U.T. Hopt

Pancreas organ transplantation

Abstract. Diabetes mellitus is a very common and dreadful disease which cannot be cured by exogenous insulin substitution. Many of the patients suffer from recurrent, and sometimes rather dangerous, hypo- or hyperglycemias and, in the long term, from the well-known secondary diabetic complications. At the moment, pancreas transplantation is the only known therapy to reliably reestablish endogenous insulin secretion responsive to normal feed back controls. Within the last decade, pancreas transplantation has evolved as a clinically well-established procedure. Nevertheless, the perioperative risk after pancreas/kidney transplantation is still higher than after isolated kidney transplantation. However, the benefits of a functioning pancreas graft for the patients are enormous. Ten-year survival of type-I diabetic patients with combined pancreas/kidney grafts is dramatically better than of those with an isolated kidney graft. Long-term function of the pancreas grafts is excellent, reaching more than 60% after 10xa0years. Contrary to kidney transplantation, chronic rejection does not seem to be a major problem. Blood glucose levels in the fasting state, after glucose challenge, and in the postprandial state are completely normalized. A significant peripheral hyperinsulinemia, however, is found when the pancreas graft is connected to the systemic venous circulation. Thus, portal venous drainage of the pancreas graft, which is already being performed by a few transplant centers routinely, might be the procedure of choice for the future. Beneficial effects on secondary diabetic lesions can only be expected after a rather long observation period. In addition, for all secondary diabetic complications, there is a point of no return. Nevertheless, significant improvement of diabetic polyneuropathy, diabetic nephropathy, and the disturbed microcirculation has been convincingly demonstrated. The effect on diabetic retinopathy, however, is still controversial. One of the most impressive effects for the pancreas graft recipients seems to be the enormous improvement in quality of life, which is reported unanimously by almost all patients. Thus, simultaneous pancreas/kidney transplantation can be regarded as the optimal and only causal therapy for type-I diabetic patients with end-stage renal disease.

Successful islet auto- and allotransplantation in diabetic pigs

BACKGROUNDnBecause of its anatomical and physiological similarities to humans, the pig appears to be a suitable large animal model for preclinical studies of islet transplantation. The aim of this study was to investigate islet auto- and allotransplantation in a pig model with diabetes induced by total pancreatectomy.nnnMETHODSnPorcine islets were isolated by a continuous digestion-filtration device at 32 degrees C and purified by a discontinuous iso-osmolar Ficoll-sodium-diatrizoate gradient on a Cobe 2991. The purified islets were autografted into the liver or the renal subcapsular space. The liver appears to be a more suitable site for the islet grafts than the renal subcapsular space, and the minimal amount of islets for reversal of diabetes is >5 microl/kg of body weight.nnnRESULTSnPersistent normoglycemia (fasting blood glucose level: 72.4+/-44.38 mg/dl) with a normal insulin secretion response to glucose stimulation was successfully achieved in five of six diabetic pigs by implanting a sufficient islet mass into the liver. Triple-drug immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone did not prevent porcine islet allografts from experiencing early failure. However, the addition of 15-deoxyspergualin to the triple-drug immunosuppressive regimen significantly prolonged the function of the islet allografts. When antithymocyte globulin was added to the above-mentioned immunosuppressive drug regimen, the normoglycemic period was prolonged to more than 1 month (fasting blood glucose level: 75.4+/-17 mg/dl).nnnCONCLUSIONnWe conclude that autotransplantation with a sufficient islet mass can induce normoglycemia with a normal insulin secretion response to glucose stimulation in pancreatectomized diabetic pigs and that allotransplantation can be successfully achieved when 15-deoxyspergualin and antithymocyte globulin are combined with the triple-drug immunosuppression described above. However, this immunosuppressive protocol results in a high rate of infectious complications.

Critical islet mass for successful porcine islet autotrasplantation

A major reason for the failure of clinical islet transplantations may be a limited islet mass. The aim of this study was to determine the critical islet mass necessary for normalization of glucose metabolism in a porcine model. Diabetes was induced by total pancreatectomy. The splenic lobe of the pancreas was intraductally distended with UW-solution containing 2.67–3.33 mg/ml collagenase, and the distended pancreas was digested in a continuous digestion filtration device. The islets were purified on a isoosmotic Ficoll-sodium-diatrizoate gradient. The survival period of the diabetic recipients in group 2 and 3 receiving, respectively, a low (2.14±0.39 µL/kg body weight) and a high (4.99±0.83 µL/kg body weight) islet mass was significantly prolonged compared to that of diabetic recipients in group 1 receiving no islet transplantation. However, the survival period of the recipients in group 2 was not significantly different to that in group 3. Three recipients of an islet mass of >5 µl/kg body weight became normoglycemic (fasting blood glucose <100 mg/dl) for more than two months. Furthermore, the glucose and insulin release reactions to the glucose challenge were comparable to that before pancreatectomy. Contrarily, another five diabetic recipients of an islet mass of <4 µL/kg body weight became a fasting blood glucose level of <200 mg/dl. The glucose and insulin release reactions to the glucose challenge were improved only, but not normalized compared to that before pancreatectomy. The data presented in this study demonstrate that metabolic normalization in pancreatectomized diabetic minipigs can be established by autotransplantation of an islet mass of >5 µl/kg body weight.

Typing of leukocytes in pancreatic tissue surrounding human pancreatic carcinoma.

There are tumor infiltrating lymphocytes between carcinoma cells and at the border of carcinoma suggesting antitumor immune response.1 Pancreatic tissue surrounding carcinoma was expected to be nearly free of infiltrating cells. Recently, we compared quantitatively the patterns of infiltrating leukocytes in normal human pancreas, in chronic pancreatitis tissues, and in the vicinity of pancreatic carcinoma.2 The leukocyte subset pattern was similiar in pancreatic tissue surrounding carcinoma and in chronic pancreatitis. Here, we present results from a larger number of carcinoma patients using an extended panel of monoclonal antibodies specific to the leukocyte subsets to characterize the cell infiltration.

First clinical application of a newly developed device for intragastric surgery for the treatment of pancreatic pseudocysts

BACKGROUNDnInstruments that have been used during GI endoscopy have always been confined to the accessory channel of the endoscope. We have therefore developed a device that allows transabdominal manipulation in the stomach under gastroscopic control. Here we report the first clinical application of this device, which was used for the drainage of pancreatic pseudocysts.nnnMETHODSnThe device is similar to a PEG tube and consists of a 7 mm polyethylene tube that is inserted by the thread pull through method. A trocar valve is mounted at the external tip of the tube. Four pseudocysts were treated in three patients. The retrogastric pseudocysts were punctured through the device under endoscopic (n = 2) and CT (n = 2) guidance. External drainage was used for 3 to 5 days; thereafter the drain was cut and internalized. The device was also cut and sealed. After 10 days it was removed as with a standard PEG tube.nnnRESULTSnNo complications related to the device occurred. In two patients the pseudocysts resolved completely. One patient had to undergo pseudocystojejunostomy for an infected pseudocyst containing large amounts of necrotic material.nnnCONCLUSIONSnWe believe that our new device is valuable to the further development of intragastric surgery and can be used to safely perform pseudocystogastrostomy.