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Schnitzbauer A.A.,University of Regensburg | Zuelke C.,University of Regensburg | Graeb C.,Ludwig Maximilians University of Munich | Rochon J.,University of Regensburg | And 49 more authors.
BMC Cancer | Year: 2010

Background: The 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/Design: The 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.Discussion: If 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. © 2010 Schnitzbauer et al; licensee BioMed Central Ltd.

Polacco M.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | Vitale A.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | Valmasoni M.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | D'Amico F.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | And 9 more authors.
Transplantation Proceedings | Year: 2010

Tumor progression before orthotopic liver transplantation (OLT) is the main cause of dropouts from waiting lists among patients with hepatocellular carcinoma (HCC). Performing a porto-caval shunt (PCS) before parenchymal liver transection has the potential to allow an extended hepatectomy in patients with decompensated liver cirrhosis, reducing portal hyperflow and therefore the sinusoidal shear-stress on the remnant liver. We report the case of a 59-year-old man affected by hepatitis C virus (HCV)-related decompensated liver cirrhosis (Child Pugh score presentation, C-10; Model for End Stage Liver Disease score, 18) and HCC (2 lesions of 2 and 2.8 cm). The patient began the evaluation to join the OLT waiting list, but, in the 3 months required to complete the evaluation, he developed tumor progression: 3 HCC lesions, the largest 1 with a diameter of about 4.4 cm. These findings excluded transplantation criteria and the patient was referred to our center. After appropriate preoperative studies, the patient underwent a major liver resection (trisegmentectomy) after side-to-side PCS by interposition of an iliac vein graft from a cadaveric donor. The patient overcame the worsened severity of cirrhosis. After 6 months of follow-up, he developed 2 other HCC nodules. He was then included on the waiting list at our center, undergoing OLT from a cadaveric donor at 8 months after salvage treatment. At 36 months after OLT, he is alive and free from HCC recurrence. Associating a partial side-to-side PCS with hepatic resection may represent a potential salvage therapy for patients with decompensated cirrhosis and HCC progression beyond listing criteria for OLT. © 2010 Elsevier Inc. All rights reserved.

Cillo U.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | Vitale A.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | Dupuis D.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | Corso S.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | And 6 more authors.
PLoS ONE | Year: 2013

The aim of this study was to demonstrate the safety and efficacy of laparoscopic ablation for cirrhotic HCC patients. Between January 2004 and December 2009, laparoscopic ablation was applied prospectively in 169 consecutive HCC patients (median age 62 years, 43% hepatitis C positive) considered ineligible for liver resection and/or percutaneous ablation. There was clinically relevant portal hypertension in 72% of cases. A significant proportion of subjects (50%) had multinodular tumors or nodules larger than 25 mm. The main ablation techniques used were radiofrequency in 103 patients (61%), microwave ablation in 8 (5%), and ethanol injection in 58 (34%). The primary endpoint was 3-year survival. There was no perioperative mortality. The overall morbidity rate was 25%. The median postoperative hospital stay was 3 days (range 1-19 days). Patients survived a median 33 months with a 3-year survival rate of 47%. Cox's multivariate analysis identified patient age, presence of diabetes, albumin ≤37 g/l, and alpha-fetoprotein >400 μg/l as significant preoperative predictors of survival, while the chance to undergo liver transplantation and postoperative ascites were the only independent postoperative predictor of survival. Laparoscopic ablation is a safe and effective therapeutic option for selected HCC patients ineligible for liver resection and/or percutaneous ablation. © 2013 Cillo et al.

Tuci F.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | Vitale A.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | D'Amico F.,University of Padua | Gringeri E.,Unita di Chirurgia Epatobiliare e Trapianto Epatico | And 10 more authors.
Transplantation Proceedings | Year: 2014

Background Liver transplantation (LT) for hepatocellular carcinoma (HCC) can be used for tumor recurrence after liver resection (LR) both for initially transplant-eligible patients as conventional salvage therapy (ST) and for non-transplant-eligible patients (beyond Milan criteria) with a goal of downstaging (DW). The aim of this study was to compare the intention-to-treat (ITT) survival rates of patients who are listed for LT, according to these two strategies.Methods We analyzed a prospective database of 399 consecutive patients who underwent hepatic resection for HCC from 2002 to 2011 to identify patients included in the waiting list for tumor recurrence. Intention-to-treat (ITT) survivals were compared with those of patients resected for HCC within and beyond Milan criteria in the same period and not included in the LT waiting list.Results The study group consisted of 42 patients, 28 in the ST group (within Milan) and 14 in the DW group (beyond Milan). The 5-year ITT survival rate was similar between the 2 groups, being 64% for ST and 60% for DW (P =.84). Twenty-five patients (15 ST and 10 DW) underwent LT, 13 (10 ST and 3 DW) were still awaiting LT, 4 (3 ST and 1 DW) dropped out of the waiting list because of tumor progression, and 7 (5 ST [33%] and 2 DW [20%]) had tumor recurrence. The 5-year ITT survival of ST patients was similar to that of 252 in-Milan HCC patients resected only (P =.3), whereas 5-year ITT survival of DW patients was significantly higher (P <.01) than that of 105 beyond-Milan HCC patients resected only.Conclusions LR seems to be a safe and effective therapy both as alternative to transplantation and as downstaging strategy for intermediate-advanced HCC. The survival benefit of salvage LT, however, seems to be higher in the 2nd than in the 1st group. © 2014 Elsevier Inc. All rights reserved.

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