De novo cancer in cyclosporine-treated and non-cyclosporine-treated adult primary renal allograft recipients.

We compared the incidence of de novo tumors developing in 1165 primary adult renal allograft recipients treated with azathioprine (AZA)-prednisone (Pred)-antilymphocyte globulin (ALG) (CONV group) with that in 722 patients receiving cyclosporine (CSA) as part of double (CSA-Pred), triple (CSA-Pred-AZA), or quadruple-therapy (CSA-Pred-AZA-ALG) protocols. Mean +/- SD follow-up was 9.5 +/- 6.4 years for the CONV group and 6.2 +/- 2.7 years for the CSA group. Overall, 124 patients (10.6%) in the CONV group and 34 patients (4.7%) in the CSA group developed malignancies, with nonmelanoma skin cancers and lymphomas comprising 55% and 13% of cancers in the CONV group and 65% and 3% of cancers in the CSA group, respectively. There were no significant differences in overall cancer (p = 0.41) or skin cancer (p = 0.97) incidence between non-CSA-treated and CSA-treated patients by Kaplan-Meier life-table analysis; however, CONV-treated patients demonstrated a higher incidence of lymphoma (p = 0.05). The mean (+/- SD) time to overall and skin cancer occurrence was significantly shorter in the CSA group: 37 +/- 22 versus 90 +/- 52 months (p < 0.001) and 40 +/- 24 versus 92 +/- 52 months, respectively. When the Cox Proportional Hazard Model was utilized to assess the relative importance of age, diabetic status, donor source, sex, and immunosuppressive regimen in determining cancer development, age > or = 50 years and nondiabetic status were significant independent prognostic indicators, while immunosuppressive regimen was not. Graft and patient survival were significantly greater in CONV-treated patients developing cancer than in those who did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of 15-deoxyspergualin on immediate function and long-term survival of transplanted islets in murine recipients of a marginal islet mass.

15-Deoxyspergualin (DSG), a macrophage immunomodulatory agent, was used as a probe in a murine model of islet transplantation to examine 1) the significance of the nonspecific, macrophage-mediated effector arm of beta-cell injury in recipients of a marginal mass of isologous islets by analyzing the duration of temporary posttransplant hyperglycemia, a parameter of immediate beta-cell function; and 2) whether long-term (> 100 days) functional survival could be achieved in recipients of a marginal mass of allogeneic islets. A dose-response study of the number of islets required to ameliorate diabetes showed that 150 isologous islets per recipient resulted in a 75% incidence of cure at a mean of 39.2 +/- 5.8 days posttransplant. DSG-treated (0.625 mg.kg-1.day-1 intraperitoneally) recipients of isologous islets demonstrated a significant (P < 0.01) reduction in the duration of temporary posttransplant hyperglycemia (16.8 +/- 3.2 vs. 39.2 +/- 5.8 days), and DSG-treated recipients of allogeneic islets demonstrated a significant (P < 0.03) improvement in the rate of achieving long-term functional survival (75 vs. 22% in untreated control animals). Finally, identical rates of islet engraftment were found among control animals and DSG-treated animals by measurement of tissue insulin content in transplanted specimens. The results are consistent with the hypothesis that DSG alters the duration of temporary posttransplant hyperglycemia and extends long-term functional survival in murine recipients of a marginal mass of islets, not by affecting the efficiency of islet engraftment, but by suppression of the inhibitory effects on beta-cell function by nonspecific, macrophage mediators.

Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15-deoxyspergualin.

Islet transplantation has been slow to develop as a therapy for type I diabetes mellitus. Conventional immunosuppression does not protect islet allografts from early failure and by current techniques the yield of purified islets from a single pancreas is inadequate or only marginally in excess of the number needed to sustain normoglycaemia. We transplanted unpurified islets from a single pancreas concomitantly with a kidney to two uraemic diabetic patients. The novel agent 15-deoxyspergualin, along with antilymphocyte globulin, was used for induction immunosuppression, and azathioprine, prednisone, and cyclosporin for maintenance. Islet function has been sustained in both, and the second patient is insulin-independent and euglycaemic more than 6 months after transplantation.

Emergent middle cerebral artery embolectomy: a useful technique for cranial base surgery.

Given the poor natural history of untreated symptomatic acute middle cerebral artery occlusion, we have attempted emergent reperfusion in all three cases of acute embolic middle cerebral artery occlusion seen on our cranial base service over the last 10 years. One patient developed a massive stroke requiring a life-saving "strokectomy" within 48 hours, which left him permanently hemiplegic, hemianopic, and hemihypesthetic after a failed attempt at reperfusion by superselective endovascular injection of urokinase. The other two patients, who were aphasic and densely hemiparetic, underwent successful emergent embolectomy with reperfusion established within 5 and 12 hours, respectively. One of the two is now neurologically normal, and the second is left with a subtle monoparesis but is independent in activities of daily living. Since middle cerebral artery embolism in cranial base patients usually occurs in a closely monitored hospital setting, we are presented with a unique opportunity for early successful operative intervention. Principles for optimizing outcome include: early recognition and diagnosis, maximization of medical therapy during the diagnostic workup prior to embolectomy (induced hypertension, intravascular volume expansion, and pharmacologic cerebral metabolic demand reduction), confirmation that the involved region does not have absent blood flow by xenon/computed tomography, early operative intervention, and careful surgical technique.

Conversion of exocrine secretions from bladder to enteric drainage in recipients of whole pancreaticoduodenal transplants.

Between September 1984 and August 1991, 265 whole pancreaticoduodenal transplants were done at our institution, with bladder drainage of exocrine secretions through a duodenocystostomy. Seventeen patients subsequently underwent conversion from bladder to enteric drainage at 2 to 64 months after transplant. Eight conversion procedures were done to correct chronic intractable metabolic acidosis due to bicarbonate loss from the allograft: seven to alleviate severe dysuria, presumed secondary to the action of graft enzymes on uroepithelium; one to prevent recurrent allograft pancreatitis, presumed secondary to back pressure from the bladder; and one because of graft duodenectomy for severe cytomegalovirus duodenitis with perforation. None were done to correct technical complications from the initial transplant operation. The conversions were done by dividing the graft duodenocystostomy, then re-establishing drainage through a graft duodenal-recipient jejunal anastomosis. A simple loop of recipient jejunum was used for the duodenojejunostomy in 15 cases, and a Roux limb in two. One of those two cases had a previously created Roux limb that was available for use. The other was in the patient who underwent graft duodenectomy and subsequent mucosa-to-mucosa anastomosis of the pancreatic duct to a newly created Roux limb of jejunum. All patients experienced relief of their symptoms after operation. Two patients had surgical complications (12%), an enterotomy in one case, which was closed operatively, and an enterocutaneous fistula in the other case, which healed spontaneously with bowel rest and parenteral nutrition. The drawback to conversion is loss of urine amylase as a marker for rejection, particularly in recipients of solitary pancreas grafts (n = 5). In recipients of simultaneous pancreas-kidney (SPK) allografts (n = 12), the kidney can still be used to monitor for rejection (two with follow-up < 1 year, 10 with follow-up > 1 year). None of our solitary pancreas recipients, however, have lost graft function (follow-up, 10 to 36 months). The only pancreas allograft loss was in an SPK recipient who also rejected the kidney 6 months after conversion. She received a second SPK transplant with enteric drainage, and is insulin independent and normoglycemic 10 months after retransplantation. Patients converted for metabolic acidosis tended to have impaired renal function (mean creatinine, 2.14 +/- 0.98 mg/dL at time of conversion) due to chronic rejection, progression of native kidney diabetic nephropathy, or cyclosporine toxicity, and possibly could not compensate for bicarbonate loss from the pancreas allograft.(ABSTRACT TRUNCATED AT 400 WORDS)

Facial nerve repair by interposition nerve graft: results in 22 patients.

Resection of tumors of the posterior cranial base may incorporate a segment of the facial nerve because of tumor infiltration, or may result in unplanned nerve injury. Immediate repair of the facial nerve by resuture or with an autogenous nerve graft is highly desirable to ensure optimal recovery of facial function. Twenty-four patients who underwent extensive surgery of the posterior skull base and facial nerve reconstruction were studied. Of these, 12 patients had preoperative facial weakness and 3 had facial palsy. All patients underwent graft reconstruction from the subarachnoid or labyrinthine portion of the facial nerve to the fallopian or extracranial segment. The greater auricular nerve was used as a graft in 14 patients, and the sural nerve in 10. Two patients died of their disease soon after surgery, and, therefore, were excluded from our follow-up. In the remaining 22 patients, the median follow-up time was 20 months. As evaluated by the House-Brackmann grading system, 45% (10/22) of the surviving patients achieved a good recovery of facial function, 36% (8/22) attained a fair recovery, and 18% (4/22) had minimal or no recovery. There was no statistical correlation between the length of the graft used and the degree or timing of clinical recovery. The surgical result obtained in all patients with complete preoperative facial palsy and in one patient with dense facial paresis was poor.

Successful 96-Hr cold-storage preservation of canine pancreas with UW solution containing the thromboxane A2 synthesis inhibitor OKY046.

Prostanoids, such as prostacyclin (PGI) and thromboxane A2 (TxA), have been recently suggested to play an important role in preservation-induced injury of pancreas grafts. We have previously shown that the TxA synthesis inhibitor OKY046 prevents a decrease of both the PGI/TxA ratio and blood flow in pancreas grafts after 24-hr preservation with Euro-Collins solution. In our present study, we analyzed whether OKY046 added to University of Wisconsin (UW) solution could extend successful cold-storage preservation of segmental canine pancreas grafts, compared with UW alone. We divided 30 dogs into four preservation groups: Group 1, UW solution for 72 hr (n = 7); Group 2, UW solution for 96 hr (n = 8); Group 3, UW solution plus OKY046 (10(-4) M) for 72 hr (n = 7); and Group 4, UW solution plus OKY046 (10(-4) M) for 96 hr (n = 8). After the cold storage period, segmental pancreas auto-transplantation with immediate completion pancreatectomy was done. Preservation was deemed successful if serum glucose less than 150 mg/dl was maintained for at least 5 days. Intravenous glucose tolerance tests and biopsies were done in those dogs with functioning grafts 14 days post-transplant. Successful preservation rates were as follows: Group 1, 57.1%; Group 2, 12.5%; Group 3, 100%; and Group 4, 75%. The mean K values (+/- standard error) were: Group 1, 1.54 +/- 0.13; Group 2, 0.59; Group 3, 1.54 +/- 0.14; and Group 4, 1.59 +/- 0.24 (not statistically different).(ABSTRACT TRUNCATED AT 250 WORDS)

Prolongation of canine islet allograft survival by 15-deoxyspergualin.

Previously we have shown that nonsteroidal, multimodal immunosuppression consisting of cyclosporine (CsA), azathioprine (AZA), and RBC-absorbed goat anti-dog lymphoblast globulin (ALG), at doses considered tolerable in humans, results in limited canine islet allograft survival. Regimens including the diabetogenic agent prednisone are even less successful. In our search for an immunosuppressive regimen that could be applied to human islet transplantation, we tested the effect of 15-deoxyspergualin (DSG) in a canine model. Animals received either CsA, 20 mg/kg/day; AZA, 2.5 mg/kg/day; and ALG, 20 mg/kg/day x 14 days (Group I) or CsA, AZA, ALG at the same doses with the addition of low dose DSG, 0.5 mg/kg/day (Group II). Trough CsA levels by high pressure liquid chromatography ranged in both groups between 100 and 200 micrograms/liter. Rejection of the islets was diagnosed when serum glucose remained greater than 200 mg/dl for 3 consecutive days. There was no significant difference in the number of islets per kilogram of body weight of recipient transplanted in Group I and Group II (5754 +/- 2544 islets/kg versus 7953 +/- 3440 islets/kg, respectively). Animals receiving ALG, CsA, and AZA alone achieved a median islet allograft survival of 4 days, with a mean of 10.8 days. However, with the addition of low-dose DSG, median islet allograft survival was improved to 22 days, with a mean of 32.4 days (P = 0.012, Mann-Whitney test). We conclude that the addition of low-dose DSG to an ALG induction, cyclosporine-based immunosuppressive regimen enhances canine islet allograft survival and has potential for application in clinical islet allotransplantation.