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Background: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second-line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post-progression survival (PPS), similar to hepatocellular carcinoma. Methods: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). Results: We included 206 patients from 5 centres. The median OS was 14.1months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509-0.961], performance status >2.445 [1.788-3.344], permanent first-line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin >3mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independently predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for second-line treatment, PPS was 16.8 and 5.9months in cases without and with NEH, respectively (P=.001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333-2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3mg/dl and ascites. Conclusions: PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.

Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.

Background: The liver is involved in disseminated tuberculosis in more than 80% of cases while primary liver involvement is rare, representing

Liver cirrhosis is a leading cause of death worldwide, with 1-year mortality rates of up to 57% in decompensated patients. Hepatocellular carcinoma (HCC) is the most common primary tumor in cirrhotic livers and the second leading cause of cancer-related mortality worldwide. Annually, up to 8% of patients with cirrhosis develop HCC. The diagnosis of HCC rarely requires histological confirmation: in fact, according to the most recent guidelines, the imaging features of HCC are almost always sufficient for a certain diagnosis. Thus, the role of the radiologist is pivotal because the accurate detection and characterization of focal liver lesions in patients with cirrhosis are essential in improving clinical outcomes. Despite recent technical innovations in liver imaging, several issues remain for radiologists regarding the differentiation of HCC from other hepatic lesions, particularly benign lesions and pseudolesions. It is important to avoid misdiagnosis of benign liver lesions as HCC (false-positive cases) because this diagnostic misinterpretation may lead to ineligibility of a patient for potentially curative treatments or inappropriate assignment of high priority scores to patients on waiting lists for liver transplantation. This review presents a pocket guide that could be useful for the radiologist in the diagnosis of benign lesions and pseudolesions in cirrhotic livers, highlighting the imaging features that help in making the correct diagnosis of macroregenerative nodules; siderotic nodules; arterioportal shunts; hemangiomas, including fast-filling hemangiomas, hemangiomas with pseudowashout, and sclerosed hemangiomas; confluent fibrosis; pseudomasses in chronic portal vein thrombosis; and focal fatty changes.

Background An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC). Aims We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival. Methods Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching. Results The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9–64.0]) was not significantly different from the observed (47.0 months [35.0–58.9]; p = 0.43) and adjusted (44.9 months [33.4–56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients. Conclusions A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics.

Background: Due to its poor survival, intrahepatic cholangiocarcinoma (ICC) is held to be a much more aggressive cancer than hepatocellular carcinoma (HCC). In most published series, patients were diagnosed when symptomatic. However, ICC is now increasingly being discovered during the surveillance for HCC in cirrhosis. Whether this earlier detection of ICC is associated with an equally dismal prognosis or not is unknown. Methods: This is amulticenter retrospective study of consecutive ICC patients. Patients were stratified into subgroups according to the absence/presence of cirrhosis. A propensity score matching was performed to reduce the potential biases. Cirrhotic patients were further stratified according to their surveillance status. The lead-time bias and its potential effects were also estimated. Results: We gathered 184 patients. Eighty-five patients (46.2%) were cirrhotic. Liver cirrhosis was not related to a worse overall survival (33.0 vs. 32.0 months, p = 0.800) even after the propensity score analysis (43.0 in vs. 44.0 months in 54 pairs of patients, p = 0.878). Among the cirrhotic population, 47 (55.3%) patients had received a diagnosis of ICC during a surveillance programme. The 2 subgroups differed in maximum tumour dimensions (30 vs. 48 mm in surveyed and non-surveyed patients, respectively). Surveyed patients were more likely to receive surgical treatments (59.8 vs. 28.9%, p = 0.003). Overall survival was higher in surveyed patients (51.0 vs. 21.0 months, p < 0.001). These benefits were confirmed after correcting for the lead-time bias. Conclusions: Cirrhotic patients have different clinical presentation and outcomes of ICC according to their surveillance status. In our series, ICC in cirrhosis was not associated with worse OS. Cirrhosis itself should not discourage either surgical or non-surgical treatments.

Background: Lung ultrasound (LU) is becoming an increasingly important diagnostic tool in detecting lung involvement in Corona Virus Disease 2019 (COVID-19). The aim of this study was to ascertain the likelihood of finding LU abnormalities; mimicking lung involvement; in COVID-19 negative healthy individuals. Methods: We performed LU on 265 healthcare workers; not presenting COVID-19 major symptoms and in good health; during the course of a serological screening program for COVID-19 in our General Hospital. LU results were reported as total Lung Ultrasound Score (LUS) using a 12-zone method of reporting. Results: 250/265 subjects were included in the COVID-19 negative group. LU was not completely normal (LUS ≠ 0) in 65/250 COVID-19 negative subjects (26%) and in 12/15 (80%) poorly symptomatic COVID-19 positive subjects; with a multifocal pattern in 12.7% vs. 66.7% of cases respectively. Age and COVID-19 positivity were independent predictors of total LUS. A total LUS ≥ 2 had a sensitivity of 66.67% and a specificity of 85.60% in detecting COVID-19 positivity. Conclusions: A slightly altered LU can be quite frequent in healthy COVID-19 negative subjects. LU can have a role in confirming but not screening COVID-19 poorly symptomatic cases.

Background: Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field. Objective: The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma. Patients and methods: A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed. Results: A negative prognostic impact of low baseline eosinophil counts (< 50*109/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6-216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24-16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83-5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care. Conclusions: Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.

Aims: The therapeutic scenario of systemic treatments for hepatocellular carcinoma (HCC) is rapidly changing. There is much interest in the possibility of combining new therapies with surgery, but clinical data is lacking. We aimed to provide an example of such integration. Patients & methods: We report a patient with metastatic HCC who received regorafenib in the setting of the RESORCE trial. Results: A brilliant response led to a tumor downstaging and a subsequent adrenal metastasectomy with radical intent. Conclusions: New agents will change the therapeutic perspectives in advanced HCC and lead to a higher rate of objective responses, with possibilities of associating systemic therapy and surgery. Thus, the management of HCC will require more and more of an integrated, multidisciplinary and personalized approach., Graphical abstract

Introduction: Gallbladder cancer (GC) is a rare malignancy with a dismal prognosis. When diagnosed early enough, it can be cured by surgical removal. Unfortunately, only few GC patients can be amenable to surgery, though, with a high relapse rate. Conventional chemotherapy remains the golden standard for unresectable or metastatic GC, both in the first and second-line settings, even if leading to a fair outcome improvement. Areas covered: In recent years, according to the concept of ‘precision medicine’, new potential molecular targets have been examined. We provided a general outline of the current first- and second-line chemotherapies. New therapeutic possibilities are also reviewed, particularly HER2, EGFR, VEGF, TKI, MEK and BRAF inhibitors, and immunotherapy. Furthermore, published clinical trials are utilized to analyze the principal drug effectiveness in GC. Expert opinion: GC is characterized by vast cancer heterogeneity and individual’s efficacy to different drugs. The ongoing trials have the potentiality of reshaping the landscape of systemic treatments for GC in the very next years. Nowadays, amongst therapeutic combinations, the addition of ICIs to chemotherapy has yielded encouraging results needing confirmation. In the next future, systematic implementation of gene profiling and further explorations of combination therapies will likely change the treatment scenario.

INTRODUCTION: Prognostic classifications for patients treated with sorafenib for hepatocellular carcinoma (HCC) facilitate stratification in trials and inform clinical decision making. Recently, 3 different prognostic models (hepatoma arterial-embolization prognosis [HAP] score, sorafenib advanced HCC prognosis [SAP] score, and Prediction Of Survival in Advanced Sorafenib-treated HCC [PROSASH]-II) have been proposed specifically for patients treated with sorafenib. This study aimed to compare the prognostic performance of different scores. METHODS: We analyzed a large prospective database gathering data of 552 patients treated with sorafenib from 7 Italian centers. The performance of the HAP, SAP, and PROSASH–II models were compared with those of generic HCC prognostic models (including the Barcelona Clinic for Liver Cancer and Italian Liver Cancer staging systems, albumin–bilirubin grade, and Child-Pugh score) to verify whether they could provide additional information. RESULTS: The PROSASH-II model improved discrimination (C-index 0.62) compared with existing prognostic scores (C-index ≤0.59). Its stratification significantly discriminated patients, with a median overall survival of 21.5, 15.3, 9.3, and 6.0 months for risk group 1, 2, 3, and 4, respectively. The HAP and SAP score were also validated but with a poorer performance compared with the PROSASH-II. DISCUSSION: Although suboptimal, PROSASH-II is the most effective prognostic classification model among other available scores in a large Italian population of patients treated with sorafenib.

Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1 alpha-mutated HCA, inflammatory HCA, beta-catenin-mutated HCA, and unclassified HCA. beta-catenin-mutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1 alpha-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization.

Introduction: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

Introduction: The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods: An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. Results: The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10–1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. Conclusion: An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.

New Antibodies to hexokinase 1 (HK1) and kelch-like 12 (KLHL12) has been reported by Reig et al as potential biomarkers in primary biliary cholangitis (PBC). They also reported changes of these antibodies over time, and described the association with clinical outcomes. The authors found that anti-HK1 and anti-KLHL12 were positive in 46.1% and 22.8% of patients, respectively, and changed overtime in 13.3% and 5.5% of patients, respectively. Interestingly, anti-HK1 or antiKLHL12 antibodies were detected in 6 (37.5%) of the 16 patients with antimitochondrial antibody (AMA), and in 4 (40%) of the 10 AMA, anti-gp210– and anti-sp100–seronegative patients. Moreover, a lower response to ursodeoxycholic acid was observed in antiHK1–positive patients according only to Toronto criteria (74% vs 87%, P , 0.02). It is well known that antinuclear antibodies (ANA) demonstrated high PBC specificity and high diagnostic value in AMA-negative PBC patients, particularly the anti-sp100 and anti-gp210 antibodies corresponding to the immunofluorescence PBC-specific ANA patterns of multiple nuclear dots (MND) and rim-like membranous (RL/M), respectively. It would therefore be relevant to test the new antibodies described by Reig et al. in multicenter studies in different geographical areas on a subgroup of patients who are negative for both AMA and all ANAs as detected by immunofluorescence and/or by immunoenzymatic assays with recombinant antigens.

Background: Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field. Objective: The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma. Patients and Methods: A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan–Meier method. Univariate and multivariate analyses were performed. Results: A negative prognostic impact of low baseline eosinophil counts (< 50*109/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6–216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24–16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83–5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care. Conclusions: Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.

Tocilizumab is a humanised interleukin-6 receptor-inhibiting monoclonal antibody that is currently approved for the treatment of rheumatoid arthritis and other immune-related conditions. Recently, tocilizumab has been investigated as a possible treatment for severe coronavirus-induced disease 2019 (COVID-19). Despite the lack of direct antiviral effects, tocilizumab could reduce the immune-induced organ damage caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) infection. Until recently, most reports on tocilizumab for COVID-19 included a limited number of patients, preventing an overall evaluation of its efficacy and safety for this specific condition. Therefore, we reviewed the literature regarding the physiopathological rationale of tocilizumab for COVID-19 and its outcomes. We searched the MEDLINE database with the string “(SARS-CoV-2 OR coronavirus OR COVID-19 OR MERS- cov OR SARS-cov) AND (IL-6 OR interleukin 6 OR tocilizumab)”. While the scientific rationale supporting tocilizumab for COVID-19 is solid, the evidence regarding the outcomes remains controversial. Available data and results from ongoing trials will provide useful information in the event of new COVID-19 outbreaks or future pandemics from different coronaviruses.

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.

Multiple focal liver lesions were incidentally detected in a patient screened by ultrasound for a recent diagnosis of lower limb deep vein thrombosis, for which anticoagulation had been initiated. Past medical history reported a post-traumatic splenectomy 15 years before. Magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) showed a subcapsular lesion in liver segment 5 consistent with focal nodular hyperplasia (FNH) and multiple other nodules, with a different pattern from the former, judged as probable hepatic adenomas by MRI but probable hemangiomas by CEUS (hyperenhancement in the late phase). Therefore, another MRI with gadoxetic acid was performed. The diagnosis of FNH was confirmed. The other lesions showed an hyperenhancing pattern in the arterial phase with progressive wash-out in the portal and late phase and marked hypointensity in the hepatobiliary phase. This pattern apparently confirmed the hypothesis of adenomas, with a potential risk of malignancy due to the hepatobiliary phase pattern and the recent occurrence of deep vein thrombosis. Due to the inherent risk of spontaneous bleeding from subcapsular adenomas increased by the ongoing anticoagulant therapy and the recommendation of international guidelines to resect adenomas in male subjects, the patient was directly offered surgery. Pathology of the resected specimens confirmed one FNH but demonstrated intrahepatic splenosis for all other lesions. This case suggests that in the setting of previous splenic trauma any discrepancy between MRI and CEUS findings should lead one to consider also the hypothesis of intrahepatic splenosis.

Background: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic involving 20-40% of the general population. NAFLD is rapidly becoming the leading cause of hepatocellular carcinoma (HCC) worldwide. Knowledge about NAFLD-HCC peculiar features is needed to understand this emerging disease better. Objective: To review the current literature about the epidemiological, pathogenic and clinical features characterising the NAFLD and distinguishing it from HCC of other etiologies. Methods: A systematic review of the literature (PubMed and Medline) using the following string ("Non-alcoholic Fatty Liver Disease"[Mesh] and "Carcinoma, Hepatocellular"[Mesh]). Particular relevance was given to papers published in the last five years as well as previously published manuscript very relevant to this topic according to the experience of the authors. Results: A total of 244 original papers in humans in English literature were analysed. Inherent difficulties in the identification of high-risk subjects and the possibility of occurrence in non-cirrhotic livers are peculiar characteristics of NAFLD-HCC hampering surveillance programs. The consequently delayed diagnosis limits access to surgical procedures and impacts on survival. After correction for tumour burden, however, the survival is not different from that of viral HCC, suggesting that NAFLD-HCC is not intrinsically a more aggressive malignancy. Conclusions: A great deal of effort is needed to improve the clinical outcome of NAFLD-HCC, especially in terms of prevention, surveillance protocols, and identification of drug modifying the natural history of the underlying liver disease. The outcome of these efforts will significantly impact global HCC-related costs and mortality.

Background: Previous studies demonstrated that objective response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) is an independent predictor of overall survival (OS) in patients with hepatocellular carcinoma (HCC). The European Association for the Study of the Liver indicates additional studies are needed to further validate the predictive value of tumor response. In this post hoc retrospective analysis, we investigated the association between objective response by investigator-assessed mRECIST and OS for patients from the REFLECT trial, a randomized, open-label, non-inferiority phase 3 trial of lenvatinib versus sorafenib in first-line treatment of patients with unresectable HCC. Methods: We evaluated the association between objective response per investigator-assessed mRECIST and OS for the overall REFLECT population. We also conducted landmark analyses of OS by objective response status at 2, 4, and 6 months after randomization. Findings: Median OS was 22·4 months (95% CI: 19·7–26·0) for responders compared with 11·4 months (95% CI: 10·3–12·3) for nonresponders (hazard ratio [HR]: 0·61; 95% CI: 0·49–0·76; p

Introduction Prognostic classifications for patients treated with sorafenib for hepatocellular carcinoma (HCC) facilitate stratification in trials and inform clinical decision making. Recently, 3 different prognostic models (hepatoma arterial-embolization prognosis [HAP] score, sorafenib advanced HCC prognosis [SAP] score, and Prediction Of Survival in Advanced Sorafenib-treated HCC [PROSASH]-II) have been proposed specifically for patients treated with sorafenib. This study aimed to compare the prognostic performance of different scores. Methods We analyzed a large prospective database gathering data of 552 patients treated with sorafenib from 7 Italian centers. The performance of the HAP, SAP, and PROSASH-II models were compared with those of generic HCC prognostic models (including the Barcelona Clinic for Liver Cancer and Italian Liver Cancer staging systems, albumin-bilirubin grade, and Child-Pugh score) to verify whether they could provide additional information. Results The PROSASH-II model improved discrimination (C-index 0.62) compared with existing prognostic scores (C-index ≤0.59). Its stratification significantly discriminated patients, with a median overall survival of 21.5, 15.3, 9.3, and 6.0 months for risk group 1, 2, 3, and 4, respectively. The HAP and SAP score were also validated but with a poorer performance compared with the PROSASH-II. Discussion Although suboptimal, PROSASH-II is the most effective prognostic classification model among other available scores in a large Italian population of patients treated with sorafenib.

The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.

Computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluorideoxyglucose positron emission tomography (18FDG-PET) are historically the most accurate imaging techniques for diagnosing liver metastases. Recently, the combination of diffusion-weighted imaging and hepatospecific contrast media, such as gadoxetic acid in MRI, have been demonstrated to have the highest diagnostic accuracy, sensitivity, and specificity for detecting liver metastases. Various recent meta-analyses have confirmed the diagnostic superiority of this combination (diffusion-weighted imaging and gadoxetic acid-enhanced MRI), especially in terms of per lesion sensitivity, as compared with CT and 18FDG-PET, even for smaller lesions (≤1 cm). However, none of the oncological guidelines have suggested the use of MRI as a first-line technique for liver metastasis detection during the staging process of oncological patients. This review analyzes the history of the principal imaging techniques for the diagnosis of liver metastases, in particular of colorectal liver metastases, focusing on the most accurate method (diffusion-weighted imaging combined with gadoxetic acid-enhanced MRI), possible reasons for the lack of its diffusion in the guidelines, and possible future scenarios.

Background: A gluten-free diet (GFD) is known to be associated with altered macronutrient intake and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic hallmark of metabolic syndrome. The risk of NAFLD in patients with coeliac disease (CD) adhering to a GFD remains to be fully investigated; in particular, data from real-life clinical settings are lacking. Aim: To assess the prevalence and relative risk of NAFLD in CD patients treated with a GFD. Methods: Case–control study, with prospective enrolment of CD outpatients following a GFD and controls. Patients were matched for demographic characteristics (age and gender) and metabolic risk factors (overweight, diabetes mellitus, total cholesterol, and triglycerides) using a 1:1 ratio. NAFLD was diagnosed according to the European Association for the Study of the Liver criteria. Results: 202 CD patients and 202 controls were compared. The raw prevalence of NAFLD was 34.7% and 21.8% in the CD and control group, respectively (P = 0.006). Binary logistic regression confirmed an increased risk of NAFLD in the CD group (adjusted odds ratio = 2.90, 95% confidence interval: 1.64-5.15, P < 0.001). Additionally, the relative risk for NAFLD was notably higher in non-overweight CD patients (adjusted odds ratio = 5.71, 95% confidence interval: 2.30-14.19, P < 0.001). Conclusions: More than one-third of CD patients adhering to a GFD had concurrent NAFLD, accounting for a three-fold increased risk compared to the general population. Dietary advice provided using a patient-tailored approach should assist CD patients with NAFLD in achieving an appropriate nutritional intake whilst reducing the risk of long-term liver-related events.

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The aim of the present study was to correlate laboratory data and postprocedural parameters after conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma (HCC) with the radiological response. The study consisted of a retrospective analysis of prospectively collected data from 70 consecutive patients who underwent cTACE. Laboratory parameters were assessed daily after cTACE and compared to pretreatment values. Post-treatment radiological response was assessed using mRECIST at one month from cTACE, and factors associated with treatment response (complete and objective response) were assessed by logistic regression analysis. The optimal cutoff points in predicting the complete response of target lesions were a 52% ALT and a 46% AST increase after cTACE compared to the pre-treatment values. Using multivariate analyses, &gt, 46% AST and &gt, 52% ALT increases with respect to the pre-treatment value were significantly correlated with the objective response (p = 0.03 and p = 0.04, respectively) and the complete response (p = 0.02 and p = 0.02, respectively). No patients experienced liver function deterioration after cTACE, and no specific treatment was required. This study showed that post-treatment transient transaminase elevation was predictive of objective response to superselective cTACE in clinical practice, representing a simple tool to guide treatment strategy of HCC patients in a tailored approach.

Purpose: Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). Methods: 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Results: Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7)months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8)months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. Conclusions: MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

none 5 no Sorafenib has been the only approved systemic therapy for hepatocellular carcinoma until very recently. However, the radiologic assessment of its biological activity is a disputed matter as at least five different criteria have been proposed. In this review, we describe the characteristic of the Response Evaluation Criteria In Solid Tumors (RECIST), European Association for the Study of The Liver (EASL), modified RECIST (mRECIST), Response Evaluation Criteria In the Cancer of the Liver (RECICL) and Choi criteria. The existing comparative studies are reported together with recent pieces of evidence, analyzing the reasons behind the split between recommendations of the scientific societies and regulatory agencies. Future perspectives in the wake of the impending results of the immunotherapy trials are also discussed. mixed Tovoli, Francesco; Renzulli, Matteo; Granito, Alessandro; Golfieri, Rita; Bolondi, Luigi Tovoli, Francesco; Renzulli, Matteo; Granito, Alessandro; Golfieri, Rita; Bolondi, Luigi

none 7 no Background & Aims: Pain management in cirrhosis is a clinical challenge. Most analgesics are metabolized in the liver and cirrhosis may deeply alter their concentration, favouring the appearance of side effects. We aimed to assess the efficacy and safety of oral prolonged-release association of oxycodone/naloxone tablets (OXN) in the treatment of moderate/severe cancer pain in cirrhotic patients with metastatic hepatocellular carcinoma (HCC). Methods: We enrolled n = 32 HCC patients with moderate/severe cancer pain unresponsive to paracetamol alone or associated with codeine or tramadol. All patients received an initial OXN dose of 5 mg bid to be gradually increased in case of insufficient analgesia. At baseline and follow-up visits, we evaluated: pain intensity (using the Numerical Rating Scale, NRS), patients' autonomy in daily activities (Barthel Functioning Index); bowel dysfunction (Bowel Function Index, BFI), signs of hepatic encephalopathy (HE) and other opioid-induced side effects. Results: No clinically significant adverse effects were reported (median follow-up 122 days). No significant worsening of the BFI score was noted and no cases of HE were detected. Two patients (6.3%) discontinued treatment before T14 because of mild nausea and dizziness. The remaining n = 30 patients were assessed for efficacy. Treatment led to a significant reduction in the mean of pain scores both at T14 (-37.1 ± 16.3%, P < .001) and at T28 (-55.6 ± 21.5%, P < .001); Barthel scores showed gradual and significant increase from T0 (81.6 ± 13.0) to T14 (86.5 ± 11.4, P = .001) and to T28 (88.3 ± 13.6, P = .009). Conclusions: OXN may be considered a safe and effective option in the fragile population of cirrhotic patients. Tovoli, Francesco; De Lorenzo, Stefania; Samolsky Dekel, Boaz G.; Piscaglia, Fabio; Benevento, Francesca; Brandi, Giovanni; Bolondi, Luigi Tovoli, Francesco; De Lorenzo, Stefania; Samolsky Dekel, Boaz G.; Piscaglia, Fabio; Benevento, Francesca; Brandi, Giovanni; Bolondi, Luigi

Background: The screening modalities for women at high risk for breast cancer has received an increasing role during the last years. The aim of this study was to evaluate the performance of our screening program comparing the diagnostic sensitivity of clinical breast examination, mammography, ultrasonography (US) and magnetic resonance imaging (MRI). Methods: Clinical Breast examination, mammography, US and MRI for each patient with BRCA1 and BRCA2 mutation who underwent breast surgery in our Institution from October 2008 to April 2016 were retrospectively evaluated. The diagnostic accuracy for MRI and for the other surveillance tests in identifying early breast cancer were assessed. Results: Twenty-six female patients with genetic mutation underwent breast surgery. Twenty-two out of 26 (85%) developed cancer during the dedicated screening protocol whereas 4 women who underwent surgery did not have cancer. Imaging was able to detect cancer in all 22 patients (per patient sensibility of 100%), identifying all 35 neoplastic lesions (per lesion sensibility of 100%). The combination of Clinical Breast Examination, US and mammography aided the cancer diagnosis in 14 (64%) of patients with a sensitivity of 64% and specificity of 100%. MRI identified all the cancers, with sensibility and specificity of 100%. Moreover, in 8 (36%) of the 22 patients who developed breast cancers, the cancers were detected only by MRI, revealing a significant superiority respect to the other surveillance modalities (P

Hepatocellular carcinoma (HCC) is a worldwide healthcare problem, with a rising incidence. In its advanced stage, the prognosis of untreated HCC is very poor. Only in 2007, after a long series of failed trials, the multi-tyrosine kinase inhibitor sorafenib demonstrated its superiority over placebo, becoming the first approved frontline therapy for advanced HCC. For a decade, all of the frontline trials using sorafenib as a comparator systematically failed, leaving this drug as the only available treatment in this setting. In 2018, lenvatinib mesylate (another multitarget tyrosine kinase inhibitor) demonstrated noninferiority compared to sorafenib in the phase III, randomized, controlled REFLECT trial. Currently, lenvatinib represents the only available alternative to sorafenib as a frontline systemic treatment of advanced HCC. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of lenvatinib, with particular attention to the features differentiating this drug from sorafenib.

Hepatocellular carcinoma (HCC) is currently the second cause of cancer-related death worldwide and its incidence has been estimated to increase of about 20% by 2020 (1).

Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. The impact of the physicians experience on the management of these AEs and the relative implications on clinical outcomes are unknown. We verified if the AEs management changed over time and if these modifications impacted on treatment duration and overall survival (OS). Background & Aims: Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians’ experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS). Methods: We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008–2012; n = 154), and Group B (2013–2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. Results: Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p

Background: Diagnosis of hepatocellular carcinoma can be achieved by imaging in cirrhotic patients. Combined hepatocellular-cholangiocarcinoma is a primary liver tumor and its imaging patterns have been poorly investigated. Misdiagnosis for either hepatocellular carcinoma or benign lesions can occur. We aimed to evaluate the enhancement pattern of combined hepatocellular-cholangiocarcinoma in cirrhosis with imaging techniques and to estimate the risk of misdiagnosis for hepatocellular carcinoma. Methods: All histology-confirmed combined hepatocellular-cholangiocarcinoma in cirrhosis seen in two Italian centers between 2003 and 2016, in which at least one imaging technique had been performed, was retrospectively collected. The enhancement pattern was analyzed for all available imaging modalities. Results: A total of 37 combined hepatocellular-cholangiocarcinoma nodules were identified. Contrast-enhanced ultrasound, computed tomography, and magnetic resonance imaging had been performed in 27, 34, and 17 nodules, respectively. Contrast-enhanced ultrasound was at higher risk of misdiagnosis for pure hepatocellular carcinoma than computed tomography (p = 0.005) or magnetic resonance imaging (p = 0.040). Only six of 24 combined hepatocellular-cholangiocarcinoma lesions submitted to both contrast-enhanced ultrasound and computed tomography showed coincident patterns; contrast-enhanced ultrasound correctly suggested a condition of malignancy in a higher number of cases than computed tomography (p < 0.001) and magnetic resonance imaging (p = 0.002). Conclusions: Contrast-enhanced ultrasound misdiagnosed a higher number of combined hepatocellular-cholangiocarcinoma as hepatocellular carcinoma than computed tomography and magnetic resonance imaging. However, the latter techniques were able to identify features of malignancy less often.

The editorial is presenting the role of modern ultrasound techniques in the assessment of the efficacy of treatment of various malignant tumors

In the latest years, antineoplastic immunotherapy revolutionised the therapeutic landscape in oncology. First shown to be effective in melanoma and non-small cell lung carcinoma, immune checkpoint inhibitors are now being tested for the treatment of hepatocellular carcinoma (HCC). Preliminary results have been particularly promising. As a consequence, an increasing number of clinical trials are underway. The role of the immune system in carcinogenesis (with particular reference to tumour escape immune mechanisms), as well as the current immunotherapy trials for HCC in its different clinical scenarios, are the subject of this review. In particular, we aim to provide fresh updates about these novel therapeutic agents which promise to shape the future therapeutic scenario of HCC.

Hepatocellular carcinoma (HCC) remains among the neoplastic diseases with the most unfavorable prognosis. Historically, systemic treatments for HCC have been scarce. In particular, sorafenib was the only registered drug for the treatment of unresectable HCC until 2017. Last year, regorafenib was approved by the global regulatory agencies as second-line therapy. Since then, further randomized, controlled trials have been successful in this patient population. This paper deals with the most recent data concerning cabozantinib and ramucirumab, the two drugs that have recently demonstrated efficacy in phase III, randomized, controlled trials in HCC patients who failed previous treatment with sorafenib.

269 Background: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) followed by NIVO 240 mg Q2W is approved in the US for sorafenib-treated pts with aHCC based on initial results from CheckMate 040 (NCT01658878), which reported objective response rate (ORR) of 32% and median overall survival (mOS) of 22.8 months (mo).1 We present 44-mo long-term follow-up results from the CheckMate 040 NIVO+IPI cohort. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Safety and tolerability, ORR (blinded independent central review per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS were assessed. Data cutoff was May 26, 2020. Results: 148 pts were randomized. Minimum follow-up was 44 mo. mOS remained at 22.2 mo in arm A, 12.5 mo in arm B, and 12.7 mo in arm C; 36-mo OS rates were 42%, 26%, and 30%, respectively. Durable responses were achieved across treatment arms, with DOR approaching 4 years in some cases. DCR was higher in arm A than arms B and C. In all arms, responses were observed regardless of baseline programmed death ligand 1 expression ( < 1% or ≥ 1%) or baseline alpha-fetoprotein level ( < 400 µg/L or ≥ 400 µg/L). Pts with hepatitis B or C virus (HBV or HCV) etiology had higher ORR than uninfected pts in arms B (29% vs 43% vs 9%) and C (31% vs 42% vs 0%). ORR was independent of etiology in arm A (HBV, 32%; HCV, 29%; uninfected, 31%). Additional efficacy data are in the table. There were no additional discontinuations due to treatment-related adverse events or immune-mediated adverse events (IMAEs) since the primary analysis. IMAEs were reported more frequently in arm A than arms B and C; the most common were rash, hepatitis, and adrenal insufficiency. Most IMAEs were reversible and resolved when treated using established algorithms. Conclusions: At a minimum follow-up of 44 mo, second-line NIVO1+IPI3 continued to demonstrate clinically meaningful responses and long-term survival benefit in aHCC. The safety profile was manageable and no new safety signals were identified with longer follow-up. Clinical trial information: NCT01658878. [Table: see text]

Hepatocellular carcinoma (HCC) is a worldwide problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Its close association with chronic liver diseases and liver cirrhosis represents a significant challenge in its treatment. Sorafenib, the first front-line systemic treatment for unresectable HCC cases, was approved only in 2007. The role of sorafenib remained largely unchallenged until very recently, with the sole exception of a trial demonstrating the noninferiority of lenvatinib, another tyrosine kinase inhibitor. The therapeutic scenario changed dramatically in 2020, when the combination of atezolizumab and bevacizumab proved to be significantly superior to sorafenib and, thus, establishing a new standard of care. In this monograph we provide an update about the safety and efficacy of atezolizumab reported in the clinical trials of HCC, as monotherapy or in combination with other agents.

Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib’s efficacy in HCC that led to regorafenib’s approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib’s potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.

Importance Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. Objective To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. Design, Setting, and Participants CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). Interventions Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). Main Outcomes and Measures Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). Results Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). Conclusions and Relevance In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. Trial Registration ClinicalTrials.gov Identifier:NCT01658878

Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA (n = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723&ndash, 7.626, p &lt, 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, p = 0.003) and similar to that of patients with known risk factors (31.9 months, p = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156&ndash, 2.718, p = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.

Immune checkpoint inhibitors (ICIs) are beginning to show promise in the clinical management of hepatocellular carcinoma (HCC). Most recently, the anti-programmed death protein-1 (PD-1) agent atezolizumab combined with bevacizumab demonstrated superiority to sorafenib in a Phase 3 randomised clinical trial in the frontline setting. Other ongoing trials of immunotherapy for HCC are exploring different drug combinations, such as a double checkpoint blockade with PD-1 and anti-Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents or with tyrosine kinase inhibitors. Moreover, ICIs are being tested in the adjuvant and neoadjuvant settings trying to resolve long-time unmet needs in HCC. The results of the ongoing trials will be critical to understanding the extent of the therapeutic role of ICIs in the complex and multifaceted clinical scenario of HCC. Still, there are some critical points which need further attention to clarify the best use of ICIs in HCC patients. For instance, the actual eligibility rate of patients in the real-life scenario, the prompt identification and correct management of immune-mediated adverse events, the identification of biomarkers predicting response or resistance, and strategies to prevent the tumour escape from ICI effect.