Results of human islet allotransplantation in cystic fibrosis and type I diabetic patients.
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Biomedical subjects
Publications and source records attributed to L Bühler.
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OBJECTIVE: To assess the relationship between postoperative infective complications and the CD4 count. DESIGN: Retrospective and biometric study. SETTING: Two university hospitals, Switzerland. SUBJECT: 40 HIV-positive patients who had had CD4 counts done during the three months before operation. INTERVENTIONS: Clean and contaminated gastrointestinal and orthopaedic procedures. MAIN OUTCOME MEASURE: Postoperative infective complications. RESULTS: 15 patients developed postoperative infective complications (38%), 6 of which (40%) were HIV-related. CD4 cell count, as well as the type of operation (contaminated or clean), influenced the infective complication rate. The risk of infective complications after a contaminated procedure when the CD4 count was below 200 mm3 was more than 50%. In clean operations, even when the CD4 cell count was close to 0, the rate of infective complications was never as high as 50%. Patients with a CD4 cell count of 500 or more have a similar rate of infective complications as HIV seronegative patients. CONCLUSION: Indications for operation in HIV-positive patients must take into account the CD4 cell count and the type of operation.
Currently type-I diabetes mellitus is treated with exogenous insulin administration, but traditional insulin therapy does not prevent long-term systemic complications and therefore alternatives should be sought. Presently the only option is to substitute the insulin-producing beta cells in order to obtain a more physiological way to deliver insulin. Simultaneous kidney and pancreas transplantation is an established procedure. Pancreas transplantation, however, is a major surgical procedure with a high rate of complications. Transplantation of the isolated insulin-secreting islets of Langerhans is an alternative approach, which is easier and safer than whole organ transplantation. Since 1990, clinical trials of islet transplantation have begun in a few specialized centers worldwide and the International Islet Registry counting 305 human islet allografts at the end of 1995. Insulin independence at 1 year was achieved in 8% of the patients, but 20% of cases showed a graft function with a normal basal C peptide and improved glycemic regulation. We review here the different aspects of human islets of Langerhans allotransplatation, namely historical aspects, indications, isolation and purification procedures and the results obtained.
OBJECTIVE: To review patients who presented lesions of the pancreas following blunt abdominal trauma, in order to determine which elements contributed to or on the contrary delayed the diagnosis. Construction of a diagnostic procedure which could be followed in order to maximize the rapidity and efficency of treatment. DESIGN: Retrospective study. PATIENTS AND METHOD: Patients from 1985 to 1997 having suffered blunt trauma were studied. The lesions of the pancreas were classified according to Lucas. The grounds for indication and the information that the echography, the CT-Scan and the wirsungographie brought to the diagnosis was determined for each patient. Elements which delayed diagnosis were retrospectively evaluated. RESULTS: We treated 11 patients having suffered blunt abdominal trauma resulting in pancreatic damage. 7 patients were operated. Five had emergency laparotomies. Three of these were unable to reveal an existing rupture of the pancreatic duct. CONCLUSIONS: Surgical exploration is difficult and pancreatic lesions are frequently missed. The wirsungography done before or during the operation should, therefore, be more often used as a diagnostic tool.
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Chronic pancreatitis resulting from alcohol abuse might in some rare cases require a total surgical resection of the pancreas to treat severe local complications. We have learned from the new techniques developed for islet isolation that it is now possible to obtain a sufficient number of good quality islets from one single pancreas to be transplanted into one recipient. We present a case of total surgical pancreatectomy for chronic pancreatitis in a previously non-diabetic patient with immediate islet isolation and autotransplantation. At operation, a cirrhotic liver was found, but no portal hypertension. We still decided to embolize a non purified preparation of endocrine tissue into the liver without alteration of liver function or durable modification of the portal pressure. One year after this procedure, the patient remains insulin-independent with a close to normal glycemic regulation as demonstrated by stimulation tests. Islet autotransplantation does not appear to be generally contra-indicated in the presence of a cirrhotic liver; provided the portal pressure is within normal limits. Under these circumstances, satisfactory glycemic control is achieved.
Since the development of new immunosuppressive agents, as FK506, the results of small bowel transplantation have greatly improved. The patient survival at one year has increased from 25% during the cyclosporin era to 65% in 1995 and the graft survival from 19% to 57% respectively. Clearly, the postoperative complications are still frequent and severe and do not allow a wide generalisation of this method. However, total parental nutrition is not an appropriate solution for the long term management of patients with terminal intestinal insufficiency. In Switzerland, these patients survive for several years and finally die of problems that small bowel transplantation could already successfully overpass.
Surgery is the conventional form of treatment for perforated peptic ulcer. Conservative treatment has however been described, and is still used in rare situations. The present study analyzes the indications and results of conservative therapy in our hospital. Between 1978 and 1995, 332 patients were admitted for perforated peptic ulcer. Twelve (3.5%), with a mean age of 85 (67-93) years, underwent conservative treatment (gastric suction, H2-blockers and broad-spectrum antibiotics). The diagnosis was established on the basis of epigastric pain and the finding of a pleuriperitoneum on the plain film of the abdomen. The indication for conservative treatment was a prohibitive anesthesiological risk in 11 patients and absence of peritoneal sign in one. The evolution was favourable only in 4 patients, who were discharged after a median stay of 18 days. Mortality was 8/12 patients. In one of these, autopsy showed ischemic colonic perforation. Conservative treatment of perforated peptic ulcer is associated with very high mortality. The results suggest that frequent and careful clinical monitoring is essential during the first 24 hours. In the event of deterioration, surgery must be reconsidered. In addition, the diagnosis should be confirmed by ruling out perforation of another abdominal organ.
One way to prevent the occurrence of insulin-dependent diabetes after major pancreatic resection is to perform islet of Langerhans autotransplantation. Thus far, we have performed nine autotransplantations. The last three autotransplantations were performed in patients with benign tumoral pathology (one corporeal mucinous cyst, one isthmic insulinoma and one corporeal cystadenoma). In these three cases, we performed a distal 40%, 75% and 80% pancreatectomy respectively, since enucleation was not indicated or not feasible. After resection and removal of the tumoral lesion, pancreatic segments were injected intraductally with collagenase and digested according to a modified semi-automated Ricordi's technique. We obtained 105,000, 415,000 and 144,300 non-purified islets which were then embolized into the liver by intraportal injection during the same operative procedure. After surgery, all patients were insulin-independent. There was no morbidity or mortality. In a patient who presented acute pancreatitis of the residual pancreas five months after transplantation, insulin therapy was introduced. More than one year after the graft, the two other patients remain insulin-independent. In conclusion, we propose islet autotransplantation after pancreatic resection for benign focal pathology, to prevent or delay the occurrence of insulin-dependent diabetes.
Small bowel transplantation is theoretically the best treatment for patients with short bowel syndrome and receiving total parenteral nutrition (TPN). The aim of our study was to determine the number of potential candidates for small bowel transplantation in Switzerland. We analyzed the clinical parameters of patients treated by TPN for short bowel syndrome obtained from university pediatric clinics, the SVK (Schweizerischer Verband für Gemeinschaftsaufgaben der Krankenkassen) and referring physicians. In 1995, 7 adults and 2 children were under TPN for short bowel syndrome. In the adult group (mean age 57), the causes of short bowel syndrome were 3 cases of mesenteric infarct, 2 cases of mechanical ileus, one Gardner syndrome and one inflammatory bowel disease. In the pediatric group, the causes of intestinal insufficiency were in one chronic enteropathy with malabsorption and in one congenital malformation. The average duration of TPN was 4.4 (1-10) years for the adults and 13 months for the children. The various complications related to TPN were repeated catheter sepsis in 5 patients, 2 cases of catheter thrombotic occlusion and 3 cases of cholestatic hepatopathy. The contraindications to small bowel transplantation were age, a history of malignant tumor, pulmonary hypertension and a psychiatric disorder. 4 patients were considered potential candidates for transplantation: 2 adults and 2 children, corresponding to an incidence of 0.5/million inhabitants. Considering that the prevalence and incidence of short bowel syndrome in Switzerland are comparable to those in other western countries, we think it should be possible to initiate a small bowel transplantation program in Switzerland.
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Binding of recipient natural antibodies to the endothelium of the graft, complement activation, endothelial cell activation, and microvascular thrombosis are major events in the hyperacute rejection of organ xenografts. The aim of this study was to investigate the effects of two new synthetic sulfated oligosaccharides (A and B) on the survival of discordant cardiac xenografts in the guinea pig-to-rat model. In untreated recipients, hyperacute rejection occurred in 5 min (median; range, 4-6 min) and immunohistological analysis of all the grafts revealed deposition of IgM and C3 along the endothelium. Administration of oligosaccharides A and B prior to revascularization prolonged the survival of xenografts in a dose-dependent manner, up to 113 min (median; range, 42-145 min) and 86 min (median; range, 35-108 min), respectively, when doses of 20 mg/kg were used. There were no bleeding complications. Histological examination of the rejected grafts showed a picture of hyperacute rejection, with no difference in IgM and C3 deposition as compared with the untreated animals. In cell culture experiments, the release of heparan sulfate from guinea pig cardiac endothelial cells induced by rat serum was inhibited by both saccharides in a dose-dependent manner. The results indicate that these new synthetic sulfated oligosaccharides are effective for prolongation of discordant xenograft survival, possibly by interfering with endothelial cell activation. Such substances may be of value in other xenotransplant combinations.
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Islet transplantation represents an alternative to whole pancreas transplantation for the treatment of patients suffering from diabetes type I. The transplantation of a sufficient number of islets is an essential condition for successful allograft. Islet cryopreservation allows the storage of islet preparations for subsequent pooling, at the time of transplantation, of cryopreserved islets with a fresh preparation in order to increase the mass of transplanted pancreatic endocrine tissue. From May 1994 to April 1995, islets were isolated from 22 human pancreases using a modified automated method, and 19 preparations were cryopreserved. The function of cryopreserved islets was tested in vitro (static incubation and perifusion). The results of static incubation experiments confirmed that the insulin secretion of cryopreserved human islets in response to glucose stimulation was comparable to the response of islets that have not been frozen. In static incubation experiments, the mean (+/- SEM) insulin secretion of islets, prior to cryopreservation, was 239.3 (+/- 58.9) and 479.5 (+/- 59.5) pg/islet/15 min at 2.8 mM glucose and 16.7 mM glucose respectively. The mean (+/- SEM) insulin secretion of cryopreserved islets was 274 (+/- 103.2) and 468.5 (+/- 191.9) pg/islet/15 min at 2.8 mM and 16.7 mM glucose respectively. The perifusion experiments also demonstrated a significant increase of insulin secretion from cryopreserved islets perifused with a stimulating glucose concentration. Our experiments allow us to envisage the use of cryopreserved islet preparations for allotransplantation in diabetic patients.
From January 1986 to September 1995, 4 patients were hospitalized in our ward for gastrointestinal bleeding from ectopic varices. The patients were all female, aged 30 to 65 years. The etiology of portal hypertension in these patients was alcoholic cirrhosis, cirrhosis in Wilson's disease and previous alveolar echinococcosis treated by right hepatectomy, complicated by post-operative portal thrombosis. Clinical presentation in all 4 cases was lower gastrointestinal bleeding. Diagnosis was by emergency arteriography in 3 cases; no source was found in one case with recurrent hemorrhage. The 4 patients had a history of abdominal surgery. The location of the ectopic varices was small bowel and cecum. 3 patients were treated surgically: right colectomy, partial small bowel resection and porto-caval shunt with complete lysis of adhesions. One patient was treated conservatively with emergency placement of a TIPS (transjugular intrahepatic porto-systemic shunt), with simultaneous embolization of cecal varices. Upon laparotomy, all 3 surgical cases presented ectopic varices in post-operative adhesions. In conclusion, in a patient with portal hypertension presenting with lower gastrointestinal bleeding, hemorrhage from ectopic varices should be kept in mind and investigated by arteriography. A history of abdominal surgery seems to be a predisposing factor in development of ectopic varices by adhesion formation.
The prevalence of insulin-dependent diabetes mellitus (IDDM) in cystic fibrosis patients ranges from 2 to 8% and glucose intolerance up to 15%. In recent years, lung transplantation has helped to prolong life expectancy of cystic fibrosis patients and represents 10 to 30% of all indications for lung transplantation. The postoperative need for immunosuppressive therapy using diabetogenic agents has decompensatory effects on glucose regulation and will probably increase the number of insulin-dependent cystic fibrosis patients. We report the case of an insulin-dependent cystic fibrosis patient transplanted with a combined islet-lung allograft. The pre-transplantation C-peptide level was below 0.04 nmol/l and preoperative insulin requirement was some 100 U per day. A sequential bipulmonary lung transplantation was performed and, using the pancreas of the same donor, we isolated and purified the islets of Langerhans by a modified automated method. We obtained 232,200 islets equivalent, which were injected into the liver by portal embolization. The postoperative course was uncomplicated, the insulin requirement decreased to 50% of the preoperative need and the C-peptide value increased to normal values and remained with the normal range during a follow-up period of 15 months. In conclusion, we believe that, besides type I diabetic patients, insulin-dependent cystic fibrosis patients with a negative C-peptide value could also be good candidates for combined islet-lung allotransplantation.
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Up to now, liver resections have been the initial treatment of almost all cancers and benign tumors limited to a liver lobe. This retrospective review assesses the results of a consecutive series of 113 major elective hepatic resections during a ten-year period. Major hepatectomy was defined by the resection of at least 3 Couinaud segments. Mean age was 52 years (20 to 79 years). There were 62 women and 51 men. 35 resections were performed for colorectal metastases, 22 for a benign tumor, 20 for non-colorectal metastases, 11 for hydatid disease, 10 for hepatocarcinoma, 7 for cholangiocarcinoma and 8 for other indications. The resections performed were 86 right hepatectomies with 18 extended right hepatectomies, 24 left hepatectomies with 4 extended left hepatectomies and 3 trisegmentectomies. Total vascular exclusion was used in 22 patients (19%). Mortality rate was zero. Significant morbidity was encountered in 24 patients (21%). These results suggest that the mortality rate may be independent of the extent of liver resection, provided that hepatic function is normal and preoperative selection adequate. With improving surgical management and techniques, and the use of intra-operative sonography, extensive liver surgery can now be performed with a very low mortality rate.