Metabolic Changes in Humans Following Total Body Irradiation, 01 May 1966 Through 30 April 1967 (Dasa 2179)

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METABOLIC CHANGES I N HUMANS May 1, 1966 through April 30, 1967 DEFENSE ATOMIC SUPPORT AGENCY

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This document has been approved for public release a d sale; its distribution is unlimited.

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May 1, 1966 through April 30, 1967 Defense Atomic Support Xgencjr University of Cincinnati Coil eee of HeSicir,e

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METABOLIC CHANGES IN HUMANS May 1 , 1966 through April 30, 1967 DEFENSE ATOMIC SUPPORT AGENCY Reproduced by tho lor fedaral Scientitlc 8 Technical Information Springfield Va. 22151 5Y

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METABOLIC CHANGES IN HUMANS May 1, 1966 through April 30, 1967 DEFENSE ATOMIC SUPPORT AGENCY University of Cincinnati College of Medicine Cincinnati General Hospital d8 research ha8 been sponsored by the Defense Atomic Support Agency NWER

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.s report was prepared by the following members of the tty of Cincinnati College of Medicine: ' e ' research was supported by the Medical Division, Defense Support Agency, Washington, D.C. The Project Officer I conducting the research described in this report the gators adhered tothe "Principles of Laboratory Animal 1 Established by the National Society for Medical Research."

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.d cartie.1 body radiation to the lower body and one patient .ea'ced with 150 rad total body radiation have par all ed obeerA simple infusion filtration system for reinfusion of m a bone marrow has been made. A rapid and sensitive SSS ~ ethod f o r urinary deoxycytidine k"iich allows the detection of tro separate strains of phage t o be used for anti bow titration ue being grown on synthetic culture media.

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This resort presents data accumulateb from May 1, 1966 rough April 30, 1967. Included a r e clinical studlee on three - tients who received 100-200 rad midline absorbed tissue dose (145 to 310 R midline sir exposure) of partial body rsdlatfon (PBR) One additional patient Major laboratory accomplishments occurred dwing thia year. 1F ret was the completion of em infiaion filtration system f o r nfusion of autologous stored human bone mesfow. Since thi8 inbtrumentation will make inhaion of marrow a safer cnd more ea Ily controlled procedure we feel that earlier infusion to ptevent th hemtologic depression from rudiatLm sh l d be lnveatigated. Second was the perfection by T\r. I-Wen Chen of a new, much inpraved fr m humans and from rata. in understanding the metabolic pathways of nucleic acid metabolism This step portends future progress The third laboratory "break through" has been the growth of wo strains of phage on synthetic culture medium in the Imm ology Laboratory of D r . Evelyn Hess. After these strain8 hav been checked for pyrogenicity and safety, it vi11 be

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131e t o :!tratc antibody production i n cxperlmental mikalsPo' n u berore and after irradiation .I An extensive report of all our studies through April 30, 1966 been published (DASA 1844). This interim repcrt will discuss Aims of the Prolect, Desinn of Study, Technique of Study, Collection, and Dosimetry remain essentially as reported. Clinical Observations: Observations have been eimilar t o B 1066-070. Included with than are two figures (Figures 1 and rich graph the hematologic course of patients 166 and 170 t o it rate representative differences between respnmee to partial tal body radiation. The pattern after reinfusion of the bone (Figure 2) may suggest repopulation 05 the marrow space, but rrow was infused too late to definitely Interpret the results nclosed with this report is a copy of a paper t o be presented is, Prance, June 26, 1967 (Attachment A - figures omitted). is dercribed an easy-to-use infusion filtration system for stored goue human bone marrow. It can be sterilized and made pyrogen In vitro tests indicate that filtered autologous human bone would effectively contro1,the heamtologic deprersion f oll wing

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The stud lee investigating the effects of radiation on .eosides, eepeciclly deoxycytidine, have been limited by L rapid cclorlmetric method for detennining deoxycytidine 0 m l of urine can be assayed. oxyribose containing compounds by cation and anion exchange been better than 905. The enclosed report (Attachment B) covers progrees As little M4x 10-3 m l ~ sof deoxycytidine It is separated from other Recovery, as evaluated using deoxycytidine-2-llr(:, Inthe paat we have attempted t o study the c ffe cte of total partial body irradiation on immuaologic function through w e of C-reactive protein, thyroglobulin agglutination, K fixation sad the quantitative pre c ip it in reaction described 1 be titrated before and aiter rdi ation. u lou strains of phage are canparable, charges inti ter 1 eubetantiate a radiation effect. The phage m u s t be grown on non-antigenic synthetic media. .the la et year the method for growing phage on synthetic Strains of phage were proposed as antigens which we mediun was not functioning. It Is possible now. After ;en studies have been completed on rabbits, Dr. Evelyn HISS

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rision of Ionnimology is going t o study t it ers in experibale for reproducibility. T it ers will be conpared mental a n a d s before and after radiation. If 811 Of dies are safe,they will be carried out in hws receiving r i c Evaluation and Testing approach used has been ourmarized in D a A 1844. of the data studied t o date, there has been confinnation kesults noted previously. e results in all patients treated during this project dicated a need f o r furt'Icr investigation of the ptOCeSSes rtion. Assessmen+. of the value of stored human bone marroy wing the lpmatologicsl aspects of radiation icjury is nov le. Developents inthe assay of deoxycflidine m.y ultimately n 'the determination of abl o logic d dosimeter. Alterati03S ; i ~ nme going t o be evaluated. These observations of tbe LB of radiation exposure will yield a better understanding

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1This patient VES a 63 year old Negro male who WBB admitted td Cincinnati General Hospital February lbs 1966, witha bleeding r c t a l mass. Biopsy at sigmoidoscopy February lb, 1966, revealed tu/ inoperable acenocarcinoma of the rectum with peritoneal hp lr rats c lostomy was performed March 5 , 1966, A double barrel sigmoid nvolvanent of the bladder neck. He was re-admitted June 6, 1966 for rectal bleeding. ::pproximately 200 m l of bone mww was stored without difficulty ' n June 7* 1966. He received sham ir radi at ioc June 9 * 1966, it11 no crdvtrse ef i arts. June 11, 1966, the patient received 200 rad midline absorbed 1tissue dose (310 R midline air exposure) of lower partial body 1 hemogram remained stable. He experienced no symptoms following PBR,and t h e He expired January 10, 1967, in a nursing home, 212 day6I

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This ~ patient ,a 52 year old Negro female, war admitted to. left lowe quadrant pain. revealed obstructed eilpnoid colon. A tranavrrse colostomy and a liv r biopsy were performed September 1 4 , 1966.. The biopey liver * ( lagnosis: Carcinoma of the Sigmoid Colon with Liver Generel Hospital September 5 , 1966, with nausea and On September 8, 1966, a barium etema tober 7, 1966, approximately 100 m3 of bone marrov 4 1966, with no adveree aide effoctr. treated with 100 rad midline absorbed tissue air axpoclure) of psr ti al body radiation tothe on October 13, 1966. She experienced no ill effects L.treatment. Blood counts remained stable. patist: was discharged October 21, 1966. Iovember 2, 1966, ah8 had nawea and vmi+.ing and was Her appetite improved,and she On March 25, 1967 (163 daye post PBR), she expired.

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is patient, a 76 year old Negro female, was admitted Octob r 10, 1966, with left lower quadrant pain, weight loss of p roximately 17 pound8 and anorexia, tn September, 1953, she had 8 cervical carcinoma, stage I, treat d w i t h radium and external x-rsy. ' In May, 1954, seve e post radiation proc t it is necessitated loop colostomy, "her were admissions i n June, 1955, and June, 1956, for post radi tion stenosis of the rectum, but surgery was not required. In J uary, 1957, poet radiation stenosis of the rectum repulred an teri or resection of the recto-sigmoid colon with end t o end anaitqnosis. I n May, 1957, a revision of the co lost w and cec st@my was performed. On January 7, 1965, pelvic exemination revealed a midline cys ic mass, inseparsble from the uterus, an lcf%salpingo-ooph6rectomy. The biopsy repcrt (#SP 65-244) re arled.andmetrial papillary carcinoma. S e was shammed October 25, and 26, 1966, with no adverse s i d e The patient was itted January 13, 1965, for an exploratory laparoton;y, hyoterectomqy, I On October 21, 1966, approximately 200 ml of bone marrow aspirated iron the l e i t and right posterior crests and stored.

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The patient was treated with 150 rad midline absorbed c dose (226 R midline air exposure) of lower partial body tion on October 27, 1966. She experienced severe abdominal diarrhea, weakness, anorexia, and confusiun, On October 28, emperature rose t o 102.6O F., due toa urinary tract inf'ecticn was controlled w i t h Cantriain. She was discharged on On December 1, 1.966, she w a s admitted because of disorientation amition. On December 5, 1966, sternal and l e i t emterior llness with the exception of elevation or her white counts The patient remained anorexic, extremely lethargic and nued a downhill course until December 22, 1966, when she Her hemogram remained stable throughout Chis patient, a 71 ye-r old Caucasian remale, was r&nitte, icinnati General Hospital February 15, 1966, with a history :testinal troubler" for a duration of years. Her complaint6 at t h i r time were anorexia vithout wwriting,

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to partial body radiation was not given. She was ondition remains unchanged. As of April 27, 1967, her last visit to clinic, her

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of the si mtient, a 62 year old Negro male, was admitted t o Oeneral Hospital vith hemoptysis and left ple uri tic tum was positive. A brain SCM on December 9, 1966 A chest x-ray revealed a coin lesion On October 28, 1966, a Papanicolaou smear I t was treated with 250 KVP t o the head, 3000 R minimal : t o the midline from December 19, 1966 t o February ated and stored. The patient was shannned February 28 Wch 1, 1967 with no adverse side effects. ach 2, 1967, the patient was treated with 150 rad sine air exposure) total body radiation. He experienced 'fects from his treatment. WBC dropped from an average of 5,500 prior to therapy i at i eot was given 180 ml of bone marrow suspension intrawithout filtration on March 14, 1967 (12 days post

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He tolerated the prOCedW8 well with no c-8 in tamperature, I , rerplratlon, or blood prersure. Treatment with 60 Cobalt, 3000 R to the whole head, was ated on March 28, 1967, due t o revere puer lr of the left nd moderate paresis of the left leg. On May 8 , 1967, h i 8 hslnoqram had returned t o no&; but ho ncreaslng mental dirorlontation m d progrrrrive left - aided On Msy 9 , 1967, 68 dryr port TBR, t h e patient expired.

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THE EFFECTS OF FILTRATION ON STORED HUMAN BONE MARROW Departments of Radiology and Medicine University of Cincinnati Medical Center Defense Atomic Support Agency DA-49-146-XZ-315

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During t h e last five years, we have been studying the effects man belngs of a single expos9:re of total body radiation which een given for Ltie palliation of metastatic malignancy. To forty patients have been so treated with 25 to 200 rad midline bed tissue dose (41 to 336 R midline air dose) of total body tion. Eighteen of these patients were given 150 to 200 rad. . Marked hematologic depression occurred in all eighteen nts who received more than 125 rad total body radiation. otal elucocyte count fell below 2000 WBC/mm3, 25 to 40 days irradiation. The mean minimum leucocyte count of previously ated patients who received 150 rad total body radiation alone 264 t 1140 and was 1140 2 816 when there had been previous py. The nadir of the leucocyte counts of patients who received Since bone marrow depression was the most iife-threatening tion effect at the doses ueed. we began storing bone marrow Iqtologous infusion after irradiation. To date, we have d marrow from twenty five patients and have infused autologous d human bone marrow intravenously withaut filtration into six nts. One patient had hemoglobinuria €or twelve hours after Ion at 100 drops per minute. Autopsies were performed In patients five days, eight days, and nine days respectively relnfusion. No evidence of pulmonary emboli, pulmonary rctlon,or other di sea neas a result of marrow f nf union was Ion microscopic examination.

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The hone marrow has he en stored by a modification0.the hod previously described by Kur nick (1). Approximately100ml material is is pirated from each poste i or iliac crest. The ' row suspension is diluted with an equal amount of 30% glycerol 1491s cooled at 1' Centi era de per minute to -10' Centigrade. : tubes are then placed in polyethylene bags and stored 3t On the dav of infusion,the frozen morrow - glycerol - Os Rood iia i s thawed at 1' Centigrade.Two parts of it are diluted th one part 331 / 3%dextrose in water and placed in a Fen wal itrtic transfer pack. It was this mixture vhicl, was infused There is disajireernent as to the need for filtration. Kur nick es not think it is necessary prior to infusion. d Pillow (2.3.1) recommend filtration to ml nim ize the incidence .pulmonary em boll ration.Though we have not encountered embo li - tion, ve have developed a simple method of filtration for use The complete infusion filtration system consists of a n wal transfer pack, plastic tubing, filter assembly, and pv a motor pump(Figure1).The pump has avar la hle speed

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I , but :c+r the experiments to be reported,has been run 60 drops par minute.Within the filter esse m bly a2),there .re n ucc en niven umber 850, 1100 and 1200 Lfters corresponding KO openings of 297, 149, and 7 4 I. ?he filter assembly is c un struct ed of Rta in less steel kflcn vas he ts no that it can be dir assembled for cleaninu. then be reassembled,sterilized,and made pyr oxen free. rn the pump was used without a filter assembly,the plastic would separate from the17gauge needle because of the iieces of fi brin and marrow which would occlude the needle. ieedle has been used without encountering any obstruction have in v anti gated the total cell count of a volume of suspension and the viability of stored marrow cells before .et filtration through the infusion filtration system bed. Cell counts are report cd zs cells per nil (1). Viastudies,as determined by dye exclusion,utilized try pan I). By a modification of the method of Hoo rh cad(6). 'row from several patients has been cultured under phytout in stimulation for6 days. llanted in a culture media of 70% TC199 and 30% pooled human 7). Onthe …