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MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in regulating gene expression. Many studies, mostly conducted on pediatric patients, suggested that oxidative stress and several miRNAs may play an important role in coeliac disease (CeD) pathogenesis. However, the interplay between oxidative stress and miRNA regulatory functions in CeD remains to be clarified. In this review, we aimed to perform a literature review on the role of miRNAs and oxidative stress in adult CeD patients and to analyze their potential interactions. In this direction, we also reported the preliminary results of a pilot study we recently performed.

Background: Gastroesophageal reflux disease (GERD) is a challenging condition that involves different physicians, such as general practitioners (GPs), gastroenterologists, and ears, nose and throat (ENT) specialists. A common approach consists of proton-pump inhibitors (PPIs) administration. Adjunctive pharmacological treatment may have a role in the management of non-responders to PPIs. Objectives: We aimed to survey GPs and different medical specialists to investigate the medical approaches to patients reporting GERD symptoms. In addition, we examined the use of adjunctive pharmacological treatments in patients with GERD symptoms who do not respond to PPIs. Design: Retrospective observational study. Methods: A survey was conducted among a large sample of gastroenterologists, GPs, and ENT specialists. Symptoms were divided into typical and extraesophageal, and their severity and impact on quality of life were explored with the GERD Impact Scale and with Reflux Symptom Index (RSI). All therapies administered usually for GERD were investigated. Results: A total of 6211 patients were analyzed in this survey. Patients with typical symptoms were 53.5%, while those with extraesophageal symptoms were 46.5%. The latter were more frequently reported by ENT patients (53.6%, p

Introduction: Psychosocial pre-transplant evaluation in patients undergoing liver transplantation (LT) could help identify those patients at higher risk of pharmacological non-adherence, organ rejection, and mortality. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a validated tool for assessing LT candidates’ psychosocial well-being. Data on the ability of the SIPAT evaluation to predict post-transplant outcomes are sparse. Material and Methods: clinical and psychosocial data from a sample of 134 candidates for LT were analyzed. Moreover, the association between pre-transplant psychosocial evaluation and post-transplant clinical outcomes, including organ rejection, mortality, and immunosuppressant drug adherence, was calculated. Results: At the pre-transplant evaluation, patients who showed high SIPAT scores (77, 57%) also had more liver disease assessed by model for end-stage liver disease (MELD; F = 5.04; p < 0.05), alcoholic etiology (F = 35.80; p < 0.001), encephalopathy (F = 5.02; p < 0.05), and portal hypertension (F = 7.45; p < 0.01). Of the 51 transplant patients, those who had a high pre-transplant SIPAT score showed lower post-transplant immunosuppressive adherence, linked to more frequent immunological events. Conclusions: Patients with an alcoholic etiology of liver disease and more severe liver dysfunction are likelier to not adhere to medical prescriptions following transplantation. Current data suggests that this specific group of patients could benefit from early psychological pre-habilitation before undergoing liver transplantation.

Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intra-epithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a gluten-independent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an in situ aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management.

IntroductionMicroRNAs (miRNAs) have been proposed as diagnostic markers, biomarkers of neoplastic progression, and possible therapeutic targets in several immune-mediated diseases. We aimed to analyze the expression profile of selected miRNAs (miR21, miR142, miR223, miR155) in patients with autoimmune atrophic gastritis (AAG), patients with non-autoimmune multifocal atrophic gastritis (MAG), and healthy control subjects (HC).Materials and methodsA total of 103 patients with AAG were consecutively recruited for this study among those attending our gastroenterology outpatient clinic. Participating patients were divided into two groups: primary, not Helicobacter pylori (HP)-associated related AAG (n=57, P-AAG) and HP-associated AAG (n=46, HP-AAG); this subgroup included HP-positive patients, patients with previously reported HP infection, and patients harboring antral atrophy, considered as a stigma of HP infection. We also included 20 sex-age-matched MAG patients and 10 HC. Upper endoscopy with gastric biopsies were performed on each AAG and MAG patient. Circulating levels of miR21-5p, miR142-3p, miR223-3p, and miR155-5p were measured by RT-PCR in all groups.ResultsMiR-21 was over-expressed in P-AAG (p=0.02), HP-AAG (p = 0.04), and MAG (p=0.03) compared with HC. By contrast, miR-142 was more expressed in HC than in HP-AAG (p=0.04) and MAG (p=0.03). MiR-155 showed no significant differences among the four subgroups, while, unexpectedly, miR-223 was overexpressed in HC compared to P-AAG (p=0.01), HP-AAG (p=0.003), and MAG (p

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the “primum movens” of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies.

BackgroundTransarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy.MethodsData of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment.ResultsThe proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC).ConclusionsDespite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis.

Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages.

Worldwide, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) significantly increases mortality and morbidity. The Coronavirus Disease 2019 (COVID-19) outbreak has had a considerable impact on healthcare systems all around the world, having a significant effect on planned patient activity and established care pathways, in order to meet the difficult task of the global pandemic. Patients with hepatocellular carcinoma (HCC) are considered a particularly susceptible population and conceivably at increased risk for severe COVID-19 because of two combined risk factors: chronic advanced liver disease and HCC itself. In these challenging times, it is mandatory to reshape clinical practice in a prompt way to preserve the highest standards of patient care and safety. However, due to the stay-at-home measures instituted to stop the spread of COVID-19, HCC surveillance has incurred a dramatic drop, and care for HCC patients has been rearranged by refining the algorithm for HCC treatment to the COVID-19 pandemic, permitting these patients to be safely managed by identifying those most at risk of neoplastic disease progression.

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.

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.

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: 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.

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.

Among scores and staging systems used for HCC, none showed a good prognostic ability in patients with advanced HCC treated with Sorafenib. We aimed to evaluate predictive factors of overall survival (OS) and drug response in HCC patients undergoing Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. Patients in the ITA.LI.CA database treated with Sorafenib and updated on 30 June 2019 were included. Demographic and clinical data before starting Sorafenib treatment were considered. For the evaluation of predictive factors for OS, a time-dependent Cox proportional hazard model was used. A total of 1107 patients were included in our analysis. The mean age was 64.3 years and 81.7% were male. Most patients were staged as BCLC B (205, 18.9%) or C (706, 65.1%). The median time of Sorafenib administration was 4 months (interquartile range (IQR) 2–12), and the median OS was 10 months (IQR: 4–20). A total of 263 patients (33.8%) out of 780 with available evaluation experienced objective tumoral response to Sorafenib. The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (hazard ratio (HR) 1.284), maximum tumoral diameter (HR 1.100), plasma total bilirubin (HR 1.119), aspartate amino transferase assessed as multiple of the upper normal value (HR 1.032), alpha-fetoprotein ≥200 ng/mL (HR 1.342), hemoglobin (HR 0.903) and platelet count (HR 1.002) were associated with OS at multivariate Cox regression analysis. Drug response was predicted by maximum tumoral diameter and platelet count. A novel prognostic nomogram for patients undergoing Sorafenib is hereby proposed. The novelty introduced is the comprehensive patient’s assessment using common markers of patient’s general status, liver damage and function and HCC biology. Further studies are required to test its accuracy and provide external validation.

Purpose: We aimed at assessing the impact of surveillance on long-term survival in HCC patients. Methods: From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with short-term survival (p < 0.0001), and had more favorable baseline characteristics. Surveillance was an independent predictor of LS (OR = 1.413, 95% CI 1.195–1.671; p < 0.0001). The observed and the lead-time corrected survival of surveilled patients were significantly longer compared to the survival of not surveilled patients (p < 0.0001 and p = 0.0008, respectively). In IPW adjusted populations, no survival differences were demonstrated between the two groups (p = 0.30). Conclusions: Surveillance, increasing early-stage diagnosis and applicability of curative treatments, is a fundamental determinant of long-term survival in HCC patients. A wide implementation of surveillance programs should be pursued in order to improve HCC patients’ prognosis.