Marcus-Alexander Wörns

HCC therapies—lessons learned

The antiangiogenic multikinase inhibitor sorafenib was the first systemic agent to demonstrate a significant improvement in the overall survival of patients with advanced hepatocellular carcinoma (HCC), thereby introducing molecularly-targeted therapy in a therapeutic field of unmet needs. However, survival benefits for patients on sorafenib treatment are modest in clinical practice and advancing the field is far more challenging than initially anticipated. Molecular and clinical heterogeneity diminishes signals of potential activity in unselected populations, and underlying liver cirrhosis seals the fate of many novel targeted agents by causing relevant toxicity and mortality. The failure of subsequent randomized controlled phase III trials underscores the urgent need to identify the driver targets and to develop matched active agents with manageable toxicities in specific phase I studies in patients with cirrhosis. Refinement of phase II–III trial designs with a biomarker-enriched patient-selection process and stratification according to prognostic baseline factors is indispensable to prevent another 5-year vain endeavour in systemic therapy of HCC.

Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation

BACKGROUNDnRecurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome.nnnAIMSnRetrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence.nnnMETHODSnPatients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version 3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours.nnnRESULTSnFirst-line therapy after recurrence was surgery (n=6), radiation therapy (n=1), chemotherapy (n=1), and sorafenib (n=3). Finally, 11 patients were treated with sorafenib. Nine patients (82%) received an additionally targeted therapy with sirolimus as part of their immunosuppressive regimen. Most common grade 3 adverse events included diarrhoea (46%), hand-foot skin reaction (27%), nausea, fatigue, and leucopoenia (all 18%). Sorafenib had to be discontinued in two patients due to adverse events and six additional patients required a dose adjustment. No deterioration of liver graft function occurred. Median time to progression was 4.1 months; however, patients were treated with ongoing sorafenib in case of clinical benefit (median 8.9 months). Median overall survival after initiation of sorafenib treatment was 20.1 months.nnnCONCLUSIONnSorafenib in combination with immunosuppression including sirolimus may be administered to patients with post-transplant hepatocellular carcinoma recurrence with acceptable toxicity and without deterioration of liver graft function.

Systemic Therapy and Synergies by Combination

After years of therapeutic nihilism due to the inefficacy of conventional cytotoxic chemotherapy, the multikinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in the survival of patients with advanced hepatocellular carcinoma (HCC). However, survival benefits on sorafenib treatment remain modest in clinical practice and developing more effective systemic therapies is challenging. No other targeted agent or regimen has proven efficacy to improve survival in a phase III trial in the first- or second-line setting, and no standard treatment option currently exists outside of clinical trials for patients with acquired resistance or intolerance to sorafenib. In contrast to other malignancies, no oncogene addiction has been identified in hepatocarcinogenesis thus far, which may explain why currently tested agents do not achieve sustained partial or complete response in the majority of patients. Several agents with mainly antiangiogenic properties are currently in phase II and III development, including brivanib, ramucirumab, everolimus, tivantinib and resminostat. In addition, the role of molecularly targeted therapy (MTT) in earlier stages of the disease in combination with transcatheter arterial chemoembolization or in the adjuvant setting after potentially curative approaches is under investigation. The identification of the key driver mutations and the assessment of relevant targets for specific subpopulations of patients according to their biomarker-based profile will hopefully lead to a more personalized medicine. This article attempts to provide a concise overview on recent developments of MTT in the phase II-III setting in advanced HCC with an additional focus on synergistic combinations and combined treatment approaches.

Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells

The endemic occurrence of obesity and the associated risk factors that constitute the metabolic syndrome have been predicted to lead to a dramatic increase in chronic liver disease. Non-alcoholic steatohepatitis (NASH) has become the most frequent liver disease in countries with a high prevalence of obesity. In addition, hepatic steatosis and insulin resistance have been implicated in disease progression of other liver diseases, including chronic viral hepatitis and hepatocellular carcinoma. The molecular mechanisms underlying the link between insulin signaling and hepatocellular injury are only partly understood. We have explored the role of the antiapoptotic caspase-8 homolog cellular FLICE-inhibitory protein (cFLIP) on liver cell survival in a diabetic model with hypoinsulinemic diabetes in order to delineate the role of insulin signaling on hepatocellular survival. cFLIP regulates cellular injury from apoptosis signaling pathways, and loss of cFLIP was previously shown to promote injury from activated TNF and CD95/Apo-1 receptors. In mice lacking cFLIP in hepatocytes (flip−/−), loss of insulin following streptozotocin treatment resulted in caspase- and c-Jun N-terminal kinase (JNK)-dependent liver injury after 21 days. Substitution of insulin, inhibition of JNK using the SP600125 compound in vivo or genetic deletion of the mitogen-activated protein kinase (MAPK)9 (JNK2) in all tissues abolished the injurious effect. Strikingly, the difference in injury between wild-type and cFLIP-deficient mice occurred only in vivo and was accompanied by liver-infiltrating inflammatory cells with a trend toward increased amounts of NK1.1-positive cells and secretion of proinflammatory cytokines. Transfer of bone marrow from rag-1-deficient mice that are depleted from B and T lymphocytes prevented liver injury in flip−/− mice. These findings support a direct role of insulin on cellular survival by alternating the activation of injurious MAPK, caspases and the recruitment of inflammatory cells to the liver. Thus, increasing resistance to insulin signaling pathways in hepatocytes appears to be an important factor in the initiation and progression of chronic liver disease.

New onset of diabetes after transplantation is associated with improved patient survival after liver transplantation due to confounding factor

BACKGROUNDnThe influence of NODAT on survival of liver transplant recipients has not been clarified. Therefore, we evaluated the effect of NODAT on survival in LT recipients.nnnMETHODSnData from 352 LT patients were totally analyzed. 97 patients with pretransplant diabetes mellitus were excluded, and 255 patients without diabetes mellitus at time of transplantation were included.nnnRESULTSnNODAT was diagnosed in 41 patients (16.1%). There was no difference in frequency of NODAT according to the etiology of liver cirrhosis. NODAT was associated with a higher body weight (p=0.004) and BMI (p=0.002) 5years after LT, but not with weight gain (p=0.201) or increase in BMI (p=0.335) 5years after LT. HbA1c 5years after LT was significantly higher in patients with NODAT (p=0.001), but mean HbA1c still remained lower than 6.5% (6.4(±1.2) %). Patients with NODAT showed better survival rates (log rank: p=0.002) compared to LT recipients without diabetes. According to all existing knowledge of diabetes mellitus (DM) better survival cannot be a direct effect of this disease. Our results are rather influenced by an not known confounding factor (possibly recovery from cachexia) associated with better survival and NODAT, while complications of NODAT will not appear during the relatively short postoperative time and observation period (mean follow up 6.08 (±2.67) years).nnnCONCLUSIONnNODAT is frequently diagnosed in LT recipients and is associated with an improved 5year survival after LT due to a not exactly known confounding factor.

Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma

Background Inhibition of the renin–angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies. Objective The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC). Methods Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survival (OS) was evaluated in univariate and multivariate analyses. Results In the Vienna cohort, 43 of 156 patients received RASi for hypertension. RASi treatment was associated with longer OS (11.9 vs. 6.8 months (mo); pu2009=u20090.014) and remained a significant prognostic factor upon multivariate analysis (HRu2009=u20090.6; 95% CI 0.4–0.9; pu2009=u20090.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5u2009mo) compared to those treated with either sorafenib (10.9u2009mo) or RASi (9.7u2009mo) alone (pu2009=u20090.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (nu2009=u200976). Conclusion RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A.

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the anti-apoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and anti-inflammatory therapies in acute organ failure.

Ätiologie und Komplikationen der Leberzirrhose: Daten eines deutschen Zentrums

BACKGROUNDnLiver cirrhosis develops as a terminal complication of chronic liver disease. The clinical course is determined by the underlying etiology and the accompanying risk factors, which are influenced by the geographic and cultural background.nnnMETHODSnA total of 236 patients (159 men, 77 women, median age 57 [22-81] years) were included for retrospective analysis between July 2012 and February 2014 using standardized questionnaires during an outpatient visit at a hepatology clinic.nnnRESULTSnThe most common etiologies of liver cirrhosis were related to alcohol consumption (52u200a%), chronic hepatitis C (28u200a%) or hepatitis B (14u200a%) infection and NASH (nonalcoholic steatohepatitis, 6u200a%). At the time of presentation 55u200a% patients had compensated cirrhosis corresponding to Child-Turcotte-Pugh (CTP) stage A, while 45u200a% were in a decompensated stage (30u200a% CTP B and 15u200a% CTP C). Subgroups were analyzed for the incidence of complications and the emergence of infections. Most frequently esophageal varices (60u200a%) and ascites (49u200a%) were observed, followed by pleural effusion (14u200a%), hepatic encephalopathy (25u200a%) or hepatorenal syndrome (18u200a%). 16u200a% of patients exhibited infection based on clinical criteria. An infective agent was isolated in 38u200a% of all cases with infection and of those 50u200a% were gram positive bacteria. In multivariate analysis only the presence of ascites was an independent risk factor for infection.nnnCONCLUSIONnDespite improved medical therapies for viral hepatitis, these were the most frequent causes of liver cirrhosis, closely followed by alcoholic cirrhosis. The observed complications included bacterial infection and complication related to portal hypertension.

Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort.

Goals and Background: Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. Study: We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. Results: Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fibrolamellar carcinoma was more frequent in young versus old patients (20% vs. 0.7%; P<0.001). There was a trend toward more potentially curative treatment options in young patients, and overall survival was longer in the young group compared with older patients (56.0 vs. 15.2 mo; P=0.048). Conclusions: This western cohort of young patients is distinctly different from described Asian cohorts, especially with regard to a lower rate of underlying liver disease and particularly hepatitis B virus. Young patients had a better overall survival than older patients.

Leberzirrhose und hepatorenales Syndrom: Das Ansprechen auf Terlipressin und Albumin ist mit besserem Überleben assoziiert

BACKGROUND AND AIMnHepatorenal syndrome (HRS) is a severe but potentially reversible complication in patients with cirrhosis. Untreated it is associated with a poor prognosis. Several randomized controlled trials (RCT) demonstrated that treatment with terlipressin and albumin improves renal function. However the effect on overall survival is unclear. Aim of the study was to gain further insight into the effect of terlipressin treatment in patients with HRS on renal function, overall survival and survival without liver transplantation or renal replacement.nnnMETHODSnAll patients presenting with HRS and treated with terlipressin in our tertiary referral liver and transplantation center between April 2013 and April 2014 were included. Clinically relevant parameters such as response to therapy, overall survival and transplant- and renal-replacement-free-survival were prospectively investigated.nnnRESULTSnOverall 57 patients were prospectively followed over a median of 65 days. In the majority of patients cirrhosis was in an advanced stage (Child-Pugh C: 46; 81%). Median cumulative terlipressin dosage and treatment duration were 20 mg and 5 days, respectively. Complete or partial response to terlipressin with recovery from HRS was observed in 20 and 3 out of 57 patients (51%; 5%). Median overall survival was significantly better in patients with response to terlipressin than in patients with non-response (167 vs. 27 days; p > 0.0001), as well as median survival free of liver transplantation and renal-replacement-therapy (81 vs. 4 days; p > 0.0001). In uni- and multivariate analysis, non-response was associated with a high baseline serum-bilirubin-concentration.nnnCONCLUSIONnTerlipressin in combination with albumin is effective in the majority of patients with HRS. Response to therapy is associated with improved survival.