Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics Stage IIIC ovarian carcinoma.

BACKGROUND: Patients with advanced ovarian carcinoma of International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC should be treated by radical surgical tumor debulking with the goal of complete tumor resection. Prolonged median survival can be achieved in those patients entirely free of tumor after surgery by the administration of postsurgical platinum/taxane-based chemotherapy regimens. However, residual tumor is present in the majority of patients, which limits survival prognosis. Different therapy approaches should be utilized to improve prognosis in these patients. Neoadjuvant chemotherapy could induce "downstaging" of the tumor and thus improve operability. Here, evidence of large ascites volume (>500 mL) can be used to identify those patients who could benefit from neoadjuvant chemotherapy. METHODS: In a prospective, nonrandomized Phase II study, 31 patients with advanced FIGO Stage IIIC ovarian carcinoma and large ascites volume (>500 mL) received 3 cycles of platinum/taxane-based combination chemotherapy, followed by tumor debulking surgery and 3 additional cycles of platinum/taxane-based combination chemotherapy. During the same period, 32 patients with advanced FIGO Stage IIIC ovarian carcinoma and large ascites volume (>500 mL) received conventional therapy (tumor debulking surgery followed by 6 cycles of platinum/taxane-based combination chemotherapy). The two groups were investigated and compared with respect to tumor resection rates, blood transfusion requirements, morbidity, and mortality during surgery, duration of surgery, and median survival. RESULTS: The tumor resection rate in the patient group receiving neoadjuvant chemotherapy was significantly higher (P = 0.04) than that of the conventionally treated group; the median survival time of 42 months versus 23 months also was significantly longer (P = 0.007). Time spent in surgery, blood transfusion requirements, morbidity, and mortality during surgery were not significantly different. CONCLUSIONS: Patients with advanced ovarian carcinoma of FIGO Stage IIIC who will benefit only marginally from conventional therapy can be identified by evidence of large ascites volume. Higher tumor resection rates and longer median survival can be achieved in these patients by the use of neoadjuvant chemotherapy. A prospective randomized multicenter study currently is being performed by the Society for Gynecological Oncology in Germany to confirm these findings.

Function of transplanted human pancreatic allografts after preservation in cold storage for 6 to 26 hours.

Preservation of cadaveric pancreas allografts has been a difficult problem in clinical pancreas transplantation; most institutions use Collins solution and limit preservation time to less than 6 hr. Longer preservation times have been used at the University of Minnesota. Between August 1983, and December 1985, 47 human cadaveric pancreas grafts were transplanted into Type I diabetic recipients after cold storage at 4 degrees C in a modified, hyperosmolar silica-gel filtered plasma (SGFP), a solution previously found to allow dog pancreas grafts to be successfully preserved for up to 48 hr. Ten grafts were preserved for 2-5 hr (group 1); 20 for 6-11 hr (group 2; 17 for 12-26 hr (group 3). Graft function and late outcome were compared between these groups and another group of 7 cadaveric grafts (group 4), which were transplanted immediately and without any preservation. Analysis of exocrine pancreatic function early after transplantation showed a maximum mean serum amylase (IU/L) of 557, 440, 429, and 307 in groups 1, 2, 3, and 4, respectively. Primary preservation failure rates of 0, 5%, 5.8%, and 0%, and endocrine graft function rates at 1 month of 80%, 80%, 76%, and 86% were obtained for groups 1, 2, 3, and 4, respectively (P = NS). Only patients who were insulin-independent were counted as having functioning grafts. Detailed functional studies at 1 month showed that mean plasma glucose levels during 24-hr metabolic profiles were in the normal range in 71%, 68%, 72%, and 50%, while oral glucose tolerance test results were within the normal range in 38%, 81%, 76%, and 66% of groups 1, 2, 3, and 4, respectively (P = NS). At 1 year, patient survival rates were 57%, 88%, 75%, and 100% (P = NS), and the graft functional survival rates were 0, 25%, 33%, and 29% (P = NS) in the respective groups. Five patients in group 2, and 6 in group 3 have currently functioning grafts at 4 to 37 months after transplantation. We conclude that cadaver pancreas grafts can be safely preserved for 12-24 hr in modified SGFP solution, thus making the sharing of these organs between different centers practical and the transplant operation less of an emergency procedure.

Comparison of two methods of islet preparation and transplantation in dogs.

Seventy-nine mongrel dogs underwent total pancreatectomy. Fifteen dogs served as apancreatic controls and died 7.0 +/- 4.2 days later (mean +/- SD). The pancreases of 44 dogs (group 1) were intraductally distended by manual injection of Hanks' balanced salt solution (HBSS). Thereafter each organ was mechanically disrupted and subjected to collagenase digestion as described by Mirkovitch et al. The pancreases of 20 dogs (group 2) were intraductally distended and subsequently perfused with collagenase by a roller pump. The organs were then mechanically disrupted and filtered through screens as described by Horaguchi et al. The resulting tissue suspensions were injected into the spleens of the dogs as autotransplants in both groups, by direct punction of the splenic capsule in group 1 and by retrograde infusion via a splenic vein tributary in group 2. The functional outcome was better in group 2 than in group 1, as assessed by the number of animals that became normoglycemic after transplantation [15/20 (75%) vs. 13/44 (30%); P = .0025]. The degree of islet purification, as measured by an increase in the tissue insulin/amylase ratio, was higher in group 2, and in both groups it was higher in normoglycemic than in hyperglycemic animals. The percent engraftment [i.e., amount of insulin recovered from spleen as percent of tissue transplanted (mean, 15.4% in group 1 and 14.5% in group 2) or as percent of original pancreas (mean, 4.9% in group 1 and 4.4% in group 2)] was low in both groups but again was higher in normoglycemic than in hyperglycemic animals within each group. In conclusion, both the degree of engraftment and purification and the route of implantation influenced the functional outcome after dispersed pancreatic islet autotransplantation to the spleen of totally pancreatectomized dogs, with purified tissue injected retrogradely functioning better than unpurified tissue injected directly.

Definition of normothermic ischemia limits for kidney and pancreas grafts.

Normothermic ischemia tolerance is an important aspect of organ procurement and transplantation. The function of pancreas and kidney autografts was investigated in totally pancreatectomized or nephrectomized canine recipients. In 30 dogs the left limb (tail) of the pancreas was removed but left in the abdominal cavity after cessation of blood flow to produce warm ischemia for 30, 60, and 120 min (10 dogs at each time point), and then was flushed with cold Ringers' lactate and transplanted to the iliac vessels. Twenty dogs with fresh pancreatic transplants were controls. The success rate of pancreas transplants with warm ischemia of 1/2 and 1 hr was the same as that of controls (80%); however, after 1 hr normothermia 5/10 dogs had episodes of hyperglycemia for 1 week before glucose levels came back to normal. All but one graft with 2 hr warm ischemia failed. Intravenous glucose tolerance test (IVGTT) mean (+/- SEM) K values were not different in the successful groups, i.e., no warm ischemia: -1.55 +/- 0.15%; 1/2 hr warm ischemia: -1.81 +/- 0.18%; 1 hr warm ischemia: -1.64 +/- 0.09%. Amylase levels increased after transplant with maximum values at Day 2, then returned to normal, but the levels remained elevated in recipients of grafts subjected to longer normothermia with evidence of pancreatitis after 1 hr warm ischemia. Fifteen kidney grafts were treated similarly with warm ischemia exposure of 1/2 hr (n = 9) and 1 hr (n = 6) before being flushed and autotransplanted, and were compared to 16 fresh kidney transplants. After 1/2 hr warm ischemia none of the kidney grafts failed but 78% of the recipients had elevated serum creatinine and urea nitrogen levels which returned slowly to normal after 3 to 4 weeks. There was only one long-term survivor after 1 hr warm ischemia. Thus the pancreas seems to be more resistant to warm ischemia damage than is the kidney. This difference should be taken into consideration in regard to organ procurement for clinical transplantation.

Current status of clinical pancreas transplantation.

Pancreas transplantation (PT) has become increasingly effective for the treatment of human diabetes. Islet transplants have been successful only in the laboratory; clinical human islet transplantation needs to be improved with a search to reduce islet cells immunogenicity. Up to now, the only effective method of endocrine replacement therapy in diabetic patients is vascularized pancreas transplantation. Analysis of the International Human Pancreas Registry shows that the best options in 1985 are enteric diversion of the exocrine function, simultaneous kidney graft from the same donor and cyclosporin combined with other immunosuppressive agents in the recipient.