Peter Schemmer

A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus After Liver Transplantation—PROTECT

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal‐sparing alternative. In this randomized 1‐year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post‐LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft‐Gault formula (−2.9 mL/min in favor of EVR, 95%‐CI: [−10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (−7.8 mL/min, 95%‐CI: [−14.366; −1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy‐proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI‐based to EVR‐based immunosuppression proved to be a safe alternative post‐LTx that deserves further investigation in terms of nephroprotection.

Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors

To identify new tumor‐suppressor gene candidates relevant for human hepatocarcinogenesis, we performed genome‐wide methylation profiling and vertical integration with array‐based comparative genomic hybridization (aCGH), as well as expression data from a cohort of well‐characterized human hepatocellular carcinomas (HCCs). Bisulfite‐converted DNAs from 63 HCCs and 10 healthy control livers were analyzed for the methylation status of more than 14,000 genes. After defining the differentially methylated genes in HCCs, we integrated their DNA copy‐number alterations as determined by aCGH data and correlated them with gene expression to identify genes potentially silenced by promoter hypermethylation. Aberrant methylation of candidates was further confirmed by pyrosequencing, and methylation dependency of silencing was determined by 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) treatment. Methylation profiling revealed 2,226 CpG sites that showed methylation differences between healthy control livers and HCCs. Of these, 537 CpG sites were hypermethylated in the tumor DNA, whereas 1,689 sites showed promoter hypomethylation. The hypermethylated set was enriched for genes known to be inactivated by the polycomb repressive complex 2, whereas the group of hypomethylated genes was enriched for imprinted genes. We identified three genes matching all of our selection criteria for a tumor‐suppressor gene (period homolog 3 [PER3], insulin‐like growth‐factor–binding protein, acid labile subunit [IGFALS], and protein Z). PER3 was down‐regulated in human HCCs, compared to peritumorous and healthy liver tissues. 5‐aza‐dC treatment restored PER3 expression in HCC cell lines, indicating that promoter hypermethylation was indeed responsible for gene silencing. Additionally, functional analysis supported a tumor‐suppressive function for PER3 and IGFALS in vitro. Conclusion: The present study illustrates that vertical integration of methylation data with high‐resolution genomic and transcriptomic data facilitates the identification of new tumor‐suppressor gene candidates in human HCC. (HEPATOLOGY 2012;56:1817–1827)

Everolimus and Early Calcineurin Inhibitor Withdrawal: 3-Year Results From a Randomized Trial in Liver Transplantation

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open‐label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI‐based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft‐Gault) at month 11 postrandomization. A 24‐month extension phase followed 81/114 (71.1%) of eligible patients to month 35 postrandomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1u2009mL/min (95% confidence interval [CI] −1.3, 21.5u2009mL/min, pu2009=u20090.082) in favor of CNI‐free versus CNI using Cockcroft‐Gault, 9.4u2009mL/min/1.73u2009m2 (95% CI −0.4, 18.9, pu2009=u20090.053) with Modification of Diet in Renal Disease (four‐variable) and 9.5u2009mL/min/1.73u2009m2 (95% CI −1.1, 17.9, pu2009=u20090.028) using Nankivell. The difference in favor of the CNI‐free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy‐proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI‐free patients and five CNI patients (12.2% vs. 12.5%, pu2009=u20091.000) during the extension phase. Everolimus‐based CNI‐free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Outcome and development of symptoms after orthotopic liver transplantation for Wilson disease

Wilson disease (WD) is an autosomal recessive copper storage disease resulting in hepatic and neurologic dysfunction. Liver transplantation is an effective treatment for fulminant cases for patients with chronic liver disease. Reports on the outcome of neuropsychiatric symptoms after orthotopic liver transplantation (OLT) are limited.

Melatonin promotes sorafenib-induced apoptosis through synergistic activation of JNK/c-jun pathway in human hepatocellular carcinoma

Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma (HCC) through its antiproliferative and pro‐apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose‐dependent growth inhibition of HuH‐7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co‐treatment of HuH‐7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib‐induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase‐3 and the JNK/c‐jun pathway. Inhibition of JNK/c‐jun pathway with its inhibitor SP600125 reversed the phosphorylation of c‐jun and the activation of caspase‐3 induced by co‐treatment of HuH‐7 cells with melatonin and sorafenib in a dose‐dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC.

Hepatobiliary malignancies in Wilson disease

Reports of hepatobiliary malignancies in Wilson disease are sparse. The aim of this study was to evaluate hepatobiliary malignancies in Wilson disease patients concerning the clinical course of tumour disease and pathological analysis of tumour tissue.

Impact of Neoadjuvant Chemotherapy on Hypertrophy of the Future Liver Remnant after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

BACKGROUNDnAssociating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been demonstrated as a feasible procedure in extended liver resections as a means of successfully increasing the volume of the future liver remnant (FLR). Neoadjuvant chemotherapy (CTx) is toxic to the organ and may impair hepatic regeneration. This study was performed to assess the procedures effect on hypertrophy of the FLR, including the short-term survival.nnnSTUDY DESIGNnWe analyzed 19 consecutive ALPPS patients, of whom 58% (n = 11) received neoadjuvant CTx because of colorectal liver metastasis (CRM). Patients presented with multifocal CRM (n = 11, 58%); cholangiocarcinoma (n = 7, 37%), of which 5 were in the Klatskin position; and gallbladder carcinoma (n = 1, 5%). Hepatectomy was performed within 6 to 13 days after hepatic partition. Volumetry was performed before both liver partitioning and hepatectomy. A survival analysis was performed.nnnRESULTSnLiver partition and portal vein ligation induced sufficient hypertrophy of the FLR, with an increased volume of 74% ± 35%. Patients underwent hepatectomy after a median of 8 days; in all cases R0 resection was achieved. Neoadjuvant CTx was shown to significantly impair hypertrophy. The volume of the FLR in non-CTx patients increased by 98% ± 35%; an increase of 59% ± 22% was observed in patients who underwent CTx (p = 0.027). Chemotherapy did not have an impact on either morbidity or in-hospital mortality, which were 68% and 16%, respectively. One-year overall survival was 53%, with a 1-year survival of 67% in CRM patients and 38% in non-CRM patients (p > 0.05).nnnCONCLUSIONSnData presented here demonstrate for the first time that neoadjuvant CTx significantly impairs hypertrophy of the FLR after ALPPS.

Allogeneic Blood Transfusion Does Not Affect Outcome After Curative Resection for Advanced Cholangiocarcinoma

AbstractPurposeTon assess the impact of perioperative blood transfusion on overall and disease-free survival in patients undergoing curative resection for cholangiocarcinoma.MethodsIn a single-center study, 128 patients undergoing curative resection for cholangiocarcinoma between 2001 and 2010 were assessed. The median follow-up period was 19xa0months. Transfused and nontransfused patients were compared by Cox regression and propensity score analyses.ResultsOverall, 38 patients (29.7xa0%) received blood transfusions. The patient characteristics were highly biased with respect to receiving transfusions (propensity score 0.69xa0±xa00.22 vs. 0.11xa0±xa00.16, pxa0<xa00.001). In the unadjusted analysis, blood transfusion was associated with a 105xa0% increased risk of mortality [hazard ratio (HR) 2.05, 95xa0% CI 1.19–3.51, pxa0=xa00.010]. In the multivariate (HR 1.14, 95xa0% CI 0.52–2.48, pxa0=xa00.745) and the propensity score-adjusted Cox regression (HR 1.02, 95xa0% CI 0.39–2.62, pxa0=xa00.974), blood transfusion had no influence on overall survival. Similarly, in the propensity score-adjusted Cox regression (HR 0.62, 95xa0% CI 0.24–1.58, pxa0=xa00.295), no relevant effect of blood transfusion on disease-free survival was observed.ConclusionsTo our knowledge, this is the first propensity score-based analysis providing compelling evidence that the worse oncological outcome after curative resection for advanced cholangiocarcinoma in patients receiving perioperative blood transfusions is caused by the clinical circumstances requiring the transfusions, not by the blood transfusions themselves.

Pilot study evaluating broccoli sprouts in advanced pancreatic cancer (POUDER trial) - study protocol for a randomized controlled trial

BackgroundPancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with marked resistance to chemo- and radiotherapy. PDA-cancer stem cells (CSCs) are not targeted by current therapies and may be a reason for poor prognosis. Studies indicate that diets rich in cabbage, broccoli, and cauliflower offer cancer preventative and therapeutic benefits. Recent experimental studies have confirmed these findings and demonstrated that isothiocyanate, sulforaphane, and the polyphenol, quercetin, effectively reduced tumor growth and enhanced the sensitivity of the cancer cells to current chemotherapeutics. The aim of the present study is to test the feasibility of a randomized controlled trial on the application of freeze-dried broccoli sprouts in patients with advanced PDA.Methods and study designThe study is designed as a prospective randomized, double-blinded pilot trial with a treatment and a placebo-controlled arm in a single center setting. A total number of forty patients (18xa0years or older) in two parallel groups with advanced, surgically non-resectable PDA under palliative chemotherapy are planned for recruitment. Patients in the treatment group will receive fifteen capsules of the study substance per day (90xa0mg of active sulforaphane) during the chemotherapy treatment course. Patients in the placebo group will receive the same capsule size and portion distribution with inactive substances (mainly methylcellulose). The follow-up duration is one year. Feasibility of the study substance, adverse effects, and patient compliance, as well as levels of serum tumor markers (CEA, CA 19-9), quality of life, and patient overall survival rates will be assessed at defined points of time.DiscussionThe POUDER trial is expected to transfer promising experimental and epidemiological data into a clinical pilot study to assess the effectiveness of broccoli sprout extracts in the treatment of advanced PDA. The study objectives will provide data on the clinical feasibility and acceptability of a supportive treatment option accompanying palliative chemotherapy. Based on these results, future clinical studies to create further evidence in this field are possible.Trial registrationThe POUDER trial has been registered at ClinicalTrials.gov with an ID NCT01879878 and WHO with an ID U1111-1144-2013 on June 13th 2013.

Factors influencing long-term quality of life and depression in German liver transplant recipients: a single-centre cross-sectional study.

BACKGROUNDnHealth-related quality of life (HRQOL) following orthotopic liver transplantation (OLT) has become increasingly important. Therefore, we aimed to identify factors affecting HRQOL after OLT.nnnMATERIAL AND METHODSnThis cross-sectional, single-centre study surveyed 281 OLT patients. Survey tools included the Short Form (SF-36) Health Survey, the Patient Health Questionnaire 9 (PHQ9), and a self-designed employment questionnaire. Patient medical records were reviewed.nnnRESULTSnParticipants included 187 men (mean age at OLT: 50 [± 11; 13-69] years). Primary indications for OLT were viral hepatitis (28%), alcoholic liver disease (35%), cholestatic liver disease (11%), and others (26%). Follow-up ranged from 2 to 136 months. Clinical factors associated with improved HRQOL were age ≤ 45 years at OLT and current MELD score <=≤ 13. Time after OLT and indication for transplantation affected SF-36 HRQOL. SF-36 physical component summary scales plateaued at 3-years post-OLT and then stabilized. For the SF-36 HRQOL, scores were the lowest in all domains for OLT recipients transplanted for chronic viral hepatitis and for unemployed patients, whereas sex and number of transplantations showed no significant differences. The PHQ9 results showed that depression was significantly more frequent among patients with current MELD score ≥ 13 or impaired liver function and those transplanted for chronic viral hepatitis or unemployed patients. Age and sex did not influence PHQ9 results.nnnCONCLUSIONSnMedical and psychosocial support is crucial for long-term HRQOL after OLT. Developing multidisciplinary interventions to address issues such as employment, age, MELD score, and liver function may improve long-term HRQOL in these patients.