Michael Heise

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.

Liver transplantation for treatment of intrahepatic Osler's disease: first experiences.

BACKGROUND Intrahepatic Oslers disease with multiple arteriovenous malformations and high intrahepatic shunting may lead to secondary pulmonary hypertension followed by right-heart stress and insufficiency. Until now, therapy with arterial embolization, banding, or ligation of the hepatic arteries is still limited and provides unsatisfactory long-term results. Liver transplantation offers another therapeutic option. METHODS We report on four patients with intrahepatic involvement of Oslers disease who were liver transplanted between 1995 and 1999. All patients suffered from restricted liver function and right-heart insufficiency with multiple cardiac decompensations. One patient received one course of embolization, and another received six courses of embolization and then banding of the main hepatic artery before transplantation. In both patients, the clinical symptoms improved for only a few months. RESULTS All patients had high degrees of intrahepatic arteriovenous shunting, and cardiac output measurements were between 8.0 to 13.3 L/min preoperatively. Preoperative mean pulmonary artery pressure was between 24 to 35 mmHg. After liver transplantation, cardiac output and right-heart diameter decreased or normalized and pulmonary pressure reached the normal range after 2 months. All patients received tacrolimus and steroids for primary immunosuppression. In one case, temporary hemodialysis was necessary for 2 weeks after transplantation, but renal function recovered completely. After follow-up time of 12 to 65 months, all patients had normal graft function and good cardiopulmonary condition. CONCLUSIONS Indication for liver transplantation should be considered in patients with intrahepatic Oslers disease, high arteriovenous shunting with right-heart stress, and restricted liver function before irreversible fixed pulmonary hypertension leads to severe right-heart insufficiency or failure. Our therapeutic regimen of early liver transplantation in the case of intrahepatic Oslers disease in four patients has promising results.

A new method of intraoperative hydraulic impedance measurement provides valuable prognostic information about infrainguinal graft patency

PURPOSE Prognostic information about graft outcome, obtained by using a new method for intraoperative measurement of vascular impedance, was evaluated. METHODS Hydraulic impedance was measured in 136 infrainguinal bypass grafts that were entered into a multicenter trial. Seventy femoropopliteal and 66 femorocrural polytetrafluoroethylene (PTFE) grafts were used. The arterial impedance measurement involved a silicon bypass graft temporarily inserted between the proximal and distal anastomoses sites. A flowmeter probe and a pressure transducer were incorporated into the tube. The digitally stored waveforms were subjected to a fast Fourier transformation and both input (Z(x)) and characteristic (Z(0)) impedances, as well as phase relations, were computed and related to graft outcome after 3 years. RESULTS Significant prognostic information for both popliteal and crural grafts was provided by means of the phase angle of the first harmonic. Primary and secondary patency rates for popliteal bypasses were 45% +/- 1% and 65% +/- 2% for phase angles greater than -40 degrees (n = 57) and 37% +/- 1% and 40% +/- 1% for phase angles less than -40 degrees (n = 13, p(prim ) = not significant, p(sec) < 0.01). For crural grafts, the secondary patency rates were 49% +/- 1% and 61% +/- 2% for phase angles greater than -40 degrees (n = 53) and 15% +/- 1% and 0% for phase angles less than -40 degrees (n = 13, P <.01). All crural bypass grafts with phase angles less than -40 degrees occluded within 16 months. Steady flow resistance, as well as Z(x) and Z(0), failed to indicate a significant relation to graft prognosis. CONCLUSION This method provides reliable prognostic information regarding graft patency and opens hydraulic impedance measurement to clinical surgery. The phase lag between flow and pressure curves, as expressed by the phase angle of the first harmonic, provides significant prognostic information.

Impact of stable PGI2 analog iloprost on early graft viability after liver transplantation: a pilot study

Bärthel E, Rauchfuß F, Hoyer H, Habrecht O, Jandt K, Götz M, Voigt R, Heise M, Marx G, Settmacher U. Impact of stable PGI2 analog iloprost on early graft viability after liver transplantation: a pilot study. 
Clin Transplant 2012: 26: E38–E47. 
© 2011 John Wiley & Sons A/S.

Living donor liver transplantation in adults in the MELD era in Germany – a multi‐center retrospective analysis

The aim of this analysis was to provide an update on the current trend in living donor liver transplantation (LDLT) for adult recipients in the model of end stage liver disease (MELD) era in Germany and to encourage a wider implementation of LDLT. We descriptively analysed the data of LDLTs in Germany from 15 December 2006 to 31 December 2009 using a multi‐center retrospective analysis via a questionnaire and data provided by Eurotransplant. Ten German centers performed LDLTs in adults. Eighty four transplantations in 50 male recipients and 34 female recipients were performed during the review period, ranging from 1 to 16 LDLTs per center. Hepatocellular carcinoma in cirrhosis (15/84) was the most common transplantation indication. The recipient mean lab‐MELD score was 15 (±8). Six re‐transplantations were necessary after initial LDLTs. The 1‐year patient survival was 81%. We obtained data of 79/84 donors. The incidence of complications was 30.4% (n = 24). There were no grade 5 complications according to the Clavien classification. LDLT is an established treatment option that may reduce the waiting time, provides high quality split liver grafts and should be advocated in the MELD era to reduce organ shortage and ‘death on the waiting list’.

Liver Transplantation Utilizing Old Donor Organs: A German Single-Center Experience

INTRODUCTION Due to the current profound lack of suitable donor organs, transplant centers are increasingly forced to accept so-called marginal organs. One criterion for marginal donors is the donor age >65 years. We have presented herein the impact of higher donor age on graft and patient survival. PATIENTS AND METHODS Since 2004, 230 liver transplantations have been performed at our center, including 54 donor organs (23.5%) from individuals >65 years of age. We performed a retrospective analysis of recipient and graft survivals. RESULTS The overall 1-year mortality was 22.2% (12/54) among recipients of organs from older donors versus 19.5% among recipients whose donors were <65 years. When donor organs were grouped according to age, the 1-year mortality in patients receiving organs from donors aged 65-69 years was 30% (6/20); 70-74 years, 29.4% (5/17); and donors >75 years, 5.9% (1/17). There was no significant correlation between mortality rate and the number of additional criteria of a marginal donor organ. DISCUSSION The current lack of donor organs forces transplant centers to accept organs from older individuals; increasingly older patients are being recruited for the donor pool. Our results showed that older organs may be transplanted with acceptable outcomes. This observation was consistent with data from the current literature. It should be emphasized, however, that caution is advised when considering the acceptance of older organs for patients with hepatitis C-related cirrhosis.

Implantation of the Liver During Reperfusion of the Heart in Combined Heart-Liver Transplantation: Own Experience and Review of the Literature

BACKGROUND There are only a few reports about combined heart-liver transplantations. The surgical techniques differ widely, ranging from sequential implantation of the organs to simultaneous transplantations. We report our experience with simultaneous, combined heart-liver transplantations without using a veno-venous bypass demonstrating that this is a feasible surgical technique. METHODS Since 2005, we performed 4 combined heart-liver transplantations by implanting the liver during the reperfusion period of the newly implanted heart. We retrospectively reviewed patient clinical data and outcomes. RESULTS The mean operative time was 534 ± 247 minutes and the ischemia times for heart and liver were 190 ± 72 minutes (cold ischemia time for the heart), 98 ± 96 minutes (warm ischemia time for the heart), 349 ± 101 minutes (cold ischemia time for the liver), and 36.25 ± 3.5 minutes (warm ischemia time for the liver). Three patients were discharged from the hospital after an uneventful clinical course. One patient died due to multi-organ failure during the intensive care unit stay on the 23rd postoperative day. CONCLUSION We suggest that combined, simultaneous heart-liver transplantation without veno-venous bypass is a feasible surgical technique.

Comparison of straight and Venaflo-type cuffed arteriovenous ePTFE grafts in an animal study

BACKGROUND The long-term prognosis of arteriovenous (AV) polytetrafluoroethylene (PTFE) hemodialysis grafts is dissatisfying. Responsible for the poor outcome is a stenosis of the venous anastomosis. This originates from both pseudointimal (PI) and neointimal hyperplasia (IH) development. Although cuffed grafts have a better short-term prognosis than straight grafts, the late results of both types are poor. This current study aimed to compare both arteriovenous straight and Venaflo-type (Bard, Tempe, Ariz) prostheses in an animal study with regard to patency, PI, and IH development. METHODS Sixteen iliac arteriovenous expanded polytetrafluoroethylene (ePTFE) loops were inserted into 16 pigs. Animals were randomized into two groups. Group 1 animals received straight configured ePTFE grafts and group 2 animals received grafts with a Venaflo-type cuffed venous anastomosis. After insertion of the shunts and immediately before graft harvest, the shunt flows were measured. Six weeks after implantation, patency rates and development of pseudointima (PI) within the grafts were noted. The thickness of the venous intimal hyperplasia was measured using digital planimetry. RESULTS Patency rates after 6 weeks were 25% for straight and 62% for Venaflo-type grafts. In both groups a significant decrease of the graft blood flow compared with the preoperative levels was observed, which was attributed to the marked development of pseudointima. The reduction in flow at graft harvest was greater in the straight ePTFE group (658 ± 68 vs 260 ± 42 mL/min, P < .05) than for the Venaflo-type grafts (770 ± 107 vs 661 ± 284 mL/min, P = ns), but the differences between the groups were statistically not significant. A marked pseudointima developed in the Venaflo cuff. The PI development was significantly higher in the graft hood (2.9 ± 0.6 mm) than in the heel (2.5 ± 0.4 mm, P < .05). In both groups, an intimal hyperplasia formed on the vein wall just opposite to the graft inflow. The intimal hyperplasia development was more pronounced in the straight configured shunts. CONCLUSIONS The results of the present study confirm the inferior clinical results of ePTFE grafts used for hemodialysis access. Although the patency rates of cuffed grafts were superior, in both graft types a significant pseudointima leading to subtotal graft stenosis was observed in all grafts. Both straight and Venaflo-grafts. The Venaflo grafts have a slightly bettertype cuffed ePTFE grafts have major hemodynamic drawbacks that have to be addressed in future graft design efforts.

Indikationen und Ergebnisse der palliativen Magenresektion beim fortgeschrittenen Magenkarzinom

BACKGROUND Gastric carcinoma is often diagnosed at UICC stage 3 b or 4. R0 resection can be achieved only in very few such cases. Even for these patients the 5-year survival rate is less than 5 %. Surgical palliation is traditionally reserved for the treatment of severe tumour complications not responding to other forms of treatment. PATIENTS AND METHODS We report on 21 patients who underwent palliative resection for gastric carcinoma at our institution between 2004 and 2007. Ten of these were assigned to palliative surgical treatment pre-operatively while this choice was made for 11 patients on the grounds of the intra-operative findings. We performed 17 gastrectomies, 3 proximal gastric resections and one distal gastric resection. RESULTS It has been shown that the patients have an improved overall survival time as compared to patients who received non-surgical treatment. The perioperative risk was reasonable when patients were carefully selected. Median survival for resected patients was 16 months. 80 % of patients were alive after 6 months and approximately 60 % of patients were alive after 12 months. The perioperative mortality was 0 % with a mean hospital stay of 12 days. All patients were discharged home with proper bowel passage and analgesia as individually required. CONCLUSIONS We are convinced that palliative gastric resection provides a pronounced survival benefit over any other palliative treatment options. Patients also have an improved quality of life.