NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

BACKGROUND & AIMS: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

Prediction of Survival Among Patients Receiving Transarterial Chemoembolization for Hepatocellular Carcinoma: A Response-Based Approach.

BACKGROUND AND AIMS: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. APPROACH AND RESULTS: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. CONCLUSIONS: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.

Transarterial chemoembolization: modalities, indication, and patient selection.

Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma (BCLC B). Further improvement of the use of TACE was the subject of intense clinical research over the past years. The introduction of DEB-TACE brought more technical standardization and reduction of TACE related toxicity. The use of dynamic radiologic response evaluation criteria (EASL, mRECIST), uncovered the prognostic significance of objective tumor response. Finally, new approaches for better patient selection for initial and subsequent TACE treatment schedules will limit the use of TACE to some extent but have the potential to improve outcome for patients at risk for TACE-induced harm.

The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE.

BACKGROUND & AIMS: Recently, we developed the ART score (assessment for re-treatment with TACE) to guide the decision for a second transarterial chemoembolization (TACE-2) in patients with hepatocellular carcinoma (HCC). Patients with an ART score of 0-1.5 points gained benefit from a second TACE session, while patients with an ART score ≥2.5 points did not. Here, we investigated (1) the prognostic significance of the ART score prior to the third (TACE-3) and fourth TACE (TACE-4), and (2) the feasibility of an ART score guided re-treatment strategy by sequential assessment of the ART score in HCC patients treated with multiple TACE sessions. METHODS: 109 patients, diagnosed with intermediate stage HCC and treated with ≥3 TACE sessions between January 1999 and December 2009 at the Medical Universities of Vienna and Innsbruck, were included. The ART score prior to each TACE session was assessed in comparison to the TACE naïve liver. The prognostic performance of the ART score before TACE-3 and 4 was evaluated with and without stratification based on the ART score prior to the respective last intervention. RESULTS: The pre-TACE-3 ART score discriminated two groups with different prognosis and remained a valid predictor of OS independent of Child-Pugh score (5-7 points), CRP-levels and tumor characteristics. Even in patients with an initially beneficial ART score (0-1.5 points) before TACE-2, repeated ART score assessment before TACE-3 identified a subgroup of patients with dismal prognosis (median OS: 27.8 vs. 10.8 months, p<0.001). Similar results were observed when the ART score was applied before TACE-4. CONCLUSIONS: The sequential assessment of the ART score identifies patients with dismal prognosis prior to each TACE session.

How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma.

BACKGROUND & AIMS: We aimed to establish an objective point score to guide the decision for the first treatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: 277 patients diagnosed with HCC and treated with transarterial treatments between 1/2002 and 12/2011 at the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the impact of baseline liver function and tumour load on overall survival (OS, log-rank test) and developed a point score (STATE-score: Selection for TrAnsarterial chemoembolisation TrEatment) in the training-cohort (n=131, Vienna) by using a stepwise Cox regression model. The STATE-score was externally validated in an independent validation cohort (n=146, Innsbruck) and thereafter combined with the Assessment for Retreatment with TACE (ART)-score to identify patients who are (un)suitable for TACE. RESULTS: The STATE-score starts with the serum-albumin level (g/L), which is reduced by 12 points each, if the tumour load exceeds the up-to-7 criteria and/or C-reactive protein (CRP) levels are ⩾1 mg/dl (maximum reduction: 24 points). The STATE-score differentiated 2 groups (<18, ⩾18 points) with distinct prognosis (median OS: 5.3 vs. 19.5 months; p<0.001) and a lower STATE-score was associated with short-term harm and increased mortality after TACE-1 (39% vs. 14% p<0.001). Sequential use of the STATE and the ART-score (START-strategy) identified the most (un)suitable patients for TACE. Results were confirmed in the external validation-cohort and were independent from recently proposed baseline selection tools. CONCLUSION: The STATE-score identifies patients who are (un)suitable for the first TACE. The START-strategy identified the best candidates for multiple TACE sessions.

Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma.

UNLABELLED: We investigated the prognostic value of C-reactive protein (CRP) in patients with hepatocellular carcinoma (HCC) not amenable to surgery. A total of 615 patients diagnosed with HCC not amenable to surgery between April 1999 and December 2009 at the Department of Gastroenterology of the Medical Universities of Vienna and Innsbruck were included. We assessed the optimal CRP cutoff by regression spline analysis and tested its impact on median overall survival (OS) by the Kaplan-Meier method, univariate analysis (log-rank test), and multivariate analysis (Cox proportional hazard regression model) in a training cohort (n = 466, Vienna) and an independent validation cohort (n = 149, Innsbruck). We found a sigmoid-shaped association of CRP and the hazard ratio of death upon regression spline analysis and defined a CRP level <1/≥1 mg/dL as optimal cutoff for further survival assessments. Elevated CRP (≥1 mg/dL) at diagnosis was associated with poor OS (CRP-elevated versus CRP-normal; 4 versus 20 months; P < 0.001) and remained a significant negative predictor for OS upon multivariate analysis (hazard ratio, 1.7; P < 0.001), which was independent of age, Child-Pugh class, tumor characteristics, and treatment allocation. Analyses with respect to Barcelona Clinic Liver Cancer (BCLC) stage and Child-Pugh class supported the relevance of CRP (BCLC-stage C and Child-Pugh A: OS for CRP-elevated versus CRP-normal, 6 versus 14; P < 0.001; BCLC-stage C and Child-Pugh B: OS for CRP-elevated versus CRP-normal, 4 versus 15 months; P < 0.001). The prognostic significance of elevated CRP was reproducible at a second CRP determination timepoint and confirmed in the independent validation cohort. CONCLUSION: Elevated CRP is associated with a dismal prognosis in HCC patients and may become a useful marker for patient selection in HCC management. (HEPATOLOGY 2012).

The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma.

UNLABELLED: We aimed to establish an objective point score to guide the decision for retreatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). In all, 222 patients diagnosed with HCC and treated with multiple TACE cycles between January 1999 and December 2009 at the Departments of Gastroenterology/Hepatology of the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the effect of the first TACE on parameters of liver function and tumor response and their impact on overall survival (OS, log rank test) and developed a point score (ART score: Assessment for Retreatment with TACE) in the training cohort (n = 107, Vienna) by using a stepwise Cox regression model. The ART score was externally validated in an independent validation cohort (n = 115, Innsbruck). The increase of aspartate aminotransferase (AST) by >25% (hazard ratio [HR] 8.4; P < 0.001), an increase of Child-Pugh score of 1 (HR 2.0) or ≥2 points (HR 4.4) (P < 0.001) from baseline, and the absence of radiologic tumor response (HR 1.7; P = 0.026) remained independent negative prognostic factors for OS and were used to create the ART score. The ART score differentiated two groups (0-1.5 points; ≥2.5 points) with distinct prognosis (median OS: 23.7 versus 6.6 months; P < 0.001) and a higher ART score was associated with major adverse events after the second TACE (P = 0.011). These results were confirmed in the external validation cohort and remained significant irrespective of Child-Pugh stage and the presence of ascites prior the second TACE. CONCLUSION: An ART score of ≥2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions. (HEPATOLOGY 2013;57:2261-2273).

Incidence and mortality trends for biliary tract cancers in Austria.

BACKGROUND & AIMS: The epidemiology of biliary tract cancers (BTC) varies between geographical regions and has changed over time globally. We investigated the incidence and mortality trends of patients diagnosed with BTC over a 20-year period in Austria. METHODS: Patients diagnosed with intrahepatic (iCCC)/extrahepatic cholangiocarcinoma (eCCC), ampullary carcinoma, gall bladder carcinoma (GBC), overlapping lesions or unspecified carcinomas of the biliary tract and liver were included. Data on age-adjusted incidence were obtained from the Austrian National Cancer Registry which compiles data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). RESULTS: Between 1990 and 2009, 15201 patients were diagnosed with BTC (m/f=42/58%; mean age, 73 years). The median survival of all patients with BTC was 4.8 months with a 1-/5-year survival rate of 31%/10%. In iCCC, the incidence and mortality rates increased from 1990 to 2009 in both men and women while in eCCC, the incidence and mortality rates decreased over time in both sexes. In ampullary carcinoma, the incidence slightly decreased in men and remained stable in women. The mortality rate remained stable in both sexes. In GBC, the age-adjusted incidence and mortality rates dramatically decreased in both sexes. CONCLUSIONS: GBC and iCCC were the most common entities amongst BTC. While incidence and mortality rates of iCCC increased in men and women over time, incidence and mortality rates of eCCC and GBC decreased in both sexes. Other carcinomas of the biliary tract i.e. ampullary carcinoma were rarely diagnosed.

Epidemiological trends of hepatocellular carcinoma in Austria.

BACKGROUND/AIMS: The heterogeneous epidemiology of hepatocellular carcinoma (HCC) with the highest incidence rates in East Asia, sub-Saharan Africa and Melanesia results from variations in the main risk factors. We investigated epidemiological trends, including incidence and mortality, of patients diagnosed with HCC over a 20-year period in Austria. METHODS: Data on age-adjusted incidence rates of HCC were obtained from the Austrian National Cancer Registry, which compiles nationwide data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). RESULTS: Of 24,939 patients diagnosed with hepatobiliary tumors between 1990 and 2009, 8,561 subjects had HCC (m/f ratio 75/25%; mean age 69 years). Lymph node and distant metastases were present in 7.5 and 12.2%, respectively. The age-adjusted incidence rate was significantly higher in men than women (m/f ratio 4.5/1) and markedly increased in men (4.68/5.10) but remained stable in women (1.18/1.11). Similarly, the age-adjusted mortality rate was significantly higher in men than women (m/f ratio 4.5/1), increased in men (4.02/4.98) and remained stable in women (0.92/1.0). The median overall survival was 4.5 months for men and 3.2 months for women with 1-/5-year survival rates of 33/11% and 28/10%, respectively. CONCLUSION: HCC is the most common hepatobiliary neoplasia in Austria and has a very poor prognosis. The age-adjusted incidence and mortality rates were higher in males, increased over time in men and remained stable in women. Extrahepatic metastases were rarely diagnosed and associated with dismal survival.

Changes in the Epidemiology of Hepatocellular Carcinoma in Carinthia, Austria, 2012-2023.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths and remains a major burden on healthcare systems worldwide. The incidence of HCC continues to rise globally, despite preventative efforts being made. AIMS: This study aimed to investigate epidemiological changes observed in the etiology and survival outcomes of HCC patients at Klinikum Klagenfurt am Wörthersee between 2012 and 2023. METHODS: This was a retrospective, single-center cohort study. Two time-periods (2012-2017 and 2018-2023) were created to enable comparison between the respective intervals. IBM SPSS was used to analyze statistical data. RESULTS: More patients were diagnosed with HCC during the second time period (n = 128, n = 148). The median age of diagnosis was 72.5 years (SD 8.6). Patients were on average 2 years younger in the second time period compared to the first (p = 0.042). Alcohol remained the leading underlying etiology of HCC and no statistically significant change was seen over time (p = 0.353). Nevertheless, a clear upward trend in the number of NASH cases was evident over time (n = 15, n = 28, respectively). Nearly half of the patient population had a normal AFP (<7 µg/L) level at the time of diagnosis (n = 116, 42.6%). The survival time for HCC patients remained similar between time periods, with a median overall survival time of 20.5 months (95% CI 16.8-24.2, p = 0.841), despite improvements in management strategies and the availability of new systemic treatments. More advanced-stage HCC cases were documented in the second period (BCLC-C, n = 23 to n = 46, p = 0.051). An increased number of HCC patients without liver cirrhosis were identified during the second time period (n = 22, n= 47, respectively, p = 0.005). NASH was the most common underlying etiology in patients without liver cirrhosis (50%) compared to alcohol use in being the primary cause in cirrhotic patients (65%, p < 0.001). CONCLUSION: HCC continues to be an important health concern in our society. The number of HCC patients without liver cirrhosis is steadily increasing, with NAFLD/NASH, due to underlying lifestyle diseases playing an important etiological role. Continued efforts should be made to prevent HCC and to screen at-risk population groups. Preventative strategies and screening techniques should be adjusted in light of the changing epidemiological landscape of HCC, where more focus will have to be placed on detecting HCC in patients without underlying cirrhosis.

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma.

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy.

Advanced-stage hepatocellular carcinoma: transarterial chemoembolization versus sorafenib.

PURPOSE: To compare the efficacies of transarterial chemoembolization (TACE) and sorafenib in patients with advanced-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The retrospective analysis of the data was approved by the institutional review board; the requirement to obtain informed consent was waived. Three hundred seventy-two patients with HCC were treated between January 1999 and December 2009. Patients with advanced HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Child-Pugh class A or B, Eastern Cooperative Oncology Group performance status of 1-2, and/or macrovascular invasion or extrahepatic metastasis) were included in the study (n = 97). Thirty-four patients underwent conventional TACE with doxorubicin plus lipiodol or TACE with drug-eluting beads; 63 patients were treated with sorafenib. RESULTS: The median duration of sorafenib treatment was 4.6 months (95% confidence interval [CI]: 3.2, 6.0 months). The median number of TACE sessions per patient was 3 ± 2. Side effects of TACE and sorafenib were comparable to those reported in the literature. The median time to progression was similar between the two treatment groups (P = .737). The median overall survival was 9.2 months (95% CI: 6.1, 12.3 months) for patients treated with TACE and 7.4 months (95% CI: 5.6, 9.2 months) for those treated with sorafenib (P = .377). Only Child-Pugh class was associated with a better overall survival at uni- and multivariate analysis. CONCLUSION: TACE achieved a promising outcome in select patients with advanced HCC (BCLC stage C).

Changing Epidemiological Trends of Hepatobiliary Carcinomas in Austria 2010-2018.

Using national registries, we investigated the epidemiological trends of hepatobiliary carcinomas in Austria between 2010 and 2018 and compared them to those reported for the periods of 1990-1999 and 2000-2009. In total, 12,577 patients diagnosed with hepatocellular carcinoma (n = 7146), intrahepatic cholangiocarcinoma (n = 1858), extrahepatic cholangiocarcinoma (n = 1649), gallbladder carcinoma (n = 1365), and ampullary carcinoma (n = 559), between 2010 and 2018, were included. The median overall survival of all patients was 9.0 months. The best median overall survival was observed in patients with ampullary carcinoma (28.5 months) and the worst median overall survival was observed in patients with intrahepatic carcinoma (5.6 months). The overall survival significantly improved in all entities over the period 2010-2018 as compared with over the periods of 2000-2009 and 1990-1999. Age-adjusted incidence and mortality rates remained stable for most entities in both, men and women; only in gallbladder carcinoma, the incidence and mortality rates significantly decreased in women, whereas, in men, the incidence rates remained stable and mortality rates showed a decreasing trend. We showed that age-adjusted incidence and mortality rates were stable in most entities, except in gallbladder carcinoma. The overall survival improved in almost all entities as compared with those during 1990-2009.

Challenges in hepatitis C elimination despite highly effective antiviral agents in patients with and without intravenous drug use.

AIM: To assess the adherence to treatment, sustained virologic response (SVR) rate, and reinfection rate in hepatitis C patients with and without intravenous drug use. METHODS: This retrospective study included hepatitis C patients, evaluated and treated in our hepatology outpatient clinic between January 2014 and October 2019. The following information was extracted from the patient's file: the presence of positive viral load for hepatitis C virus (HCV), active and recent (in the last 6 months) use of i.v. drugs, HCV genotype, treatment regimen, SVR, HCV reinfection rate, coinfection with human immunodeficiency virus (HIV) and ongoing opioid substitution therapy (OST). RESULTS: We included 431 hepatitis C patients, 234 people who inject drugs (PWID) and 197 non-PWID. Most patients were treated with direct-acting antivirals (DAA) only. The rate of documented SVR by treated patients was significantly higher in the non-PWID cohort (91.5% vs. 61.5%, p < 0.0001), while noncompliance (did not show up to start treatment) rate or refusal of treatment was significantly higher in the PWID cohort (19.4% vs. 8.9%, p = 0.004). In the PWID cohort, younger age and recent (in the last 6 months) or ongoing i.v. drug use was associated with noncompliance: 31.1 ± 8.4 years vs. 35.8 ± 10.6 years (p = 0.02) and 33.3% vs. 12.8% (p = 0.0008), respectively. Ongoing OST was associated with better compliance: 61.1% vs. 46.1% (p = 0.04). CONCLUSION: To achieve elimination of hepatitis C better treatment strategies are needed, especially in PWIDs.

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.

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.