A review of the literature reveals few references to the use of

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1 AN EXPERIMENTAL STUDY: THE EFFECT OF RADIUM EMANATION ON THE PANCREAS OF DOGS N. LOQAN LEVEN, M.D. (From the Departmmt of Swrgery and ihe Canoer Znetitnte, Uniueruity of hfinneuotaj Because of the extreme technical difficulty and the high mortality incident to resection of the pancreas for carcinoma, few cures may be expected from radical surgical measures. While those carcinomas limited to the body or tail of the pancreas may be favorable for resection, the majority involve the head of the gland and would require a pancreatoduodenectomy for removal, a procedure which has been survived for a long period (nine months) by only one patient (Kausch). It seems evident that surgery can offer definite palliation of symptoms but little toward an ultimate cure in these cases. A review of the literature reveals few references to the use of high-voltage x-rays in the treatment of carcinoma of the pancreas. No reports of irradiation by meam of radium element or emanation were found. Richards in 1922 reported favorable results in two cases of carcinoma of the pancreas. In both cases the tumor was found to be inoperable on exploration. Biopsies showed adenocarcinoma. Following courses of high-voltage therapy both patients improved remarkably, being symptom-free ten and twenty months later. No mass could he demonstrated by x-ray following high-voltage therapy. In 1925 Flecker and Cameron in their study of the alteration in blood sugar values after intensive high-voltage roentgen irradiation, mentioned remarkable results with x-rays in carcinoma of the pancreas. In their experimental and clinical work they found a temporary depression of blood sugar values within twenty-four hours of exposure, followed by a return to normal limits within four to eight days. Redwitz reported that he had seen no value in radiation therapy in carcinoma of the pancreas. The effect of high-voltage x-ray therapy on the normal pancreas has been studied experimentally by several investigators. Kmietowicz and Tumidajski observed a decrease in pancreatic seoretion with an activation of proferments following irradiation with 2.8 human S. E. D. Ivy, McCarthy and Orndoff in 1924, in studying the effect of roentgen rays on gastric secretion, found a marked fibrous atrophy of the pancreas to lj6 to 1/7 the normal size, following one human 5. E. D. 899

2 FIO. 1. PAKCREAS or Doo No. I1 Two FIO. 2. PANCREAS OF Doo No. I1 FOUR MONTHS AFTER IMPLANTATION OF RADON MONTHS AFTER IMPLANTATION or RADON SEEDS, BHOWINQ MAEKED FIBROSIS WITH SEEDS, SHOWING INCREASE IN FIBROStS; ATROPHY OF ACINAR TISSUE LITTLE ACINAR TISSUE R~MAININO FIQ. 3. PANPILEAS OF Doa No. I11 56 FIO. 4. PANCREAS or Doo No. IV 47 DAYS AFTFJt IMPLANTATION OF RADON DAYS ADTB IMPLANTATtON OF RADON SEEDS: DECREASE IN ACINAR TISSCE AND SEEDS, SHOWIN0 THICKENED DUODENAL RELATIVE INCREASE OF INSULAR TIESUE WALL AND NOEMAL MucosA

3 EFFECT OF RADIUM EMANATION ON PANCREAS OF DOGS 901 Fisher, Oroot and Bachem studied the effect of direct irradiation of the pancreas at operation in dogs. They found that application of 3 S. E. D. caused marked fibrosis and diabetes. There was a gradual recovery from this condition by proliferation of the gland from the periphery. This power of regeneration has been studied by Shaw and Latimer, Fisher, and Grauer. Application of 4 or 5 S. E. D. caused complete disappearance of the gland, with complete carbohydrate intolerance in one case. Orndoff, Farrell and Ivy prepared dogs with a chronic fistula of a part of the pancreas so placed that it alone was exposed to the action of the roentgen rays. They concluded that, although FIQ. 5. PANCREAS OF Doo No. v 37 DAYS Amm IMPLANTATION OF RADON SEEDS, SHOWING INCREASE OF FIBROUS TISSUE the pancreas may be temporarily impaired by one human S. E. D., the power to regenerate may compensate for the injury. Because of the fact that high-voltage x-rays in large dosages may exercise a deleterious effect on the bowel wall, it was felt that irradiation by means of radium emanation in the form of gold seeds, which can be accurately placed, would be preferable. EXPERIMENTS Laparotomies were performed in 7 dogs, under ether anesthesia and aseptic technic, and gold seeds containing radium emanation were implanted into the pancreas. Dosages varied from 528 to 1,584 millicurie hours. The seeds were placed chiefly in the head of the pancreas, with some very close to the duodenal wall to determine any effect on the adjacent bowel. Biopsies of the pancreas were taken at various intervals. The series included 3 dogs in which the major pancreatic ducts were ligated at the

4 ~~ 902 N. LOQAN LEVEW TABLUI I: Experid Obuervdwne Duration of Experi- Doe Dog Date Procedure ment age I 6/28/29 Implantstionof radium emanation days millicurie 7/6/29 Biopsy hours 7/26/29 Died 11 5/22/29 Implantgtion of radium emanation days millicurie hours 7/22/29 Biopsy 9/24/29 Biopsy 11/4/29 Died 111 7/29/29 Implantation of radiumemanation days millicurie hours 9/23/29 Killed by ether IV 8/7/29 Implantation of radium emanation days millicurie hours 9/23/29 Killed by ether GToB Microwpic Fibrous atrophy of Increase in fibrous pancreasmost tissue. Atrophy marked in head. of acinar tissue Bilateral pneumonia Fibrosis of h d of Fibrosis with depancreaswitham creeee in acinar of necrosis tiseue Entirepancress Increased fibrosis. fibrotic Little acinar tieaue remaining Verylittlepancre- Cellular infiltraatio tissue found tion Fibrosis and area Fibrosis with atroof necrosis about 2 phy of acinar tiecm. diameter in sue. Insulartiasue head of pancreas normel Atrophy of pan- Moderate fibrosis creas with area of of duodenal wall, necroeis 2-3 cm. in with fibrous atrodiemeter. Bowel phy of gland adjacent to pancreas normal time the radium seeds were inserted. Microscopic sections of pancreatic tissue obtained at biopsy or autopsy were studied in all animals. Gross changes consisting of fibrosis and atrophy of the pancreas were observed in all cases. In 4 dogs small areas of necrosis were observed at the site of implantation of radium seeds. In 3 of these a rather large dosage was concentrated in a small area. In no case, however, was there any evidence of damage to the adjacent duodenal wall. Microscopic examination of pancreatic tissue showed a marked fibrosis and atrophy of the pancreas, especially of the acinar

5 EFFECT OF RADIUM EMANATION ON PANOREAS OF DOGS 903 TABLE I (conlitwed) Dog Date Procedure Dunrtion of Experi- DOSment age Gross Microscopic V 6/29/29 Implantation of radium emanation. days milli- Ligation of major curie pancreatic duct hours 7/6/29 Biopsy 9/24/29 Killed by ether VI 6/29/29 Implantation of radium emanation. days milli- Ligation of major curie pancreatic duct hours 7/29/29 Died (wound infection) VII 8/6/29 Implantation of radiumemanation. days milli- Ligation of major curie pancreatic duct how 9/12/29 Biopsy 9/13/29 Died (did not recover from sodium amytal anesthesia) Fibrosis of head Increaeed fibrous witharegofne- hue crosia Fibrosis of head Fibrosis. Duodewith moderate nrrl wall normal fibrosis throughout. Atrophy of pan- ClW&3 Fibrosis with atrophy of acid Fibrosis and atro- Fibrosis and atro- PhY PhY tissue. The degree of atrophy varied considerably. In dog No. 2 it was so extreme that very little pancreatic tissue remained. In the 3 dogs in which the major pancreatic ducts had been ligated, a marked weight loss was observed, while the other animals maintained a fairly constant weight throughout. This difference was undoubtedly due to digestive disturbances caused by exclusion of the pancreatic secretion from the bowel. In dogs No. 2 and 4 urinalysis showed no glycosuria. The other animals were not studied in this regard. As may be seen in the accompanying table, one dog died as the result of pneumonia, one from wound infection, one from amytal anesthesia, and three were killed by ether. Although the longest period of survival in these experiments was 166 days, it is felt that, some of the animals, if they had not been killed, would have lived indefinitely, inasmuch as their general condition was satisfactory at the conclusion of the experiment.

6 904 N. LOGAN LEVEN CONCLUSIONS The experiments described indicate that implantation of seeds of radium emanation into the pancreas would be a safe procedure in suitable cases of carcinoma of the pancreas at the time of exploration or secondary to cholecystogastrostomy. Radium emanation in gold seeds would be preferable to highvoltage x-ray therapy, since the effect can be more accurately directed to the desired area. That the pancreas has definite power of regeneration has been adequately indicated experimentally. This should prove to be an additional factor of safety in the use of radiotherapy in carcinoma of the pancreas. Obviously these experiments should not be considered as constituting a claim that carcinoma of the pancreas can necessarily be cured by radiation. SUMMARY An experimental study is reported showing the effect of inter- Rtitial irradiation by implantation of seeds of radium emanation in the pancreas of dogs. B tbliograp11y FIsiim, N. F.: Regeneration of the pancreas from the pancreatic duct, a. -4. M. A. 83: , FISHER, N. F., UROOT,.J. T., AND BACHEM, A. : The effects of x-ray on the pancreas, Am. J. Physiol. 76: , FLECRER, H., AND CAMF~ON, Q.: A note on thc alteration in blood sugar value8 after intensive deep roentgen irradiation, M. J. Austrnlia 1: , GRAUER, T. P. : Regeneration in pancreas of rabbit, Am. J. hat. 38: , IVY, A. C., MCCARTHY, J. E., AND ORNDOFF, 3. H. : Studies on the effect of roentgen rays on glanclulur activity, J. A. M. A. 83: , KAUSCH, W.: Das Carcinom der Papilla duodeni und seine radikale Entfernung, Beitr. z. klin. Chir. 78: 43-86, KMIETVWICZ, F., AND TUMIDAJRKI, J. : Stimulating action of roentgen rays on proferments, Compt. rend. Soc. de biol. 92: , ORNDOFF, B. H., FARRELI,, J. T., AND IVY, A. C.: Studies on the effeat of roentgen rays on the external pancreatic secretion, Am. J. Roentgenol. 16 : , REDWITZ, E. : Die Chirurgic der Bauchspeicheldriise, Miinchen mcd. Wchnschr. 71 : , I RICHARDS, cf. E.: Possibilities of roentgen ray in cancer of the pancreas, Am. J. Roentgenol. 9 : , SHAW, J. W., AND LATIMER, E. 0.: Regeneration of pancreatic tissue from the transplanted pancreatic duct in the dog, Am. J. Physiol. 76: 49-53, 1926.