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We aimed to explore the activation of monoacylglycerol lipase (MAGL)/cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) axis in hepatocellular carcinoma (HCC), evaluating circulating PGE2 as prognostic biomarker in HCC patients. PGE2 levels were measured in blood samples from 24 cirrhotics, and 34 HCC patients were consecutively collected between January 2016 and December 2017. In a subgroup of patients, tissue expression of MAGL mRNA and immunohistochemistry for MAGL and COX-2 were obtained. Despite tumor tissues showing overexpression of MAGL mRNA and higher levels of both MAGL and COX-2 at immunohistochemistry, PGE2 levels were not significantly different in HCC and cirrhotics. HCC patients with circulating PGE2 levels > 14 pg/mL had a significantly shorter overall survival (19.4 vs. 49.9 months; p = 0.03), the finding being confirmed by the multivariate analysis (HR 3.37 [95% CI 1.00–11.60]; p = 0.05). The MAGL/COX-2/PGE2 axis is activated in HCC, and circulating PGE2 proved to be a potential prognostic biomarker.

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.

Simple Summary Celiac disease (CeD) is an multiorgan autoimmune disease precipitated by the ingestion of gluten in genetically predisposed individuals. After the initiation of a gluten-free diet, CeD generally has a benign course, with the complete remission of symptoms and a normal life expectancy; however, robust evidence suggests that subjects with CeD are at increased risk of developing malignancies compared to the general population. Peculiar associations with lymphomas, including enteropathy-associated T-cell lymphoma (EATL), and small bowel carcinoma (SBC), as well as correlations with other cancers, have been thoroughly investigated. In this review, we will examine the risk of developing malignancies in patients with CeD, as well as clinical aspects of and therapeutic options for EATL and SBC. Abstract Celiac disease (CeD) is an immune-mediated enteropathy precipitated by ingestion of gluten in genetically predisposed individuals. Considering that CeD affects approximately 1% of the Western population, it may be considered a global health problem. In the large majority of cases, CeD has a benign course, characterized by the complete resolution of symptoms and a normal life expectancy after the beginning of a gluten-free-diet (GFD); however, an increased risk of developing malignancies, such as lymphomas and small bowel carcinoma (SBC), has been reported. In particular, enteropathy-associated T-cell lymphoma (EATL), a peculiar type of T-cell lymphoma, is characteristically associated with CeD. Moreover, the possible association between CeD and several other malignancies has been also investigated in a considerable number of studies. In this paper, we aim to provide a comprehensive review of the current knowledge about the associations between CeD and cancer, focusing in particular on EATL and SBC, two rare but aggressive malignancies.

Background: MicroRNAs (miRNAs) have been proposed as biomarkers in hepatocellular carcinoma (HCC). We aim at evaluating miR-21 and miR-122 in HCC patients treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) as prognostic biomarkers and investigating their correlation with hypoxia inducible factor-1α (HIF-1α) serum levels. Methods: In this retrospective study, 12 healthy subjects, 28 cirrhotics, and 54 HCC patients (tested before and four weeks after DEB-TACE) were included. Whole blood miR-21 and miR-122 levels were measured by quantitative real time (qRT)-PCR, while serum HIF-1α was assessed by an enzyme-linked immunosorbent assay (ELISA) test. Results: The highest level of miR-21 was found in cirrhotics, while HCC patients had the highest level of miR-122 (which was even higher in “viral” HCC, p = 0.006). miR-21 ratio (after/before DEB-TACE) and miR-122 below their respective cut-offs identified patients with longer progression-free survival (p = 0.0002 and p = 0.02, respectively). The combined assessment of alpha-fetoprotein and miR-21 ratio, both independent prognostic predictors, identified early progressors among patients with complete or partial radiological response. miR-21 levels positively correlated with HIF-1α before (p = 0.045) and after DEB-TACE (p = 0.035). Conclusions: miR-21 ratio and miR-122 are useful prognostic markers after DEB-TACE. miR-21 correlates with HIF-1α and probably has a role in modulating angiogenesis in HCC.

Simple Summary Hepatocellular carcinoma (HCC) is one of the mostly lethal cancers, with a prognosis which is still very poor. Novel reliable biomarkers, useful in early diagnosis and prognosis assessment, are urgently needed in order to improve HCC patient survival. In recent years, several studies focused on liquid biopsy, the molecular analysis of circulating cancer by-products, as a source of novel biomarkers. Extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA provided very interesting results in a large number of studies published recently, but none of them has entered the clinical routine. In this review we will summarize the available evidence on these novel circulating biomarkers as diagnostic, prognostic, and predictive tools. Liquid biopsy proved to be a very useful source of biomarkers, some of which will probably be applied soon in clinical practice. Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.

Simple Summary Hepatocellular carcinoma (HCC) is an increasingly important indication for liver transplantation (LT) worldwide. However, LT in the setting of liver cancer is burdened by the risk of tumor recurrence. The prognosis of patients with post-LT HCC recurrence is still very poor and several areas of uncertainty remain in the management of these patients. In this paper, we provide a comprehensive evaluation of available evidence regarding the management of HCC recurrence after LT, starting from the pre- and post-transplant stratification criteria and encompassing post-LT surveillance, preventive strategies and treatment. Much work has been done in the last several years but further effort is still needed in order to improve the outcome of these patients. Abstract Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10–15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.

Few studies have focused on COVID-19 patients' hepatic histopathological features. Many of the described morphological landscapes are non-specific and possibly due to other comorbidities or to Sars-CoV-2-related therapies. We describe the hepatic histopathological findings of 3 liver biopsies obtained from living COVID-19 patients in which active SARS-CoV-2 infection was molecularly confirmed and biopsied because of significant alterations of liver function tests and 25 livers analyzed during COVID-19-related autopsies. Main histopathological findings were (i) the absence of significant biliary tree or vascular damages, (ii) mild/absent lymphocytic hepatitis; (iii) activation of (pigmented) Kupffer cells, (iv) hepatocellular regenerative changes, (v) the presence of steatosis, (vi) sinusoidal ectasia, micro-thrombosis and acinar atrophy in autopsy specimens No viral particle actively infecting the hepatic or endothelial cells was detected at in situ hybridization. The morphological features observed within the hepatic parenchyma are not specific and should be considered as the result of an indirect insult resulting from the viral infection or the adopted therapeutic protocols.

EoE incidence and prevalence have sharply increased in the last decade and management of these patients is changing rapidly. Standard regimens as elimination diet, proton pump inhibitors and topical swallowed steroids are not able to achieve remission in all patients. Moreover, loss of efficacy and safety concerns for long-term medical treatments are rising questions. As for other chronic immune-mediated diseases, biologics have been evaluated for treatment of EoE. Several targets in the Th2-mediated inflammatory cascade with eosinophilic mucosal infiltration, have been tested with alternating results. This review provides a comprehensive discussion of the available studies evaluating biologics in EoE and the possible future options most desirable for these patients.

Aim: Squamous cell carcinoma antigen immune complexed with immunoglobulin M (SCCA-IgM) is a useful but not completely satisfactory biomarker of hepatocellular carcinoma (HCC). Considering its gender-specific behavior in preclinical models, we investigated gender-related differences of SCCA-IgM as a prognostic marker in HCC. Patients & methods: Two hundred and eight prospectively recruited patients treated with transarterial chemoembolization in a single tertiary care hospital were retrospectively evaluated. Correlations between SCCA-IgM levels, clinical characteristics and survival were assessed according to gender. Results: When the disease was advanced, SCCA-IgM was higher in males and lower in females. Levels below 130 AU/ml predicted a significantly longer survival in males (p = 0.007) and a shorter survival in females (p = 0.01). Conclusion: In predicting the prognosis of HCC patients, the interpretation of SCCA-IgM should consider gender as a relevant variable.

Immune checkpoint inhibitors (ICIs) are the new frontier for the treatment of advanced hepatocellular carcinoma (HCC). Since the first trial with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 inhibitor, increasing evidence has confirmed that these drugs can significantly extend the survival of patients with advanced hepatocellular carcinoma (HCC). As a matter of fact, the overall survival and objective response rates reported in patients with advanced HCC treated with ICIs are the highest ever reported in the second-line setting and, most recently, the combination of the anti-programmed death ligand protein-1 atezolizumab with bevacizumab—an anti-vascular endothelial growth factor monoclonal antibody—demonstrated superiority to sorafenib in a Phase III randomized clinical trial. Therefore, this regimen has been approved in several countries as first-line treatment for advanced HCC and is soon expected to be widely used in clinical practice. However, despite the promising results of trials exploring ICIs alone or in combination with other agents, there are still some critical issues to deal with to optimize the prognosis of advanced HCC patients. For instance, the actual proportion of patients who are deemed eligible for ICIs in the real-life ranges from 10% to 20% in the first-line setting, and is even lower in the second-line scenario. Moreover, long-term data regarding the safety of ICIs in the population of patients with cirrhosis and impaired liver function are lacking. Lastly, no biomarkers have been identified to predict response, and thus to help clinicians to individually tailor treatment. This review aimed to summarize the state of the art immunotherapy in HCC and, by analyzing a large, multicenter cohort of Italian patients with HCC, to assess the potential applicability of the combination of atezolizumab/bevacizumab in the real-life setting.

Background Recent data suggest a potential activity and a good tolerability of capecitabine in advanced hepatocellular carcinoma (HCC). Aims To evaluate capecitabine activity and safety in a wide cohort of advanced HCC patients. Methods Retrospective analysis of 143 capecitabine-treated patients (January 2010 to December 2017) in three centers of the Veneto Oncology Network. Results Capecitabine was administered in second and third line, but also in first line instead of sorafenib in Child-Pugh B patients (70%), compromised clinical conditions (14%) or contraindications to antiangiogenetics (16%). Median overall survival (OS) and time to progression (TTP) were 6.9 and 2.8 months, respectively. There were no differences in OS and TTP between the 32 patients treated with non-metronomic scheme (2000 mg/day for 14 days) and the 111 patients treated with metronomic scheme (1000 mg/day) after correction for prognostic factors at baseline with a propensity score analysis. Capecitabine was more active in patients intolerant to sorafenib than in those progressing during treatment (p = 0.024). At least one adverse event (mainly hematological) was experienced by 73% of patients but discontinuation was necessary only in 11 (8%). Conclusions Capecitabine can be considered an active and safe option in advanced HCC, especially for patients unfit for other treatments.