Heiner Wolters

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

BackgroundThe potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.Methods/DesignThe study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.DiscussionIf our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial RegisterTrial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36)

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ⩽60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial.

Background. Cytomegalovirus (CMV) prevention can be achieved by prophylaxis or preemptive therapy. We performed a prospective randomized trial to determine whether renal transplant recipients with a positive CMV serostatus (R+) had a higher rate of CMV infection and disease after transplantation when treated preemptively for CMV infection, compared with primary valganciclovir prophylaxis. Methods. Prophylaxis was 2×450 mg oral valganciclovir/day for 100 days; preemptive patients were monitored by CMV-polymerase chain reaction (PCR), and after a positive PCR test received 2×900 mg valganciclovir/day for at least 14 days followed by secondary prophylaxis. Valganciclovir dosage was adjusted according to renal function. Patients are followed up for 5 years and initial 12-month data are presented. Two hundred and ninety-six recipients were analyzed (168 donor/recipient seropositive [D+/R+], 128 donor seronegative/recipient seropositive [D−/R+]; 146 receiving prophylaxis and 150 preemptive therapy). Results. Overall, CMV infection (asymptomatic CMV viral load ≥400 CMV DNA copies/mL proven by CMV-PCR) was significantly higher in recipients under preemptive therapy (38.7% vs. 11.0%, P<0.0001), with the highest incidence in D+/R+ preemptive patients (53.8% vs. 15.6%, P<0.0001). D+/R+ recipients with preemptive therapy also had the highest rate of CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) (19.2% vs. 4.4%, P=0.003). Renal function assessed by creatinine clearance was similar for both groups. Graft loss occurred in 7 vs. 4 patients on preemptive versus prophylactic therapy (P>0.05). Tolerability was similar for both treatment groups. Conclusions. Oral valganciclovir prophylaxis significantly reduces CMV infection and disease, particularly for D+/R+ patients. Hence, our study supports routine prophylaxis for all D+/R+ recipients.

Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study.

The long‐term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12‐month, open‐label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m2, 95%CI 4.3, 11.0 mL/min/1.73 m2; p < 0.001) and month 36 (7.5 mL/min/1.73 m2, 95%CI 3.6, 11.4 mL/min/1.73 m2; p < 0.001). The incidence of biopsy‐proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

Cadaveric "two-in-one" kidney transplantation from marginal donors: experience of 26 cases after 3 years.

Background. Because of the problem of organ shortage, the use of renal transplants from marginal donors has been tested by different procedures. Methods. In our center 26 recipients (59±7 years) underwent double renal transplantation from July 1996 to August 1999 using marginal donors (71±6 years). A special scoring was applied that included donor age, serum creatinine, the grade of glomerulosclerosis, and kidney weights leading to the decision whether single or dual or no kidney transplantation was performed. Results. After an average follow-up of 18±10 months 22 of 26 (85%) double kidney transplant recipients are alive and have functioning grafts. Three patients died with well-functioning grafts. The actuarial 1-year patient and graft survival rate was 94% (n=18), the 2-year rate 92% (n=12). Two patients lost one graft each without becoming dialysis dependent. The average serum creatinine was 1.6±0.5 mg/dl after 12 months (n=17) and 1.9±0.6 mg/dl after 24 months (n=11). Primary nonfunction occurred in 31%, acute rejection within the first 6 months in 14%. Ten patients who received single old grafts according to our score had similar transplant survival rates but worse graft function after 1 year. Conclusions. Transplant function and survival of patients after dual kidney transplantation indicate that this procedure is reasonable to ameliorate the problem of organ shortage. The most crucial point is to establish a widely accepted standardized scoring for the donors leading to single, dual, or refusal of transplantation.

Outcome of Kidney Transplantation in Patients with Inherited Thrombophilia: Data of a Prospective Study

Inherited prothrombotic risk factors predispose patients to thromboembolic events. In kidney transplant recipients, thrombophilia may manifest itself with venous thrombosis, microvascular occlusion, or acute rejection with major consequences for allograft survival. This is a prospective study on 165 renal allograft recipients to evaluate the contribution of genetic thrombophilic risk factors to transplant outcome. Besides antithrombin, protein C, and protein S deficiencies, none of which was found in our patient group, factor V G1691A (FV G1691A), prothrombin G20210A (PT G20210A) mutations, and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms were studied. The primary endpoint of the study was occurrence of an acute rejection within the first 90 d and transplant loss within 1 yr. Heterozygous FV G1691A and PT G20210A mutations and the MTHFR T677T variant were significantly associated with acute rejections with rejection rates of 68%, 67%, and 71%, respectively, as compared with 35% in patients not carrying these genotypes. Many rejections that were histologically proven were acute vascular ones. Transplant loss was significantly associated exclusively with the PT G20210A group (50% 1-yr graft survival; odds ratio, 10.0; 95% confidence interval, 1.8 to 56.1). PT G20210A patients exerted the highest prothrombotic activity pretransplant, as determined by prothrombin 1.2 fragments (PT F1.2), which may be the background for minor outcome. In conclusion, common prothrombotic mutations are significantly associated with acute rejections, especially vascular rejections, and for PT G20210A also with early transplant failure. Screening for hypercoagulable states pretransplant is recommended to intensify anticoagulatory treatment posttransplant.

Segmental resection of the duodenum for gastrointestinal stromal tumor (GIST)

BackgroundGastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. The biological appearance of these tumors reaches from small lesions with benign appearance to aggressive sarcomas. Only 3–5% of GISTs are localized in the duodenum. There is a controversy, if duodenal GISTs should be treated by a duodenopancreatectomy or by a limited resection of the duodenum.Case presentationA 29-year-old man presented with an acute upper gastrointestinal bleeding from a submucosal tumor located in the proximal part III of the duodenum, 3 cm distal of the papilla of Vater. After an emergency laparotomy with ligation of tumor-feeding vessels in a primary hospital, definitive surgical therapy was performed by partial resection of the duodenum with a duodenojejunostomy. Histology revealed a GIST with a diameter of 2.5 cm and <5 mitoses/50 high power fields, indicating a low risk of malignancy. Therefore no adjuvant therapy with Imatinib was initiated.ConclusionGISTs of the duodenum are a rare cause of upper gastrointestinal bleeding. Partial resection of the duodenum is a warranted alternative to a duodenopancreatectomy, as this procedure has a lower operative morbidity, while providing comparable oncological results.

Laparoscopic simulation training: Testing for skill acquisition and retention.

BACKGROUND Simulation in laparoscopy leads to skill acquisition. Although many curricula for simulation training have been described, the nature of skill deterioration remains unclear. We evaluated skill acquisition and retention after laparoscopic simulation training. METHODS Thirty-six novices in surgery (medical students) underwent a 5-day curriculum consisting of 9 skills of increasing complexity. Each subject underwent baseline and post-training evaluation after completion of the course. Skill retention testing was measured after 6 weeks (group 1; n = 18) and after 11 weeks (group 2; n = 18). Neither group had access to a training facility during this interval. Task completion was measured in time (s) with penalties for inaccurate performance. RESULTS Comparison of the baseline and post-training values revealed a significant learning outcome for all exercises in both groups (P < .001). In group 1, skill retention testing found no significant decrease in skill level when compared to post-training values in all but 1 task (extracorporeal knot tying; P = .007). In group 2, differences between skill retention and post-training evaluation were observed for 5 of the 9 tasks (transfer task, positioning, loop tie, extracorporeal knot, and intracorporeal knot; P ≤ .05 for each). CONCLUSION Basic laparoscopic skills can be learned successfully by novices in surgery using a compact curriculum. These skills are retained for at least 6 weeks. Eleven weeks after initial training, skill deterioration is likely, and therefore an opportunity for practice and repetition is desirable.

Impact of failed allograft nephrectomy on initial function and graft survival after kidney retransplantation

The management of an asymptomatic failed renal graft remains controversial. The aim of our study was to explore the effect of failed allograft nephrectomy on kidney retransplantation by comparing the outcome of recipients who underwent graft nephrectomy prior to retransplantation with those who did not. Retrospective comparison of patients undergoing kidney retransplantation with (group A, n = 121) and without (group B, n = 45) preliminary nephrectomy was performed, including subgroup analysis with reference to patients with multiple (≥2) retransplantations and patients of the European Senior Program (ESP). Nephrectomy leads to increased panel reactive antibody (PRA) levels prior to retransplantation and is associated with significantly increased rates of primary nonfunction (PNF; P = 0.05) and acute rejection (P = 0.04). Overall graft survival after retransplantation was significantly worse in group A compared with group B (P = 0.03). Among the subgroups especially ESP patients showed a shorter graft survival after previous allograft nephrectomy. On the multivariate analysis, pretransplant graft nephrectomy and PRA >70% were independent and significant risk factors associated with graft loss after kidney retransplantation. Nephrectomy of the failed allograft was not beneficial for retransplant outcome in our series. Patients with failed graft nephrectomy tended to have a higher risk of PNF and acute rejection after retransplantation. The possibility that the graft nephrectomy has a negative impact on graft function and survival after retransplantation is worth studying further.

Exocrine drainage into the duodenum: a novel technique for pancreas transplantation

Simultaneous pancreas–kidney transplantation is the treatment of choice for patients suffering from type 1 diabetes mellitus and end‐stage renal failure secondary to diabetic nephropathy. Until 1995, about 90% of pancreas transplantations were performed with exocrine drainage into the bladder. Since then the proportion of pancreas transplants with enteric drainage increased steadily because of frequency of complications and long‐term disadvantages of bladder drainage. However, the use of enteric drainage removes the opportunity to monitor pancreatic allograft function either by measuring urinary amylase or by carrying out biopsy via cystoscopy. We report a new technique of exocrine pancreatic drainage into the recipient duodenum. This modification places the pancreas graft including the duodenal anastomosis in a retroperitoneal location and, importantly, allows easy graft monitoring via gastroscopy.