Oak Ridge Institute of Nuclear Studies Medical Division Research Reports 1960-1963

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Studies on the effects of radiation i n man have continued t o occupy a prominent place i n the clinical research program during the past year, The new total-body irradiation facility was completed and this permits giving a more uniform radiation dose over a wide range of dose rates. Emphosio ha8 shifted from attempts t o obtain successful graft8 of bone marrow i n patients given larg doses of total-body irradiation t o rrtudying the effects of srnall dose8 of radiation given t o the whole body i n various diseases. This program has been broadened t o include immunological studies by t h e addition of Dr. Nazareth Gengozian, an immunologist, t o the rtaff in midyear. Special studies of the effects of local port irradiation on normal bone marmu are being done i n patients receiving radiation therapy for nonhematologic diseases . Applications of radio i ~ otope si n the study and treatarent of hematologic disorders i n general continues t o be of great interest .Special projects started in this area during the year include studies on isotopically labeled blood platelets and plaema cells. The long-range program pert aid ng to diagnostic and therapeutic I n addition t o theiruse8 of internal radioisotopes have been pUr8Ued. research value, these programs give basic training for resident Phyrfcians. They also provide the basis for most of the scanning, which cmstituter a program in itself. improve scanning equipment, techniques and interpretation, and t o extend the applications of this procedure. Continual attempts have been made t oi The outpatient service has grown considerably both i n scope and number Of patients. for thi-8 = mice, which is an integral part of the over-all clinical Dr. David A. White has had the major responsibility lk,Prank Comas, radiotherapist, has been afisisted by Dr. Ra-ring Samapurnavanitya, visiting scientist from Thailand, i n the teletherapy program, which includes special clinical studies in this field in addition t o contributing to the clinical program in geWra1-

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Dr. Ret be tt B. Gerstner joined the staff on a temporary basis i n mfdpear and has been met helpful,er pec i ally in problems of radiobiology. Dr. Orren W. Hyman, Jr., served a temporary appointment ab postresident assistant in radiology during the first part of the year. Curing the reamirder of the year, the diagnostic radiology has been done by several radiology residents inthe short-term residency training program; they have performed this work in addition to their other duties. Again the clinical staff has relied heavily for consultant help on a number of Oak Ridge physicians whose cooperation contributes greatly to the clinical program. These consultants include Dr, Robert R. Bigelow, Dr. Eidson Smith and Dr, Robert Newman of Knoxville, and Dr. George Minor of Charlottesville,Vi rg ida, have continued their contributions i n Dr, Flora Pascasio and Dr. Prank Oda performed a major p a r t of the work i n providing clinical care for patients i n addition t o conducting specific research studies before t h e terminat ion of their appointments appointments as post-resident assistant in medicine , research fellow and resident in clinical investigation. They have taken over the primary d utf es involved i n caring for patients i n addition to special research from Japan, have partkipated actively in clinical rounds although their primary work has been i n special research areas. A major contribution to the clinical program has been made by the nursing staff under the superpision of Mary E. Su tli ff (Mrs. Adren R.). In addition to providing nursing care for the patients, their help in performing special studies and collecting data from patients has been The resident physicians stafE, representing various medical specialty fields, has performed excellent work in caring for the patients and ha13 been a source of stimulation i n the research and teaching

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Boston City Hospital Mas sachu sett s Genera1 Hoa pit a1 Massachusetts General Hospital Cleveland Metropolitan General Rospit a1 Tumor Institute of Seattle Massachusetts General Hospit a1 Massachusetts General Hospital Massachusetts General Hospital Boa ton City Hospital Massachusetts General Hospital Rapundo Villa lva RESIDENT IN PATHOLOGY Southwestern Medical School Meharry Medical College University of Tennessee Medical School

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nitrogen mustard therapy was given again. There was temporary bale fit, but about one month later he was admitted tothe Eledical Division hospital for the first tim because of progressbn of his disease. this time there was evidence of metastatic lesions in the brain, soft tissues of the scalp and chest wall, parietal ple ura bilaterally, and i n mustard with only temporary benefit. A month later all areas oE disease previously mentioned had progressed and additional lesions were present in the scalp, chest wall and bones, and the patient had developed a partial paraplegia, Just before the irradiation, blood counts showed a hemoglobin of 12.9 tug, hematocrit 38, WRC 6100, platelet count 107,503. The patient was treated with another course of nitrogen He was given 400 r mid-line air dose total-body irradiation at a rate of 1.53 r/minute using t h e cobalt-60 source and technique used previously in treating patients with acute leukemia. Thore was brief improvement i n hCs symptoms and slight decrease in the size of soft tissue masses, but by the tenth postirradiation day there was again evidence of advancement of the disease. The beneficial effect of the total-body irradiation on this malignancy was only slight and very brief, Patient 2 was a 30-year-old maan witha poorly differentiated malignant neoplasm (probably neuroblastoma). external radiation therapy toa mediastinal mass with striking decrease inthe size of this lesion, At the tine of admission t o ORINS Medical. Division,,chest X rays showed multiple discrete nodules of metastatic tunor measuring up to7 an i n diameter scattered thro qh out both lung total-body irradiation at a rate of 1-53 rhin ute, using the same cobalt-60 source and technique used in the first patient, She had previously received Bone marrow aspiration showed no invasion of the marrow by The patient was given 360 r mid-line air dose Just before the irradiation 200 c c bone marrow was aspirated Erom cells were labeled with tritiated thymidine. The marrow was given back t o the patient intravenously 30 minutes after the irradiation was completed, (Details of this study are reported separately.) From subsequent routine peripheral blood counts there was no evidence that thia marrow altered the patient ' s course, While she was receiving the radiation therapy the niarrow Six day8 after irradiation chest X rays showed a marked decrease i n the size of the tumor masses and this regression was still present on the thirteenth post irradiation day. irradiation, however, chest films showed the lesions t o be increasing i n size again. Thus thh dose of total-body irradiation did have a definCts effect in producing regression inthe size of the tumor massee, but the improvement proved t o b e of only short duration, By t h e seventeenth day aEter Patient 3 was a 12-gear-old girl with HodgkLn's disease of three and one-half years duration. She had received local port irradiation theraw t o the. left cervical and mediastinal areas with good response

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early in her dise.a.oe. A few months later enlarged hilar nodes appoared and responded t o treatment vith Chlorambucil . Except for anesb, there was no evidence of recurrent disease during the, next t*ayears. one year beforra h e r admission t o the ORINS Medical Division the diseaes became active again and progressed in spite of therapy with nitrogen mustard, mannitol mustard, and X-ray therapy to the spleen. The l a s t three months before her admiasion t o the Medical Division, ab2 required frequent blood transfusions for a nea h. When admitted t o the Medical Division hospital, the patient had enlarged lymph nodes inall the peripheral lymph-node areas with a particularly large mass of nodes in the right cervical region. The spleen w a s markedly enlarged and cheat X-ray filrns showed widening of the mediastin~~m,enisrged hilar nodes, and multiple nodular densities up to1 cm in size scattered throughout both lung fields. Blood counts . showed hemoglobin 4 g, hematocrit 21.556, WBC 9250, and platelet count 170,000. The bone marrow sh0W-d hyperplasia involving both red cell and granulocytic series with increased hemosiderin, consistant with a hemolytic process, and no evidence of Hodgkin's disease i n t h e marrow. It was felt that this patient was a candidate for total-body irradiation therapy, especially since she had a healthy identical twin who could serve as a bone marrow donor. air dose, total-body irradiation at a rate o f 0.74 rhin ute, using the new total ao dy irradiator with cesium-137 sources. During the ensuing six weeks, there wa9 no significant change in the size of enlarsed lymph She was given 300 r mid-line nodes or spleen and no improvement inthe appearance of the 1e.sions demonstrable by cheat X-ray films. beneficial effect of the total-body itradiatZon on Hodgkin's disease i n this patient . Thus there was no demonstrable The thrombocytopenia and leukopenia resulting from the radiation became quite profound in this patient and on the twentieth postirradiation day she wad given an infusion of bone marrow with her identical twin serving as donor. evidence of a successful graft of the infused marrow as judged by the dee;tee of depression of the white blood cell and platelets and the ti= relationship of their subsequent recovery. Clinically, there was no definite The changes in the peri pb ral blood cells for the three patients are Shown i n Pigs. 1, 2 , and 3.

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Blood plata le tar The gensr.1 pattern of changes in blood plat8leta wa8 ai8il.r for all three patxentr, a8 shown i n Pig. 1, but there we= aoan in did dual diff a rama within the over-oll pattern. Pati an tr2 end 3, thare tmded t o ba a a light rise in platelets during the first mek, follaued by a decline t o very low levels. Patient 1 did not $bow an early tima but rather 8 gradual decrease from the beginning, tmnty - first day in all three patiantr. However, thete wa8a sharper drop inPatient3 80 that her pl8tslet count was down t o 10,000 ab early considerably hiqher than that of the other two patients originally and, therefore, during the parfod of f a l l her absolute values were considerably higher tban tho- of the otherr. depresrion persisted for about 12 dqr follased by a rather abrupt 1ncreau theraafter , beginning on. the thirty - third post ir tadi at ion day. A Ui mum d8pr8irdOn in Patient 3 a180 persfstad for about 12 days, However, inasmuch a8 her countr fell to 10,000 as early as the thirteenth day, recovery rtarted about the twenty-fifth day, a week earlier than that of Patient 2. thsre wao a plateau p8rsirting f o r about 10 days followed by an abrupt rise t o a level of 130,000. Instead of continuing upward, however, there wab another 2.11 during the nut tan daw with a gradual rLsa thereafter. The fact that recov8ry i n Patient 3rt art ed earlier i n the post irradiation period and auffar8d another decline after having reached levels of 130,000 might be interpreted an abortiva period of recovery resulting from 8 temporary ruccesaful graft of donor bolt~marrw. But, as seen in Fig. 2, there waa no ouch abortive recoverg i n the total white blood cell Count a8 might ham been expected ifa temporary ruccessful graft of bone depresrion in platelet8 occurred between the eighteenth and I n her case the period of maximum I n the aarlg part of the racovery period in Patient 3, InPatient1 there war no rfgnfficant in crea ~ ei n platelet a from During the latter part of his course he vas inthe maximum depression. extremely critical condition and died on the forth - fifth post irradiation Whita Blood Cella. Aa shorn i n Fig, 2, the white blood cell count fell rapidly during the first post irradiation week toa level of about 2,000 in a l l three patientr. I n Patients 1 and 2, 8 plateau then occurred with the countr remaining at this approximete level for an additional two r~aeks. A further drop then took place with maximum depression Occurring between the twnty - fifth and thirtieth days, with gradual recowry beginning about the thirty-second day and progreseing thereafter In Patient 3, h-ver, the plateau during the second and third Portirradiation weeks was not seen and instead t h e r e was a steady decline; the level of maximum depreoaion was reached on the sixteenth day, about white blood cells folloved the ia~lleooursa as the platelets in this w tien t.Unlike the platelet a, however, recovery did not also begin 8ar lier than in the other patient8, but rather the period of maxhuum dems8fon persisted longer and it war not until about the forty-third dry that gradual recovery began. days earlier than in the other two patients, Inthi8 regards the

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Ret icu ~ o cyte r. Experfence at the OR IS Medical Division does not indicate as clear-cut a sequence of events i n reticulocyte counts after total-body irradiation as occurs in platelet and white blood cell counts. I n these three patients there tended t o be a fallin the ret icu lo cyte s during the firert week, followed by ar light rise a t abaut the fifteenth appears that this dose of total-body irradiation duzs not cause a cmp let e disappearance of reticulocytes. A further decline then occurred with prsistent lcu counts for the ItReticulocyte counts %ere not followed beyond this tine. Hemoglobin and Hematocrit. Because of their underlying diseases and the thrombocytopenia m sul ting from radiation, all three of these patients required multiple transfusions of f reah whole blood and platelet-rich plasma, The hemoglobin and hematocrit values fluctuated accordingly and the effect of radiation alone on tkese values wae All three patfenta developed nausea and vomiting during the latter half of the period of irradiation. The vomiting subsided as soon as the radiation therapy was completed i n Patient 1 and 2. twice during the next twelve hours and once daily for the next two dayo. There were no other specific clinical developments related to the irradiation in the immediate postirradiation period. Epilation occurred i n all three patients, having its onset on the seventeenth postirradiation day i n two of them and about the twentieth day i n the other. Petechiae and nosebleeds developed inall three patients at the time of the most marked thrombocytopenia, Progress report on Y-12 radiation accident patiento. Examinations of the patients from the Y-12 Plant radiation accident of June 16, 1958, have been conducted on an outpatient basis a t interval6 of approximately 8 h months, remained well and continued t o work f u l l time. There has been slawly progressive decrease i n indtcations by t h e men …