Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up-to-7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09-6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04-7.62; P = 0.01; up-to-7 HR, 3.58; 95% CI, 1.17-10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up-to-7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha-fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16-4.91; P = 0.019; up-to-7 HR, 2.21; 95% CI, 1.05-4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.

Short- and long-term effects of transarterial chemoembolization on portal hypertension in patients with hepatocellular carcinoma.

Background: Transarterial chemoembolization (TACE) affects hepatic perfusion, and might have an impact on portal pressure in patients with hepatocellular carcinoma (HCC). Objective: The objective of this article is to report the secondary outcome "hepatic hemodynamics" from the AVATACE trial, a prospective randomized, placebo-controlled trial on the efficacy of conventional TACE in combination with bevacizumab or placebo. Methods: Hepatic venous pressure gradient (HVPG) was measured at baseline (prior to first TACE), within nine days ("acute effects"), two months ("intermediate effects") and six months ("long-term effects") after the first TACE. Results: Of 28 patients with early-intermediate stage HCC, n = 20 (71%) had clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) at baseline (median, 12 (interquartile range (IQR): 9-19) mmHg). TACE had neither "acute effects" nor "intermediate effects" on HVPG. However, in 13 patients with available HVPG measurement at month 6, there was a significant increase in HVPG (median, 16 (IQR: 11-19) mmHg) compared with baseline (median, 10 (IQR: 5-12) mmHg; p = 0.007). Portal hypertension-related complications occurred exclusively in patients with CSPH (8 (40%) vs 0). Conclusions: Repeated TACE was associated with a significant long-term increase in HVPG. This should be considered when deciding whether to continue with TACE or switch to systemic treatment, since CSPH drives the development of complications.

Association of Platelet Count and Mean Platelet Volume with Overall Survival in Patients with Cirrhosis and Unresectable Hepatocellular Carcinoma.

BACKGROUND: Platelets have been reported to influence tumor biology and may promote metastasis. Traditionally, thrombocytopenia, a hallmark of cirrhosis, was associated with hepatocellular carcinoma (HCC) development. However, the impact of platelet count on outcome in patients with established HCC is not well studied. METHODS: Outcomes of patients with cirrhosis diagnosed with HCC between 1995 and 2013 (derivation cohort) and 2000-2016 (validation cohort) who were not eligible for surgical treatment and did not receive antiplatelet therapy were retrospectively studied. Thrombocytopenia was defined as platelet count < 150 g/L. High mean platelet volume (MPV) was defined as ≥median value of the respective cohort (derivation cohort: ≥11 fL; validation cohort: ≥10.6 fL). RESULTS: Among 626 patients with unresectable HCC, thrombocytopenia was present in 378 (60.4%) and was associated with favorable baseline tumor characteristics: lower diameter of the largest nodule (5.6 ± 3.2 vs. 7.6 ± 4.2 cm), less extrahepatic spread (9.5 vs. 20.2%, both p < 0.001), less macrovascular invasion (21.2 vs. 31.0%, p = 0.005), and lower BCLC stages (63.0 vs. 73.4% BCLC C/D; p = 0.007) as compared to patients with normal platelet count. On univariate analysis, thrombocytopenia and larger MPV were associated with longer overall survival (OS) (thrombocytopenia: median OS [95% CI], 11.5 [9.3-13.8] vs. 5.5 [3.8-7.1] months; p = 0.001; MPV ≥11 fL: 11.7 [9.1-14.2] vs. 6.0 [4.4-7.6] months; p < 0.001). In multivariate analysis, the combined variable of thrombocytopenia and larger MPV was independently associated with longer OS (HR [95% CI], 0.80 [0.65-0.98]; p = 0.029). These results were confirmed in an independent external validation cohort of 525 patients with cirrhosis and HCC. Again, patients with thrombocytopenia and high MPV had significantly longer OS (15.3 [11.7-18.9] vs. 9.3 [7.4-11.2] months; p < 0.001). CONCLUSIONS: Thrombocytopenia and higher MPV are associated with better outcome in patients with advanced HCC. These findings may prompt further clinical research on additive antiplatelet therapy in the prevention and management of HCC.

C-reactive protein is an independent predictor for hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: Serum C-reactive protein (CRP) is a prognostic factor for overall survival (OS) and recurrence of hepatocellular carcinoma (HCC) in patients treated with resection or non-surgical treatment. Here, we investigated the association of elevated CRP (≥1 vs. <1 mg/dL) with (i) recurrence of HCC and (ii) OS after liver transplantation (LT). METHODS: Adult HCC patients undergoing orthotopic deceased donor LT at the Medical University of Vienna between 1997 and 2014 were retrospectively analysed. RESULTS: Among 216 patients included, 132 (61.1%) were transplanted within the Milan criteria and forty-two patients (19.4%) had microvascular invasion on explant histology. Seventy patients (32.4%) showed elevated CRP (≥ 1 mg/dL). On multivariate analysis, a CRP ≥ 1 mg/dL was an independent risk factor for HCC recurrence with a 5-year recurrence rate of 27.4% vs. 16.4% (HR 2.33; 95% CI 1.13-4.83; p = 0.022). OS was similar in patients with normal vs. elevated CRP levels. CONCLUSIONS: Elevated serum CRP is associated with HCC recurrence after LT and may be a marker for more aggressive tumor biology. Future studies should evaluate whether patients with elevated pre-transplant CRP levels benefit from closer monitoring for HCC recurrence.

Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort.

BACKGROUND: Programmed cell death protein-1-targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma. AIM: To evaluate safety and efficacy of nivolumab and pembrolizumab in an international, multicentre, real-world cohort of patients with advanced hepatocellular carcinoma. METHODS: Sixty-five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut-off) across six centres in Austria and Germany were retrospectively analysed. RESULTS: Child-Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first-/second-/third-/fourth-line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty-four patients had at least one follow-up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5-7.4) months, median progression-free survival was 4.6 (95% CI, 3.0-6.2) months, and median overall survival was 11.0 (95% CI, 8.2-13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child-Pugh A and B patients; however, median overall survival (OS) was shorter in Child-Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first-/second-line and third-/fourth-line respectively. CONCLUSIONS: Programmed cell death protein-1-targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child-Pugh stage B and patients with intensive pretreatment.

Transforming Growth Factor-ß and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma.

Transforming growth factor (TGF)-ß suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-ß switch toward dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-ß. Both HCC models showed reduced proliferation and clonogenic growth behavior following TGF-ß stimulation, although they exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of anti-oncogenic TGF-ß. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF-ß expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression, suggesting that CXCL5 is a TGF-ß target gene collaborating with Axl signaling. Loss of either TGF-ß or Axl signaling abrogated CXCL5-dependent attraction of neutrophils. In mice, tumor formation of transplanted HCC cells relied on CXCL5 expression. In HCC patients, high levels of Axl and CXCL5 correlated with advanced tumor stages, recruitment of neutrophils into HCC tissue, and reduced survival. Conclusion: The synergy of TGF-ß and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. Intervention with TGF-ß/Axl/CXCL5 signaling may be an effective therapeutic strategy to combat HCC progression in TGF-ß-positive patients.

Point Shear Wave Elastography for Non-invasive Assessment of Liver Fibrosis in Patients with Viral Hepatitis.

Elastography point quantification (ElastPQ) is a new ultrasound-based shear wave elastography method for non-invasive assessment of liver fibrosis. We evaluated the diagnostic accuracy of ElastPQ in patients with chronic viral hepatitis. Fibrosis stage (F) was determined by transient elastography (F0/F1: <7.1 kPa, F2: 7.1-9.4 kPa, F3: 9.5-12.4 kPa, F4: ≥12.5 kPa). Area under the receiver operator characteristics curve (AUROC) analysis was performed to assess ElastPQ cutoffs for significant fibrosis (≥F2) and cirrhosis (F4). Paired transient elastography and ElastPQ measurements were obtained from 217 patients (mean age ± SEM: 49 ± 0.79 years, 68.2% male, F0/F1: n = 98 [45.0%], F2: 47 [21.6%], F3: 22 [10.1%], F4: 50 [22.9%]). AUROC for ≥F2 was 0.843 (95% confidence interval: 0.791-0.895), and for F4, 0.933 (95% confidence interval: 0.894-0.972). The optimal ElastPQ cutoff for F2 was 6.68 kPa (sensitivity: 80.7%, specificity: 70.4%, positive predictive value: 78.5%, negative predictive value: 72.3%), and for F4 11.28 kPa (sensitivity: 86.0%, specificity: 85.6%, positive predictive value: 60.52%, negative predictive value: 97.16%). In conclusion, ElastPQ represents an accurate tool for non-invasive staging of liver fibrosis in patients with viral hepatitis.

Long-term remission in advanced stage hepatocellular carcinoma? A chance for cure?

Liver resection, transplantation, and local ablation are potential curative treatment options but can only be offered to patients with early stage hepatocellular carcinoma (HCC). Patients with macrovascular tumor invasion and extrahepatic metastases are candidates for palliative systemic therapies. Achieving radiological complete response can be associated with long-term remission and excellent outcome. However, despite recent advancements in the medical treatment of advanced stage HCC, complete remission with available systemic treatment options still remains a rare event. This review summarizes data on radiological complete response to systemic therapies and discusses issues that may complicate the goal of achieving cure in advanced stage HCC.

Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.

BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

Transjugular intrahepatic portosystemic shunts (TIPS) for the prevention of variceal re-bleeding - A two decades experience.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunts (TIPS) are used in patients with cirrhosis for the prevention of variceal rebleeding. METHODS: We retrospectively evaluated re-bleeding rate, patency, mortality, and transplant-free survival (TFS) in cirrhotic patients receiving TIPS implantation for variceal bleeding between 1994-2014. RESULTS: 286 patients received TIPS (n = 119 bare metal stents, n = 167 polytetrafluorethylene (PTFE)-covered stents) for prevention of variceal re-bleeding. Mean age was 55.1 years, median MELD was 11.8, and the main etiology of cirrhosis was alcoholic liver disease (70%). Median follow-up was 821 days. 67 patients (23%) experienced at least one re-bleeding event. Patients with PTFE-TIPS were at significantly lower risk for variceal re-bleeding than patients with bare metal stents (14% vs. 37%, OR:0.259; p<0.001) and had less need for stent revision (21% vs. 37%; p = 0.024). Patients with PTFE stent grafts showed lower mortality than patients with bare stents after 1 year (19% vs. 31%, p = 0.020) and 2 years (29% vs. 40%; p = 0.041) after TIPS implantation. Occurrence of hepatic encephalopathy after TIPS was similar between groups (20% vs. 24%, p = 0.449). CONCLUSIONS: PTFE-TIPS were more effective at preventing variceal re-bleeding than bare metal stents due to better patency. Since this tended to translate in improved survival, only covered stents should be implemented for bleeding prophylaxis when TIPS is indicated.

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); p = 0.014) and remained a significant prognostic factor upon multivariate analysis (HR = 0.6; 95% CI 0.4-0.9; p = 0.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5 mo) compared to those treated with either sorafenib (10.9 mo) or RASi (9.7 mo) alone (p = 0.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (n = 76). CONCLUSION: RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A.

Oxidative stress mediates an increased formation of vascular endothelial growth factor in human hepatocarcinoma cells exposed to erlotinib.

The tyrosine kinase inhibitor erlotinib targets the receptor of epidermal growth factor (EGFR) involved in development of hepatocellular carcinoma (HCC). Although inefficient in established HCC, erlotinib has been recently proposed for HCC chemoprevention. Since Cyp3A4 and Cyp1A2 enzymes metabolize erlotinib in the liver, the insights into the mechanisms of erlotinib effects on liver cells with maintained drug metabolizing activity are needed. We applied erlotinib to both commercially available (SNU398, Huh7) and established in Austria HCC cell lines (HCC-1.2, HCC-3). Cyp3A4 and Cyp1A2, microarray gene expression, cell viability, LDH release, DHFC fluorescence were assessed. VEGF expression was analysed by real-time RT-PCR and ELISA. Higher cumulative expression of erlotinib metabolizing enzymes was observed in HCC-1.2 and HCC-3 cells. Gene expression microarray analysis showed upregulation of VEGF signalling by erlotinib. VEGF was increased up to 134 ± 14% (n = 5, p = 0.002) in HCC-1.2, HCC-3 and Huh7 cells. Interventions by Cyp1A2 and Mek2siRNA, MEK inhibitor UO126, diphenylene iodonium, as well as a combination of N-acetylcysteine with selenium all inhibited VEGF upregulation caused by erlotinib. Thus, erlotinib increases VEGF production by mechanisms involving Cyp1A2, oxidative stress and MEK1/2. VEGF may favour angiogenesis and growth of early HCC tumours limiting the therapeutic and chemopreventive effects of erlotinib.

Re-bleeding rates and survival after early transjugular intrahepatic portosystemic shunt (TIPS) in clinical practice.

BACKGROUND: Early implantation (<72h) of a transjugular intrahepatic portosystemic shunt (TIPS) after acute variceal bleeding (AVB) improves survival in highly selected patients. METHODS: We retrospectively assessed bleeding control and survival of unselected cirrhotic patients undergoing early TIPS implantation within 72h. We compared the outcomes to patients meeting early TIPS criteria but receiving late TIPS within 3-28days after AVB and endoscopic/medical treatment. RESULTS: Forty-nine patients were included. Mean MELD was 14.4 (±4.4). Thirteen patients (26.5%) presented characteristics that were exclusion criteria in previous early TIPS trials (age>75, CPS>13, HCC>Milan, previous beta-blocker/band-ligation, renal insufficiency). Bare metal and PTFE-covered stents were used in n=32 (65.3%) and n=17 (34.7%) patients, respectively, and showed similar early re-bleeding rates (9.9% vs. 7.1%; p=0.6905) and bleeding-related mortality (25.0% vs. 23.5%; p=0.9906). However, overall re-bleeding rate was lower with PTFE-TIPS (7.7% vs. 64.2%; p=0.0044) over a median follow-up of 18.5 months with a tendency towards improved survival (median 70.5 vs. 13.8 months; p=0.204). Additional 68 patients meeting stringent criteria but receiving late TIPS also showed a favorable bleeding-related mortality (8.8%), which was not achieved in similar n=34 patients by a medical/endoscopic strategy with bleeding-related mortality of 35.7%. CONCLUSIONS: An early TIPS strategy using covered stents and implementation of 'stringent criteria' results in a favorable outcome in patients with acute variceal bleeding.

The impact of thyroid hormones on patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Hypothyroidism has recently been proposed as predisposing factor for HCC development. However, the role of thyroid hormones (TH) in established HCC is largely unclear. We investigated the impact of TH on clinical characteristics and prognosis of HCC patients. METHODS: Of 838 patients diagnosed with nonsurgical HCC at the Division of Gastroenterology and Hepatology/Medical University of Vienna between 1992 and 2012, 667 patients fulfilled the inclusion criteria. The associations of thyroid function tests with patient, liver, and tumor characteristics as well as their impact on overall survival (OS) were investigated. RESULTS: Thyroid hormone substitution was more often observed in patients with low thyroid-stimulating hormone (TSH) concentration and in patients with elevated free tetraiodthyronine (fT4). Patients with high TSH (>3.77uU/ml) concentrations had larger tumors, while the opposite was true for patients with low TSH (<0.44uU/ml) concentrations. Subjects with elevated fT4 (>1.66ng/dl) were more likely to have elevated CRP. While TSH was only associated with OS in univariate analysis (≤1.7 vs. >1.7uU/ml, median OS (95%CI), 12.3 (8.9-15.7 months) vs. 7.3 months (5.4-9.2 months); p = 0.003), fT4 (≤1.66 vs. >1.66ng/dl, median OS (95%CI), 10.6 (7.5-13.6 months) vs. 3.3 months (2.2-4.3 months); p = 0.007) remained an independent prognostic factor for OS (HR (95%CI) for fT4>1.66ng/dl, 2.1 (1.3-3.3); p = 0.002) in multivariate analysis. CONCLUSIONS: TSH and fT4 were associated with prognostic factors of HCC (i.e., tumor size, CRP level). Elevated fT4 concentrations were independently associated with poor prognosis in HCC. Further studies are needed to characterize the role of TH in HCC in detail.

Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model.

Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced apoptosis in these cell lines whereas the GSI DAPT was ineffective. The specificity of gliotoxin was demonstrated in the well differentiated nuclear NOTCH negative cell line Huh7, which was resistant to gliotoxin treatment in vitro. In xenotransplanted 518A2 melanomas, a single day dosing schedule of gliotoxin was well tolerated without any study limiting side effects. Gliotoxin significantly reduced the tumor volume in early (83 mm3 vs. 115 mm3, p = 0.008) as well as in late stage (218 mm3 vs. 576 mm3, p = 0.005) tumor models. In conclusion, NOTCH2 appears to be a key target of gliotoxin in human neoplasias and gliotoxin deserves further evaluation as a potential therapeutic agent in cancer management.

Early response evaluation using CT-perfusion one day after transarterial chemoembolization for HCC predicts treatment response and long-term disease control.

PURPOSE: To determine the value of CT perfusion (CTP) for early response assessment after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between April 2013 and April 2015, 41 HCC (16 patients) were included in this study. CT perfusion was performed before and one day after TACE. Blood flow (BF), blood volume (BV), time to start (TTS), arterial liver perfusion (ALP), portal liver perfusion (PVP) and hepatic perfusion index (HPI) were measured. Quantitative perfusion values before and after TACE were compared to the response assessed using mRECIST criteria six weeks after TACE and long-term outcome was assessed. RESULTS: Twenty-one lesions (51%) had complete remission (CR) and five (12%) had partial response (PR) six weeks after TACE. CTP parameters were significantly reduced after TACE in responders (PR, CR, p<0.001) while no difference was observed in non-responders. ALPpost was superior in the prediction of CR compared to BFpost and BVpost (p<0.001) with a sensitivity, specificity, PPV, NPV, and accuracy of 90%, 90%, 91%, 90%, and 91%, respectively. Only 3/21 lesions with CR recurred, with a mean local-recurrence-free survival of 19.6 months. CONCLUSION: CT perfusion detects lesions with complete response one day after TACE, and is a feasible tool for early response assessment.

Non-selective beta-blocker treatment does not impact on kidney function in cirrhotic patients with varices.

GOALS AND BACKGROUND: Non-selective beta-blockers (NSBBs) are used for bleeding prophylaxis in cirrhotic patients with gastroesophageal varices (GEVs). Recent data suggested that NSBB treatment might increase the risk of renal dysfunction in patients with refractory ascites due to an impaired response to acute haemodynamic stress. STUDY: Retrospective longitudinal assessment of kidney function in a cohort of cirrhotic patients with GEVs with vs. without NSBB therapy. Serum creatinine (SCre), estimated glomerular filtration rate (eGFR), incidence of acute kidney injury (AKI), new onset of large volume ascites and TIPS-/transplant-free survival were compared. RESULTS: Among 176 patients, 93 patients received NSBBs, while 83 did not. Most patients were male (77.8%), had alcoholic aetiology (52.3%) and compensated cirrhosis (51.1% Child-A, MELD: 12.1 ± 3.8). Over a 3-year follow-up, renal function was comparable between patients with and without NSBB treatment. Incidence of AKI was similar in NSBB vs. no-NSBB patients (p = .323). Even in potential risk groups (ascites, MAP <90 mmHg, baseline creatinine > ULN, hyponatraemia, MELD score ≥15 points, Child-Pugh B/C), there was no difference in SCre or eGFR with vs. without NSBBs (p = n.s. at 74/78 and 76/78 of analysed time points). However, multivariate analysis revealed that the presence of ascites (HR: 3.901, 95%CI: 1.352-11.251; p = .012) and pre-existing renal impairment (HR: 4.315, 95%CI: 1.054-17.672; p = .042) were independent risk factors for AKI. Importantly, NSBB use (HR: 0.319, 95%CI: 0.120-0.848; p = .022) was independently associated with improved TIPS-/transplant-free survival. CONCLUSIONS: In our cohort of unselected, mostly compensated cirrhotic patients with GEVs, NSBB treatment was neither associated with worsening of kidney function nor with increased incidence of AKI. On the contrary, NSBB treatment improved TIPS-/transplant-free survival.

Personalized treatment of patients with very early hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), in its very early stage, is heterogeneous both in terms of liver function (i.e., presence or absence of portal hypertension, model for end-stage liver disease score, Child-Pugh score 5 or 6, bilirubin level) and tumor characteristics (i.e., location, alpha-fetoprotein values, pathological features such as microvascular invasion, tumor grade and satellitosis). Existing evidence in comparing different curative options for patients with very early HCC is poor due to small sample sizes and lack of solid subgroup analyses. Large observational studies are available, with the potential to identify effective interventions in different subgroup of patients and to discover which treatments work "in a real world setting". These studies suggest some important treatment selection strategies in very early HCC patients. According to extent of liver resection, and liver function, percutaneous ablation or liver resection are the recommended first line therapies in these patients. Laparoscopic surgery (resection or ablation) is the preferable strategy when the tumor is in the surface of the liver or close to extra-hepatic organs. Due to scarce donor resources and competition with patients at high transplant benefit (HCC patients unsuitable for non-transplant radical therapies and non-HCC patients with decompensated cirrhosis), transplantation is recommended only as second line therapy in patients with very early stage HCC in case of tumor recurrence or liver failure after ablation or liver resection.

Cancer and liver cirrhosis: implications on prognosis and management.

Liver cirrhosis, the end-stage of every chronic liver disease, is not only the major risk factor for the development of hepatocellular carcinoma but also a limiting factor for anticancer therapy of liver and non-hepatic malignancies. Liver cirrhosis may limit surgical and interventional approaches to cancer treatment, influence pharmacokinetics of anticancer drugs, increase side effects of chemotherapy, render patients susceptible for hepatotoxicity, and ultimately result in a competitive risk for morbidity and mortality. In this review, we provide a concise overview about the impact of liver cirrhosis on the management and prognosis of patients with primary liver cancer or non-hepatic malignancies.