HCC is one of the most common cancers worldwide, and the third leading cause of cancer‐related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno‐oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first‐line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T‐cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.

The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the prognostic ability of the CALLY index for patients with HCC undergoing transarterial chemoembolization (TACE). We retrospectively identified 280 treatment-naïve patients with HCC that underwent an initial TACE at our institution, between 2010 and 2020. We compared the CALLY index to established risk factors in univariate and multivariate regression analyses for associations with median overall survival (OS). A low CALLY score was associated with low median OS (low vs. high CALLY: 9.0 vs. 24.0 months, p < 0.001). In the multivariate analysis, the CALLY index remained an independent prognostic predictor (p = 0.008). Furthermore, all factors of the CALLY index reached significance in univariate and in-depth multivariate analyses. However, the concordance index (C-index) of the CALLY index (0.60) was similar to the C-indices of established immunonutritive and inflammation scoring systems (range: 0.54 to 0.63). In conclusion, the CALLY index showed promise as a stratification tool for patients with HCC undergoing TACE. Notably, the CALLY index was not superior to other immunonutritive and inflammation scoring systems in predicting the median OS. Thus, future studies should re-evaluate the mathematical calculation of the index, particularly the contributions of individual parameters.

Summary: Background: In light of the global rise in the burden of chronic liver diseases and liver cirrhosis, the number of patients suffering from decompensation events is expected to increase. Transjugular intrahepatic portosystemic shunts (TIPSS) provide effective long‐term symptom control and may prolong transplant‐free survival in portal hypertension‐driven recurrent ascites and variceal bleeding. New‐onset or recurrent hepatic encephalopathy (HE) after TIPSS insertion (post‐TIPSS HE) represents the most severe post‐interventional complication.Aims: To provide insight into the epidemiology and risk factors for post‐TIPSS HE and scrutinize the current state of the art in treatment and drug therapy options.Methods: We conducted a literature search on post‐TIPSS HE in patients with liver cirrhosis.Results: Post‐TIPSS HE occurs in up to 54.5% of cases and particularly early recurrent HE is associated with a dismal prognosis. In recent years, several risk factors for the development of post‐TIPSS HE have been identified. These include not only parameters reflecting liver function (model for end‐stage liver disease score/Child‐Pugh score) as well as cognitive dysfunction caused by minimal HE but also extrahepatic factors such as sarcopenia and common medications such as proton pump inhibitors. In addition, new data on the benefit of rifaximin and of smaller stent grafts emerged and may improve the prevention of post‐TIPSS HE.Conclusions: Careful selection of TIPSS candidates is of utmost importance to reduce the risk of post‐TIPSS HE. In this narrative review, we provide a concise overview of the current epidemiology and risk factors of the treatment options for post‐TIPSS HE.

Objectives: The Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are immunonutritive scoring systems with proven predictive ability in various cancer entities, including hepatocellular carcinoma (HCC). We performed the first evaluation of the CONUT score for patients undergoing transarterial chemoembolization (TACE) and compared CONUT and PNI in the ability to predict median overall survival (OS).Methods: Between 2010 and 2020, we retrospectively identified 237 treatment-naïve patients with HCC who underwent initial TACE at our institution. Both scores include the albumin level and total lymphocyte count. The CONUT additionally includes the cholesterol level. Both scores were compared in univariate and multivariate regression analyses taking into account established risk factors. In a second step, a subgroup analysis was performed on BCLC stage B patients, for whom TACE is the recommended first-line treatment.Results: A high CONUT score and low PNI were associated with impaired median OS (8.7 vs. 22.3 months, p<0.001 and 6.8 vs. 20.1 months, p<0.001, respectively). In multivariate analysis, only the PNI remained an independent prognostic predictor (p=0.003), whereas the CONUT score lost its predictive ability (p=0.201). In the subgroup of recommended TACE candidates, both CONUT and PNI were able to stratify patients according to their median OS (6.6 vs. 17.9 months, p<0.001 and 10.3 vs. 22.0 months, p<0.001, respectively). Again, in the multivariate analysis, only the PNI remained an independent prognostic factor (p=0.012).Conclusion: Both scores were able to stratify patients according to their median OS, but only the PNI remained an independent prognostic factor. Therefore, PNI should be preferred when evaluating the nutritional status of patients undergoing TACE.

Diagnosis of minimal hepatic encephalopathy (MHE) requires psychometric testing, which is time‐consuming and often neglected in clinical practice. Elevated Interleukin‐6 (IL‐6) serum levels have been linked to MHE. The aim of this study was to investigate the usefulness of IL‐6 as a biomarker in a stepwise diagnostic algorithm to detect MHE in patients with liver cirrhosis. A total of 197 prospectively recruited patients without clinical signs of hepatic encephalopathy (HE) served as the development cohort. Another independent cohort consisting of 52 patients served for validation purposes. Psychometric Hepatic Encephalopathy Score (PHES) was applied for the diagnosis of MHE. Fifty (25.4%) patients of the development cohort presented with MHE. Median IL‐6 levels were more than twice as high in patients with MHE than in patients without HE (16 vs. 7 pg/mL; P < 0.001). On multivariable logistic regression analysis, higher IL‐6 levels (odds ratio 1.036; 95% confidence interval [CI] 1.009‐1.064; P = 0.008) remained independently associated with the presence of MHE. IL‐6 levels ≥ 8pg/mL discriminated best between patients with and without MHE in receiver operating characteristic (ROC) analysis (area under the ROC 0.751). With a cutoff value of ≥7 pg/mL, further elaborate testing with PHES could be avoided in 38% of all patients with a sensitivity of 90% (95% CI 77%‐96%) and a negative predictive value (NPV) of 93% (95% CI 84%‐98%). This diagnostic accuracy was confirmed in the validation cohort (sensitivity 94%; NPV 93%). Conclusion: Using IL‐6 serum levels as a biomarker in a stepwise diagnostic algorithm to detect MHE could substantially reduce the number of patients requiring testing with PHES and in turn the workload. IL‐6 may have especially helped in patients who are unable to perform other screening tests.