE 8 Hypophysectomy In Elecen Cases with Precious Therapeutic Castration and Adrenalectomy Failure Arrest of disease (Lasting 2, 2, and 3 months) Regression of disease (Lasting 7 months) 7 3 1 beneficial effects of the other glandular ablations It is speculative whether this additional effect can be explained on the basis of removal of ACTH effect on accessory adrenal glands or whether in some patients there are other factors such as removal of the source of somato TABLE 9 Hypophysectomy in Thirty four Postmenopausal Cases Failure Arrest of disease Regression of disease Average duration of remission Shll in remission 13 2 19 7+ months 10 patients tropic hormone We believe we have some evidence in support of the latter possibility which will be presented hereafter Table 9 shows the results of hypophysectomy in thirty four postmenopausal patients Some of the patients had undergone a natural menopause while others had under gone artificial menopause prior to the development of ·20 Hypophysectomy both oophorectomy and adrenalectomy performed prior to hypophysectomy Though the numbers are relatively small some inferences and tentative conclusions can be deducted Table 6 shows results of primary hypophysectomy in six TABLE 6 Premenopausal Hypophysectomy in Sir Cases 3 Failure Arrest of disease 2 months (Patient died of brain damage from uradiation) Regression of disease (lastıng 7 and 11+ months) 1 2 premenopausal women none of whom had received hor monal therapy Three patients showed objective remission of their disease Table 7 shows the results of hypophysectomy in sixteen patients previously treated by oophorectomy The table TABLE 7 Hypophysectomy in Sixteen Cases with Previous Oophorectomy 8 2 5 Failure Arrest of disease Regression of disease Not evaluated Response to castration No response to castration Unevaluated castration 1 5 4 7 5 Response to hypophysectomy 1 Response to hypophysectomy 2 Response to hypophysectomy shows that of the five patients known to have had a tem porary remission following oophorectomy all obtained a new remission from hypophysectomy Of four patients who failed to improve as a result of oophorectomy one obtained a remission from hypophysectomy The effects of previous oophorectomy on the remaining seven pa ·In Paticnts with Cancer 23 This table shows that the average survival period of the thirty-one patients who were not benefited by hypoph ysectomy was 44 months and that only seven of the thirty one are still living The figures give mute evidence of the advanced stage of disease existing in the majority of the patients who have been operated on There is noth ing to indicate that hypophysectomy if it is not beneficial accelerates the disease The average survival period of the patients who obtained objective remission thus far is twice as long as the average of patients who did not respond to hypophysec tomy and twenty one of the thirty six patients are still living Summary and Conclusions The results of seventy five hypophysectomies in seven ty four women with advancing mammary carcinoma who were operated on between March 1954 and January 1 1956 are reviewed There were seven deaths in the first thirty days after operation with three deaths directly attrbutable to the operation Of the sixty seven patients who survived operation thirty six had objective remissions of their disease and thirty one were not benefited New rernissions can be obtained by hypophysectomy in patients who have been temporarily benefited by ooph orectomy or by a combination of oophorectomy and adrenalectomy Every patient that was temporarily bene fited by oophorectomy obtained a new remission after hypophysectomy and four of eleven patients having had adrenalectomy obtained a new remission from hypoph ysectomy It is suggested that if hypophysectomy is not employed ·22 Hypophysectomy breast carcinoma The effects of hypophysectomy were the same in the two groups on the whole, the results are better than in any other group of cases with 62 per cent demonstrating remissions following hypophysectomy TABLE 10 Influence of Endocrine Status on Results of Hypophysectomy in Sixty seven Patients Who Surgiced Operation Cases Remissions Premenopausa) Postmenopausal Spontaneous Induced pon therapeutic Previous therapeutic oophorectomy Previous therapeutic oophorectomy and adrenalectomy 6 34 (22) (12) 16 3 21 (14) (7) 8 11 4 Table 10 shows in summary the influence of the endo crine status on the results of hypophysectomy Now that a satisfactory technique of operation has been developed it is of importance to determine whether or not hypophysectomy prolongs life It has been demon TABLE 11 Survival after Hypophysectomy of Sirty set en Patients Aterage Still Living 36 with remission 31 no remission 93+ mo 4 4+ mo 21 7 strated that objective remission occurs in 50 to 60 per cent of the patients While more time must elapse before conclusions can be drawn analysis of cases of this series in which operation was performed from 24 to 25 months ago shows a statistically significant figure of increased survival in patients who responded favorably (Table 11) ·DR B J KENNEDY Surgical hypophysectomy has been carried out at the University of Minnesota Medical School by Drs William Peyton and Lyle French of the Division of Neurosurgery The rationale for hypophysectomy has been based on animal investigations previous experiences in the hor monal management of breast cancer and postulations re garding the characteristics of breast cancer growth The inhibition of tumors in mice following hypophysectomy has been demonstrated by various investigators * • Fur thermore the administration of growth hormone to ani mals has produced a number of neoplasms of various organs other than the pituitary gland. From the clinical point of view it has been postulated that the favorable effects on breast cancer during administration of andro genic and estrogenic hormones were in part due to pitu tary suppression earlier referred to as chemical bypophy sectomy : It has also been observed that breast can cer has not been reported in patients with Sheehan s syti drome Dr Fuller Albright many years ago suggested that growth hormone might possibly be responsible for some breast cancer growth The apprrent stimulating effect of growth hormone in breast cancer was reported by Dr Olof Pearson I have two patients in whom an exacerbation of prostatic cancer was demonstrated during the administration of growth hormone These data established further criteria for a rationale for total hypophysectomy It was apparent that with present facilities total irradiation of the pituitary gland was impossible Total surgical hypophysectomy was undertaken at the University Hospitals primarily as an investigative tool in the study of breast cancer which would provide a means for further evaluation of breast 25 ·24 Hypophysectomy as the initial ablative operation in altering endocrine in fluence on the disease, at least it is preferable to adrenal ectomy as a second operation following oophorectomy The survival period is more than hyvice as long in those patients who obtain a remission after hypophysectomy as in those who do not ·In Patients with Cancer 27 The extent of metastatic breast cancer in patients has been demonstrated by the presence of microscopic me tastases in the brain wedge removed and by the presence of metastases in the pituitary itself Hormonal Replacement Preoperatively the patients receive 100 mg of cortisone intramuscularly every twelve hours for at least forty eight hours before the operation when patients are treated longer than this, the postoperative course seems even smoother The morning of the operation an additional 100 mg of cortisone is administered orally and 5 mg of desorycorticosterone acetate is given intramuscularly Postoperatively all medication is placed on an oral basis as soon as possible The cortisone is reduced to an average dose of 50 mg a day Complications Certain complications were observed Four patients had rhinorrhea which was temporary in nature This was largely due to puncturing the sinus at the time of ron geuring away the anterior clinoids Meningitis occurred in three patients The first patient had uremia and hyper calcemia preoperatively and continued to be confused postoperatively though the serum calcium decreased to normal The confusion was later proved to be due to an Escherichia coli meningitis The patient died of localized brain abscess The other two patients had a proteus men ingitis and a paracolon meningitis Both recovered Loss of smell occurred in one patient This could not be ex plamed since to our knowledge there was no interfer ence with the olfactory nerve All patients have been questioned regarding the loss of sense of smell There were two instances of visual disturbance The first was a ·26 Hypophysectomy cancer growth and guide future studies in this disease Though hypophy sectomy obviously has produced favor able regressions in breast cancer growth, the study of hypophysectomy represents a means of perfecting future chemical therapy rather than promoting the surgical pro cedure Total surgical hypophysectomy has been carried out in twenty two patients followed for more than three months In addition there were two patients in whom extensive dural metastases discovered at the time of craniotomy made it impossible to carry out the surgical procedure This series is not statistically significant It represents selection of patients based upon theories of breast cancer growth Operative Procedure The scalp incision is made behind the hair line, and the flap retracted forward All the operations were done on the right, except in one case in which there were exten sive metastases on the right The anterior medial portion of the right frontal lobe is removed in a wedge three centi meters wide and extending directly down The procedure provides 1 direct approach to the pituitary gland and further provides an area of expansion in case cerebral edema shoul occur In this way postoperative decom pression was avoided No such complication has occurred In those instances in which the optic nerves were short the anterior clinoids were rongeured away to provide better visualization Once the pituitary fossi is visualized the stalk is picked up anterior to the chiasm, clipped and cut The diaphragma sellae is torn by blunt dissection going from the medial portion radially The pituitary is visualized and removed either in small picces or on oc casion as one large mass ·In Patients with Cancer 29 Case 2 This 42 year old woman had had a definute recalcification of osseous metastases six months earlier following oophrectomy At the end of the six months there was exacerbation of the disease with extensive pelvic metastases Following hypophysectomy there was cal cification of these osteolytic lesions Fifteen months post operatively the remission was still maintained Metabolic studies have been camed out in selected patients Examples of these studies follow Case 3 Only one of the patients of this hypophysectomy series had had an adrenalectomy This 43-year old woman had been oophorectomized at the time of the radical mastectomy Osseous and pulmonary metastases re sponded favorably following adrenalectomy One year after the adrenalectomy there was exacerbation of the disease manifested by hypercalcemia and hypercalcuria A total hypophysectomy was carried out This was fol lowed by a decreased serum calcium and a very slow de crease in urinary calcium excretion over a two month period There was a slow increase in serum alkalıne phos phatase and concomitant relief of pain Initially there was evidence of spinal cord compression The reflexes returned following hypophy sectomy though recalcifica tion of osseous metastases did not occur Case 4 This patient a 28-year old premenopausal woman had extensive osseous metastases On an intake of 150 mg a day of calcium the urinary calcium aver aged 400 to 500 mg daily and hypercalcemia was present One objective of the hypophysectomy was to measure the rate at which an effect in such a patient would occur and to attempt to determine whether or not hypophysectomy would be as rapid in its effect as bilateral oophorec tomy Postoperatively there was a rapid decrease in urinary calcium excretion and serum calcium The serum alkaline phosphatase increased there was relief of pain and calcification of osteolytic lesions occurred Case 5 An extensive metabolic study was carried out ·1 28 Hypophysectomy loss of peripheral vision in the right eye The second pa tient six days postoperatively and concomitant with the development of a paracolon meningitis had a loss of vision of the right eye It was felt that the visual loss was sec ondary to the meningitis and not due to trauma Three of the patients have had thrombophlebitis of the leg post operatively There was no subsequent complication of the entire twenty two patients eleven developed one or more of the above mentioned complications One patient demonstrated an alteration that may rep resent a complication Postoperatively the patient had re calcification of all osseous metastases The bone flap, however showed progressive reabsorption An attempt to demonstrate metastatic disease by needle aspiration of this flap was unsuccessful This patient was the longest surviving patient and has not had evidence of recurrence within the bone flap that can be demonstrated Clinical Response The following are examples of patients undergoing hypophysectomy for advanced breast cancer Case 1 This 42 year old woman had previously re sponded favorably following oophorectomy There had been calcification of osseous metastases Subsequently there was exacerbation the disease with multiple osteo lytic defects ſotal hypophysectomy was carried out and the patient survived twenty five months Relief of pain and recalcification of the osseous metastases were evi dent for twenty months at the end of this turne the urinary calcium excretion began to increase The patient re mained asymptomatic for twenty five months postopera tively Because of the recurrent hypercalcuuia however the patient was regarded as having a 20-month remission During the remission there was regeneration of the right second nb which had been totally destroyed by the dis ease ·In Patients with Cancer 31 creased feeling of well being in seventeen patients It would not appear that pain relief is a result of removing the anterior lobe of the brain There was no response either objective or subjective in four of the patients Of twenty two patients twelve are dead five of these demonstrated objective regressions Ten patients are alive all having had objective regressions Mortality Of the twelve patients now dead seven died because of progression of the cancer some after a period of im provement One patient demonstrating improvement died four days after the famly discontinued cortisone therapy One patient died of meningitis as a postoperative complı cation Three deaths occurred immediately postoperative ly two of these patients had bilateral pleural effusion and one had extensive liver and cardiac metastases Such patients would not undergo operation under our present criteria of selection Regression Data The average duration of improvement of the patients in this series is very similar to that reported by Dr Ray including those patients still maintaining improvement it has been 72 months The average duration of survival of the living patients of which there are ten has ranged from three to twenty five months the average period be ing 94 months The longest survival time of the patients who died (the other twelve patients) was less than thir teen months This included two patients dying two and four days postoperatively The average survival of this group is four months The duration of survival of the en ture series at the present time ranges from two days to twenty five months The average survival has been 73 months ·30 Hypophysectomy in this 46 year old woman The purpose of this study was to measure the extent to which 50 mg of cortisone would affect metastatic cancer so the hypophysectomized patient Before hypophysectomy the patient was placed on a controlled constant intake and unnary calcuum serum calcium and serum alkaline phosphatase deter minations were done Following administration of 50 mg of cortisone daily there was an increase in calcium ex cretion suggesting that the cortisone was imitraang an acceleration of the disease in the bones The dose of corts sone was then increased to 300 mg daily Calcium er cretion decreased but she still remained in negative cal cium balance The serum calcium decreased to a normal range It was postulated that thus negative calcium bal ance was a result of the decalcifying effect of cortisone at the larger dose levels and the cancer was in part inlubsted by the larger dose of cortisone Subsequently a total hypophysectomy was performed with the patient maintained on the same dose (300 mg) of cortisone There was no obvious alteration in the serum calcium or calcium balance Since the pituitary was absent it was postulated that the persistent negative calcium balance either was due to the decalcifying ef fect of cortisone or that cortisone in small amounts main tained a certain rate of tumor growth Only a sught nse of serum alkaline phosphatase occurred Finally after approximately one month the cortisone was reduced to 50 mg daily Immediately there was a nise in serum alka Ine phosphatase and a positive calcium balance was achieved Subsequently there was recalcification of the Osseous metastases Summary of Clinical Results The results in this series of hypophysectomized patients are not statistically significant, since the series consists of of group of selected patients Objective regressions oc curred in fifteen of twenty two patients There was no objective response in seven There was pain relief or in ·In Patients with Cancer 31 would not appear creased feeling of well being in seventeen patients It that pain relief is a result of removing the anterior lobe of the brain There was no response, either objective or subjective in four of the patients Of twenty two patients twelve are dead five of these demonstrated objective regressions Ten patients are alive all having had objective regressions Mortality Of the twelve patients now dead seven died because of progression of the cancer some after a period of un provement One patient demonstrating improvement died four days after the family discontinued cortisone therapy One patient died of meningitis as a postoperative compli cation Three deaths occurred immediately postoperative ly two of these patients had bilateral pleural effusion and one had extensive liver and cardiac metastases Such patients would not undergo operation under our present criteria of selection Regression Data The average duration of improvement of the patients in this series is very similar to that reported by Dr Ray including those patients still maintaining improvement it has been 72 months The average duration of survival of the living patients of which there are ten has ranged from three to twenty five months the average period be ing 94 months The longest survival time of the patients who died (the other twelve patients) was less than thir teen months This included two patients dying two and four days postoperatively The average survival of this group is four months The duration of survival of the en tire series at the present time ranges from two days to twenty five months The average survival has been 73 months ·30 Hypophysectomy in this 48-year old woman The purpose of this study was to measure the extent to which 50 mg of cortisone would affect metastatic cancer in the hypophysectomized patient Before hypophysectomy the patient was placed on a controlled constant intake and urinary calcium serum calcium and serum alkaline phosphatase deter minations were done Following administration of 50 mg of cortisone daily there was an increase in calcium er cretion suggesting that the cortisone was initiating an acceleration of the disease in the bones The dose of corti sone was then increased to 300 mg daily Calcium er cretion decreased but she still remained in negative cal cium balance The serum calcium decreased to a normal range It was postulated that this negative calcium bal ance was a result of the decalcifying effect of cortisone at the larger dose levels and the cancer was in part inhibited by the larger dose of cortisone Subsequently n total hypophysectomy was performed with the patient maintained on the same dose (300 mg ) of cortisone There was no obvious alteration in the serum calcrum or calcium balance Since the pituitary was absent it was postulated that the persistent negative calcium balance either was due to the decalcifying ef fect of cortisone or that cortisone in small amounts main tained a certain rate of tumor growth Only a slight rise of serum alkaline phosphatase occurred Finally after approximately one month the cortisone was reduced to 50 mg daily Immediately there was a rise in serum alla bne phosphatase and a positive calcium balance was achieved Subsequently there was recalcification of the osseous metastases Summary of Clinical Results The results in this series of hypophysectomized patients are not statistically significant since the series consists of of group of selected patients Objective regressions oc curred in fifteen of twenty two patients There was no objective response in seven There was pain relief or in ·DR. DONALD D MATSON We performed our first hypophysectomy in January, 1952 our enthusiasm waned abruptly, however, after experience with three or four cases and has only been within the last year that this study has been resumed This entire project has been under the supervision of Dr Francis Moore the Chairman of our Department of Surgery and closely supervised by Dr Andrew Jessiman We have received close cooperation and much assistance from Dr Kendall Emerson of our Medical Department in particular and many other people in the hospital The first patient that we operated upon a woman with cancer of the ovary demonstrated no evidence of any alteration in the course of her disease We also have performed hypophysectomies in one patient with cancer of the testi cle one with prostatic cancer and one with cancer of the adrenal In none of these was there evidence of sig nificant alteration of the disease although these patients did experience some pain relief and some increased sense of well being One patient was operated upon for diabetes mellitus with vascular renal and retinal disease and thirteen pa tients were operated upon for metastatic mammary car cinoma eleven of these within the past fourteen months Our experience with hypophysectomy is therefore limited to eighteen patients Operative Procedure Patients are operated upon under light general anes thesia with nitrous oxide through endotracheal tube with the addition of muscle relaxants We have not used ether or induced hypotension in any patients in this group The nght frontal bone is exposed by a coronal incision 33 ·32 Hypophysectomy In conclusion, each investigator has to choose a method of therapy for breast cancer patients In our experience all patients who responded to therapeutic oophorectomy were improved by hypophysectomy Two patients who improved following hypophysectomy subsequently dem onstrated another regression with androgen therapy Estrogenc hormone therapy has failed to affect the disease in sıx patients demonstrating reactivation of the disease after transient improvement following hypophysectomy In the postmenopausal patient estrogenic hormone ther apy would appear to be the preferential treatment The decision as to whether or not a woman is postmenopausal is based upon the degree of ovarian function most usually measured by the vaginal smear which usually shows cornification five years or more after the last menstrual period It is possible that hypophysectomy would be of value in those patients in the postmenopausal group who have obtained regressions from estrogenic therapy ·In Patients with Cancer 35 to them We have done this in only one patient, operated on approximately eight weeks ago Hormonal Replacement Patients are prepared with cortisone previous to opera tion Those already receiving cortisone are given an increased amount just prior to operation All of these pa tients have been started on intravenous compound F after the gland has been removed usually receiving 150 to 200 mg duning the first twelve hours I think in every case we have switched directly from the intravenous Cortef to oral cortisone within twelve hours of operation The cortisone is then diminished usually to a level of 50 mg within a week to ten days after operation We have never been able to carry any patient on less than 50 mg of cortisone per day even when gradual reduction has been attempted the patients have always experienced extreme fatigue hypotension etc Mortality Two patients in our series of eighteen have died within thirty days of operation without leaving the hospital One of these patients died of strangulation from a huge mediastinal mass causing acute bronchial obstruction She also had an acute myelophthisic anemia due to virtual replacement of her bone marrow with tumor tumor cells were actually seen in a smear of circulating blood It was felt that her overwhelming disease and not the operation was the cause of death The other patient who died within thirty days also had extensive pulmonary and pleural lesions She died of an aspuation pneumonitis seven days after operation in what I think must be considered an operative death Among the other sixteen patients sie died from one to ·34 Hypophysectomy and the bone flap is carried to the midline and as low as possible As the dura is opened 30 to 40 cc of spinal fluid is drained The right olfactory tract is sacrificed as Dr Ray outlined The pituitary stalk is exposed between the optic nerves and cut At first we exposed the stalk rather high up putting our silver clip on it coagulating distal to this and cutting through the coagulated area In the last five cases, in an effort to combat diabetes insipidus I have made a special effort to free the arach noid as carefully as possible completely avoiding the stalk, and have simply placed a nerve hook around the stalk gently and cut it without any clipping or coagula tion There has been very little bleeding A small pledget of cotton on a silk string is used to tuck the stalk back under the chi ism This is left in place until the operation is finished and then removed We try not to touch the proximal stalk or have it handled during the operation After removing the gland as thoroughly as possible by dissectors and curettes we wipe the sella briskly with dry cotton and swab it thoroughly with Lenkers solution In the last patient treated we sutured a piece of polyethylene film over the surface of the sella turcica tacking it to the margin of the diaphragm of the sella at the conclusion of the operation It has been shown in rabbits that if small amounts of pituitary tissue are left in the se lla within ten days to two weeks after hypophy sectomy one can trace new vessels growing down from the portal circulation from the brain into the sella to revascularize the remaining cells. Since it is possible that the function of the anterior pituitary gland is under the control of receptors in the hypothalamus it may be that if a few cells are left behind we can reduce their activity or at least delay their regeneration and resumption of function of we can minimize the return of blood supply ·In Patients with Cancer 37 One-half of our patients that is nine developed diabetes insipidus requiring continuing treatment with pıtressin tannate in oil Sıx patients had no diabetes insipidus or at least not enough to require any treatment and the three remaining had only very transient or mild diabetes Three of the five patients in whom the stalk bad been cut without any clipping or cautery did not develop diabetes at all Four of these five patients interestingly enough on test ing with nicotine and hypertonic salıne showed that they still have the capacity to secrete antıdıuretic hormone The fifth patient has not been tested It is certainly a clinical impression that low stalk section without chipping cautery, or any trauma to the upper stalk is going to result in a decrease in the incidence or at least in the severity of diabetes insipidus We do not yet know however whether or not this procedure is going to result in leaving anterior pituitary cells in the lower end of the stalk We have the impression that the stalk varies considerably in size from one patient to another and I do not know the significance of a thickening of the stalk just above the sella We have seen gross evidence of metastatic cancer in the pituitary in three of thirteen patients with cancer of the breast Laboratory and Clinical Studies Among ten of the patients with breast cancer who have had adequate testing uptake of radioactive iodine varied from 155 to 56 per cent and postoperatively from 1 to 16 per cent Among the last seven patients who are the most satisfactory cases from a surgical point of view the uptake of radioactive iodine postoperatively has never been higher than 65 per cent PBI values have been between 13 and 3 FSH assays in the breast cancer pa tients showed preoperative values of 10 to 200 mouse ·36 Hypophysectomy five months after operation of progression of their cancer The remaining ten are still alive from eight to thirteen months after operation Of these ten, one is the diabetic patient and the other nine are mammary cancer patients Morbidity We have been impressed with the low morbidity of the procedure Most of the patients have been alert within two to four hours after the operation and able to take fluids and cortisone by mouth the following day in per fectly adequate amounts Complications of surgery have been rare One patient developed a wound infection due to technical error in the handling of an open frontal sinus There has been no men ingitis no rhinorrhea There have been no intracranial hematomas and no hemiplegias one transient weakness of the left arm We have had no visual disturbances in the way of visual field defects or diminished visual acuity in our patients with the exception of the diabetic patient who was essentially blind at the time of operation Two or three of our patients have complained rather bitterly of the loss of smell One patient had a mild seizure the day after operation and we have had three other patients who had single convulsive seizures one six weeks one eight weeks and one ten months after operation This ex cludes the diabetic patient who had many convulsions in the period six to twelve weeks following operation I understand this has also been your experience Dr Luft in diabetic patients Another complication seen in one of the two patients in our series who had been treated previously by adrenalectomy was two episodes of acute severe hyponatremia We have not seen any difficulty in sodium or other electrolyte regulation in any of the hy pophysectomized patients who still had adrenals in place ·In Patients with Cancer 39 taken thirty minutes after the stalk was cut showed com plete disappearance of all the ACTH in the circulating blood This was also true in samples tahen after the hypophysis was removed Clinical Results Of the thirteen patients with mammary cancer who are still living the longest survival thirteen months is that of a male patient This patient who has had the most sat isfactory subjective and objective remission observed so far was previously treated by orchiectomy to which he had an equivocal response Following hypophysectomy he has had extensive recalcification of osteolytic lesions throughout the spine and pelvis He has been completely free of bone pain since the day of operation and his cond. tion has been very satisfactory throughout Four of our thirteen patients have been failures two died in the postoperative period and two failed to show any halt in the course of the disease All four of these patients had extensive pulmonary and pleural lesions and widespread soft tissue lesions Two of them had liver lesions as well It is too soon to give any statistically valid results on our other nine patients At least three of them have had striking objective remissions and are still in remission At least three others seem to have marked arrest of a rapidly advancing disease process It is possible that the nine surviving patients will show objective relief of significance As to subjective relief it is difficult to grade and probably one should not even try but I would say that in a third to a half of our patients the subjective relief has been very great and in the other half it has been mild but definite One question that I am hoping those of you who have had longer follow ups will discuss is how many of these patients are actually returning to ·38 Hypophysectomy units Postoperatively the values were five units or less in all but one who had a positive FSH of 75 mouse units In patients with bony metastases we have done urine calcium excretion studies on low calcium diets All patzents with bony metastases have not shown increased calcium ercretion With only one exception however, when n creased calciuria was present it diminished following hypophysectomy Preoperative estrogen stimulation stud ies were found to be very disturbing to some of these patients They may develop fever tremendous malaise and mcreased bone pain and one or two patients have gone into coma In our experience whether or not a patient responds to cortisone has not proved to be satisfactory indication of what hypophysectomy will accomplish from a thera peutic point of view Certainly some patients who have not shown decreased calciuria on up to 300 mg of corti sone preoperatively have still obtained some reduction in calciuria after hypophysectomy Dr David Hume of our physiology group has been carrying out bro assays of circulating ACTH in some of our patients He has found that stimulation of ACTH production is markedly reduced when the pituitary stalk is cut Almost all of our previous patients have received some cortisone preoperatively The last patient however had not had any cortisone for a period of two to thre months before operation She was given no preoperative cortisone and none during the first part of the operation Following craniotomy the stalk was exposed but neither the stalk nor the gland were touched A sample of the arterial blood was taken Bio assays made with it on hy pophysectomized dogs with the adrenal vem cannulated showed a large amount of circulating ACTH presumably as the result of the trauma of the craniołomy Samples ·DR LEONARD P ELIEL The work which I am presenting has resulted from the collaborative efforts of the Oklahoma Medical Re search Foundation and the Department of Neurosurgery of the University of Oklahoma School Medicine Since July, 1955 we have done nine craniotomies in patients with advanced carcinoma six of which were surgical hypophysectomies for advanced carcinoma of the breast and three of which were craniotomies for installation of radioactive isotopes in patients with advanced prostatic cancer We will discuss the latter tornorrow The technique that has been used in Oklahoma City for hypophysectomy is essentially that which Dr Ray has described The patients are usually anesthetized with mtrous oxide although light ether anesthesia with pento thal induction also has proved satisfactory in a few cases The stalk has been cauterized in all the cases reported here Hormonal Replacement We have tried in two cases to maintain the patient with intravenous soluble hydrocortisone only rather than with intramuscular cortisone This technique was found un satisfactory because of the marked fluctuations in blood pressure necessitating frequent regulations of the intra venous drip Two attempts to maintain patients post operatively on prednisone have proved unsatisfactory with the patients developing weakness gastrointestinal symptoms and general malaise I would be interested to hear if any other conferees have had any experience with this steroid as the sole maintenance therapy Mortality and Morbidity There was one postoperative death which occurred two weeks after hypophysectomy as a result of progres 41 ·40 Hypophysectomy jobs or to housework We have been impressed that some of these patients who seem to have both subjective and objective improvement with clear evidence of regression of disease are still not interested in doing very much If any summary can be made from our clinical experi ence to date, it is that this operation seems to be entirely feasible with low morbidity and mortality The patients all feel better the next day and are glad they have gone through with the operation The relief of pain and the increased sense of well being has been very rewarding regardless of whether or not there has been any demon strable alteration in the disease course There are certain disadvantages to the procedure Cer tainly the loss of smell is a minor one The problem of diabetes insipidus is a definite one which requires regu lation and management We may be able of course to control that better with more surgical knowledge The patients who have had adrenalectomy plus hypophysec. tomy are difficult patients to manage postoperatively, and I believe that it is probably not feasible to care for such patients except in the hospital ·In Patients with Cancer 43 sectomy include absence of unnary FSH a drop in radio active iodine uptake in twenty four hours to 5 per cent or less and a drop in protein bound iodine to 3 micro grams or less Later on I will present some other physio logic tests which I think may also be some indication of completeness of hypophysectomy I would like to discuss the failures in a little more de taal One of these patients who was considered to be com pletely hypophysectomized from the physiologic point of view was a patient of 54 years who had an unequivocal regression of tumor after the administration of testoster one and who upon administration of estrogen had shown unquestionable acceleration of tumor growth This patient did not obtain a remission following hypophysectomy The hypophysectomy was easy and it was the feeling of the operator that there was no residual tissue However at death the sella was excised en bloc serial sections made and a few sheets of viable pituitary cells were shown to be present This raises the very interesting question of course as to whether or not a few viable pituitary cells can maintain tumor growth even in the presence of physiologic tests which indicate virtual absence of pitui tary function One 49 year old patient with osseous me tastases who had obtained a remission after oophorectomy two years previously failed to obtain a remission after physiologically complete hypophysectomy Two of the patients who failed to respond had incomplete hypophy sectomies Each had very close approximation of the clinoids leaving only a small aperture Our group has not had the courage to rongeur away the anterior chinoids for fear of getting into the sphenoid sinus One patient preoperatively had mild diabetes charac terized by slight elevation of blood sugar and intermittent glycosuna not enough to require the administration of ·42 Hypophysectomy sive disease All of our patients developed diabetes in sipidus Our only other complication was a temporal vis ual field defect which persisted postoperatively Clinical and Laboratory Results The longest survival in our very recent series is now about seven months with the patient still in excellent remission of the two remissions (Table 12), one is clas sified as excellent, meaning actual objective evidence of tumor regression and one as partial which corresponds to arrest of disease with a fall of unne calcium ercretion to normal values and no radiographic evidence of pro gression Completeness of hypophysectomy is judged by physiologic testing Our criteria of complete hypophy TABLE 12 Surgical Hypophysectomy for Carcinoma of the Breast in Sir Patients INDUCED REVIESSION No Pts Oophorec tomy Induced relapse with estrogen Hypo-X Complete (Phystolog Ically) Testos terone I Remissions Excellent Partial 1 + Not done post menop Not done Not done Equiv Not done Yes No 1 II Failures I Not done post menop 0 Probable No 1 + Not done Mot done Yes 1 Not done + + Yes post menop 1 Not done post menop 0 Mot done No Postoperative mortality 1 patient two weeks postoperatively from progression of disease + Indicates remission produced O No remission produced ·DR SAMUEL G TAYLOR, III Our group has attempted hypophysectomy on eleven patients The operations were done by Dr Wesley Gus tafson University of Illinois, and Dr Adrien VerBrugghen of Presbyterian Hospital Chicago both highly qualified neurosurgeons of the eleven cases in which hypophy sectomy has been attempted, it was completed in nine Two patients were inoperable one because of an anatomi cal variation that would have required sacrifice of the optic nerve which we did not feel was justified and the other patient because of cerebral metastases that were in the way We had one surgical complication resulting in a loss of vision except on the nasal side of the right eye this patient no longer has adequate vision We have three operatue deaths Two were due to surgical trauma and one to renal shutdown on the eighth postoperative day in a patient with extensive liver metastases Clinical Results The three patients who died did so before there was any evidence of tumor regression Two patients have had very remarkable definite and outstanding regressions The other four patients have not shown any regression Neither of the patients who responded favorably had had any form of therapy for their metastatic disease before the hypophysectomy Both were premenopausal The first patient a woman of 43 had a tremendous primary tumor in situ that extended to the axılla She also had osseous metastases The tumor to all intents and purposes had disappeared Sixteen months have passed without any evidence of recurrence The other patient is a 35 year old woman who had osseous and pleural metastases which necessitated emptying the chest weekly or at biweekly 45 ·44 Hypophysectomy insulin After hypophysectomy, which was physiologically complete this patient had a normal fasting blood sugar and no further glycosuria I would like to reiterate the feelings of Dr Matson Dr Kennedy and Dr Ray that this is a procedure which in the hands of competent neurosurgeons is certainly easy to accomplish In this particular group even though it is our first six cases of surgical hypophysectomy the results have been very gratifying not in terms of remis sions but certainly from the point of view of their post operative course ·DR. WILLIAM H BAKER We have not been completely successful in removing the total hypophysis Our first patient was done early in 1951 on the advice of Dr Fuller Albright and that patient had a functioning adrenal carcinoma She was a 22 year-old female with Cushings syndrome, including acne hypertension elevated ketosteroids and formalde hydogenic corticoids and polycythemia Studies done prior to hypophysectomy showed that this tumor was responsive to large amounts of ACTH and on 500 mg of ACTH daily she had an increase of 17 ketosteroids and formaldehydogenic corticoids Her pituitary was removed without instillation of Zenker s fluid and about 07 gram of pitutary tissue was removed Following operation the levels of all the previously elevated steroids decreased to normal levels within twenty four hours In addition her hypertension lessened and in fact disappeared after fif teen days However a gradual increase in her 17 keto steroids then appeared accompanied by an increase in her formaldehydogenic corticoids and then there was a gradual increase in her hypertension and acne Four months after operation she died An autopsy revealed metastatic adrenal carcinoma involving the laer and lung The fossa contained about 07 gram of pituitary tissue and a microscopic examination showed active mi tosis in many of the cells probably representing active regeneration We abandoned this procedure until the report by Dr Olivecrona and Dr Luft of their excellent results in pa tients with breast cancer At the present time we have hypophysectomized seven patients six with breast cancer and one with melano carcinoma The patient with melanocarcinoma received 47 ·46 Hypophysectomy intervals Since hypophysectomy, there has been no accumulation of fluid She has been in remission for fourteen months ·DISCUSSION DA LIPSETT Dr Luft what is the lowest value you can get and be sure you are measuring ketosteroids? DR. LUFT Thus is a difficult question to answer I would think about 1 to 2 mg DOCTOR Did Case 16 (p 7) have evidence of adrenal pitu tary function? DR LUFT The excretion of 17 ketosteroids was 28 mg while she was on cortisone That is a low value The ACTH test was negative all the time DR KENNEDY What type of response did she have? Was the pain relies ed? DR LUFT The pain was relieved She had a marked decrease in the infiltration in the left breast where she had her primary tumor She had a wound in the skin over the primary tumor that was very painful before the operation The wound did not dis appear completely DR KENNEDY Dr Ray could I ask you why you drain the spinal flud? DR RAY The drainage allows further retraction of the brain DR KENNEDY You are emptying the ventricles? DR Ray We drain all the spinal fluid but not until the dura is opened From time to time we remove an additional amount dur ing the operation One of the reasons for this is to get a "slack brain and often once the field is exposed I can remove the re tractor and work without it The other advantage of draining the Aud is that the field in the region of the sella is kept dry DOCTOR Are antibiotics used? DA RAY Yes if the sinuses are opened Also all patients are given anticonvulsants for about ten days since seizures may occur during this time DR KENNEDY Are convulsions frequent? DR RAY I would not say they are frequent They occur in possibly 5 per cent of the patients no more than that DR KENNEDY Do you cut the olfactory nerves? DR RAY The nght olfactory nerve is divided if the left nerve pulls away and tears as it may then patients lose smell function I do not know exactly how many patients have lost the sense of smell We perhaps have not followed thus as carefully as we 49 ·48 Hypophysectomy no benefit and there was no effect on the course of the disease the patient died four months after the operation with a widespread melanocarcinoma of the lungs and brain Functioning pituitary tissue was again found in the sella Sıx patients with cancer of the breast were hy pophysectomized who had not had a previous ovariec tomy or adrenalectomy and all of whom were five years postmenopausal or post bleeding of these six four repre sented incomplete removal of the hypophysis and were unsuccessful as judged by physiological tests after the operation and corroborated by autopsy Tuo patients did show complete hypophysectomy as measured by protein bound iodine determinations and inability to respond to epinephrine as measured by blood eosinophils In both of these latter patients there was little change qantitatively in their urinary output of 17 ketosteroids corticoids or estrogens as measured by fluo rogenic phenols They were both maintained on 50 mg cortisone daily and in both cases androsterone and etro cholanolone completely disappeared from their urine A similar disappearance of androsterone and etiocho lanolone was encountered in adrenalectomized patients maintained on cortisone We are unable to demonstrate any change in chemical measurements of estrogens either as fluorogenic phenols or by countercurrent distribution In both of these latter patients follicle stimulating hormones disappeared after operation ·In Patients with Cancer 51 DocTon You dont relieve the edema? DA RAY Edema has not been an important factor and the wound is closed without decompression Doctor How quickly do the tumors regress within a few days? DR. RAY No we sometimes do not see an obvious regression in a lesion for three weeks or more DR KENNEDY Could you tell me whether the pituitaries of your patients who have been previously castrated appear any larger grossly than patients who have not been castrated? DR RAY I dont think we would be able to answer that, un fortunately While we have sometimes weighed glands some tissue as lost in suction Pituitaries vary in size just as noses do It brings to mind also the fact that we have come to recognize usually at the table those who have metastases in the gland Do you know how many there are Dr Lipsett? DR LIPSETT Sıx of our patients have had metastatic nodules in the pituitary DR ADAIR How did you recognize thern? DR RAY You can tell usually by the gross appearance of the tissue DR BERGENSTAL Dr Kennedy what is your interpretation of the data obtawed in your Case 5 (p 29)? DR KENNEDY The interpretation of these data was that 50 mg of cortisone may initiate a stimulating effect on the breast cancer This has been seen during the initiation of therapy with androgenic and estrogenic hormones However with the latter hormones per sistence in hormone therapy may be followed by a remission It is quite possible that had the 50 mg of cortisone been continued a similar type of remission would have occurred Certainly during the period the patient received 300 mg there is indication that the growth rate of the cancer was partially suppressed Yet at the same time there may be a mild degree of maintenance of a growth rate because of a mild stimulating effect on the tumor In other words cortisone may have a dual effect 1) that of suppressing the pituitary and adrenal glands with respect to a stimulating factor of breast cancer and 2) supplying at the same time as metabolic breakdown products substances that are also stimulating to the breast cancer certainly after hypophysectomy it is evident that reduction of cortisone to 50 mg a day is followed by objective evidence of improvement Clearly therefore the 50 mg of corta ·50 Hypophysectomy might but the patient who does lose the sense of smell is usually not greatly upset by it DOCTOR How about the loss of taste sensation that goes with it? Dr Ray They do not lose taste SAME DOCTOR Only smell? DR RAY laste is one thing smell is another Taste us preserved that is they can discriminate mong salt bitter sour and sweet There are also other aspects to enjoying food such as savoring its consistency If the stalk is not coagulated diabetes insipidus which requires pitressin is less likely to develop We think there usually is some degree of change in fluid balance that can be measured on testing Fluid intake may increase to 2000 to 2500 a day but patients can easily handle this amount without the need for pıtressin DR M B LIPSETT Are you disturbed by those cases in which the stalk is very broad? DR RAY I am because there is the po sibility of leaving an terior lobe cells but maybe the cells are not important The dia betes insipidus is not an unsurmountable complication but it is a nusance Probably between 40 and 50 per cent of our patients thus far have required putressin DR KENNEDY Was there increased intracranial pressure in those patients who had clots? De Rax For the first twenty four hours after operation pa trents usually look well in the beginning we transferred every patient back to Memorial Hospital from New York Hospital on the day of operation The afternoon of operation patients look well and they are able to have visitors that might During the pight or the next day they may develop signs of progressive drowsiness or stupor and some left sided weakness as the result of an intracranial clot Usually this complication comes on within the first forty eight hours For the past few months we have not transferred the pa tients for the first two or three days after operation and we have piched up two clots in that time DOCTOR Is it sometimes true that there is this picture without clot being presenti DA RAY The patients upon whom we have re opened the wounds have all had clots and the patients listed as "dying from surgical complications" all had clots either extradural or subcorti cal ·In Patients with Cancer 53 lytic lesions to undergo spontaneous conversion to osteoblastic If such change does occur it would tend to invalidate radiological evidence of recalcification as a cnterion of response to treatment DA KENNEDY Much of the data are based on clinical and xray findings Actually pathological data are required to answer these questions Certainly an osteolytic lesion of the rate of growth is reduced might appear osteoblastic but the lesion may still be growing In other words the rate slows so that there can be osteoblastic activity about the lesion On x ray it looks more calcified This would represent an osteolytic changing to an osteoblastic lesion but it is still growing so it is really not under control On the other hand with an osteolytic lesion and a decrease of the unne calcium to a normal level a more normal bone structure or highly calcified structure may occur Biopsy will reveal bone with an occasional trapped tumor cell In contrast to the previous type where a little calcium is deposited around the tumor those tumor cells usually are quite active This is my interpretation of this phe nomenon based on metabolic changes supported by bone biopsies CHAIRVIAN PEARSOV The physiologic effects of cortisone in large doses on normal bone is to produce osteoporosis and negative calcium balance If cortisone in a patient with an abnormal bone condition who has high calcium excretion puts the patient in positive calcium balance then you cannot reconcile this with any known effects of cortisone on normal bone Therefore I think that you must interpret it as positive evidence of suppression of bone destruction You infer that if the destruction had been due to tumor that the progress of the tumor has subsided Measurement of calcium excretion is like any other test it is like the v rav They are all indirect tests and you have to use inference DR TAYLOR This is such an important point that I think we Ought to have some information on the effects of cortisone in other Metabolic diseases in which you have a high calcium excretion and high serum calcium CHAIRMAN PEARSOV It has been studied There are many can cer patients in whom cortisone has no effect at all on high calcium excretion DR LEVNEDY Having established the fact that this patient did have a regression in terms of calcification of bones the interpreta tion is that cortisone is good hypophysectomy is better DR. FORREST Following implantation of the pituitary with ·52 Hypophysectomy sone used as maintenance therapy is not responsible for the type of regression that is being obseryed after hypophy sectomy DR BERGENSTAL That brings up the whole question of whether or not cortisone can be converted to substances that have estrogenic activity DR KENNEDY You can go one step further Androgens can be converted to estrogen DR BERGENSTALL. Estrogenic activity by bio assay was found in the urine of patients after a dose of cortisone DR KENNEDY This was one of the postulations we considered working on and possibly explains the metal increase in calcium etcretion but regardless it would seem that the 50 mg after hypophysectomy is not doing any damage to the patient It does not appear to be responsible for the remissions and therefore removing the pituitary would appear to have been the factor responsible for the regressions DR TAYLOR Arent we making a mistake in relating the decrease in calcium excretion to tumor regression? Might it not be the effect of cortisone on normal bone? DR KENNEDY The 300 mg of cortisone muy produce a de calcifying effect since the negative calcium balance was main, tained Actually the serum calcium dad come down to normal ranges the answer to that question is not yet clear This study was reduplicated using prednisone in a patient of the same age a dose of 250 mg a day produced an almost identical effect DR ELIEL We can show you a metabolic study which is almost the exact duplicate of that one except that the patient was not hypophysectomized and an excellent remission was achieved with 75 mg of cortisone I still dont think that it is clear that the re mission is the result of hypophysectory I still think it might be due to the cortisone DR TAYLOR You cannot call it remission I think it is wrong to call it remission It is a metabolic change How do you know it is remission of the disease in the bone? Why isnt that an effect on the bony system instead of necessarily on the tumor? DOCTOR You might go one step further Maybe you just changed the tumor to a blastic type of lesion DR FORREST I had the impression that it was rare for osteo lytic and osteoblastic lesions to occur simultaneously or for osteo ·In Patients with Cancer 55 to suppression of ovarian function The patient in the postmeno pausal age group who has responded to estrogenic or androgenic hormone therapy with subsequent exacerbation is regarded as an other candidate for hypophy sectomy Two patients in this group have demonstrated regressions The latter consideration is based on the theory that estrogenic and androgenic homones in postmeno pausal women inhibit the pituitary function in part and this is responsible for regressions of the breast cancer Subsequent re activation of the disease in these patients may represent an escape of the pituitary from the inhibitory effect of the hormones A few patients were selected for operation who had not responded to castration In such patients no response was anticipated and the results justified this opinion Hence very few hypophysectomies have been carried out in patients previously castrated for recurrent disease who did not show a response to the castration As previous ly mentioned therefore the selechon of patients in this series for hypophysectomy makes the series not statistically significant DOCTOR Have you operated on any patients who failed to re spond to estrogen? DR KENNEDY No DR JESSIMAN In relation to what Dr Kennedy said about the response to hypophysectomy as judged by calcrum excretion studies I would like to say that many of these patients have shown a response not manifest until some four or five weeks after the operation as compared to the almost immediate responses that we frequently see with ovariectomy Dr RHOADS How many of your patients have had oophorecto my and adrenalectomy? Da Matsov Just one The other adrenalectomy was a prostate cancer patient DA RHOADS You are really not in a position to say whether not hypophysectomy has a role beyond that of adrenalectomy? DR MATSON We are not able to say DA Ray They had all been castrated? DR MATSON Yes DR RAY What were their ages? DA MATSON We have not done any patients ten years post menopausal at all DR RHOADS One more question do you feel that this procedure is any more difficult to perform than an adrenalectomy? DR MATSON Much less difficult in the experience of our hos ·54 Hypophysectomy radon cortisone is not required for the first two or three postopera tive weeks Several of our patients with skeletal metastases have shown a falling serum calcium and rising alkaline phosphatase which commenced two to three days after the implant and co incided with relief of pain These changes could not have been due to cortisone for they had not had any We do not regard these changes as evidence of regression of disease unless they are later followed by skeletal recalcification DOCTOR Dr Kennedy s cases are very carefully selected Is this true of yours Dr Ray? DR RAY I did not mention the type of case that we exclude One of these is the patient with evident intracranial metastases We have included some who have had metastases to the skull and have cranial nerve palsy but no one who has increasing hemiplegia aphasia or increased intracranial pressure We exclude those with impaired hver function due to extensive liver metastases We also exclude the patient whose pulmonary metastases are so great that the lung capacity is limited to the degree that they are unsafe for operation DR KENNEDY Dr Ray I agree with you We do not operate on anybody with bilateral effusion or with extensive liver me tastases If the patient will not surynve there is little to be gained by hypophysectomy DA RAY We were pleasantly gratified by our results in patients who had a lot of pleural fluid In many of these the fluid has not reaccumulated after operation If we can show that the lung ca pacity is adequate with the fluid drained we do not regard pleural fluid as a contraindication to operation DR KENNEDY We operate on those who have unilateral effusion but not those with bilateral effusion In our experience they will continue to be all with pulmonary disease DR JESSIMAN Dr Kennedy on what grounds did you select your patients? DR KENNEDY The patients were selected for operation by the following criteria The patient who was therapeutically castrated for recurrent disease and demonstrated an objective improvement was regarded as an ideal candidate for hypophysectomy Patients undergoing a spontaneous menopause during the time of recurrence of the disease frequently have a slowly progressive course Up to three years after the last menstrual period such a patient will respond to hypophy sectomy This result of course could be due ·In Patients with Cancer 55 to suppression of ovarian function The patient in the postmeno pausal age group who has responded to estrogenic or androgenic hormone therapy with subsequent exacerbation is regarded as an other candidate for hypophysectomy Two patients in this group have demonstrated regressions The latter consideration is based on the theory that estrogenic and androgenic hormones in postmeno pausal women inhibit the pituitary function in part and this is responsible for regressions of the breast cancer Subsequent re activation of the disease in these patients may represent an escape of the pituitary from the inhibitory effect of the hormones A few patients were selected for operation who had not responded to castration In such patients no response was anticipated and the results justified this opinion Hence very few hypophysectomies have been carried out in patrents previously castrated for recurrent disease who did not show a response to the castration As previous ly mentioned therefore the selection of patients in this series for hypophysectomy makes the series not statistically significant DOCTOR Have you operated on any patients who failed to re spond to estrogen? DA. KEVVEDY No DR JESSIMAN In relation to what Dr Kennedy said about the response to hypophysectomy as judged by calcium excretion studies I would like to say that many of these patients have shown a response not manifest until some four or five weeks after the operation as compared to the almost immediate responses that we frequently see with ovanectomy DR RHOADS How many of your patients have had oophorecto my and adrenalectomy? DR MATSOV Just one The other adrenalectomy was a prostate cancer patient DR RHOADS You are really not in a position to say whether or not hypophysectomy has a role beyond that of adrenalectomy? DR Matsov We are not able to say DR RAY They had all been castrated? DR MATSON Yes DR RAY What were their ages? DA MATSON We have not done any patients ten years post menopausal at all DR RHOADS One more question do you feel that this procedure is any more difficult to perform than an adrenalectomy? DR MATSOY Much less difficult in the experience of our hos ·56 Hypophysectomy pital where a good many adrenalectomies are done for various reasons There is one other thing I did not mention This procedure is not something for the itinerant neurosurgeon to do once or twice a year It should be done in a center by a neurosurgeon cooperat ing in a well organized project not as an occasional technical exercise DR BERGENSTAL When adrenalectomy was first considered I remember Dr Huggins statement This will be something we will never be able to do except in centers where we have a topnotch team of internists and surgeons Now as we have had increasing experience with the operation and found the ease with which it can be done many small centers with good internists good sur geons can successfully carry out this procedure I think it is again a matter of experience Four or five years have shown us what we can do the same thing I believe would happen here too DR RAY If hypophysectomy is going to be done in poorly staffed hospitals it is sure to fall into disrepute I would expect that most well trained neurosurgeons can do the operative job but a poorly trained one is sure to get into more trouble than is warranted On the other hand you can never regulate that kind of thing or insist that an operation is so technically difficult re quires such skill that it can only be done in a few hospitals DR BERGENSTAL At this phase we must try all types of cases of breast cancer because I dont think we are in any position to select cases as yet we have no idea what we are doing with hypophysectomy whether we are doing more than with oophorec tomy or adrenalectomy Until we can get a large number of cases of various types and groups of carcinoma we are not going to know what potential we have here DR KENNEDY From Dr Rays data and our own we do know that the majority of patients who respond to oophorectomy are going to improve with hypophysectomy I am convinced of this Thus is a therapy I can offer the patient In other types of patients we dont know There hypophysectomy is a research procedure which should be done but it should be selective and carefully considered DR MATSON Is that correct? Is it true Dr Pearson ercept for the patient who has gotten a good response to oophorectomy you at the moment have no preoperative cnteria as to whether or not a patient may get a good result from hypophysectory?

·In Patients with Cancer 57 CHAIRMAN PEARSON I think that is true There are a few other things besides response to castration which make us feel that the patient has a good chance The patient who responds favorably to testosterone we think is likely to get a good response to hypophy sectomy We cannot demonstrate that statistically at the moment with a larger number perhaps we can Exacerbation of the disease by estrogen is felt to be a good criterion Again statistic wise we need more information because we dont believe that a test of estrogen in all patients is a wise thing it may lead to serious trouble DR KENNEDY I would like to ask a question about estrogen stimulation of the tumor There is a case that Dr Ira T Nathanson and I studied back in 1948 This 63 year-old patient was given stilbestrol immediately had exacerbation of pain developed hy percalcemia and was very ill According to Dr Kendall Emerson this represents stimulation of breast cancer DR JESSIMAN What dose? DR KENNEDY 15 mg a day in the face of persistence of therapy this patient had regression of pulmonary metastases re gression of osseous metastases and the subsequent calcium balance study demonstrated a positive balance The hypercalcemia dis appeared The testing of tumors to establish estrogen dependence is misleading DR. JESSIMAN Dont you think that such a result will be seen mn 5 per cent of the cases only? DA TAYLOR No DA KENNEDY I think this is too specific to be regarded as a coincidence DR JESSINLAN Is there another patient like this? DR KENNEDY Not that I have ever studied DR TAYLOR I have not done calciumn balance studies on such a patient but I have seen cases in which patients have been given estrogen and the soft tissue lesions have progressed and the patient has had an increase in bone pain Then if estrogens are continued after about two weeks definite regression of disease may occur ! dont think this is uncommon I dont think that you can discard estrogen therapy on the basis of a short term observation CHAIRMAN PEARSON I agree that the only definite criterion we have for the selection of patients at the moment is the response to castration The other things are suspicions DR TAYLOR Unfortunately response to castration is not imme- ·58 Hypophysectomy diate you have to wait about three months before you can make a decision on this basis DR BERGENSTAL What about patients who are already in spontaneous menopause? There our criteria for castration are gone DR JESSIMAN You can use the stimulation test perfectly well in the postmenopausal woman to find out whether or not she has a "hormone stimulated tumor We prefer this term to “dependent." DR TAYLOR How long do you continue this test? DR JESSIMAN For about three days DR KENNEDY Then you would have discarded the patient I described who did not improve under estrogen therapy for some time DR JESSIMIAN No I should have said that this woman had hormone stimulated tumor a tumor that could be stuulated by estrogen and that therefore she would then possibly respond to hypophysectomy DR TAYLOR Let us put it this way the tumor is stimulated by estrogen the estrogens suppress the pituitary regression occurs DR JESSIMAN That is what happened in this case but all we are trying to do is pick out the hormone stimulated tumor as op posed to the entirely autonomous tumor which goes on wrespec tive of ablation therapy Dr Kennedy has shown us a very nice test Your patient had a hormone stimulated tumor and probably would have done well with hypophysectomy You did a hypophy sectomy on her with estrogens Dr ELIEL On the other hand estrogen is an extraordinarily dangerous thing to give in estrogen dependent tumors and in the presence of osteolytic metastases might lead to hypercalciuria and hypercalcemia DR TAYLOR It is not such a dangerous thing to give Fifty per cent of women well past the menopause will show objective regression with estrogens It is good therapy DA ELIEL In 50 per cent it will stimulate the tumor I dont thunk we should persist DA LIPSETT I dont think it is possible in discussing estrogen therapy to group premenopausal and postmenopausal women to gether As you demonstrated Dr Kennedy some of the women respond to estrogen and respond to hypophysectomy in the pre menopausal women I dont think anyone has ever seen an estrogen response I have been trying to find such a case ·In Patients with Cancer 59 DR KENNEDY We have a senes of premenopausal women who have responded to estrogen It required 1 000 mg of stilbestrol With that dose regressions may occur Dr Nathanson and I had fourteen cases and he referred to this in several articles but the series as yet is not reported We are still adding to it DR RAY You got suppression of pituitary function? DR KENNEDY So I assume I dont know Giving that dose produces amenorrhea Whatever is suppressed the patients con dition improves Eye lesions pulmonary lesions and cutaneous lesions have disappeared During the time the dose is being ad ministered if there is trouble getting up to 1000 mg acceleration of the disease may occur We have two or three patients in whom the disease was accelerated DR MATSON Should not every premenopausal woman with metastatic cancer be oophorectomized or do you think you should go directly to hypophysectomy? CHAIRMAN PEARSON I would think the best way to answer that would be to find out whether or not the premenopausal patient who fails to respond to oophorectomy has a response to hypophy sectomy If in a series of twenty or twenty five of these patients all failed to respond to hypophysectomy then I think you can say do oophorectomy first If you find 20 per cent or so of those who failed castration will respond to hypophysectomy then I would think you can go directly to hypophysectomy We have done primary hypophysectomy in six patients that Dr Ray presented Three of these had remissions and it appears that ovarian function is markedly suppressed The vaginal smears and endometrium be came atrophic There does not seem to be any measurable function of the ovary in the absence of gonadotrophın I think this is quite an important point and in a group of investigators like this we ought to be able to accumulate twenty five such patients It is possible that some patients will benefit from hypophysectomy who do not benefit from oophorectomy DA RHOADS Have you seen responses to hypophysectomy in women who are more than ten years postmenopausal? CHAIRMAN PEARSOV Yes even twenty five years postmeno pausal DR RHOADS In your paper Dr Ray you did not distinguish between responses to hypophysectomy in women with a spontane ous menopause and those with induced menopause ·ER 58 Hypophysectomy diate you have to wait about three months before you can make a decision on this basis DR BERCENSTAL What about patients who are already in spontaneous menopause? There our criteria for castration are gone DR JESSLIAN You can use the stimulation test perfectly well in the postmenopausal woman to find out whether or not she has a "hormone stimulated” tumor We prefer this term to dependent DR TAYLOR How long do you continue this test? DR JESSIMAN For about three days DR KENNEDY Then you would have discarded the patient I described who did not improve under estrogen therapy for some time DR JESSIMAN No I should have said that this woman had a hormone stimulated tumor a tumor that could be stimulated by estrogen and that therefore she would then possibly respond to hypophysectomy DR TAYLOR Let us put it this way the tumor is stimulated by estrogen the estrogens suppress the pituitary regression occurs DR JESSICAN That is what happened in this case but all we are trying to do is pick out the hormone stimulated tumor as op posed to the entirely autonomous tumor which goes on irrespec tive of ablation therapy Dr Kennedy has shown us a very nice test your patient had a hormone stimulated tumor and probably would have done well with hypophysectomy You did a hypophy sectomy on her with estrogens DR ELIEL On the other hand estrogen is an extraordinarily dangerous thing to give in estrogen dependent tumors and in the presence of osteolytic metastases might lead to hypercalciuria and hypercalcemia Dr TAYLOR It is not such a dangerous thing to give Fifty per cent of women well past the menopause will show objective regression with estrogens It is good therapy DR ELIEL In 50 per cent it will stunulate the tumor I dont think we should persist DR LIPSETT I dont think it is possible in discussing estrogen therapy to group premenopausal and postmenopausal women to gether As you demonstrated Dr Kennedy some of the women respond to estrogen and respond to hypophysectomy In the pre menopausal women I dont think anyone has ever seen an estrogen response I have been trying to find such a case ·In Patients with Cancer 61 means anything I think you need a much larger senes for the per centage to mean anything DR RAY Dr Taylor do you know what kind of surgical pro cedure was used in your group of patients? I know Dr VerBrug ghen was doing one type of procedure one day when I was out there in which he took the tuberculum sella off DR TAYLOR That is the patient who was blinded I remember when you were out there Now they are both apparently doing your procedure DR RAY They gave up removing the tuberculum sella then as a routine part of the operation? DR TAYLOR Ver Brugghen has been chiselling the anterior clinoids DR Ray That is something we have not done except in three patients where we were unable to get into the sella safely or ade quately Otherwise we have assiduously avoided taking off any bone because I think it adds materially to the possibility of com plications DR TAYLOR We have encountered complications of the two deaths one occurred in Dr VerBrugghens service and one oc curred on the service of Dr Gustafson I cannot tell you whether or not he removed any of the anterior Clinoid DR RAY One cannot chisel or rongeur bone without the pos sibility of transmitting trauma to the optic nerves or to blood vessels in the region After all the carotid artery is adjacent to the anterior clinoids I am sure that it is a more tune consuming pro cedure and I think it carries with it more risk of trauma to impor tant adjacent structures DR Matsov That is absolutely right I have done it two or three times in these patients and once or twice in other types of cases It lengthens the procedure a great deal The main problem we had was venous bleedung It is easy to crack the bone off and stay out of the sphenoid sinus packing the mucosa ahead of you DR RAY A lot of manipulation is required DR MATSON There is a lot of communication between the cavernous sinuses anteriorly It is easy to get into this when the tuberculum sella is removed DA KENNEDY It certamly takes only a few minutes to chip off the antenor clinoids ·60 Hypophysectomy DR RAY We broke that down but the slide looked too compli cated to present There is no difference in the response of the two groups DR Matsov I wonder if that might not be because some of these elderly people who dont menstruate are still producing estrogen and have cortical stromal hyperplasia DR KENNEDY How many regressions have you seen in women who are ten years or more past the menopause? DR RAY Would you say women over 60 would you choose Some age like that? DR KENNEDY That is the age group we are interested in DR LIPSETT There were eighteen patients in the spontaneous postmenopausal group and a number were over 60 one patient was 72 years old many were ten years postmenopausal We had ten responses in this group of eighteen patients DR MATSOV Am I not correct concerning the Smiths bio assays of urinary estrogens 10 that they have found a significant amount of urinary estrogens in some patients in their seventies ten fifteen twenty years past the menopause and that 80 per cent of those patients have shown cortical hyperplasia? DR BERGENSTAL Dont forget the adrenals produce estrogens in an unknown amount and it varies a great deal I am sure from individual to individual CHAIRMAN PEARSOV The incidence of remissions from castra tion in postmenopausal patients is about 10 per cent, so why put a patient through a procedure like this when you only have one chance in ten to help them DR JESST\EAN In your series of about twenty patients you find that castration is helpful in 10 per cent The only reason I bring up this point is that in our series which is much smaller we have found a relatively higher percentage than 10 per cent I would say at the moment about 25 per cent He have done many fewer pa tients than you have DR TAYLOR Twenty five per cent show regression after ooph Orectomy? DR JESSIMIAN In patients 65 years or older CHAIRMAN PEARSOV Of fifteen patients who had a spontaneous menopause thirteen obtained remissions from combined oopho rectomy adrenalectomy I dont think the percentage in this series ·In Patients with Cancer 63 active iodine uptake did not decrease at all It remained about 50 per cent as far as I can remember The PBI was six pre and post operatively yet the estrogens had dropped DR MATSON After nine months she is still one of the best examples of remission DR RAY She had been castrated? DR JESSIMIAN Yes DR BAKER That has been of some concern to us You have found the change in estrogens that we cannot find It may be that the zinc method of assay may be doing something to the active compound that we do not pick up in our hydrolysate DR JESSIVAN That is highly possible DR BAKER I dont think Engle feels that way but I do The patient changes yet we cannot find any change by our method of estrogen assay DOCTOR Do you do fluorometry? DR BAKER The method of estrogen analysis is by fluorogenic phenols and then analysis by countercurrent distribution DR JESSIMAN How long do you hydrolyze? DR BAKER We hydrolyze for twenty minutes in the autoclave at fifteen pounds pressure DR JESSIAN That is the same as we do We hydrolyze for fifteen minutes DR BAKER We don t use zinc DR JESSIMAN We do so only for a certain fraction Routine hydrolysis is for fifteen minutes with acıd no zinc In this particu lar patient I was talking about we got a change in the TO frac tion as well as the Tin DR BAKER Vaginal smears are also a complete loss as far as we have been able to see We have not been able to find any change in vaginal smears before and after castration before and after adrenalectomy and now before and after hypophysectomy They dont seem to vary much CHAIMAN PEARSON It is rather amazing that you cant find any change after castration in the vaginal smear Dr Treves would you like to comment about Dr Finkbeiner s studies? DR TREVES As far as the castration group is concerned Dr Funkbeiner has been able to give us very definite information from examination of the vaginal smear He has been able to predict when the process is reactivated due to the secretion of estrogen affecting the tumor process in the body Changes in the smear ·1 62 Hypophysectomy DR RAY That is a little bit different than the procedure of Dr Ver Brugghen DR MATSON We had to do it as Dr Ray said twice when the chiasm was prefixed and there was no room It certainly adds to the difficulty of the operation DR RAY I think that no tivo neurosurgeons are doing this exactly the same It would be pointless to insist that an operation had to be standardized but there are good and bad points to some of these procedures DR BERGENSTAL Have you done bio assays for estrogen in hypophysectomized patients? DR BALER No DR RHOADS Have you isolated estrogens in the urine after hypophysectomy? DR BAKER The estrogens were not isolated as crystalline ma terial but countercurrent distribution of the urines in the patients whom we believed to be totally hypophysectomized showed no change in any of the estrogen fractions One of the patients who had a successful hypophysectomy died suddenly six months after operation This patient had a full blown clinical myxedema and was not on thyroid medication No cause for death was found at autopsy Serum electrolytes prior to death were completely normal and myxedemna was thought to be a possible cause of her sudden death DR BERGENSTAL You find estrone after oophorectomy and adrenalectomy? DR BAKER Yes we find no difference in countercurrent dis tribution of estrogen before or after castration or after adrenal ectomy DA BERGENSTAL You were talking about the possibility of conversion of cortisone to estrogen Do you think that is possible? DR BAKER We have never been able to find any evidence that conversion of cortisone to estrogen exists either by administration of labeled cortisone to patients or by incubation of human tissue slices with carbon labeled cortisone DA JESSIMAN You asked about the estrogens We use the Smith bio assay with rats I have studied only one of our hy pophysectomized patients the estrogens dropped from a high premenopausal level to unrecordable levels It is difficult to know how to judge these tests for completeness of hypophy sectomy be cause this patient has had one of our best responses yet the radio ·In Patients with Cancer 65 DR JESSIMAX I have not done any work on that DA WEST We have analyzed urines from two hypophysecto mized adrenalectomized castrated women maintained on 50 mg of cortisone daily by mouth and failed to isolate any estrogens DA RHOADS Only 6 per cent of the administered estrone is recoverable as estrogenic material in the urine There is a big chance of other metabolites of estrone being present They may have an effect on breast cancer even though you cannot measure them CHAIRMAN PEARSOV I think the point that Dr Rhoads brought out may not be a familiar one to everyone This is work that Dr Thomas F Gallagher of our staff did with C# labeled estrone After administration of the matenal, 60 to 70 per cent of the radio activity was found in the urine but only about 10 per cent of the material could be identified as estradiol estrone or estriol In the countercurrent distribution there are other compounds present which have not been identified The bio assay technique would certainly be interesting to compare with chemical measurements Some estrogen metabolites may not have estrogenic activity and thus would not be detected by bio assay DR RHOADS Yet they could be active in breast cancer DR WEST Are you concerned about your urnary estrogen assays using the zinc method for hydrolyzing the urines? This method of hydrolysis appears to consert unknown inactive sub stances which may or may not be true metabolites of estrogens into biologically active estrogens of unknown chemical structure Wouldnt it be better to measure the naturally occurring urinary estrogens? DA JESSIMAN I really cannot argue as Mrs Smith would argue with you I understand that the substance the Smiths are measuring with the zinc hydrolysis is part of the estriol fraction The zinc hydrolysis they believe converts the metabolites or precursors or whatever you want to call them into estriol. This is what is being measured after the three hour zinc hydrolysis DR WEST Some investigators would prefer to identify what is put out by the body DR BAKER Dr Bergenstal you previously reported some changes in estrogen excretion which were measured by bio-assay Then you advanced the opinion that perhaps these data were pot accurate DA BERGENSTAL Those studies I am sure have to be done all ·84 Hypophysectomy have also been noted following adrenalectomy There have been some studies on hypophysectomy which while they are not con stant are suggestive DR LIPSETT Of the premenopausal women studied by Dr Finkbeiner three were in the progestational phase of the men strual cycle at hypophysectomy They bled two weeks after sur gery and subsequently the vaginal smears became atrophic as with patients who had oophorectomy and adrenalectomy On this basis it would seem that the estrogen suppression is pretty com plete CHAIRMAN PEARSON Dr West will comment on this a little later He has been measuring estrogens by chemical procedures DR WEST We are currently measuring urinary estrogens by means of photofluorometry To get accurate results by this method it is first necessary to separate the urinary estrogens from other fluorogenic phenolic substances which are normally present in urine This separation is not easy but can be accomplished by a combination of countercurrent distribution and paper chromatog raphy DR BERGENSTAL This is the crux of our whole problema prob ably We attempt to get rid of estrogens and we find ourselves with no good methods for measuring them or telling whether or not we are affecting them DR JESSIMAN I wonder if we are not trying to be too great purists in attempting to differentiate the sort of estrogens we are measuring I am not trying to defend bio assay All I am saying is that the material I inject into my rats produces changes in the estrus cycle and these changes can be measured pre and post oophorectomy and the levels can be shown to have changed I cannot be precise as to the exact nature of the substances I am measuring but I can look at the estrogen level I have meas ured in a post castration patient and say "This womans estrogen levels are rising and I predict that in the event of reactivation of her disease removal of her adrenals may produce a remission of her disease Therefore I remove the adrenals What I have meas ured I believe to be estrogens Following adrenalectomy the estro gen levels as measured by the bio assay method of Smith and Smith 10 have fallen DR TAYLOR You see no evidence that cortisone is converted to estrogen?

·In Patients with Cancer 65 DR JESSDIAN I have not done any work on that DR WEST We have analyzed urines from two hypophysecto mized adrenalectomized castrated women maintained on 50 mg of cortisone daily by mouth and failed to isolate any estrogens DA RHOADS Only 6 per cent of the administered estrone is recoverable as estrogenic material in the urine There is a big chance of other metabolites of estrone being present They may have an effect on breast cancer even though you cannot measure them CHAIRMAN PEARSON I think the point that Dr Rhoads brought out may not be a familiar one to everyone This is work that Dr Thomas F Gallagher of our staff did with C14 labeled estrone After administration of the material 60 to 70 per cent of the radio activity was found in the urine but only about 10 per cent of the material could be identified as estradiol estrone or estriol In the countercurrent distribution there are other compounds present which have not been identified The bio assay technique would certamly be interesting to compare with chemical measurements Some estrogen metabolites may not have estrogenic activity and thus would not be detected by bio assay Dr RHOADS Yet they could be active in breast cancer DR WEST Are you concerned about your urinary estrogen assays using the zinc method for hydrolyzing the urines? This method of hydrolysis appears to convert unknown inactive sub stances which may or may not be true metabolites of estrogens into biologically active estrogens of unknown chemical structure Wouldnt it be better to measure the naturally occurring urinary estrogens? DR JESSIMLAN I really cannot argue as Mrs Smith would argue with you I understand that the substance the Smiths are measuring with the zinc hydrolysis is part of the estriol fraction The zinc hydrolysis they believe converts the metabolites or precursors or whatever you want to call them into estriol This is what is being measured after the three hour zinc hydrolysis DR West Some investigators would prefer to identify what is put out by the body DR BAER Dr Bergenstal you previously reported some changes in estrogen excretion which were measured by bio assay Then you advanced the opinion that perhaps these data were not DR BERGENSTAL Those studies I am sure have to be done all accurate ·66 Hypophysectomy over again They showed a change after castration then a futher drop after adrenalectomy to essentially zero However there are still some patients after adrenalectomy and castration who did have still measurable estrogens in the urine DR JESSIMAN I would like to second that With my method I found that patients excreted estrogens after adrenalectomy and oophorectomy DR RHOADS What method are you using? DA BERGENSTAL Uterine weight increase DA RHOADS So in some instances there is unequivocal evidence of estrogenic activity after oophorectomy and adrenalectomy? DR BERGENSTAL That is right DR JESSIMIAN One could assume this came from adrenal rests DR ELIEL Ovarian rests have been described DR TREVES What about the hypophyseal rests? In this hos pital 33 accessory adrenal glands were found in 100 consecutive autopsies I think all patients may have accessory glands They may not be noticed at the time of operation This is one of the things that confuses the issue DR LIPSETT Didnt you mention a paper this morning on reactivation of pituitary remnants? Was there a high incidence of nasal pituitaries? DR LUFT There are no actual figures in Dr Tonnis paper but his group observed histologically reactivation of the nasal pitui tary CHAIRMAN PEARSON We might mention briefly some studies done by Dr Robert Mellors and Dr John C Hubbard of our pathology staff on the nasopharyngeal pituitary They have re moved the nasopharyngeal pituitary at autopsy is rather small about 1 mm in diameter and about 6 or 8 min long It seems to be a small cylinder They have been particularly interested in finding this in patients who have survived hypophysectomy for some period to see if they could find any evidence of hyperplasia or mitotic activity To the best of my knowledge to date they have not found any evidence that this gland is increased in size or has become hyperplastic However there are cells which ap pear to be acidophils basophils and chromophobes and they look entirely like anterior pitutary cells It is also possible apparently to remove the nasopharyngeal piturtary in patients Dr David Leisten has attempted this in one patient but I believe he was ·In Patients with Cancer 67 unsuccessful in this patient Dr Leisten has removed this gland in children at the time of tonsillectomy and has become quite proficient at finding it We are hopeful that we can get more in formation about this If this gland is of importance it would seem possible to remove it surgically at the time of hypophy sectomy Occasionally anterior pituitary cells are inside the sphenoid sinus Thus to remove all such tissue might still be rather difficult Less is known about the incidence of pitutary tissue in the sphe noid sinus but it is present in the nasopharynx in about 90 per cent of patients ·II SURGICAL HYPOPHYSECTOMY IN DIABETIC PATIENTS DR LUFT IT. T is well known that the frequency of vascular compli cations in juvenile diabetes mellitus has increased This is in part due to the increased life expectancy in these diabetics owing to the introduction of insulin in the treat ment We have performed hypophysectomy in an attempt to arrest the progression of such complications Up to June 1955 twenty patients had been subjected to the procedure During the fall of 1955 another two patients were operated on I shall first describe the initial group of twenty cases They were ten males and ten females aged between twen ty and thirty three years At the time of operation the duration of diabetes varied between thirteen and twenty two years and vascular complications had been diagnosed one to seven years earlier Diabetic retinopathy was pres ent in all cases Albuminuria was found in all although in four of them only in traces Doubly refractive lipoid ele ments were present in the urine of thirteen out of sixteen patients before and/or after hypophysectomy The sys tolic blood pressure was between 140 and 160 mm Hg in eleven cases and 160 mm or higher in five cases A di astolic pressure between 90 and 99 mm Hg was re corded in ten cases and 100 mm or more in six cases Cal cification of the peripheral vessels was observed on x ray examination in eight out of eighteen cases 68 ·In Diabetic Patients 69 Fourteen patients were alive after the first postoperative year of these two died fifteen and nineteen months after operation one during a hypertensive crisis and one from renal insufficiency In both there were advanced vascular complications before the operation and both had unfortu nately received desoxycorticosterone acetate (DCA) for many months during the postoperative period Clinical Results The therapeutic results in the twelve surviving patients up to July 1955 were as follows Circulation There was a fall in the systolic blood pres sure and a tendency for the diastolic pressure to decrease The heart size decreased in most cases In those cases in which calcification of the peripheral vessels was found before operation such calcification was still present at subsequent follow up examinations No further calcifica tion appeared In all cases except one the capillary fra gility was normal after the operation Renal Function A definite decrease in the albuminuria was observed in nearly all cases As to the occurrence of Lpoid crystals these were absent in four cases after the operation The effective renal plasma flow as measured by p amino hippurate remained practically unchanged after the operation In contrast the glomerular filtration rate markedly decreased This decrease is most probably due to the ablation of the hypophysis and cannot be re garded as a sign of progression of the renal changes Anal ogous decreases in the glomerular filtration rate were observed by us after hypophysectomy in patients suffer ing from breast cancer without demonstrable renal dis ease Eyes The visual acuity remained on the whole un changed after hypophysectomy As to the patients sub- ·70 Hypophysectomy jective impression of their visual capacity an improve ment was reported by seven no change by four, and wor seding by one These changes have been roughly assessed by the patients reading ability In ten cases the eyegrounds were followed regularly and permanent records obtained by color photography In one case a marked progression of the diabetic retinopathy was observed after a short period of improvement the progression started at a time when the patient had an exacerbation of rheuma toid arthritis In the remaining nine cases, no definite signs of progression were observed Decrease in the for mation of new vessels was observed in five cases In one case, before operation there was very advanced retinopa thy in the right fundus with hemorrhage new vessel for mation and proliferation One year later the newly formed vessels had disappeared and exudates and pro liferations were markedly diminished This improvement has been maintained to date twenty four months after the operation Sınılar improvement was also observed in the other eye progression of the We concluded from these data that hypophysectomy in a group of diabetics with advanced vascular disease in duced a lowering of the blood pressure that there were no signs of progression of the diabetic renal disease after the operation and that except for occasional retinal hem orrhages, no clear symptoms or signs of diabetic retinopathy were evident Eight months have passed since we made this review In the beginning of the fall of 1955 we operated on an other two patients with diabetes mellitus with very ad vanced vascular damage We then decided to wait for at least one year before operating on more patients as we considered the series large enough to permit an evaluation of the prognosis after hypophysectomy ·In Diabetic Patients 71 The further experience gained during the last eight months has been both positive and negative I shall sum marize it As far as the circulation is concerned nothing new can be added the results reported have not changed As to renal function, we can consider the results prom ising No deterioration has occurred and none of the sur viving patients has shown progression of renal disease One patient in particular had all the signs of progressing renal damage before the operation Now four and a half years later no further progression has taken place the sediment has become nearly normal and no lipoid crystals are seen in it the clearance values have remained stable the albuminuria is less and the blood pressure is lower In another patient who had markedly advanced renal disease with anemia and edema before operation the clınıcıl picture has changed completely and all external signs of severe renal disease are gone As to the eyes we must report unfortunately that this operation does not remove the tendency to retinal hemor rhages Even though these take place less frequently they do occur and such a hemorrhage can destroy the vision There always will be a locus minoris resistentiae ie a place of least resistance in these vessels in spite of any favorable effect of hypophysectomy ·DISCUSSION DR Ray What about the insulin requirements after hypophy sectomy? DR LUFT In our patients insulin requirements have gone down If you take away the cortisone for a couple of weeks the need for insulin drops further If you give cortisone you have to increase the dose DR FORREST How much? DR LUFT It depends on the dose of cortisone DR LIPSETT What is the most severe case you have done as far as regards uremiar DR LUFT The last patient descnbed had what may be called the nephrotic syndrome with NPV occasionally elevated DA LIPSETT Do you still feel as you indicated in one of your articles that any further elevation in NPN contraindicates sur gery? DR LUFT We do not operate on uremic or pre uremic patients DR MATSON I gather at the moment you would not recom mend operation for somebody with diabetic retinopathy who is normotensive and has normal renal function? DR LUFT If our present results are confirmed by further ex perience I would recommend the operation DR Matsov You say you concluded probably that the opera tion did not alter the course of the retinopathy? DR LUFT It does We have seen in at least five cases how the new formed vessels the real proliferative changes decrease and that they may even disappear after hypophysectomy That is an improvement On the other hand there may remain the small aneurysms and the other vascular changes from which hemor rhages may start You may see a few small aneurysms in the oph thalmoscope but there may be many more that you do not see DA MATSON Would you feel that you could define or de lineate at all the kind of a diabetic case you would recommend for hypophysectomy? DR LUFT Not yet DA BAKER After operation are they more sensitive to insulin and require less? DR LUFT Yes DR LIPSETT Have you had difficulty with insulin reactions? 72 ·In Diabetic Patients 73 DA LUFT We had one postoperative death that might have been caused by insulin hypoglycemia DR RAY I wonder if retinal aneurysms are a common finding or an unusual one? Your notion is that it is characteristic of the diabetic? DR LUFT The ophthalmologist says so That is the only thing I can say DR MATSON Did you say what had happened to the other six patrents in the first year? I gathered fourteen of the twenty pa tients survived a year Did the other six patients die operative deaths or die of diabetes or what? DA LUFT There were two immediate postoperative deaths A third patient died of cerebral anova that might have been due to hypoglycemia One patient died of a septicemia and I cannot re member the other two at the moment DR RAY What is the oldest patient? DR LUFT Thuty three DR RAY The youngest? DR LUFT Twenty DR RAY Would you have any comment about patients over 30? DR LUFT We have had no experience with any other age group we have limited our esperience to patients between twenty and about thirty years of age DR KENNEDY We have done two patients over thirty one is forty two years old and one is forty six The first man had an im paument of PSP excretion and a BUN of 30 mg per cent He was normotensive and had marked vascular changes After the operation the insulin was discontinued There was no progression of the retinopathy in the past year and four months The second patient was operated on about four months ago he was a severe diabetic requiring 60 to 80 units of insulin daily There was a reduction of insulin requirements within four months He has not had a retinal hemorrhage in these four months and up to that time he was having repeated hemorrhages We have selected our cases these two were chosen because they had very marked vascu lar disease but as yet were not blind Thus we had some practical reason for doing the hypophysectomy DR MATSON We operated on one diabetic six months ago a man of forty two who was blind in the left eye and had only the lower field of vision remainmg in his nght eye He has had no ·74 Hypophysectomy hemorrhages since the operation The vision is perhaps the same as it was preoperatively His insulin requrements have dropped from about 40 units a day preoperatively to 6 to 8 units the amount depends upon how much cortisone he is given He is doing well otherwise and is normotensive more of the time than he was before DR KENNEDY I would like to add one point to my previous remarks Our first patient was not really hypophysectomized When the diaphragm sella was cut bleeding was encountered A needle was placed in the pituitary fossa in an attempt to aspirate the pituitary This failed The patient went into adrenal and thyroid insufficiency between thirty and sixty days after the procedure About that time his insuln requirement decreased and the blood sugar decreased Pituitary insufficiency was apparently induced by the trauma DR MATSON I wonder if Dr Luft would comment on Dr Olivecrona s operative procedure We had a difficult time with our diabetic patient It is quite a different operative procedure from hypophysectomy in a cancer patient in the diabetic the vessels of the brain are about 90 years old Bleeding is much more profuse The arachnoid is thickened and gray The patient whom we hypophy sectomized had numerous seizures from the seventh to the fourteenth day which were very difficult to control as was the water metabolism All of a sudden he straightened out I was interested in going back to see that that same course of events apparently had happened in Dr Olvecrona s cases DR LUFT We have seen seizures in most of our diabetic pa tients except for the first one we operated on all the other pa trents have had epileptic seizures starting about five to eight days after the operation In most cases the seizures stopped occurring within one week DR MATSON You felt there was cerebral edema? DA LUFT Dr Olivecrona thanks so DR MATSON We reoperated on our patient and found nothing Then we read in your paper not to go back and look because you would not find anything DR LUFT We reoperated on the first patient and he died a little while later Even in cases in which the x rays showed the peripheral vessels to be normal we observed during operation that the superficial vessels on the brain surface were brittle DA MATSON I am sure that this should be a factor in whether ·In Diabetic Patients 75 or not you are going to consider this operation as a therapeutic procedure in diabetics DR KENNEDY Nobody has suggested that it is therapeutic in diabetes It will take five years to find out whether or not it is helpful to the patient DR RAY What is the life expectancy in juvenile diabetes? Isnt there a definite figure on it? DR KENNEDY It keeps getting longer as the years go on be cause of all the ancillary things such as the antibiotics that are ardıng the patients There are no reliable figures DR MATSOV After hypophysectomy did your patients have an increased incidence of incidental infections respiratory or other or more trouble with their feet? DR LUFT No DR KENNEDY The patient we described previously—the one in whom we failed to take the pituitary out—had had a two-year history of repeated furunculosis He has not had an episode for over a year after hypophysectomy Certainly he has had less in fection and complications However this might represent only close supervision of a diabetic patient DR BAKER Can you increase the glomerular filtration rate after hypophysectomy? Is this an effect of inadequate cortisone replacement? DR LUFT Yes In this connection I would like to report in more detail on one of our cases Before operation the patient had a very low glomerular filtration rate with anemia albuminuna low protein levels in the blood hypertension and now and then an elevated NPN Two years after the operation she has no nephrotic syndrome less albuminuria the protein level in the blood is nor mal and she has normal blood pressure Her filtration rate is now nineteen Despite this she is doing fine DR RAY Would you consider operating on a child? DR LUFT I do not think so at the moment DA ELIEL How do you explain the low cortisone require ments? DR LUFT They feel better of you give them more We are giving them just enough to keep them in good condition DR ELIEL Do they have any tendency to go into hypotensive collapse? The breast cancer patients do so on occasion with the Very low doses of cortisone DR LUFT I have not observed this ·76 Hypophysectomy DR MATSOv With regard to cortisone we had one interesting patient that perhaps should be mentioned She was not diabetic or at least she did not know she was a diabetic although perhaps she might have been a mild one After being on prednisone for quite a long period of time for treatment of her breast cancer she developed diabetes and required 20 to 30 units of insulin Since hypophysectomy she has not needed insulin she is seven months postoperative CHAIRMAN PEARSON Dr Laurance Kinselli2 suggested that the decreased amount of cortisone replacement necessary in hypophy sectomized diabetics may be due to unpairment of renal function They perhaps do not excrete cortisone quite as rapidly I was quite surprised when he indicated that diabetics could be main tained quite well on 15 mg a day

·III
PHYSIOLOGICAL EFFECTS OF
HYPOPHYSECTOMY
IN
DR MORTIMER B LIPSETT
N our studies of the hypophysectomized patient we
were concerned about the responses of the target
glands to this procedure because of the intrinsic interest
of the problem as well the need to determine the cor
pleteness of hypophysectomy Urinary gonadotrophins
as determined by the mouse uterine weight method have
generally disappeared promptly after surgery Occasion
ally we have noted persistence of low titers of gonado
trophins for several weeks after surgery in patients who
subsequently proved to have had complete hypophysec
tomy
Estrogen Excretion
The vaginal smears have become completely atrophic
two weeks following hypophysectomy These smears are
quite different from those seen in the average postmeno
pausal woman and indicate almost complete disappear
ance of estrogen effect In the six premenopausal women
who were hypophysectomized cessation of menses was
prompt In only one patient was there a suggestion of the
menopausal syndrome (Subsequently we have observed
two patients who had typical hot flushes following hy
pophysectomy)
Thyroid Function
Our studies of thyroid function have been reported
they confirm the data presented by Dr Luft The serum

·78 Hypophysectomy protein bound iodine and the 48 hour thyroid I""? uptake reach hypothyroid levels within two weeks The signs and symptoms of hypothyroidism do not appear until at least two months after surgery Occasionally, clinical hy pothyroidism was not evident one year after hypophysec tomy although chemical hypothyroidism was present throughout this time The incidence of obesity as the first sign of hypothy roidism has been most impressive in these patients Fol lowing this, in order of frequency are dryness of the skin thinning of the hair and lethargy Sodium Metabolism Although the control of sodium metabolism by the pa tient with panhypopituitarism has been discussed in the past no definite data were available We examined this problem in eight hypophysectomized patients by studying their response to salt restriction In all instances these patients were able to reduce the urine sodium as quickly to as low a level as a normal subject The maintenance cortisone that they were receiving was not responsible for the sodium conservation as adrenalectomized patients receiving comparable doses of cortisone are not able to reduce the urine sodium to these low levels The recent demonstration of the independence of aldosterone secre tion from pituitary control provides the explanation for this Dr John Luetscher Jr of Stanford University demon strated a marked rise in the excretion of sodium retaining corticoid in the urine of one of these patients subjected to salt restriction These facts combined with a careful re view of the pertinent literature suggest that the hypona tremia often reported as evidence of salt loss is actually a dilution hyponatremia due to fluid retention ·Physiological Effects 79 Hormone Withdrawal and Replacement Our group has previously noted the necessity of pro viding the adren ılectomized patient with cortisone It was therefore of considerable interest to evaluate the response of the hypophysectomized patient to either cortisone or ACTH withdrawal Twenty two patients have been studied following withdrawal of cortisone or ACTH this often being carried out in a gradual fashion All of the patients who had a complete hypophysectomy became ill, often severely so when they were not receiving corti sone This happened sometimes within 36 hours usually in three to five days and in one patient symptoms of adrenal insufficiency were not noted for two months The patients demonstrated the classical signs and symptoms of adrenal insufficiency anorexia nausea weakness asthe na fever and postural hypotension During the period of cortisone or ACTH withdrawal the 17 ketosteroids averaged 3 mg per twenty four hours The urine 17 hydrorysteroid levels reached zero in a smaller group of patients so studied As with the adrenalectomized pa tients there were no detectable changes in any of the metabolic parameters studied With respect to the maintenance of these patients after surgery we have been using 10 to 15 mg of prednisone or 375 to 50 mg of cortisone daily The compound 9 alpha fluorohydrocortisone has proved to have excessive salt retaining effects for satisfactory maintenance Dr Matson remarked earlier on the difficulties encoun tered when hypophysectomy was performed on adrenal ectomızed patients Our experience has been different as we have had essentially no difficulties with thirteen adren alectomized patients These patients are handled in the same way with one exception that provision needs to be ·80 Hypophysectomy made for salt replacement We have also had occasion to follow both adrenalectomized and hypophysectomized patients after subsequent major surgery, and this too has been without incidence As well as the high doses of cor tisone given to these patients throughout and after sur gery we felt that it was important to give trodothy ronine to the hypophysectomized patients to avoid the extra risk that hypothyroidism entails Carbohydrate Metabolism Carbohydrate metabolism after hypophysectomy has not been intensively studied The fasting blood sugar dropped 10 to 15 mg per cent during cortisone with drawal without resulting in clinical hypoglycemia Insu In tolerance tests were performed in five adrenalecto mized patients before and after hypophysectomy The dose of insulin and the cortisone maintenance were the same No significant differences in these tests were seen suggesting that growth hormone did not play a role in this setting Diabetes Insipidus Diabetes insipidus was observed in 90 per cent of our patients For our purposes diabetes insipidus has been defined as a decrease in concentrating ability of the kid ney related to a probably decreased titer of antı diuretic hormone The urine volume in these patients has varied from 2500 cc a day to six liters a day Replacement thera py is given when the polyuria and polydipsia are uncom fortable to the patient Inhalation of posterior pituitary powders three or four times a day or 3 to 5 units of pitressin tannate in oil intramuscularly every two to three days normally suffices We estimate that half of our pa tients have needed some therapy ·Physiological Effects 81 The marked variations in the degree of diabetes insipi dus and experimental work reported by Heinbecher and White' in 1947 suggested to us that the seventy of the diabetes insipidus depended in part upon the amount of the pars nervosa removed at surgery Thus it would be very worthwhile to preserve as much of the stalk as pos sible None of the patients with diabetes insipidus has been unable to concentrate bis urine after moderate dehydra tion The response vanes considerably probably due to the varying remnants of pars nervosa When cortisone was withdrawn the urine volume decreased This was due to reduced appetite leading to a reduced osmotic load The concurrent change in glomerular filtration rate may also have been significant The osmolality of the urine increased only slightly during this period of reduced urine flow Completeness of Hypophysectomy We have attempted to correlate these functional tests with autopsy data In the twenty five autopsies to date two patients were found to have grossly incomplete hy pophysectomies These two patients showed no significant change in gonadotrophic titer or thyroid function An other patient had a small remnant of anterior pituitary gland remaining and her urinary gonadotrophins remained positive five months after surgery Cunously enough her thyroid function was severely depressed and myxedema was noted A patient recently autopsied showed a frag ment of anterior pituitary estimated at 1 to 2 per cent of the gland This patient had a functionally complete hy pophysectomy with absence of gonadotrophins in the urine low protein bound iodine and adrenal crisis after withdrawal of ACTH The question is unanswered as to ·82 Hypophysectomy whether or not fragments such as I have described can still function In eleven instances the sella turcica vas decalcified and seral sections examined In nine of these cases 20 cells of anterior pituitary ongin could be found in the other two, there were rare microscopic clumps of cells Both of these patients had functionally complete by pophysectomies Because the hypophy sectomies have generally been complete, we cannot male any statement about the correlation of functional tests with the amount of remaining tissue It would appear that small fragments although anatomically present may not have measurable function ·DR. ELIEL I want to say a few words about a study that has been made on polysaccharides or glycoproteins in patients with advanced breast carcinoma who have been subjected to hypophysectomy This is the work of Dr Marvin R Shet lan at the Oklahoma City Veterans Hospital Serum Glycoprotein Tests The serum glycoproteins are simply carbohydrates in combination with alpha 2 globulin as identified by elec trophoretic mobilty The test for determining them is extremely simple One merely precipitates the protein releases the carbohydrate by acid hydrolysis and does a simple photospectrometric measurement of the super natant which determines the glycoprotein content The normal range is from 15 to 2 per cent of total serum proteins Any value in excess of 2 per cent is considered abnormal There are sufficient data to establish the fact that the levels above two are definitely abnormal Serun gly coproteins are uniformly elevated in patients with ma lignant neoplasms and are not elevated va benign neo plasms It is nou specific in the sense that one finds the level occasionally elevated in infections in tuberculosis and in theumatoid arthritis It is of interest that it does subside to normal levels when there has been adequate definitive therapy for malignant neoplasms I would like to suggest that thus test might serve as an objective though crude criterion of tumor growth rate to be used in patients who do not have elevated urine calcium excretions For example Table 13 shows data from a patient (LE) who did not get a remission following hypophysectomy I described this case in some detail this moming The 83 ·84 Hypophysectomy serum glycoproteins prior to hypophysectomy were defi nitely abnormal, above two A typical rise followed im mediately after surgery and subsided again to preopera TABLE 13 Serum Glycoproteins LE Rr PR% 7/ 5/55 7/14/55 7/21/55 7/28/55 8/16/55 8/30/55 12/ 2/55 Pre hypot Pre hypor Post hypor Post hypox Post hypox Post hypox Post hypor No remission 309 2 95 3 65 3 48 322 3 30 3 66 tive levels The level rose terminally as the patient s das ease became more extensive Table 14 shows data from two more patients One TABLE 14 Serum Glycoproteins LW Rr PR% 1/11/56 3/13/56 Pre hypox Post hypox Partial remission 2 42 2 30 AA 1/24/58 3/13/56 Pre hypox Post hypox No remission 243 246 (LW) showed partial arrest of her disease without much change in the serum glycoprotein content after post hypophysectomy The second patient (AA) who failed to get a remission sınılarly showed no change Table 15 shows data on the patient who was the first one listed on Table 12 presented previously (page 42) ·Physiological Effects 85 She obtained an excellent remission following hypophy sectomy She had an abnormally high glycoprotein level preoperatively which after hypophysectomy came down within the normal range She had repair of osteolytic TABLE 15 Serum Glycoproteins VT Rr PR% 9/ 7/55 Pre hypor 1/10/56 Post hypor 3/13/56 Post hypor Remission Repair osteolytic metastases Complete resolution pleural effusion 2 67 1 98 1 73 metastases in the spine and complete resolution of a massive left pleural effusion Whether or not this test will be as sensitive or rapid in its changes as the urine calcium is when a good remission is induced we cannot say yet Glucose Utilization The second part of the presentation deals with studies of glucose utilization in patients with advanced breast carcinoma who have been subjected to hypophysectomy This work was carried out by Dr A J Alvarez The test of glucose utilization that we have used is that devised by Amatuzio with the patient in the fasting state 25 gm of glucose are injected intravenously in 50 per cent solution over a time period and eleven blood samples are taken at intervals up to about 15 hours after infusion The results of this test I believe are reliable and fairly reproducible as long as they are done under constant conditions such as can be obtained on a metabolic ward The glucose levels measured after infusion are expressed as an increment over the fasting level and are plotted on ·86 Hypophysectomy semi log paper One then gets the rate of disappearance of glucose from the blood which is expressed as per cent disappearance per minute The normal rate of glucose utilization is thought to be in the neighborhood of around 2 per cent to 35 per cent or so Levels below 2 are gen erally found in diabetics and levels above 35 should probably be considered as abnormally high rates of glu cose utilization The glucose disappearance rate is merely a net rate determined by rates of utilization, gluconeo genesis and excretion This test is probably of greater significance when values are compared in the same indi vidual than when different subjects are compared TABLE 16 Glucose Utilezation VT842 ܫ KE Pre hypox Pre hypox. 3 wks po 9/13/55 26 9/22/55 21 10/21/55 51 20 steroid 11/10/55 Cortisone 39 75 mg/day Complete hypophysectomy remission 5 months Table 16 shows glucose utilization in a patient who obtamed complete remission following hypophysectomy Before hypophysectomy her glucose utilization rates were normal on two tests Three weeks postoperatively when steroids were withdraw to test the completeness of hy pophysectomy the glucose utilization rate went up to a high level 51 This patient was completely hypophysec tomized by physiologic cnteria and went into collapse on withdrawal of steroids With maintenance doses of corti sone she had a somewhat lower level of glucose utiliza tion which approximated normal values There is certain ·Plıysiological Effects 87 ly a suggestion from this test that one has a means of testing the integrity of the pituitary adrenal axis as far as ACTH is concerned Table 17 shows glucose utilization data from a patient (AA) who had mild diabetes preoperatively She had an elevated fasting glucose les el preoperatively and occa TABLE 17 Glucose Utilization AA9 49 Rr % 15 22 32 1/20/56 Pre hypos 1/24/56 Pre bypox Post hypox 3/ 6/56 Cortisone 50 mg/day 3/ 8/56 Cortisone 50 mg/day 3/16/56 No steroid Mild diabetes pre-op None post-op Complete hypor No remission 30 50 sionally spilled sugar in her urine She did not requre insulin Two glucose utilization levels were determined preoperatively one was definitely in the diabetic range (15 per cent per minute) and the other was low nor mal (22 per cent per minute) After hypophysectomy when she was taken off the steroids for testing complete ness of hypophysectomy (which was established by physiologic criteria) the value was very high (5 per cent per minute) showing a rapid rate of utilization while she was getting 50 mg of cortisone the values were both in the normal range (30 to 32 per cent per minute) It would appear that a high utilization rate is a concomitant of complete hypophysectomy in the absence of replace ment therapy Table 18 is from a patient (LW) who was incomplete ·88 Hypophysectomy ly hypophysectomized She continued to show FSH in her urine following hypophysectomy The [181 uptake remained around 30 to 40 per cent at twenty four hours and the serum protein bound 10dıne remained above 5 micrograms per cent The pre and post hypophysectomy utilization values are in the normal range and there was TABLE 18 Glucose Utilization LW 946 Rr % 26 23 1/ 5/56 Pre hypox 1/10/56 Pre hypot Post hypor 2/13/56 9 fluoro F06 mg 2/22/56 9 fluoro F10 mg Hydrocortisone 20 mg 2/28/56 Hydrocortisone 40 mg 3/16/56 None Incomplete hypor partial remission 29 35 20 22 no change when steroids were omitted from her regimen which would confirm the fact that the pituitary was prob ably functionally intact Of Interest, however is the fact that her rates of utilization when she was on 9 alpha Auorohydrocortisone were higher than either of the val ues when she was not receiving steroids I cannot say whether these values are significant because these are the only data that we have It does suggest the very interest ing possibility that 9 alpha fluorohydrocortisone suppress es pituitary function without actually interfering with glucose utilization or oudation This will certainly reqiure confirmation On the other hand when the patient was receiving moderate doses of hydrocortisone the utiliza tion values were essentially the same as the pre and post operative values ·89 Physiological Effects Sodium Metabolism Figure 1 illustrates one of the points that Dr Lipsett brought up that is, that patients who are maintained on pitressin sometimes develop hyponatremia This is our only patient in whom we have observed this phenomenon n AI? 500 200 Con 15ONE 00 2M 20 00 DOC 11 WYOMOCORTISONE to 24 forlik w2 1 20 FIGURE 1 but the degree of hyponatremia which was observed here was rather extreme We have the sodium balance plotted un conventional fashion Doses of pitressin are indicated by arrows it was given when the hourly urine volumes exceeded 150 cc Serum sodium levels here and steroid ·5 mg, 90 Hypophysectomy therapy are plotted There was a brief period of diabetes insipidus after hypophysectomy at this point which was followed by a period of some ten or twelve days when urine volumes were normal The sodium loss during this period may represent a diuresis following the high initial doses of steroid given I do not believe it represents so dium Ioss resulting from the hypophysectomy It is inter esting to note however that as soon as pitressin was given serum sodium concentration levels fell very rap dly At one point it was 118 mEq/L and we began ad ministration of desoxycorticosterone If our analyses had been a Little more current we would have waited but we were not aware of the rapid change in the sodium excretion levels At any rate it is of interest that when the DOCA dosage got up to 2 mg per day, and finally to there was a very definite rise in the serum sodium level to normal and that when the DOCA was stopped there was again an inmediate fall Coincident with this rise and fall there were changes in the water balance which would suggest that at least part of this rise was accomplished by elimination of water from extracellular flud I am sorry I have not plotted the water balance data but they were not available when this chart was made That these changes (1 e hyponatremia) were not due to primary adrenal cortical insufficiency I think is demonstrated clearly by the ACTH test–25 units intra venously on each of two days—which cut the urine sodium excretion in half and doubled the 17 hy droxycorticoid excretion I think the integrity of the adrenal cortex was established by this test The study does suggest that des oxy corticosterone under these conditions will promote a water diuresis and also that this effect may be mediated at the level of the renal tubule rather than through the pituitary ·DR KENNEDY Of twenty two patients hypophysectomized thirteen had an immediate postoperative polyuria lasting beyond the first day of these nine continued as a permanent diabetes insipidus A total of seventeen patients eventu ally developed permanent diabetes insipidus which ap peared five days or more postoperatively One patient re verted to normal at the end of five months this cannot be correlated with any other metabolic evdence of regen eration of the pituitary or with any exacerbation of the disease Ten patients received pitressin Two of these dis continued the pitressin because it was more bother than drinking the extra quart of water a day Endocrine Function Our studies are similar to others Most of the patients have had low ketosteroid excretion less than 5 mg A rise occurs in the postoperative period because of the high dose of cortisone The ketosteroids have been of little value as a test of adrenal function We encountered an interesting problem of thyroid func tion A woman in her forties who had been oophorecto mized one year previously had extensive bone metastases There was no clinical evidence of thyrotoxicosis and the serum protein bound iodine was normal She was given 250 mg daily of prednisone for a period of thirty days During this period the protein bound iodine increased steadily to 123 gamma per cent the BMR was +26 and the 1181 uptake 50 per cent There was no evidence of thyrotoxicosis The pulse was relatively normal At the end of the prednisone therapy there was a typical moon facies We could not explain the laboratory findings Hypophysectomy was performed which she tolerated ex tremely well In a study made three months postopera 91

·per cent There
92
Hypophysectomy
tively, the protein bound iodine was normal the BMR
decreased to -35, the iodine uptake was 8
was clinical evidence of myxedema with weight gain dry
skin constipation fatigue, and slow reflexes I do not
know whether we induced subclinical thyrotoxicosis with
prednisone therapy or if this was just a coincidental
change in the patient

·DISCUSSION DR TAYLOR Dr Lipsett you stated that your patients dem onstrated classic signs of adrenal insufficiency when cortisone was withdrawn Is it possible that this is not necessarily proof of com plete hypophysectomy but perhaps only a response to sudden cortisone withdrawal? DR LIPSETT We realize this is a valid objection In a con siderable number of patients maintained on ACTH however we have gradually stopped ACTH and seen the same phenomenon This might answer that objection CHAIRMAN PEARSON Also in the patient with intact adrenals f you withdraw cortisone the blood corticoids can drop to zero at something like forty eight hours but they return to normal levels again at seventy two hours The patient has a period of marked adrenal insufficiency but soon recovers DR TAYLOR Within thirty sıx hours? CHAIRVAN PFARSON In four or five days when cortisone is stopped abruptly in theumatoid arthritics for example who have been kept on cortisone for years the blood corticoids will show this very transient fall but they will recover spontaneously DR TAYLOR What value do you think ACTH stimulation has in assessing pituitary function? DR WEST We have been using the Bliss ACTH test for adrenal function This consists of the administration of 25 units of ACIH intravenously over a two hour period measuring blood corticoids before and after In patients who have been hypophy sectomized for a number of months we find no response to this However if we put these patients on intramuscular ACTH for three or four days we can show that the blood corticoids begin to rise and then the patient becomes responsive to the Bliss test The initial lack of response to ACTH may be due to adrenal atrophy DR FORREST These findings of Dr Wests agree with the failure of ACTH to derrease the eosinophils in Dr Lufts cases DR KENNEDY For your patients with diabetes insipidus do you use tannate or nasal insufflation? DR LIPSETT In some the posterior pituitary powder does not work Some patients get mflammation of the nasal mucous mem branes Those patients get the tannate DR LUFT Do you think the cauterization of the stalk can have anything to do with the development of diabetes insipidus? 93 ·94 Hypophysectomy DR LIPSETT The pars nervosa contains cells and neurons The more of these you remove the greater the degree of diabetes in sipidus If you coagulate the stalk at the critical level for the development of diabetes insipidus the greater the damage to the stalk and the greater the diabetes insipidus DR LUFT As far as I can remember we had to give pitressin for a long period of time to only two patients They had invasion of the hypothalamus by carcinoma DR LIPSETT Dr Luft were your patients eating well when the urine volume was low? The volume depends in large part on the osmotic load and if they are feeling better and eat more the urine flow goes up Dr LUFT They were eating all right DR Matsov What fluid levels are you willing for patients to maintain without pitressin turning over two four or six liters a day? DR LUFT They may have an increased urinary output for some months from two to four liters per day while on 25 mg of corti sone per day Da Matsov Can they sleep through the night without getting up? Dr LUFT I presume they have to get up once a night maybe twice DR TAYLOR Dont you find you have more polyuria in patients given 50 mg of cortisone daily? We find patients who have not been adrenalectomized put out more urine when given 50 to 75 mg of cortisone DR LIPSETT I think more of our patients are on 375 mg of cortisone or 15 mg of prednisone In these patients the polyuria may still be considerable I think it is a very rare patient who does not have to get up at least once during the night a number of them several times dunng the night DR TAYLOR They do on cortisone alone even when they are not adrenalectomized or hypophy sectomized DA LIPSETT Large doses have been reported to cause poly uria I dont think maintenance doses of 375 mg of cortisone or 15 mg of prednisone do DR TAYLOR I wonder if we should use 50 mg of cortisone for maintenance I feel despite the fact that patients dont feel well unless you keep them up to that level that we are giving more ·Physiological Effects 95 than a physiologic dose because most of these patients have some rounding of the facies and may show a little hypercorticism DR JESSEMAN We were very interested in this problem particu larly after reading Dr Lufts paper in which he reduced the main tenance dose of cortisone to 25 mg a day or lower We attempted to do this and noted two things First, although the dose could be reduced to 25 mg the patients did not do well They were anorexic nauseated and could not leave bed-they appeared to be on the verge of an Addisonian CTISIS Second once reduced to this level these patients had pitressin requirements that were just as great as they ever had been DR TAYLOR I was thinking more about the adrenalectomized patients You keep them on 50 mg of cortisone over a period of a year or more They get too fat, most of them It is hard to keep them down to normal weight The facies get a little rounded and I get the impression that they are not receiving physiologic doses of cortisone yet they cannot carry on their full duties as housewives and so forth without keeping the dose at that level sometunes 625 mg if they are doing a lot of work CHAIRMAN PEARSON I think the point that Dr Lipsett was making was that as far as the diabetes insipidus is concerned 25 50 or 75 mg of cortisone do not affect this unless it affects the amount of food the patient eats In other words this is all de pendent upon the osmolar load in the diet DA LUFT When we put our patients on a low osmotic load the urine volume decreased markedly May I ask Dr Lipsett if his patients need pitressin later on even after the suth postoperative month? DA LIPSETT The patients who needed potressin still need it We have not studied this systematically however that is by urine concentration or thurst tests many months after hypophysectomy When I state that diabetes insipidus varies in seventy what I mean is that the patients will show an increase in the osmotic concentration of urine after ten hours of fluid deprivation It is not as high as the normal patient but they are able to concentrate satisfactorily up to a specific gravity of 1008 to 1014 Diabetes insipidus is never as complete as in idiopathic diabetes insipidus where the specific gravity is 1005 This is rather a hard topic to study in patients with diabetes insipidus if you withdraw the cortisone you simultaneously reduce glomerular filtration rate ·98 Hypophysectomy You reduce appetite and osmotic load and the changes in urine flow which you see are easily explainable on the basis of decreased glomerular filtration rate and decreased osmote load resultuog from withdrawal of the cortisone In one study for instance of a hypophysectomized patent in whom cortisone was withdrawn the urinary flow decreased to approxmately 1500 cc per tiventy four hours so that on the basis of urine flow alone you would not say the patient had diabetes insipidus The glomerular filtration rate also fell With anoreva the solute intake also felt so that the load was less The change an urine concentration in mulliosmols per later of urine is rather in significant It rose from 150 milliosmols to about 210 With deby dration the patient could reach 230 miljosmols per liter so it could not be said that the diabetes insipidus improved in this pa tient because the cortisone was withdrawn The polyuna decreased but the diabetes insipidus and the concentrating ability of the kidney remained approximately unchanged Dr Luft in the paper that Dr Ilkos's presented from your Luboratory did he state that the thirst tests in your patients showed that the patients could not concentrate urine? DR LUFT That was during the first two months They can concentrate later on Dr LIPSFIT Some of these patients can concentrate somewhat in the first two months when maintained on maintenance corti sone if you dehvdrate them there is a reasonably marked ruse in the specific gravity of the urine DR LUFt I do not want to leave you with the impression that our patients have normal water balance our patients do not react promptly to a water load they cannot dilute in normal fashion DR FORRFS7 It comes out in the afternoon if you give it in the morning? DR LOFT Yes DR LIPSETT If they are receiving adequate amounts of corti cords meaning 50 to 625 mg of cortisone daily it is our impres sion that they react normally to a water load DA LUFT There still seems to be a difference between our groups of patients Our patients dont need pitressin on 25 mg of cortisone There is another difference our patients can be main tained satisfactorily on 25 mg of cortisone per day DA LIPSETT There may be a difference in the surgical tech nique ·Physiological Effects 97 DR LUFt I think Dr Olivecrona cuts the stalk at any level that he reaches dunng the operation These patients can produce pitressin after the operation We have tried the nicotine test on a few of them and in all of these we achieved a reduction of urine flow and an increase in specific gravity DA LIPSETT They all have remaining pars nervosa tissue It would appear from the animal studies done by Heinbecker and White that at some point in sectioning the stalk we get diabetes insipidus There is a crtical level and we should try to get as low on the stalk as possible DR MATSOY I wish you would find some way to stain the stalk differentially so that the critical area would be apparent. Four of our patients have been tested with hypertonic saline and with nicotine These patients had stalk section without clip ping or cautery and these four have shown a capacity to secrete antidiuretic hormone In three other patients who have severe dia betes insipidus and who had the stalks clipped and cut neither by nicotine nor sodium chloride have they shown evidence of antı diuretic hormone activity at all. I would guess these are two three or four months postoperative they are all still getting pitressin tannate in oil at home DR LIPSETT I want to make one more comment to get Dr Lufts reaction We have not made a systematic study of the changes in glomerular filtration rate before and after hypophysec tomy In five or six cases in which we used inulin clearances and creatınıne clearances there were only minor changes after hy pophysectomy with the patient maintained on cortisone The reason I bring this up is that we did not see anything like the mag nitude of change in glomerular filtration rate that has been seen in the dog by the group at Bellevue 14 and I know you stated that the glomerular filtration rate fell in many of your patients The cortisone dosage is however considerably lower This may be the difference DR LUFT As I mentioned before we have not studied our patients on different doses of cortisone That remains to be done DR BERGENSTAL We have found some of our patients needed pitressin and some have not They still are not able to respond to a solute load properly They do have some concentrating ability but with wide variations DR FORREST Several of our patients who have diabetes in ·98 Hypophysectomy sipidus complain that their thirst and polyuria is greatly increased if they take extra cortisone Conversely stopping the cortisone may reduce the fluid intake and urinary volume to normal levels although admittedly this is not in metabolic balance In two pa tients on balance studies the substitution of prednisone for corti sone did not affect the diabetes insipidus although one patient on 10 mg per day lost salt DR LIPSFTT We have not observed salt loss in seven patients we studied on sodium balance I have one case that I wanted to mention a patient who after two months without cortisone did not appear Addisonian She did however become hypothyroid We were rather convinced that hypophysectomy was incomplete because of this She was put on two grains of thyroid daily why is our usual substitution dosage Two weeks later there was a drop in blood pressure and nausea and vomiting We gave her 375 mg of cortisone and there was a very prompt response In this pa tient, unfortunately we did not have the ketosteroid determina tions We assumed it was an incomplete hypophy sectomy At au topsy she was proved to have a complete hypophy sectomy So I can say this probably represents an extreme variation in survival after complete hypophy sectomy without cortisone replacement Dr Elel I would like to know if you encountered difficulty ad ministering glucose to patients in cortisone withdrawal? DR ELIEL No we did not DR BAKER Dont cancer patients have a high diabetic type glucose utilization or is it normal? DR ELIEL No our patients have generally been in the normal range DR BERGENSTAL. Dr Eliel the only thing I am wondering about in the study shown on your chart is the lack of constancy of pitressin injection this variability may well account for some of the changes you are getting DR JESSIALAN That is a good point One of our patients was given frequent doses of pitressin This produced water retention and the serun sodium fell to 114 mEq/L We stopped the patres sin and the serum sodium rose to 140 mEq/L without any other therapy DR ELIEL That may possibly be true The doses were pur posely kept small because of the fact that this patient had hyper calciuria We were unwilling to induce oliguria and renal cal ·Physiological Effects 99 cinosis I think your point is valid and the study would have been more significant had pitressin been given regularly It does sug gest nevertheless that desoxycorticosterone has some effect on water excretion and this would in fact tend to confirm some of the previous work of Gaunt which demonstrated that desoxycorti costerone produces water duresis in water loaded animals DR Matsov May I ask Dr Luft a question? Did you say that several patients who had remissions of eighteen to twenty two months were found to have incomplete hypophysectomies at au topsy? DR LUFT I mentioned two patients who must have had in complete hypophysectomies according to the results of some func tion tests Despite this they showed regression of the tumor DA MATSON They had thyroid function left as determined by the protein bound odine and radioactive iodine uptake? These patients had prolonged clinical improvement? DR LUFT Yes DR MATSON What about post mortem findings? Were there any patients who had twenty month regressions who still had gland in the sella? DR LUFT I cannot comment on that yet DR JESSIMAN This morning you said that you operated on four patients who had had a previous oophorectomy and adrenal ectomy and three died who had apparently advanced disease What happened to the fourth? DR LUFT She was operated on three weeks ago and is living DR RAY I am surprised that Dr Luft has not observed any postoperative convulsions because any surgical exposure and ma nipulation of the brain may lead to convulsions We believe one or two patients had unrecognized metastases in the motor areas there is that possibilty to be considered also I dont think there 15 anything particularly remarkable about convulsions occurring occasionally after craniotomy performed for whatever purpose DR MATSON I had one patient in whom there were two visible metastases in the frontal lobe We took the more accessible one out and left the other one in She has had no seizures since operation She has been in remission now for six months DR ELIEL It might be worth mentioning two experiences we had with convulsions which were induced during the preoperative preparation The patients were given 100 mg of cortisone intra ·100 Hypophysectomy muscularly and each developed a generalized Jacksonian convul sion Both subsequently turned out to have cerebral metastases The operations were postponed because of the convulsive episodes Both of these patients also had hypercalcemia and hypercalciuria The serum magnesiums were low Rubin has descnbed a recipro cal relationship between calcium and magnesium When the cal cium is high the serum magnesium tends to be low We have won dered whether the combination of cortisone and hypercalcema with or without lowered magnesium levels may not have triggered the convulsive episodes DR TAYLOR We have a series of patients with cerebral metastases many of whom had convulsions When they were given 100 mg of prednisone per day the convulsions stopped and there was disappearance of the neurological abnormalities within twen ty four hours We now have about eighteen patients with cerebral metastases whose neurological abnormalities disappeared with prednisone therapy CHAIRMAN PEARSON One question of importance is whether or not the pituitary hormones per se have any effect on breast cancer There has been some suggestion of this and I wonder of anybody has any further data with growth hormone or prolactın DR JESSIMAN We have duplicated your classic experiment of giving growth hormone to a person with osseous metastases who had gonadectomy and hypophysectomy and was in a period of remission As soon as we gave growth hormone there was clinical evidence of exacerbation of the disease and a rise in urine calcium falling to within normal levels after a few days DR BERCEASTAL What dose? DR JESSIMAN 100 mg a day on two consecutive days intra venously CHAIRMAN PEARSON We have one other castrated adrenalecto mized and hypophysectomized patient who had a transient te mission and was given growth hormone We observed a rise in calcium excretion The growth hormone was stopped and the cal cium excretion decreased However her disease exacerbated again within a short time after this study We have given prolactin to one patient who was castrated and had obtained a two month re mission from hypophysectomy She was given 100 mg of prolactin daily for eighteen days There was a very prompt rise in calcium excretion in the urine which went up stepwise and hypercalemia ·Physiological Effects 101 developed after eighteen days When the prolactın was stopped hypercalcemia and hypercalciuria persisted and she died five weeks later of progression of disease We are unable to determine whether the prolactın did exacerbate her disease or whether the disease was about to relapse spontaneously at the time prolactın was given Da ELIEL Is your prolactın free of other pituitary hormones? CHARMIAN PEARSOY This prolactin was prepared by Dr CH La of the University of California He told us that this preparation was essentially free of other pituitary hormones DA TAYLOR Is your growth hormone contaminated with TSH? CHAIRMAN PEARSOV We have not been able to detect any thyroid stimulating hormone in the doses we used as measured by the patients iodine uptake and protein bound 2odine DR TAYLOR We gave growth hormone for twelve days to one patient who had been oophorectomized adrenalectomized and hy pophysectomized The patient had a marked exacerbation of bone pain While on the growth hormone the protein bound iodine was elevated and she had signs of thyrotoxicosis Our growth hormone appeared to be contaminated with TSH CHAIRMAN PEARSOV Dr Kennedy have you had any experi ence with growth hormone in breast cancer patients? DR KENNEDY I have only given it to two prostatic cancer patients Both had previously been orchiectomized and had re cerved estrogen Both had exacerbation of the disease and aggra vation of pain Therapy could not be continued for more than six days From being mobile walking around the wards they became bedridden The acid phosphatase increased in one from 13 to 19 Bodansky units in six days The urinary calcium excretion in creased from 150 mg to 280 mg a day It certainly appeared that these two patients were made worse and we felt this was due to the growth hormone I was trying to do the same type of study Dr Joseph C Aub and Dr Ira I Nathanson had done with testosterone In patients with prostate cancer one injection of testosterone may produce a marked exacerbation of bone pain Presumably it is due to stimula tion of tumor growth and may be associated with a rise in serum acid phosphatase DR BAKER Patients with acromegaly may have increased cal cium excretion Four of 10 acromegalics had evidence of over ·102 Hypophysectomy activity of the thyroid and urinary calcium excretion of over 200 mg per day DR TAYLOR On the basis of the thyroid? DA BAKER You could not be sure They had overactivity of the thyroid but the supposition was that it was growth hormone CHARAAN PEARSOY That raises some question as to whether or not growth hormone might induce hypercalciuria in normal sub jects We have given growth hormone to six patients with chronic lymphatic leukemia who appeared to have normal bones There was no significant change in the urinary calcium excretion The calcium balance remained essentially the same Dr Ephraim Shorr 8 reported some retention of calcium in a few patients who were given growth hormone DR JESSIMAN We have given growth hormone to three other patients with osseous metastases from carcinoma of the breast In none of these patients have we seen a rise in calcium but each one of them has shown a marked systemic reaction increase in malaise bone pain and so on In contrast to this we have made metabolic studies on patients who did not have cancer These patients when given growth hormone have not shown a systemic reaction We have felt that perhaps this is a systemic reaction of the disease to the hormone in the same way as we see a systemic reaction to the administration of stılbestrol in patients with a "hormone stuulated" tumor and osseous metastases DA BAKER There is some evidence that growth hormone may be species specific which may account for the lack of the expected metabolic effects of beef growth hormone in human subjects CHAIRMAN PEARSON It certainly has been very difficult to dem onstrate any other physiologic effects with beef pituitary growth hormone in man and the changes that have taken place have been minor nothing like you might anticipate It does raise the question concerning specificity DR LIPSETT I would like to ask the group of in any of the patients who failed to respond to hypophysectomy or responded and then relapsed was further therapy worthwhile? DA KENNEDY We have had two patients who responded to androgen and four that did not respond to estrogen DR LUFT We tried androgen in five or six cases and had no response DR LIPSETT We have not seen any objective response to andro gen or estrogen after hypophysectomy ·Physiological Effects 103 DR FORREST Are there any figures on the number of patients who responded to hypophysectomy and later relapsed due to re tuming function of the pituitary? Are there patients who fajled to respond to a complete removal? This seems to be a very crucial question CHAIRMAN PEARSOV In our series we have not been able to demonstrate a returning of pituitary function in association with relapse of the disease One patient who failed to respond to incom plete hypophysectomy also failed to improve after complete re moval of the pituitary DR BAKER I would like to hear some comments on red cell studies after hypophysectomy whether or not any patients devel oped so-called hypophysis type of anemia which investigators such as Robert Crafts19 have observed in animals If the anemia did occur to what did it respond? We have the other parameter myxedema type anemia which also may be occurring in these pa tients I just wondered if any studies had been done on red cells or on red cell survival before and after hypophysectomy DR LIPSETT We have not studied the problem systematically A number of patients maintain normal penpheral counts and nor mal reticulocyte counts many months after hypophysectomy There were two patients who at nine months and a year respectively following hypophysectomy had normal circulating red cell masses With these criteria we could miss a small change say of the order of 10 per cent or 15 per cent but nothing very gross Those pa tients are maintained only on thyroid and cortisone so there is certainly no evidence for any large effect of growth hormone on hematopoiesis in humans There may be a small effect which we might possibly pick up with finer techniques DR KENNEDY We have been interested in the matter of the relationship because of the earlier studies on the effect of andro gens in the red cell formation You are aware of the sexual differ ence in the hemoglobin and red counts in the male and female the male always rinning a little higher Administering androgen to patients with metastatic breast cancer produces elevations in hemoglobin even to the state of polycythemia This is a defimte erythropoietic stimulation It is very important that the andro genic hormone is an agent of this sort There are not many eryth Topoietic agents that are specific stimulators which can cause the red count to go higher than the normal range In our two male diabetic patients there has been a very striking decrease in the ·104 Hypophysectomy red cell mass and the hemoglobin in both cases fell to 10 to 11 grams This is in the same range as was originally reported in eunuchs by McCullagh20 about fifteen years ago The low herno globin is corrected with androgenic hormone Both these patients received testosterone One was treated too recently to evaluate but the first patient who had been hypophy sectomized nine months previously recovered when placed on testosterone His hemoglobin increased from 105 grims to almost 15 grams within a period of five months In this one patient we have corrected the anemia which would appear to be the hypophysectomy anemia that so many people have reported in animals This anemia probably is due to lack of androgenic hormone rather than to loss of a pitui tary hematopoietic factor You might expect the anemia to occur in women following hypophysectomy since the adrenal androgen is gone but we have not noticed this to any degree DR MATSON We have not been bothered with anemia in the females but the one male patient with carcinoma of the breast whom we hypophysectomized was extremely anemic He had quite a few transfusions DR KENNEDY I noticed last year that Dr Kinselli1 in his re port on diabetics pointed out that following hypophysectomy the hemoglobin in his patients rose He was also giving these patients methyltestosterone as a supplement I am sure the hemoglobin rise he observed was due to the methyltestosterone We have been interested in treating patients who have other anemias with testosterone The anemia of a patient with myelo fibrosis with the peripheral picture of chronic myeloid leukemia did not respond to myleran therapy The hemoglobin was 5 grams For ten months he has been given testosterone The hemoglobin is now 14 grams The marrow now is a hypercellular hyperplastic normoblastic marrow It is a very striking change It would appear that the red cell production has been stimulated by the testosterone DOCTOR We have tried the 17 ethyl 19 nor testosterone Given by mouth it had little effect on the cancer but the hemoglobin level rose DR KENNEDY Regardless of their effect on cancer of the breast all the vırılızıng androgens appear to have a hematopoietic effect Dr BAKER We have had a similar experience We have studied red cell mass using radioactive chromium phosphate and find the patients receiving potent androgens have polycythemia which by ·Physiological Effects 105 our test is indistinguishable from polycythema vera in one pa tient there is a significant uptake of Fee in bone marrow as meas ured by surface count suggesting that we are stimulating the hematopoietic tissue All ten patients had adequate blood volume before the red cells increased This effect has not been seen with estrogens although in some cases the hemoglobin increased in pa tients on cortisone We have observed the same increase in blood volume after cortisone therapy although we have not done the Fe studies in these patients DR KENNEDY Those patients have an androgen source DA KENNEDY This phenomenon does not occur in our experi ence when there is an iron deficiency Obviously you cannot make red cells and hemoglobin without the iron Those patients who have a serum iron below the normal range will have a normo blastic hyperplasia of the bone marrow but the peripheral red count will not increase Neither will the red cell mass until on is administered to correct the iron deficiency Then there is a quick nse in peripheral hemoglobin red cell mass and hematocrit DR BAKER Incidentally there is increased red cell survival in addition to more active hematopoiesis under androgen therapy Red cell survival is decreased before androgen administration and after administration it returns to a more normal survival pattern DR KENNEDY It is not increased above normal is it? DR BAKER No not above DR KENNEDY Some of your patients may have in part the hemolytic type anemia do they not? DR BAKER You have to call it a hemolytic type anemia DR KENNEDY Our patients had normal red cell survivals before androgen therapy and demon trated no changes in survival after androgen was administered We thought this important to define exactly where the testosterone is ererting its effect We concluded it is specific eryth stimulus DR ELIEL Perhaps we should treat polycythemia with castra tion and hypophysectomy DA BAKER I dont think anybody has tried castration on these patients or treated them with estrogens ·IV RADIATION HYPOPHYSECTOMY DR. A PM FORREST N the Unu ersity Department of Surgery in the West a simple method of mserting radon seeds into the pituitary fossa by means of a cannula introduced under radiological control through the nose and sphenoidal sinus * We sug gested that in this way it might be possible to avoid cra niotomy and yet achieve complete and safe destruction of the pituitary, with benefit to patients with advanced cancer We have now treated forty five patients by this method including thirty six cases of breast cancer, and I feel honored to present our results at this symposium All these patients have been in an advanced stage of malignant disease with multiple and widespread metasta ses in all cises disease had progressed despite surgery, radiation therapy and in most instances hormone meas ures They were subjected to pitutary implant only when the radiation therapists considered them unsustable for further conventional treatment In the first twenty sıx cases we followed our ongual technique the seeds being inserted through a single can nula introduced through the night postril Histological examination of autopsy material revealed that our ongunal dose of 10 mc u ho seeds, even when centrally placed, was quite insufficient to destroy the gland and so in sub sequent patients, the dose was increased to fifteen, and even, in some instances 20 mc As even 15 mc well placed may leave a run of viable cells we have, in the last nie 106 ·mc , can Radiation Hypophysectomy 107 teen cases modified Our technique to obtain a wider dis tnbution of radiation within the gland The director ap paratus has been modified to accommodate two cannulas which are inserted sunultaneously into the pituitary fossa one through either nostril Two seeds each of 8 thus be placed to le symmetrically in the gland one to either side of the midline Postoperative Course and Complications Apart from transient headache in a few of our patients the immediate postoperative course has been uneventful and patients can be discharged from the hospital three to four days after the implant Antibiotic cover appears to have prevented the occurrence of infection The only complication but that a formidable one has been late radiation damage to the optic chiasma In five patients defects of the visual fields have developed in one to seven months after the implant Two patients ultimately became completely blind Visual damage would appear to develop more readily if seeds become positioned high up in the pituitary fossa This was liable to occur when several seeds were inserted through a single cannula the first being pushed onwards by that succeeding it Since adopt ing our improved technique in which only one seed is in serted through each cannula no further case of visual damage has occurred Clinical Results In nine patients with malignant disease other than can cer of the breast no benefit has resulted from pituitary implant In this group there were five patients with ma lignant melanoma three with advanced cancer of the uterus and one with sarcoma of the breast All continued to deteriorate and all are now dead Of the thirty six patients with breast cancer treated by ·I RADIATION HYPOPHYSECTOMY DR APM FORREST I let her margt segrare, nelle recently developed 'N the University Department of Surgery in the West a simple method of mserting radon seeds into the pituitary fossa by means of a cannula introduced under radiological control through the nose and sphenoidal sinus * We sug gested that in this way it might be possible to atoid cra notomy and yet acheve complete and safe destruction of the pituitary, with benefit to patients with advanced cancer We have now treated forty five patients by this method, including thirty six cases of breast cancer and I feel honored to present our results at this symposium All these patients have been in an advanced stage of malignant disease with multiple and widespread metasta ses in all cases disease had progressed despite surgery, radiation therapy and in most instances hormone meas ures They were subjected to pituitary implant only when the radiation therapists considered them unswtable for further conventional treatment In the first twenty six cases we followed our original technique the seeds being inserted through a single can mula introduced through the right postnl Histological examination of autopsy material revealed that our original dose of 10 mc in two seeds, even when centrally placed was quite insufficient to destroy the gland and so in sub sequent patients, the dose was increased to fifteen and even, in some instances 20 1330 As even 15 me well placed may leave a rim of vzable cells we have, in the last nine- 106 ·Radiation Hypophysectomy 107 teen cases modified our technique to obtain a wider dis tribution of radiation within the gland The director ap paratus has been modified to accommodate two cannulas which are inserted simultaneously into the pitutary fossa one through either nostril Two seeds each of 8 mc can thus be placed to le symmetrically in the gland, one to either side of the midline Postoperative Course and Complications Apart from transient headache in a few of our patients the immediate postoperative course has been uneventful and patients can be discharged from the hospital three to four days after the implant Antibiotic cover appears to have prevented the occurrence of infection The only complication but that a formidable one has been late radiation damage to the optic chiasma In five patients defects of the visual fields have developed in one to seven months after the implant Two patients ultunately became completely blind Visual damage would appear to develop more readily if seeds become positioned high up in the pituitary fossa This was liable to occur when several seeds were inserted through a single cannula the first being pushed onwards by that succeeding it Since adopt ing our improved technique in which only one seed is in serted through each cannula no further case of visual damage has occurred Clinical Results In nine patients with malignant disease other than can cer of the breast no benefit has resulted from pituitary implant in this group there were five patients with ma lignant melanoma three with advanced cancer of the uterus and one with sarcoma of the breast All continued to deteriorate and all are now dead Of the thirty sıx patients with breast cancer treated by ·108 Hypophysectomy pituitary implant, sixteen have died from advancing ma lignancy Three of these sixteen patients had striking re lief of pain arising from sheletal metastases and one with paraplegia had returning sensation and voluntary move ments in her limbs A further patient, who had a history of repeated cerebral thromboses died from a cerebral hemorrhage eleven weeks after the implant Eleven pa tients are alive without regiession of their cancer, but six of them have been too recently treated for assessment Several have had subjective improvement TABLE 19 Pituitary Radon Implant for Breast Cancer 36 Patients Treated to 2/29/56 Cancer Not Improved ALIVE-Follow up under 2 months -Follow up 2 to 9 months DEAD FROM CANCER DEAD FROV OTHER CAUSE (Cerebral Hemorrhage at 3 months) Cancer Regressed ALIVE DEAD-(9 month) 6 patients 5 patients 16 patients 1 patient 7 patients I patient The remaining eight patients have derived considerable benefit from the implant with objective evidence of heal ing of their cancer In four, skeletal metastases have re calcified while the other patients have shown healing of recurrent skin nodules disa arance of pulmonary metastases, and cessation of convulsions caused by cere bral secondaries A large untreated primary tumor of the breast with shin ulceration and glandular metastases has regressed Case 1 JS (48) This woman when admitted was bed ridden and in great pain from spinal and other skeletal metastases Implant (10 mc) was performed in Febru ary 1955 Within two days marked relief of pain oc curred and she was ambulant one week later Biochemi cal evidence of bone regeneration coincided with the ·Radiation Hypophysectomy 109 symptomatic relief She remained well for nine months when she developed new metastatic nodules in the mas tectomy scu Bilateral adrenalectomy has now been car ried out and the podules have disappeared Case 2 JM (49) This woman was admitted to the hospital in March 1955 with Jacksonian convulsions and deepening coma An untreated breast cancer of two years duration was present Pituitary implant (10 mc) was performed seven days after the onset of the convulsions The convulsions have not recurred and she remained in excellent health until February 1956 when she devel oped further advancement of her prinary growth and skeletal metastases Bilateral adrenalectomy was carried out. Case 3 HD (35) This woman who had multiple me tastases in lymph nodes and bones was treated by im plantation of 15 mc of radon in April 1955 The osseous metastases have recalcified and those in the lymph glands have regressed Case 4 JC (53) Admitted with persistent cough and multiple pulmonary metastases this woman was submit ted to radon implant (20 mc) in May 1955 The cough has ceased and x ray examination demonstrates that her metastases have completely regressed Case 5 I McC (63) This woman with ulcerating nod ules in her mastectomy scar and enlarged supraclavicular lymph glands was submitted to implant of 20 mc of ra don in May 1955 The ulcers healed underlying skin nod ules disappeared and the supraclavicular glands became smaller She remained well for nine months but contracted pneumonia from which she died Case 6 MMCN (50) This patient with skeletal me tastases had pituitary implant (15 mc ) in May 1955 She gained great relief from her severe pain and x ray exam ination reveals recalcification of the affected bones Case 7 ES (66) This woman had an untreated massive growth of the breast with skin ulceration and enlarged axıllary and supraclavicular glands Following implant ·110 Hypophysectomy (15 mc) in July 1955 rapid healing of the ulcerated area and regression of tumor and glands have taken place Case 8 JD (48) Admitted to hospital with great pain and immobility from skeletal metastases this patient was treated by pituitary implant (16 mc ) in October 1955 Symptomatic relief has occurred and the affected bones have commenced to recalcify Hormone Effects In those patients who have undergone an adequate im plant evidence of hypopituitarism develops within a few weeks Cortisone maintenance therapy is requred usual ly in a dose of 25 mg per day and if this is withheld a typical cortisone withdrawal syndrome develops with anorexia vomiting and great weakness Clinical signs of myxedema appear within two or three months when tests of radioactive iodine uptake confirm the presence of hy pothyroidism A moderate rise of serum cholesterol is noted after the first month and this increase is maintained Thyroid replacement therapy is given The ability to promptly excrete a water load is lost In most of our patients diabetes insipidus appears within a few weeks of the implant and is frequently the earliest sign of hypophyseal damage The severity of the thirst and polyuria is dependent upon the amount of corti sone administered and the urinary volume returns to nor levels when this drug is temporarily withheld The diabetes insipidus is seldom severe and can if necessary be controlled with pitressin When these patients are on cortisone the output of 17 ketosteroids in the urine while lower than the pre operative values is still considerable When cortisone is withdrawn the output falls to levels of under 1 mg per day The urinary excretion of pituitary gonadotrophins ceases following pituitary implant Estrogens have disap peared in the urine of the one patient so tested ·111 Radiation Hypophyscctomy The effect of cortisone withdrawal on the clinical con dition and steroid excretion of these patients would ap pear to provide the most reliable indication of the extent of pituitary dysfunction With one exception evidence of absent pituitary func tion has been obtained in all the eight patients who have shown regression of cancer The exception was one of the patients who relapsed ten months after implant The other patient who later was adrenalectomized also showed returned pituitary function at the time of relapse of her cancer The amount of radon implanted in these two pa tients was 10 mc since discovered to be insufficient to cause other than temporary depression of gland function Many of the unsuccessfully trented patients did not survive long enough to allow adequate hormonal investi gations However, incomplete pituitary destruction was found in all of the ten patients who came to autopsy We therefore cannot say to what extent their lack of response depended upon 'hormone independence of their tumors It is first essential to devise a certain method of destroying the gland completely without risk of damage to the optic tract The use of the less penetrating radiation of an iso tope such as yttrium 90 might prove advantageous in this respect and is under trial The dramatic improvement in eight of our patients has encouraged us to proceed with this method of treatment in the hope that with improvements in technique a larger number of patients may derive benefit Addendum, July 1956 It is now established that a dose of radon sufficient to necrose the pituitary completely will damage more radio sensitive structures outside the pituitary fossa In one patient who died nine months after the implantation of 20 mc of radon areas of necrosis in the hypothalamus ·112 Hypophysectomy were present The use of radon has been abandoned Rods of irradiated yttrium oxide have now been intro duced into the pituitary in eleven patients In nine of these, two rods each 6 by 2 mm and of 6 mc each have been inserted one into each half of the gland In one pa tient, an additional rod was inserted into the bottom of the fossa while in the eleventh, 1 patient with acromeg aly and breast cancer four sources were placed within the grossly enlarged sella turcica In only two patients has post mortem examination of the pituitary been com pleted In one the patient with three sources the pituitary was necrosed except for a small area a few cells thick at the periphery In the other a patient with two 6 mo sources the gland was entirely destroyed In two patients minor defects of the visual fields were discovered at routine ophthalmological survey one month after the implantation In both of these patients, the yttrium source was high in the fossa We now place the yttrium source 8 mm from the top of the sella turcica Only one patient in the yttrium series has had diabetes in sipidus She had a small pitustary fossa and the rods were placed in the upper part In addition she had hyperphagia presumably caused by hypothalamic damage She died from progressive cancer two months after implantation Unfortunately permission for autopsy was not obtained The high incidence of drabetes insipidus in the patients treated by radon implantation would suggest that radia tion effects beyond the pituitary itself were a regular oc currence particularly in view of the absence of this com plication following the implantation of yttrium It is inter esting that the one patient in the yttrium group who had diabetes insipidus had other signs of damage to the hy pothalamic structures ·DR. DELBERT M BERGENSTAL Dunng the past three years, surgical removal of the hypophysis has been carried out at this clinic on nine pa tients who had advanced metastatic cancer The clinical response has been uniformly poor as far as the malignancy was concerned There was no significant beneficial effect on the course of the tumors of these patients following hypophysectomy At autopsy all of them had demonstra ble significant amounts of residual pitutary tissue In view of this experience it was believed that if hypophysectomy was to be useful for the control of certain types of me tastatic carcinoma some procedure had to be developed that could insure total hypophysectomy Development of Implant Procedure These considerations led us to seek a different approach for destroying the hypophysis The injection of radioac tive colloid material such as chromic phosphate or col loidal gold (Aulo) into the pituitary gland suggested itself as a possible alternative This however was aban doned because we felt that there was too great a hazard of reflux of colloid along the needle tract and infundibular stalk producing damage to such adjacent structures as the optic nerves For this reason it was decided to use discrete radioac tive sources such as those described by Kisieleska ?? With these it was believed the location of the radiation fields could be better controlled Yttriun 90 was chosen as the most suitable agent because of its strong beta radiation (23 mev) short half life (sixty two hours) and adequate activation cross section for thermal neutrons (1 24 barns) It was found that compressed pellets of yttrium oxide powder could be sintered at 1650° C for an hour to pro duce solid ceramic pellets These were formed as small 113 ·114 Hypophysectomy cylinders, 1 to 3 mm in length, to fit into a 17 gauge needle Activation of these pellets in a thermal neutron flux of 1 < 101 n/cm”/sec for twenty four hours resulted in a specific activity of about 04 mc per milligram of yttrium oxide or 1 to 2 mc per pellet Some difficulty was experienced with long lived activity from rare earth con tamination in the yttrium oxide Terbium 160 was the principal offender However, this contamination in the yttrium oxide that we used was not of significant magni tude Handling the activated pellets presented no prob lem because a centimeter of water offers complete shield ing against the beta radiation It was found that the pellets had a tendency to chip slightly when handled but this was prevented almost completely by coating them with a thin layer of lucite prior to activation A 2 mm lead shield several centimeters long was placed around the provmal end of a 4 inch 17 gauge spinal puncture needle Under water the pellet was placed in the needle behind the lead shield This reduced the radiation level to less than 20 mrep per hour at the op erator s finger tips and permitted the loaded needle to be handled without haste at the time of operation Considerable effort was devoted to measurement of the radiation dosage in the tissue surrounding the pellet This was accomplished with reasonable precision and usodose curves were constructed Animal Experiments A senes of experiments was carned out in monkeys 10 which the hypophysis was reached through an anterior midline approach 23 Yttrium pellets of various sizes were inserted and after various intervals the animals were 3 * Obtained through the kindness of Dr Spedding Vmversity of Iowa ·Radiation Hypophysectomy 115 sacrificed and the resulting areas of destruction exam ined These were uniformly found to be spherical areas of complete necrosis 4 to 8 mm in diameter depending on the activity of the pellet surrounded by apparently nor mal tissue The zone of transition between normal and necrotic tissue was extremely narrow These findings are precisely what was anticipated from the isodose curves TABLE 20 Radiation Dosage Required to Produce Necrosis Anterior lobe of hypophysis Hypothalamus Optic chiast or tract Oculomotor nerve 110 000 to 190 000 rep B0 000 to 120 000 rep 60 000 to 140 000 rep 30 000 to 60 000 rep The gradient of the radiation field is so steep that the transition from a cauterizing radiation dose to an insignifi cant dose must necessarily be sharp The apparent dose level at which transition occurred varied somewhat due probably to variations in the tissue swelling fixation artı fact, etc The point at which necrosis occurred in the hy pophysis and various parasellar structures is shown in Ta ble 20 On the basis of measurements taken on typical hunan pituutary glands it was felt that the whole gland could be destroyed by four properly placed I mc pellets with out risk of radiation damage to the neighbonng structures Preliminary Clinical Trials After completion of the preluninary experiments on monkeys the clinical application of this procedure was first undertaken in February 1954 The patient was a 52 year old woman with carcinoma of the cervix that had me tastasized and failed to respond to radiation therapy Four ·116 Hypophysectomy 088 mc yttrium beads were inserted into the sella on the following day, a 67 year old man who had had wide spread disseminated cancer of the prostate that had re sponded previously but only temporarily to castration and estrogen therapy, was subjected to the same procedure Four 063 mc pellets were inserted into the sella The first patient had a smooth course after operation until the fifth day at which time she began to show evi dence of diabetes insipidus On the seventh postoperative day an increasing paresis of the left third and fourth cramal nerves was encountered and the lesion progressed to complete paralysis of these nerves Roentgenographs of the skull in the lateral and stereoaxial projection were obtained and revealed that all four beads were located in the posterior half of the sella turcica One bead had been placed well out to the left of the clinoid process These roentgenographic findings explained the diabetes insipi dus as resulting from incomplete destruction of the hy pophysis and the paresis of the left third and fourth cra nial nerves from the misplaced pellet The second patient failed to respond after operation remained comatose exhibited episodes of hypotension and hypothermia and expired on the fourteenth postoperative day A second operation was performed on the first patient and two additional pellets of 0 75 mc activity were in serted into the sella Within four days after surgery the diabetes insipidus which had necessitated daily injections of 1 cc of pitressin began to decrease From that time un til the time of her death three months later, no further evidence of diabetes insipidus was noted Roentgeno graphs on the tenth postoperative day after the second operation revealed that both of the additional pellets lay in the anterior sella ·Radiation llypophysectomy 117 Roentgenographs that were taken on the second patient postmortem revealed that all four pellets were situated in the posterior half of the sella It became apparent that in the standard craniotomy position for exposure of the optic chiasm and sella turcica the angle of approach al most precluded placement of the beads in the antenor half of the sella if a straight needle was used The needles were then modified by curving the ends Sıx patients were subsequently subjected to the pro cedure in each instance four pellets were placed within the bony sell a Attempts were made to insert one pellet in the midlıne in the anterior portion of the sella two on either side of the midline in the midportion of the gland and one in the midline in the posterior aspect of the gland Of these four additional patients one died on the first postoperative day one survived four months and devel oped moderately severe diabetes insipidus on the eighth postoperative day which persisted until death and an other survived eight months developing diabetes insipidus of moderate degree on the fourteenth day which de creased somewhat but was present to a slight degree un til the time of death The last patient survived two months without evidence of diabetes insipidus No cranial nerve damage was noted in these patients At this time it became apparent on the basis of autopsy findings that four pellets were not sufficient to yield ana tomically complete hypophysectomy It also became ob vious that the proper placement of the pellets in the pi tuitary was not as easily accomplished as had been thought Review of the histologic sections revealed that because of the sharp border of the region of radiation necrosis a pellet that deviated as little as 1 or 2 mm from its proper position left histologically undamaged pituitary remnants ·118 Hypophysectomy It was then decided to increase the number of pellets Three additional patients were subjected to the procedure, and in each patient six pellets were inserted into the hy pophysis The intent at this time was to place four beads in the anterior half of the sella and two beads in the posterior half Two of these patients died during the first postoperative week The third survived five months and did not develop diabetes insipidus However, on the fourth postoperative day semi coma ensued which deepened for three days and then rapidly disappeared There was an associated transient paresis of the right sixth cranial nerve It seems probable that the altered consciousness and cra nial palsy were direct results of reversible radiation dam age In the subsequent eight patients seven to eight radio active pellets averaging a total dose of 60 mc, were in serted into the sella Five of the seven operations were carried out using local anesthesia It was believed that because many of these patients had advanced metastatic lesions particularly to the lung and to the liver, the use of a general anesthetic would increase the hazard The un eventfulness of the course after operation may be due ma terially to the choice of the anesthetic We consider local anesthesia indicated in patients who are in poor preopera tive condition One of the eight patients died suddenly one week after operation of a cause unrelated to the procedure One of the eight patients exhibited symptoms of cerebral edema for four days postoperatively After this period of time he improved rapidly and was asymptomatic by the eighth postoperative day No other complications were observed As pointed out previously the choice of anesthetic de pends upon the condition of the patient The procedure can be carried out quite easily under local anesthesia and ·Radiation Hypophysectomy 119 this should be the choice for patients who have wide spread hepatic or pulmonary metastases or in those pa tients whose preoperative condition is poor and in whom general anesthesia would increase the surgical risk For those patients who present a fairly stable general condi tion and in whom no specific contraindication exists the choice is endotracheal anesthesia The surgical technique as used at present is essentially as follows A standard right frontal craniotomy is per formed The infundibular stalk is always clipped and di vided The stalk should be clipped as close to the hypo thalamus as possible Eight to ten pellets of yºu are in serted into the hypophysis four into the anterior most portion approumately 4 mm apart three in the midpor tion and three in the posterior region of the gland 4 mm apart Results of Anatomical Studies Twelve of the total of twenty patients have died and autopsies have been obtained on each of these The body sella was removed in toto and the entire content of the sella was embedded Each of the preparations was sec tioned serially Ten micron sections were obtained and every fortieth section was mounted and studied By this means an average of twenty to twenty five sections of each pituitary gland was studied to determine the com pleteness of the hypophysectomy The hypothalamus was Likewise imbedded and studied Observations of the specimens have revealed histolog cally normal appearing remnants of the pitutary gland in each of the twelve cases that came to autopsy The amount of this portion varied from patient to patient depending upon the number of pellets that had been inserted and their implantation site It became clear that in the major ·120 Hypophysectomy ity of instances these remnants of functioning pituitary tissue are present usually in the lateral extremities of the gland close to the dural covering and usually in either the anterior or posterior most portion on the right side These areas escaped radiation destruction because one or the other beads was placed as little as 1 mm from its proper locus The demarcation between completely ne crosed pituitary tissue and normal appearing tissue is ex tremely sharp so that precise positioning of the pellets is of paramount importance to obtain complete destruction of all pituitary tissue Clinical Results A brief discussion has been given of certain patients in the preceding discussion mainly to point out the applica tion of the technique of placing the / pellets and post operative complications that have been observed It seems clear that further research is necessary to de velop better methods of placement of the 10 pellets if adequate hypophy sectomy is to be achieved Increasing the number of pellets (ten to twelve are now used) has helped to accomplish greater destruction since the over lapping and extension of the radiation fields tend to de stroy more pituitary tissue In the last 14 months we have done nineteen Yeohy pophysectomies for metastatic carcinoma of the breast Many of these had only four to sıx pellets placed in the pituitary gland and no remissions in this group were seen At autopsy sectioning of the pituitary showed small areas of cells which were not necrotic In the group of pa tients still living there are five who have had excellent objective regression of their lesions One of these patients had relapsed after adrenalectomy and showed remission following the hypophysectomy Three of these patients ·Radiation Iłypophysectomy 121 have had remissions of over a year others showing re gression have been followed for only three to five months There does not appear to be any single group of endo crine tests that will yield unequn ocal proof of the com pleteness of hypophysectomy We have observed the de velopment of pituitary myxedema in sıx patients who had had hypophysectomy and at putopsy were found to have small amounts of anterior pituitary tissue remaining in the pituitary fossa The patients who have had intact adrenals at the time of hypophysectomy have on occasion been maintained without any adrenal hormone replace ment for brief periods During this period they did not have a sense of well being nor a good appetite However their electrolyte balance remained essentially normal and their blood pressure although some what lowered did not reach shock levels In at least six patients who were main tamed on a very small maintenance dose of DOCA and/or cortisone there were rather stressful reactions secondary to complications from the metastatic carcinoma During these periods they developed symptoms of what ap peared to be adrenal insufficiency with low serum sodiums and hypotension The onset of diabetes insipidus occurs shortly after operation and it does seem clear that all of the patients who had significant amounts of anterior pituitary tissue remaining in the pituitary foss? following hypophysec tomy developed moderate diabetes insipidus There have been a few patients in whom the diabetes insipidus gradu ally disappeared However these patients still did not have normal water or solute balance The preoperative and postoperative hormonal support for the patient undergoing hvpophysectomy is accom plished quite easily The day before surgery the patient is given intramuscularly 100 mg of cortisone acetate On ·120 Hypophysectomy ity of instances these remnants of functioning pituitary tissue are present usually in the lateral extremities of the gland, close to the dural covering and usually in either the anterior or posterior most portion on the right side These areas escaped radiation destruction because one or the other beads was placed as little as 1 mm from its proper locus The demarcation between completely ne crosed pituitary tissue and normal appearing tissue is ex tremely sharp so that precise positioning of the pellets is of paramount importance to obtain complete destruction of all pituitary tissue Clinical Results A brief discussion has been given of certain patients in the preceding discussion mainly to point out the applıca tion of the technique of placing the Yº pellets and post operative complications that have been observed It seems clear that further research is necessary to de velop better methods of placement of the 10 pellets of adequate hypophysectomy is to be achieved Increasing the number of pellets (ten to twelve are now used) has helped to accomplish greater destruction since the over lapping and extension of the radiation fields tend to de stroy more pituitary tissue In the last 14 months we have done nieteen Yºo hy pophysectomies for metastatic carcinoma of the breast Many of these had only four to six pellets placed in the pituitary gland and no remissions in this group were seen At autopsy sectioning of the pituitary showed small areas of cells which were not necrotic In the group of pa tients still living there are five who have had excellent objective regression of their lesions One of these patients had relapsed after adrenalectomy and showed remission following the hypophysectomy Three of these patients ·DR JOSEPH P EVANS I should first like to say how delighted I am to have been included in this conference which has been so stim ulating and productive I am a latecomer in this field Dr Bergenstal has reported to you on the work carried out at the University of Chicago by him and by Dr Theo dore Rasmussen before the latters departure for the Montreal Neurological Institute and he has told you of the role played by Dr Paul Harper in the development of the yttrium technique Subsequent to the departure of Dr Rasmussen in May 1954 a number of additional yttruum hypophysectomies were done by Dr Eric Yuhl and he continued to do most of them following my trans fer to the University in October 1954 until his departure in June 1955 when I assumed full responsibility for the operative procedure Operative Procedure I shall address myself entirely to the matter of the sur gical problems because Dr Bergenstal has already cov ered the other aspects As already noted Dr Rasmussen had not been happy with the results of his own efforts at Temoval of the hypophysis by the standard surgical tech niques Dr Harper and he thought that it might be possi ble using a beta emitter such as yttrum to secure com plete destruction of the gland with less bleeding less danger to the optic nerves and less prolonged retraction of the frontal lobe than is inherent in the method of surgi cal hypophysectomy Though experienced of course in the removal of tumors of the pituitary gland I have not had occasion to carry out surgical hypophysectomy and I am full of admiration for the results which Dr Ray has reported and also for those in the smaller group that Dr Matson has done Our Own results are not so good but I 123 ·122 Hypophysectomy the day of operation, the patient is given intramuscular injections of 150 mg of cortisone acetate before the opera tion Following operation cortisone acetate is contmued at 50 mg every six hours for twenty four hours beginning the first day On the subsequent days the doses of corti sone acetate are reduced to about 150 mg on the second day 100 mg on the third 75 mg on the fourth and then 50 mg a day as maintenance therapy Lower maintenance doses of 25 to 375 mg have been used successfully In tramuscular injections of pıtressin (05 to 10 ml) or nasal insufflation of pitressin is used to control diabetes insipidus when it is symptomatic ·Radiation Hypophysectomy 125 tomies and thuty-one yttrium hypophysectomies of which nineteen have been done for carcinoma of the female breast Five of these latter patients are living of the cases for which I personally have been responsible there have been three early deaths One of these does not belong in the series under discussion having been an instance of male carcinoma of the breast which I unwisely chose to do The patient died the following day and was found to have a large metastasis in the medulla He should not have been subjected to operation In the nineteen cases of female breast carcinoma under discussion there have been two operative deaths I have already referred to the difficulty that I expenenced initially in placing the beads satisfactorly In the effort to correct this situation I elected to turn a bifrontal flap The underlying dura was very ad herent to the bone and two of the frontal veins described yesterday by Dr Ray were torn and required clipping This led to swelling of the frontal lobe and frontal lobe amputation became necessary Trouble was experienced with the anterior cerebral artery and the patient died on the operating table In another instance that of an elderly woman with advanced cerebroarteriosclerosis which was the first case in which the revolver device was used delay was experienced in the loading of the gun and retraction of the frontal lobe was maintained unduly long The ра tient died some five days later of softening of the frontal lobe These then are mistakes which we have slowly learned to recognize and I believe now can satisfactorily avoid It should be reported that we have produced some extra-ocular palsies by this technique four in all Two of the nerve palsies produced have been noted immediately postoperatively and it seems evident that we must have slipped our needle out of the confines of the sella and me chanically interrupted the third or the sixth nerve In one ·124 Hypophysectomy believe this fact may be attributed at least in part to the fact that three surgeons in turn have been learning this rather exacting technique The exposure of the glınd has been exactly that de scribed yesterday and shown so beautifully in the movie except that we have not used Arfonad and we have em ployed a lumbar catheter for drainage of the cerebro spinal fluid The yttrium implants have been teased into the sharp end of the large lumbar puncture needle and with a ny lon stilet were pushed up under the lead shield Loading is done under water and the lead shield protects the sur geons hands from irradiation When using this method we employed six ten or twelve needles and though these were placed near at hand it was necessary for the surgeon to take his eyes from the field on each shift of needles Since we were having difficulty in dispersing the yttrium beads throughout the gland Dr Harper developed a gun made up of a lucite barrel with a rotating disc permitting the loading of twelve pellets This device made it possible to place the beads without taking one s eyes from the field It has seemed to us that this has helped in the more ac curate placement of the beads though we are still having trouble in securing accurate placement In general I believe we may say that there has been only one case in which judging by the x ray evidence of placement of the beads we could anticipate complete destruction of the gland Serial sections in this particular case are not yet available I believe however that it will be possible to master the technical aspects of this problem and to achieve satısfactory distribution of the implants Mortalty and Morbidity As Dr Bergenstal has indicated there have been done at the University of Chicago nine surgical hypophysec ·DR JAMES J NICKSON First I would like to say that Dr Woolley has very kindly consented to discuss the effects of irradiation upon the cells of the pituitary gland using differential staining techniques If one assumes that alteration of pituitary function is useful in the management of carcinoma of the breast then the question arises as to the role of pituitary radiation as a means to that end One can consider in abstract what would be desirable from this point of view Clearly sup pression of the functions of the gland without modifica tion of the function of structures around the pituitary is the optimal position This turns out to be a rigorous qualı fication We know very little indeed about the time dose interrelationships of radiation and modification of the functions of the pituitary The pituitary may be irradiated by one of two general methods Implantation of sources of radioactivity into the gland is one of these and it was discussed this morning The question of dose distribution within the pituitary is a crucial one If only one or two pellets are used the proba bility that some of the pituitary cells will survive due to inadequate irradiation is high in the light of the studies reported here Even with the order of ten pellets being used some pitutary function may well remain Undoubt edly some of the difficulty is technical that of reducing theory to practice inherent in the development of any new technique I would like in passing to raise the possi bility that with a relatively limited number of sources a continuing dosimetry problem will continue to exist and to suggest that the use of a larger number of pellets -an infinite number-might give a more uniform dose to all of the pituitary and hence a greater chance of kill ing all of its cells This would be the application of the 127 ·126 Hypophysectomy instance, a patient upon whom I operated under local anesthesia, the sixth nerve paresis was evident as soon as the drapes were removed In the effort to avoid this complication small metal beads have been placed near the end of our needles so that we cannot push the needle too deeply In one in stance a misplaced bead produced some numbness in the distribution of the first division of the trigeminal nene In two patients there has been some reduction in visual acuity I should attribute this to handling of the optic nerve rather than radiation, in both instances A post operative clot required re elevation of the flap in one in stance and in this particular case there was a good deal of mental blunting the patients behavior after the second procedure was very much akın to that seen in some pa tients after prefrontal lobotomy Our technical procedure is now carried out more smoothly An x ray film tunnel is placed under the pa tients head at the start of the procedure and after four to sıx beads have been placed their position is checked A lateral view is obtained at the same time In some in stances we have made a second check two thirds of the way through the placement of beads The objectionable feature of the x ray check is that it requires time and lengthens the period of retraction of the lobe We discuss the employment of a stereotaxic device but it has been my belief that this would not add enough to warrant the difficulties entailed I feel quite confident that one can learn to place the beads accurately ·Radiation Hypophysectomy 129 post radiation At the other end of the time scale, we know from Lampes * work in medulloblastoma as late as ten or more years after irradiation lasting and crippling changes in the central nervous system can make them selves evident Operative Procedure Our observations here related to the use of a 22 mil Lion volt x ray beam for irradiation of the pituitary and hypothalamus We irradiated both structures primanly because of the observation of Arnold25 of the University of Illinois from his monkeys using in his instance the elec tron beam The patients were treated for the most part during the second half of 1954 We have treated no pa tients since December of that year Our interest in this study arose out of two things 1) We were able to work with Dr Pearson s excellent group and so could look at end organ function in an orderly systematic way that would give us a reasonably sensitive index of pituitary hypothalamic change in the post radia tron state thus permitting us to state with some definite ness whether radiation as given did or did not modify function of these structures Without getting into too much discussion from the radiological point of view I do not believe there is any biological difference between the electron beam and photon beam here 2) Amold observed in his monkeys uradiated with betatron produced electron beams changes which he interpreted as indicating long range depression of function as measured by clinical ob servation of end organ effects Histological changes were unquestionably present in the hypopathalamus in irradı ated monkeys We then felt that initially we should ir radiate both the hypothalamus and pituitary feeling that if no change occurred there was little point in pursuing ·128 Hypophysectomy packing technique used for the treatment of cancer cor pus uteri to the pituitary fossa If the normal tissues around the pituitary are to be preserved we will have to confine our efforts ultimately to beta ray sources in order to reduce the dose to the normal tissues as much as possi ble I think the use of gamma sources will in retrospect be no more than a phase in the development of the tech nique External Beam Irradiation External beams of radiation may also be used A beam of positively charged particles may be used The Berke ley group is the only one with experience with this class of external beam irradiation They have used protons A beam of x rays may also be used We here have had some experience with this form of pituitary irradiation Before considering the results I would like to consider briefly some of the theoretical problems of any external beam treatment The problem of damage to the intervening or adjacent normal tissues is paramount predominantly the optic nerve tract chiasm and frontal lobe or other portion of the normal brain structure that is being exposed to the beam The whole question of central nervous system re sponsivity to radiation is up in the air again For many years it has been regarded as essentially unresponsive to the effects of radiation We now hnow that this is incor rect Various portions of the central nervous system are sensitive and marked and serious alterations can occur both as a result of vascular and parenchymal primary proc esses The whole question of time dose relationships and the appearance of radiation damage is not yet understood Early changes have been noted In a month definite changes in at least one of our prtients could be seen ·Radiation Hypophysectomy 131 mnus axis We therefore started with relatively low doses 6 000 r in about twelve to fourteen days We saw no acute adverse effects We therefore increased the dose in step wise fashion the last two cases receiving 15 000 r in a period of three weeks We felt the classical pharmacologic procedure of pushing on until toxicity developed was about the only way to arrive at the maximum acutely tol erated dose Casts were made for these patients and were used with a back pointing technique for setting up the patient The actual treatment field size was 5 by 5 cm which included hypothalamus the pituitary as indicated by the sella Clinical Results Sıx patients did not show evidence of end organ re sponse Many of them lived an insufficient period of time to permit response to appear we did not see any evidence of positive modification of end organ response in less than six weeks with the external radiation This time lag fits in a general way with many other kinds of response to irradiation of the six who responded all showed changes in the urinary FSH Only two showed changes in 17 ke tosteroid levels One showed a queer change in iodine uptake As to protein bound iodine two showed a definite effect and one a questionable effect One showed a modi fication of glucose tolerance none of the others did One was not tested Four of the six patients showed a definite suppression or diminution in menses One showed a ques tionable effect and one had been surgically castrated Prior to irradiation and hence was not available for evaluation In only one patient did we have evidence of tumor response One showed a transient regression of skin nod ules This patient died in the hospital As to acute side effects some patients had nausea and ·130 Hypophysectomy one or the other If changes were noted, then we had the job of sorting out whether irradiation of the pituitary or of the hypothalamus was primarily responsible for the change We used the 22 mev beam because we wanted to do a relatively simple en bloc irradiation of both pituitary and hypothalamus It gave the depth dose distribution A 22 mev beam is also rather better and easier to control in the radiation of the area in question We had twelve patients in all nine with breast cancer two with carcinoma of the testis, and one with melanoma These patients were all suitable for surgical hypophysec tomy We did not of course use cases of early disease The patients were followed for end organ effect by Dr Pearson s group TABLE 21 Time Dose Relationships No Cases TREATMENT TIME Maximum-28 days Minimum 12 days Average-17 2 days Dose 15 000 12 500 10 000 8 000 r 7 000 65001 6 000 r SCI--019 T = AVERAGE DOSE 9700 MAXIMUM DOSE = 15 000 1 MINIMUM DOSE 6000 r The optimal time dose interrelationships were unknown for external beams either in terms of normal central ners ous system tissues or of the normal pituitary hypothala ·Radiation Hypophysectomy 133 patients should have shown changes had they lived long enough for them to develop I will return then to the initial comment The question of modification of the pituitary by radiation other than in cauterizing doses is still really unanswered particularly in terms of time and dose With major amounts of energy from external x ray beams we have I believe only sug gestive evidence of modification of pituitary function I would now like to ask Dr Woolley if he would discuss the hustologic changes that he saw in the pituitary speci mens available to him ·132 Hypophysectomy two showed nausea with vomiting The majority had headaches, the real reason for which I do not know Sub acute effects were weakness, fatigue and some epilation although none of these patients went on to a moist re action in spite of the very high dose I think this is a TABLE 02 9 Primary Diagnosis Dose Time in Days apษม) 17 Leto Steroids Uptake Tolerance Glucose Tolerance FSA Tolerance Insulin PBI но r Menses LB Ca of Breast 15 000 21 + + 0 + NR NR NR Surgi cal Castra tion RF Ca of Breast 8 000 x 15 + 0 0 + + J McGca of Breast 10 000 r 12 + 0 + BS Ca of Breast 10 000 1 15 + 0 + ololo ES Ca of Breast 6 400 / 14 + + I+ + NR + 0 0 + SS Ca of Breast|12,500 120 + 0 0 0 NR NR • Betatron therapy after partial hypophysectomy + = Response 0 = No response NR = Test not repeated function of the size of the field being used There is an other parameter that is important modest pigmentation of the skin was found Two patients developed abnormal electroencephalo grams Two developed blindness one complete and one partial Three showed mental deterioration I think all ·DISCUSSION DR LIPSETT Dr Forrest what is the dose distribution around the radon seeds? DR FORREST Our initial dose of 10 mc was based on that used by Pattison and Swan * for direct implantation of the pitu tary at craniotomy As a result of this insufficient extent of necrosis found at autopsy this dose was increased with the production of damage to structures outside the sella turcica DA ELIEL In the patient who developed skin nodules after pituitary implant what was the evidence of recovery of pituitary function? Dr FORNEST When this patient (Case I JS) developed her skin nodules we stopped her cortisone and she remained well excreting on the average 3 mg of ketosteroids a day She had only 10 mc radon implant, which we now know to be an inadequate dose DR KENNEDY In your second patient the one with brain me tastases could this conceivably be an effect such as Dr Taylor describes in the patients with brain metastases that he treats with prednisone Is it possible that you are simply getting local regres sion in the brain lesion as a result of the cortisone administration? DR FORREST I agree that we have no objective evidence of regression of this patients cerebral secondaries-her convulsions may have been due to hemorrhage in the brain metastasis At the time of her relapse she also could be maintained without corta sone and during that time she excreted 5 to 8 mg of 17 ketosteroids per twenty four hours and 8 mg of total estrogens Her 1odine uptake during that time was normal CHAIRMAN PEARSON Was cortisone given initially in this case? Dr FORREST Cortisone was started twelve days after the im plant DR BAKER When these patients are examined at autopsy Dr Forrest what do the residual pituitary cells look like? DA FORREST Dr A T Sandison who is interested in the pathology of our cases is of the opinion that the remaining pitu tary cells are histologically indistinguishable from normal pituitary One striking feature is the absence of any reaction around the zone of necrosis-only necrotic tissue surrounded by normal looking pituitary cells with a sharp line of demarcation 135 ·DR GEORGE W WOOLLEY I received four pituitaries from individuals that had had radiation directly to the pituitary and attempted to differ entiate different cells in these pitutaries The common technique of course is to differentiate at least three cell types the so called chromophobe, acidophil, and basophil We went one step further and divided the basophuls into the beta and the delta cells sometimes called gonado trophic and thyrotrophic or descriptively, a round coarse ly granular basophil and finely granular angular shaped basophil We did see differences between these patutaries and what we thought should be the normal condition The changes in the irradiated pituitaries appeared to reflect damage to the secretory cells 134 ·Radiation Hypophysectomy 137 consequent radiation near to the optic tracts The insertion of two seeds each through separate cannulas introduced on either side prevents this possibility and allows more accurate positioning of the source Furthermore as a wider distribution of dose within the gland is obtained the total dose can be reduced Finally the use of the less penetrating radiation of yttrium' to produce ne Crosis should greatly reduce the risk of visual disturbance DE MATSON So it is going to be unpredictable? DR FORREST It is a risk that is always going to be present. DR WEST Dr Charles Harrold of our Head and Neck Service has removed the pitutary by a transphenoidal approach He had quite a bit of difficulty with hemorrhage It seemed that this was due to connecting sinuses on the anterior wall of the sella I gather from what you said hemorrhage has not been a problem? DR FORREST We do not pack the nose and have had no trou ble with hemorrhage The trauma caused by the insertion of a 2 mm cannula is very slight compared to that of a transphenoidal hypophysectomy DA MATSON Dr Evans in your procedure do you mject through or tear the diaphragm? DR EVANS The needle is inserted through the diaphragm DR MATSON The diaphragm varies so from case to case DR Evans In one instance a bndged sella gave us consider able difficulty because the area through which the needles could be inserted was reduced in size As a result of that experience I think I could achieve a satisfactory distribution of beads in another comparable case DR Matsov How big is the needle? DA EVANS A 17 gauge DR RAY The curve on the end makes it possible to place the bead directly? DR EVANS We use straight needles to place the beads pos teriorly and a curved needle to place it in the central area and behind the tuberculum sella DR RAY You make more than one puncture? DA EVANS Yes we expose the diaphragm and clip the pituitary stalk which we have not been dividing Once the diaphragm is exposed it is not too difficult to see where the needle should be inserted We usually place the posterior ones first often one cen trally and then one on each side Switching to the curved needle ·136 Hypophysectomy DR JESSIMAN We all realize that this technique needs the skill not only of a surgeon but also of a good radiation therapist Si Stanford Cade with whom I was associated was very impressed by Dr Forrest s work and saw this technique being used in Clas gow He had the necessary equipment made and is using this technique in London I would not like to report his figures with authonty here but my impression is that he has done twenty-one cases of these about four developed visual disturbances including blindness A further group I believe four developed rhinorrhea and merun gitus There was one dramatic remission The complications reported by others using this technique point up the skill and care with which Dr Forrest has placed his radon seeds Such attention to detail is essential if the results are to be good and the complications few in the same way that surgical hy pophysectomy needs good surgical care of the results are to be good DR FORREST The accurate positioning of seeds depends on good radiological control In London gold grains are being im planted into the pituitary with the aid of the image intensifier which permits great accuracy and eliminates the time taken to develop several radiographs DR FORREST The insertion of small multiple sources as sug gested by Dr Nichson by our technique would entail multiple punctures of the sella turcica by a small bore instrument It could be done Dr EVANS It seems to me the difficulty of your method is that you dont have much latitude DR FORREST If small bore stout cannulas were used the sella could be punctured in several places through each nostrul The depth of penetration can easily be varied DR KENNEDY Dr Forrest have any of your patients had Thinorrhea? DR FORREST We have had only one case in which the can nula tapped cerebrospinal fluid at the time of implantation DR RAY What is the difference now in the technique that prevents visual impairment? I am not clear about that DR FORREST In the original technique several seeds were in serted through a single cannula This allowed the possibility of a seed being pushed high up in the fossa by that following it with ·Radiation Hypophysectomy 139 DR FORREST We recently obtained some yttrium metal but we have not yet attempted to form it into rods It is more expensive than the oxide DR Nicksov Have you speculated about the use of solution? DR FORREST We attempted to inject a radio-opaque oil through the nasal cannula but it failed to diffuse through the pi tuitary and finally leaked back along the cannula It would be dangerous to attempt to instill radioactive material in this way Dr RAY Dr Bergenstal did you actually try chromic phos phate? DR BERCENSTAL Our only experience has been at autopsy Dr Yuhl tred to inject non radioactive chromic phosphate inued in dye and found that he had no success at all It refluxed every time he attempted to inject it and as a result, we did not actually try it DR LUFT We injected 10 me chromic phosphate with meth ylene blue to insure that it did not come out in the arachnoid space One of the patients died shortly afterwards We knew she was go ing to die She had a big mass in the mediastinum We got activity all over the body It was absorbed The highest activity was in the sella in the pituitary We looked at the pituitary two days later We could not see very much The second patient was operated on the same day She is still alive four months after the operation The soft tissue metastases are gone but she has more skeletal metastases than before When we found that activity could be de tected all over the body we went in and tried to remove the hypophysis The tissue in the sella was found to be extremely brit tle It could not be removed A biopsy was taken Microscopic examination disclosed advanced necrosis of all cells DA EVANS We thought a good deal about this matter Dr Yuhl injected chromic phosphate into tissues in the laboratory and found there was always reflux DR LUFT We injected different spots about I cc or 2 cc got in DR EVANS Knowing how difficult it is to place beads I would think it also might be very difficult to inject the chromic phosphate accurately With each puncture one increases the chance of re flux DR ELIEL We have raised the question of chromic phosphate injection of the pituitary Tables 23 and 24 present the results in ·138 Hypophysectomy we then try to place another row of three in the central portion of the gland and then still using the curved needle attempt to place three behind the tuberculum The remaining beads may be placed according to need following the x ray check DR MATSON Have you done serial y rays for a week or ten days? DR EVANS Postoperative films are usually made a week to ten days following the procedure In my experience the beads do not move within the sella but when inserted beyond the limits of the sella I am sure they do move DR Lipsert In the area of necrosis do you have the ordinary phagocytic response? DR Evans The cauterizıng destroys pretty much all the ele ments DR RAY Dr Forrest in the cases autopsied have you seen any suggestion that there has been some reaction in the wall of the cavernous sinus? DR FORREST None that has been looked for specifically DR RAY One of the thoughts that many have had is if you get the dosage high enough and you get a bead up against the cavernous sinus there is a possibility of a necrosis and rupture of the sinus DR BERCENSTAL We have had none of that DR RAY Perhaps it is not too serious and the sinus may seal off DR BERGENSTAL I think it will be most interesting to see the effects of what we believe is a tremendous dose of yttrum In our first patients we have not gone beyond 5 or 6 mc This is predi cated on the work in monkeys It may be that much better results can be obtained with higher activity We have been so afraid of hypothalamic damage we have not done it DR MATSON Did not Dr Rasmussen report a couple of your patients went to sleep after three or four days? DR BERCEASTAL One patient did We do not have proof that that was owing to hypothalamic damage DA EVANS We have not had real trouble DR NICKSON Returning briefly to your dosage estination I did not hear what you said you used as a standard for yttrum DR BERGENSTAL Uranium oxide 238 DR FORREST Have you had any experience with yttrium metal? DR BERGENSTAL. No ·Radiation Hypophysectomy 141 cases there has been some reduction in ketosterods although the measurements in the second case are probably not significant. Diabetes insipidus is thought to be present in Case 2 although that has not been tested with measurement of solute load or with the Carter Robbins test. As Dr Luft indicated, radioactive phosphonis has been found both in blood and spmal fluid in both cases I dont have the data TABLE 24 Introhypophyseal Installation of Cr PO in Ca of Prostate Physiologic Data % uptake 17 KS mg /24 hr Duab Insp Blood SF Case 0 3 6 uks Pre Post 1 5 + 10 12 4.5 2.5 00 0.2 Ito 04 3 on the third case because that operation was performed so recently It was not possible to estimate accurately the amount which was curculating in those fluids since the distribution of phosphones is 50 difficult to measure However they felt it was probably less than 10 per cent of the total administered dose DOCTOR Are you going on with it? DR ELIEL I dont think they have been thoroughly discouraged They are going to try a higher dose of radioactive phosphorus and try to concentrate it into a much smaller concentration DR LIPSETT When Dr Jaffe-7 first started doing this his group decided to use a little larger dosag They thought they could dis tend the sella to take the chromic phosphate They observed nerve palsy and some loss of visual acuity rather soon after the injection of chromic phosphate I dont know whether they continued at or not. But they did use methylene blue in a few of these cases using between 15 and 2 cc and did not get reflux during the time that the diaphragm of the sella was exposed DR BAKER In your monkeys I wonder if you ever considered using an alkylating agent, to see if it would go through the sella. Most of it is fixed to tissue in ten minutes ·140 Hypophysectomy a group of three cases done at the Veterans Hospital Oklahoma City I have not been associated with the project but am present ing their results All three patients had advanced carcroma of the prostate The doses administered were 7 mac in Case 1 and 11 me in Case 2 The volume of 3 cc was used in Case 1 which is obviously unsuitable just from volume consideration and there must have been reflux The second case it was concentrated to a TABLE 23 Intrahypophyseal Instillation of Cr pato in Ca of Prostate Clinical Results Paint Relief Case Tumor Hegr Ac P'Ase Headache Post op Commer 1 + + 2 + + Hemiplegsa Castrated pre-op Trapsient hemiplegia 3 + + ? volume of 15 cc That also seems to reflux further concentration apparently should be used The patients have all experienced relief of pain The first two were bedridden and were able to get out of bed because of pain refsef However you will note the second patient was castrated one month preoperatively so we cannot say there was any improve ment due to the installation of the chromic phosphate He has had postoperative headache which it was felt was more than one could expect from craniotomy alone The only evidence of tumor regression is in the patient who was castrated Hemiplegia in one case came on about a month postoperatively and it is not known whether or not it can be related to the chrome phosphate injec tion A transient hemiplegia also followed very shortly after the isotope injection in Case 3 There are rather inadequate physiologic data on these patients J133 uptake was measured preoperatively and three and six weeks postoperatively In Case 1 you see there is normal J12 uptake at Six weeks The second patient had a reduction in jus uptake vistually to zero in three weeks and recovery at six weeks In both ·Raduation Hypophysectomy 143 phosphate in a plastic envelope and put it in the sella and fix at there with muscle or oudized cellulose so that the rim which may be left behind in the best surgical operation could be inactivated DA BERCENSTAL Dr Harper has been working on such a little balloon that would fit in the sella with a small plastic tube coming out in which he hoped to instill radioactive iodine if nothing else and later take it out DR MATSON You would have to stuff it in with something which could be moulded DR MATSON The sella is not round DR NICKSON Use fluid DR BERGENSTAL There are crevasses and you have to push it out DR Evans In order to use such a device one must employ lead in tubes which must pass the optic nerve in gaining access I favor leaving the matrix of the gland intact so that there is sub stance in which to set the beads Conceivably some type of sponge might be developed which could be loaded with yttrium following surgical hypophysectomy The sponge could then be inserted into the evacuated sella There might still however be considerable difficulty in obtaining a satisfactory distribution of the beads with in the sella DR LIPSETT Dr Ray has a sponge with Aud running into it DR KENNEDY Could you lay beads along the edge and pack With muscle? DR MATsoy You would have to fix them better than that I wonder if you had a solid mass something like oudized cellulose with beads sewed on the surface if you could really have some thing quite firm to work with DR ELIEL One of our group made an interesting suggestion just before I came and that was to use radioactive Zenkers solu tron radioactive mercury That has a rather low energy gamma radiation of about 2 mev I think a half life of two and one half days We did not actually make any calculations as to the dosim etry It might be difficult to fix enough mercury to get adequate radiation dose Let it sit in there half an hour during the operation and you might achieve it DR MATSON I dont think liquid media appeal to the neuro surgeons very much We value the tips of the fingers The hazard would be quite great DR ELIEL We have thought of putting solid chromic phos ·142 Hypophysectomy DR NICKSON I would like to discuss Dr Bakers comment on an alkylating agent In essence one has to ablate the pituitary whether by surgery or radiation or cauterization Cautery is one form of noxious agent radiation is only another form of noxious agent that can be used I think perhaps broadening our honzons a bit we may find an agent that will destroy pituitary tissue but still be compatible to normal structures around it DA FORREST We have constructed two electrodes that can be passed into the pituutary along the cannulas across which one could pass a high frequency current By this method a good area of necrosis can be produced in the rat liver but we have not yet had the opportunity to test it in the human DR LUFT We tried electrocoagulation five years ago in a pa tient with Cushings disease I had followed that patient for ten years she was in an advanced state of disease Dr Olivecrona electrocoagulated the pituitary Four weeks later she had her first menstruation in six years A few months later she was preg nant I saw her recently and she is doing fine She is quite normal now with normal blood pressure no osteoporosis no diabetes and she is menstruating normally DR MATSON Did he cut the stalk? DR LUFT I dont know We have been debating whether or not the stalk was clipped I do not think it was DA KENNEDY Dr Evans how much local trauma to the pituj tary do you get just from inserting the needles and beads? DR EvANS I would think, virtually none but I dont know DR KENNEDY In one of our patients Dr Peyton inserted a needle three times into the fossa to aspirate the pituitary There was gross bleeding DR BERGENSTAL We dont see excessive bleeding after we put the needles in DR Evans Not unless we put the needle through the wall of the smus In that instance there may be back bleeding but it is very easy to control and we have found that a little gel foam placed over the point of needle insertion will stop the bleeding DR MATSON What you need is a combination of two methods Certainly my feeling is that it is not much harder to take out two thirds of the pituitary than it is to expose it I dont think there is any additional hazard really now to tearing the diaphragm and taking the bulk of the pituitary gland out Possibly then one could somehow for the yttruum beads or get a thin layer of chromic ·143 Radiation Hypophysectomy phosphate in a plastic envelope and put it in the sella and fix it there with muscle or Oudized cellulose so that the rim which may be left behind in the best surgical operation could be inactivated DR BERGENS TAL Dr Harper has been working on such a little balloon that would fit in the sella with a small plastic tube coming out in which he hoped to instill radioactive iodine if nothing else and later take it out DR MATSOY You would have to stuff it in with something which could be moulded DR MATSON The sella is not round DR NICKSON Use fluid DA BERGENSTAL There are crevasses and you have to push it out DA EVANS In order to use such a device one must employ lead in tubes which must pass the optic nerve in gaining access I favor leaving the matrix of the gland intact so that there is sub stance in which to set the beads Conceivably some type of sponge might be developed which could be loaded with yttrum following surgical hypophysectomy The sponge could then be inserted into the evacuated sella There might still, however be considerable difficulty in obtaining a satisfactory distribution of the beads with in the sella DR LIPSETT Dr Ray has a sponge with fluid ninning into it DR KENNEDY Could you lay beads along the edge and pack with muscle? DR MATSOV You would have to fix them better than that I wonder if you had a solid mass something like oudızed cellulose with beads sewed on the surface of you could really have some thing quite firm to work with DR ELEL One of our group made an interesting suggestion just before I came and that was to use radioactive Zenkers solu tion radioactive mercury That has a rather low energy gamma radiation of about 2 mev I think a half life of two and one half days We did not actually make any calculations as to the dosim etry It might be difficult to fix enough mercury to get adequate radiation dose Let it sit in there half an hour during the operation and you might achieve it DA MATSOV I dont think liquid media appeal to the neuro surgeons very much We value the tips of the fingers The hazard would be quite great DR ELIEL We have thought of putting solid chromic phos ·144 Hypophysectomy phate in some kind of pliable film a balloon type thing There again you get into dosage problems from the folding of the plastic membranes in a spherical cavity Actually when you fold the film you triple the layer of solid isotope DR MATSON I think you need something bigger than the sella to stuff in DR RAY The sella is not globular There are recesses particu larly in front of the optic nerve and if you use a balloon it pouches out in all directions and is probably going to pouch out through the opening There are technical difficulties and it is not as simple as it appears DR ELIEL What about imbedding chromic phosphate in bone wax and stuffing that in? DR RAY One might stuff moldable material in the sella and devise means to have it stay in there perhaps put a couple of sutures across the top to keep it from shipping out DR ELIEL If a sphere of bone wax that size were put in is there any danger from a foreign body reaction? Might necrosis follow? DR RAY I dont think it would be well tolerated DR FORREST We had considered removing some pituitary tis sue through our cannulas and then injecting a quick setting plastic or alginate containing an isotope into the space We are first wait ing to see what yttrium does DR BERGENSTAL Our study started because we were not able to get complete hypophysectomy surgically Maybe Dr Ray has essentially solved our problem by an excellent surgical procedure Maybe it is now possible to do a really complete hypophysectomy surgically I dont think we will know untul Dr Pearson has a better chance of re evaluating the patients when they relapse to deter mine if there is any evidence of a return of pituitary function That may be all we need DR RAY Someone suggested to me that he had been hypophy sectomizing anunals by using steel wool as an abrasive We are getting tantalum fine mesh wool that I thought I might use for such purpose at the end of the operation Also the mesh could be touched with endothermy to cause coagulation of the lining of the sella DR MATSON Carbon dioxide snow has been mentioned DR LUFT We have been trying sodium hydroxide now for ·Radiation Hypophysectomy 145 some time in order to get nd of the last remnants of pituitary tissue We clear out the sella first with sodium hydroxide and then with Zenker s solution CIAMKAN PEARSOV Along this line we have to consider the nasal pharyngeal pituitary too We have one patient a postmeno pausal woman who following hypophysectomy had a remission lasting about nine months She then relapsed We then took out first her ovaries and then two weeks later her adrenals She ob tamned no improvement from this DR LIPSETT We do not have enough data to answer Dr Bergenstals question as to whether or not the completely hy pophysectomized patients will relapse Patients who have had complete hypophysectomies by serial section of the sella turcica have subsequently relapsed Unless the nasal pituitary is function ing we have to conclude that the patients who relapsed had com plete hypophysectomies DR MATSON Dr Nickson did your patients all die of neo plasm and not of radiation? De LIPSETT I think we have to say that at least two patients and possibly three had radiation damage Two patients died re cently of radiation damage All three patients had active disease but you would not have expected them to die of this amount of disease They all had clinical evidence of extensive central nervous system damage at the time they died DR ADAIR If you cut down the size of the betatron portal, what do you think the effect might be? DR NICKSON Dr Adair it is perfectly possible particularly with the betatron with the 3 by 3 cm port to have quite reason able distribution of energy although you do have fall off toward the edges which is another reason for the larger field I would still feel that we probably would have damage and with any photon beam I dont see how you are going to protect the optic nerve You have spreading out so you are going to catch the optic nerve with the charged particle beam DA BAKER No bone marrow effect no depression? DR NICKSON Nothing that we saw DR RAY There was one qute interesting case although it is not entirely pertinent A man with acromegaly who had had one series of conventional x ray treatment and then received betatron therapy subsequently developed signs of a brain tumor in the ·146 Hypophysectomy right temporal lobe he had clinical signs of increased antracranial pressure and shift of the pineal At operation I took this imme diately to be a glioblastoma It had all the appearance of degen erating ghoma but it proved to be a radiation effect We have an other acromegalic who received unwittingly I believe 10000 r with a standard machine and he developed signs of a brain tumor in the left fruntal lobe which we operated on It had the same appearance These effects have been reported by Arnold and Bailey 8 and others in the high voltage treatment of brain tumors It simply supports what Dr Nickson said that the effects on the adjacent tissues have to be taken into consideration It is too bad we dont have Dr John Lawrence here to talk about his more controlled beam but even with his methods he cannot avoid the hypothalamus and optic nerve CHAIRMAN PEARSON Dr Lawrence was unable to come His associate visited me recently and we discussed their results which are still preliminary They are using a deuteron beam They have taken great pains with the rotational technique to try to avoid damage to the tissues outside the sella turcica There is some evi dence of decreased pituitary function m their patients as measured by gonadotrophin excretion and measurements of thyroid function without signs of serious neurological damage as yet CHAIRMAN PEARSON One of the subjects studied by Dr Wool ley was particularly interesting She had been castrated for car cinoma of the breast and three months afterward developed a classical Cushings syndrome She was too sick to operate on and that is the reason we went ahead with the betatron radiation I suppose this might have some bearing too on the histopathology here DR WOOLLEY The histopathology is very difficult to interpret on a physiological basis se between storage phenomena or er cess secretion phenomena DR MATSON Why do you think she had the Cushings syn drome? CHAIRMLAN PEARSON At post mortem the adrenals were hyper plastic pot adrenal carcinoma or adenoma and we assumed that it must have been stimulation from the pituitary DR LIPSETT Hyperplastic with small adenomas as well DR. BAKER You did not find prickle cells? DR WOOLLEY I did not see them ·Radiation Hypophysectomy 147 DR. MATSOV The radiation did not affect it? CHAIFULAN PEARSOV No it did not affect it. DR BAKER Dr Woolley have you seen any of the cells that Dr Grace Field had the hypertrophic amphophuls? DR WOOLLEY I believe her amphophils are somewhat related to my delta cells DR BAKER These universally disappear when you give corta sone thyroid or estrogen or testosterone DR WOOLLEY She accuses these as being perhaps also ACTH producing cells DA ADAIR And gonadotrophin DR BAKER These disappear with the institution of hormones DR WOOLLEY We have got too many hormones to assign one to each cell type DR BAKER Isnt it possible that one cell could make a multiple number of hormones? Certainly any cell makes a number of antı bodies It is possible that a cell can make a number of hormones I dont think it is at all unreasonable DR KENNEDY Is electron microscope work being done on any of the pituitaries being removed? CHAIRMAN PEARSON I dont beheve so DR WOOLLEY There is as you well know a distnbution of cells within the pituitary which really should be differentially counted Satisfactory counts could not be obtained with the pitur tary fragments at hand DR KENNEDY It seems that all the pituutary tissues that are being removed ought to be utilized more extensively because the pathology of the pituitary is all based on post mortem data To be able to do some work with fresh tissue in staining would answer a lot of questions of what type of cells are present At the result of this particular meeting perhaps some accumulation of data regarding the pituitary tissues should be worthwhile considering DR RAWSON Are you convinced that Sommers report on the increased amphophils in his patients is relable? DR BAKER I dont think we have enough evidence to support that Most of our patients have been treated with hormones for some time prior to removal of the pituutary We have very few untreated carcinomas of the breast I went over all the material before I came down here The few that have been untreated do show a large proportion of these hypertrophic amphophil cells ·148 Hypophysectomy I think it would be wise of we followed Dr Kennedy s sugges tion and made pituitary tissue available to pathologists for study DR RAWSON Another thing that would be desirable would be to assay as many of these pitutaries as possible for growth hor mone DR LUFT We have done that we have been sending our pa tuitaries to the University of California for several years now Dr C H L has assayed them He has informed me that he gets rather high figures of growth hormone from cancer patients CHAIRMAN PEARSON We have twenty minutes left to finish our discussion of any aspects of our conference Now is the time to raise any last minute questions I would be delighted for anybody to do so DR Evans May I raise a question which can probably be quickly disposed of? I am concerned about the variations in tumor type Is this an important factor or not? Is the condition of the host far more important than the particular variant of the tumor type? CHAIRMAN PEARSON I think you are referring to the question of whether or not there is one type of breast carcinoma that will respond to alterations of endocrine environment I can state very briefly our concept about it at the moment and I am sure there are other opinions here Our general concept as the result of observa trons of removal of endocrine organs is that there is a type of tunor that is dependent upon the hormone environment, particu larly upon estrogen and possibly upon pitutary hormones There are some tumors that seem to be completely uninfluenced by al teration of endocrine environment We have tried to correlate response to endocrine therapy with pathologic characteristics of the tumor tissue and with any clinical features of the disease to see if we could find differences between the tumor type that is depend ent upon hormones and the type that is not but we have been completely unable to categorize these patients in any way either from the pathology or from the clinical course of their disease We just do not know why one tumor is dependent upon hormonal environment and another that looks exactly the same is apparently completely uninfluenced We have wondered about the possibility that the tumor and the patient may undergo many adaptations in the natural history of the disease perhaps early in the course of the disease more tumors possibly all of them are dependent upon ·Radiation Hypophysectomy 149 hormones Our data do not suggest this On the other hand we have not done much in the way of ablative therapy in patients with early tumors I am sure there are other opinions about this DA ADAIR How do you account for the fact that Dr Huggins 30 with all hus experience of over 200 cases thinks there is but one type which responds the adenocarcinoma? And this group of observers here present, disagrees with that viewpoint? DR FORREST The top pathologists in Glasgow have a consider able experience in breast cancer They do not agree with Huggins classification DR LIPSETT Dr Frank Foote of our pathology group does not agree and finds it very difficult to classify any tumor using Dr Huggins classification DR ADAIR There is one thing which I consider to be impor tant, namely the test of hormone therapy We have had the ex perience of obtaining striking improvement following adrenalec tomy in cases not of the adenocarcinoma type but which had a good previous regression with testosterone therapy DR TAYLOR We tried to make a similar correlation in our pa tients who were adrenalectomized We examined surgical speci ments in eighteen prunary untreated tumors Slides taken from one portion of the tumor appeared completely different from those of tissue from another area This so completely confused us that we could not really classify any of the breast tumor cases DR ADAIR It is very much like the classification for the grading of tuidors You find Grade II in one spot and Grade IV in another area DR. TAYLOR We could not get any real correlation There is a tendency of the tumor is mainly differentiated that it is a better responder but I certainly cannot pick it out and say this patient will respond and this one wont DR JESSIVAN It is important to accentuate the fact that there is more than one histological type of tumor in a carcinoma of the breast If one searches hard enough one may find several differ ent types of histology in the same breast I would like to reinforce something Dr Pearson said about the hormone sensitivity of tu mors We certainly found with our stimulation tests some of these tumors in their life history lose their sensitivity their ability to be stimulated by hormones In other words if you give them a stimu lation test now they may give a positive response and in a year ·150 Hypophysectomy and one half's time they will give a negative response They appear to have gone into autonomous phase and we feel that then possibly they are beyond any effective treatment by hormone ablation surgery DR KENNEDY I think too many people pay attention to cells and not enough to the stroma In the estrogen treated pahents the slow growing low degree malignancy tends to respond more frequently than the high degree malignancy Despite this sort of trend some of the best responses were Grade IV malignancy So I dont think there is any possible way that you could select from the pathological picture what patient will or will not respond DR Matsov Has anyone carried out any systematic stimula tion and inhibition tests on soft tissue metastases with biopsy studies? In other words in the Grade III type of case you were speaking about last night say with supraclavicular metastases but no bone or other distant lesions of any kind giving such a patient estrogen stimulation with pre and post biopsies or cortisone in hibition with pre and post biopsies to see if there is any possi bility of learning whether you would be justified in going ahead with ablative treatment inmediately at that phase? CHAIRVLAN PEARSON We have not done this I think the closest approximation to this were some studies that Dr Sullivan of our chemotherapy group did with skin metastases In patients he injected estrogen androgen and cortisone locally into the tumor to see whether or not he could demonstrate growth or inhibition He took small punch biopsies before and after the injection He felt that this might prove to be a useful way of selecting patients Of course not all patients have lesions on the surface that you can do this with It also raised the question of whether or not you could take a sample of the tumor at operation grow it in a guinea pigrat or hamster and see if you could stimulate it with hor mnones It has turned out that breast cancer is one of the most difficult tumors to try to grow in the anual Our group here has tried it in x ray treated rats and cortisone treated rats and have not been able to get these tumors to grow They can get survival of cells and they have seen slight changes with hormones but not enough to draw any hard and fast conclusions about DR BAKER A number of years ago in 1950 we tried to ap proach the subject using amino acid incorporation in the malig nant cells Unfortunately we could not separate the stroma from ·Radiation Hypophysectomy 151 the cells There are now some newer techniques to separate stroma from cells and I think we are going to reinvestigate this aspect of it to see whether or not we can by brochemical tests see if there is a difference in the incorporation Another comment I would like to make is that once again we neglect the host We have not been able to define by pathological type the tumor that responds to estrogen therapy but just from the clinical observation it appears to be the shriveled up elderly looking woman who seems to be de pleted of all hormones who is able to respond Take the young looking woman who appears ten or fifteen years younger than she is that is the type of woman who does not respond Once again it means that we should study the host The host is really the major criterion DR ADAIR When we were with our consultants before the Therapy Committee in Washington we set up the problem at that tune to see if our pathologic consultants Dr Ackerman Dr Stout and Dr Stewart could distinguish in a series of skin nodules which were pre treatment and which were post treatment that study brought out the fact that there appeared to be no pathologic char acteristics that distinguished the pre and post treatment nodules 1 seems to me that we have so many things in common in our at tacks on the overall problem the one tumor that is treated by estrogen the one treated by oophorectomy the one treated by the ablation of the hypophysis look all the same It may be by at tacking the major gland we are going to get further and hold our gain much longer I certainly hope so Is that the concensus here? DR BERGENSTAL. That is what I wondered this morning I have been asking Dr Luft and the others about the length of remission that we are getting and I think that certainly the feel ing of Dr Luft who has had the longest opportunity for follow up is that it is approximately two years From adrenalectomy we can obtain at best twelve months and oophorectomy may give six to nine months So it looks like we are going to get a longer re mission period from hypophysectomy which is so important if we are going to continue to use this procedure ·BIBLIOGRAPHY 1 Luft, Rolf and Olivecrona, Herbert Hypophysectomy in man Experiences in metastatic cancer of the breast Cancer 8 261 1955 2 Tonnis W Muller, W Oswald F and Brılmayer H Kann die Rachepdach hypophyse eine vikaruerende Funktion ausuben? Klin Wchnschr 32 912 1951 3 Norymberska J. Stubbs R D and West H F As sessment of adrenocortal activity by assay of 17 keto genic steroids in urine Lancet 264 1276 1953 4 Ball HA and Samuels L T The relation of the hy pophysis to the growth of malignant tumors III The ef fect of hypophysectomy in autogenous tumors Am ) Cancer 26 547 1936 5 Sittenfield M J The influence of the anterior lobe of the pituitary on the growth of sarcoma and carcinoma Proc A Res Nerv & Ment Dis 17 466 1938 6 Moon H D Simpson M EL CH and Evans H M Neoplasms in rats treated with pituitary growth hor mone I Pulmonary and lymphatic tissue Cancer Re search 10 297 308 1950 7 Nathanson IT In discussion of Arhelger S w and Huseby RA Estrogen androgen antagonism histo logical studies of mammary gland and vaginal grafts of male mice receiving estrogens in Proceedings of the First Conference on Steroid Hormones and Alammary Cancer Chicago Therapeutic Trals Committee Coun cil on Pharmacy and Chemistry AMA 1919 p 156 8 Pearson O H Ray BS Harrold CC West CD Li MC McClean J P and Lapsett, M B Hy pophysectomy in the treatment of advanced cancer Te A Am Physicians 68 101 111 1955 9 Jacobsohn D Regeneration of hypophysıal portal vessels and grafts of anterior pituitary glands in rabbits Acta endocrinol 17 187 1951 152 ·Bibliography 153 10 Smith O W and Smith GV Endocrinology and related phenomena of the human menstrual cycle in Recent Progress in Hormone Research New York Acad Press 1952, v 7 p 209 11 Kinsell L W Lawrence L Balch HE and Weyand RD Hypophysectomy in human diabetes Metabolic and clinical observations in diabetes with malignant vascular diseases Diabetes 3 358 1955 12 Heinbecker P White HL and Rolf D The essential lesion in experimental diabetes insipidus Endocrinol 40 101 1917 13 Amatuzio DS Stutzman F L Vanderbilt M J and Nesbitt & Interpretation of rapid intravenous glucose tolerance test in normal individuals and in mild diabetes mellitus J Clin Intestigation 32 428 1953 14 Bliss EI Nelson DH and Samuels L T Effects of intravenous ACTH on blood levels of 17 hydrorycorta costeroids and circulating leukocytes 1 Clin Endo crinol 14 423 1954 15 Ikkos D Luft, R and Olivecrona H Hypophysectomy in man Effect on water secretion during the first two postoperative months J Clin Endocrinol Metabolism 15 553 1955 16 Earle D P de Bodo RC Schwartz, I L Farber S J Kurtz M and Greenberg ) Effects of hypophysec tomy on electrolyte and water metabolism in the dog Proc Soc Exper Biol Med 76 608 1951 17 Rubin Martin Chelating agents in the study of calcium metabolism in Metabolic Interrelations with Special Reference to Calcium Transactions of the Fifth Con ference New Yorh, Macy 1951 p 355 18 Short E Carter AC kennedy B J and Smith RW Jr Metabolic studies in effects of crystalline growth hormone (somatotropin) in man Tr A Am Physicians 60 114 1953 19 Crafts RC Effects of endocrines on the formed ele ments of the blood I Effects of hypophysectomy thy ·154 Hypophysectomy roidectomy, and adrenalectomy on the blood of the adult female rat Endocrinol 29 596 1911 20 McCullagh E P and Jones Reid Effects of androgens on the blood count of men) Clin Endocrinol 2 243 19.12 21 Forrest APM and Peebles Brown, D A Pituitary radon implant for breast cancer Lancet 268 1054 1955 22 kisielesk. W Svihla G and Brues A M Preparation of radioactive glass beads Science 112 400 1950 23 Rasmussen T Harper P V and Kennedy T The use of a beta ray point source for destruction of the hy pophysis Surgical Forum 4 681 1953 24 Lampe I and McIntyre R S Experiences in the radia tion therapy of medulloblastoma of the cerebellum Am I Roentgenol 71 659 1954 25 Arnold Arthur Effects of x irradiation on the hypothala mus A possible explanation for the therapeutic benefits following y irradiation of the hypophysıal region for pi tuitary dysfunction ] Clin Endocrinol & Metabolism 14 858 1954 26 Pattison A R D and Swan WGA Surgical treatment of pituitary basophilism Lancet 234 1265 1938 27 Rothenberg S F Jaffe H L Putnam T J and Sunkin B Hypophysectomy with radioactive chromic phos phate in treatment of cancer Arch Neurol & Psychiat 73 193 1955 28 Arnold A and Bailey P Alterations in ghal cells fol lowing radiation of the brain in primates Arch Path 57 383 1954 29 Sommer SC Endocrine abnormalities in women with breast cancer Lab Invest 4 160 1955 30 Huggins C and Dao TL Y Adrenalectomy and oophorectomy in advanced carcinoma of the breast JAMA 151 1388 1953

·No text on this page.