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Background: Transarterial 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., Methods: Data 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., Results: The 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)., Conclusions: Despite 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pelizzaro, Haxhi, Penzo, Vitale, Giannini, Sansone, Rapaccini, Di Marco, Caturelli, Magalotti, Sacco, Celsa, Campani, Mega, Guarino, Gasbarrini, Svegliati-Baroni, Foschi, Olivani, Masotto, Nardone, Raimondo, Azzaroli, Vidili, Brunetto, Trevisani and Farinati.)

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.

Introduction: Telomere length (TL) is a potential indicator of cancer predisposition; however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL-associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet., Methods: A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100, and ZBTB46-rs755017), and 291 PanNEN cases and 1,686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN., Results: An association between genetically determined long telomeres and the risk of developing PanNEN (OR = 1.99, CI: 1.33-2.98, p = 0.0008) for highest versus median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C&#95;vs&#95;G/G = 2.27, CI: 1.58-3.27, p = 8.80 × 10-6) and TERT-rs2736100 (ORC/A&#95;vs&#95;C/C = 2.03, CI: 1.42-2.91, p = 1.06 × 10-4)., Conclusion: In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN., (© 2022 S. Karger AG, Basel.)

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm 3 (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

We aimed to explore the activation of monoacylglycerol lipase (MAGL)/cyclooxygenase-2 (COX-2)/prostaglandin E 2 (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., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The tight junction protein claudin-18 (CLDN18), is often expressed in various cancer types including gastric (GC) and gastroesophageal adenocarcinomas (GECs). In the last years, the isoform CLDN18.2 emerged as a potential drug target in metastatic GCs, leading to the development of monoclonal antibodies against this protein. CLDN18.2 is the dominant isoform of CLDN18 in normal gastric and gastric cancer tissues. In this work, we evaluated the immunohistochemical (IHC) profile of CLDN18 and its correlation with clinical and histopathological features including p53, E-cadherin, MSH2, MSH6, MLH1, PMS2, HER2, EBER and PD-L1 combined positive score, in a large real-world and mono-institutional series of advanced GCs ( n = 280) and GECs ( n = 70). The association of IHC results with survival outcomes was also investigated. High membranous CLDN18 expression (2+ and 3+ intensity ≥75%) was found in 117/350 (33.4%) samples analyzed. CLDN18 expression correlated with age <70 ( p = 0.0035), positive EBV status ( p = 0.002), high stage (III, IV) at diagnosis ( p = 0.003), peritoneal involvement ( p < 0.001) and lower incidence of liver metastases ( p = 0.013). CLDN18 did not correlate with overall survival. The predictive value of response of CLDN18 to targeted agents is under investigation in several clinical trials and further studies will be needed to select patients who could benefit from these therapies.

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.

Aim: This study investigated how material deprivation in Italy influences the stage of hepatocellular carcinoma (HCC) at diagnosis and the chance of cure., Methods: 4114 patients from the Italian Liver Cancer database consecutively diagnosed with HCC between January 2008 and December 2018 were analysed about severe material deprivation (SMD) rate tertiles of the region of birth and region of managing hospitals, according to the European Statistics on Income and Living Conditions. The main outcomes were HCC diagnosis modalities (during or outside surveillance), treatment adoption and overall survival., Results: In more deprived regions, HCC was more frequently diagnosed during surveillance, while the incidental diagnosis was prevalent in the least deprived. Tumour characteristics did not differ among regions. The proportion of patients undergoing potentially curative treatments progressively decreased as the SMD worsened. Consequently, overall survival was better in less deprived regions. Patients who moved from most deprived to less deprived regions increased their probability of receiving potentially curative treatments by 1.11 times (95% CI 1.03 to 1.19), decreasing their mortality likelihood (hazard ratio 0.78 95% CI 0.67 to 0.90)., Conclusions: Socioeconomic status measured through SMD does not seem to influence HCC features at diagnosis but brings a negative effect on the chance of receiving potentially curative treatments. Patient mobility from the most deprived to the less deprived regions increased the access to curative therapies, with the ultimate result of improving survival., Competing Interests: Conflict of interest statement None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An individual prediction of DFS and OS may be useful after surgery for gastric cancer to inform patients and to guide the clinical management. Patients who underwent curative-intent resection for gastric cancer between January 2010 and May 2020 at a single Italian institution were identified. Variables associated with OS and DFS were recorded and analysed according to univariable and multivariable Cox models. Nomograms predicting OS and DFS were built according to variables resulting from multivariable Cox models. Discrimination ability was calculated using the Harrell's Concordance Index. Overall, 168 patients underwent curative-intent resection. Nomograms to predict OS were developed including age, tumor size, tumor location, T stage, N stage, M stage and post-operative complications, while nomogram to predict DFS includes Lauren classification, and lymph node ratio (LNR). On internal validation, both nomograms demonstrated a good discrimination with a Harrell's C-index of 0.77 for OS and 0.71 for DFS. The proposed nomogram to predict DFS and OS after curative-intent surgery for gastric cancer showed a good discrimination on internal validation, and may be useful to guide clinician decision-making, as well help identify patients with high-risk of recurrence or with a poor estimated survival., (© 2021. The Author(s).)

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.

Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.

Background: Sorafenib is the gold standard therapy for the advanced hepatocellular carcinoma (HCC). No scoring/staging is universally accepted to predict the survival of these patients., Aims: To evaluate the accuracy of the available prognostic models for HCC to predict the survival of advanced HCC patients treated with Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort., Methods: The performance of several prognostic scores was assessed through a Cox regression-model evaluating the C-index and the Akaike Information Criterion (AIC)., Results: Data of 1129 patients were analyzed. The mean age of patients was 61.6 years, and 80.8% were male. During a median follow-up period of 13 months, 789 patients died. The median period of Sorafenib administration was 4 months. All the prognostic scores were able to predict the overall survival (p<0.001) at univariate analysis, except the Albumin-Bilirubin score. The Italian Liver Cancer score (CLIP) yielded the highest accuracy (C-index 0.604, AIC 9898), followed by the ITA.LI.CA. prognostic score (C-index 0.599, AIC 9915)., Conclusions: The CLIP score had the highest accuracy in predicting the overall survival of HCC patients treated with Sorafenib, although its performance remained poor. Further studies are needed to refine the current ability to predict the outcome of HCC patients undergoing Sorafenib., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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.

Background and Aims: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MaVI) limits treatment options and decreases survival. Detailed data on the relationship between MaVI extension and patients' characteristics, and its impact on patients' outcome are limited. We evaluated the prevalence and extension of MaVI in a large cohort of consecutive HCC patients, analysing its association with liver disease and tumour characteristics, as well as with treatments performed and patients' survival., Methods: We analysed data of 4774 patients diagnosed with HCC recorded in the Italian Liver Cancer (ITA.LI.CA) database (2008-2018). Recursive partition analysis (RPA) was performed to evaluate interactions between MaVI, clinical variables and treatment, exploring the inter-relationship determining overall survival., Results: MaVI prevalence was 11.1%, and median survival of these patients was 6.0 months (95% CI, 5.1-7.1). MaVI was associated with younger age at diagnosis, presence of symptoms, worse Performance Status (PS) and liver function, high alphafetoprotein levels and large HCCs. MaVI extension was associated with worse PS, ascites and greater impairment in liver function. RPA identified patients' categories with different treatment indications and survival, ranging from 2.4 months in those with PS > 1 and ascites, regardless of MaVI extension (receiving best supportive care in 90.3% of cases), to 14.1 months in patients with PS 0-1, no ascites and Vp1-Vp2 MaVI (treated with surgery in 19.1% of cases)., Conclusions: MaVI presence and extension, together with PS and ascites, significantly affect patients' survival and treatment selection. The decision tree based on these parameters may help assess patients' prognosis and inform therapeutic decisions., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

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.

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., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described.

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 χ 2 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., Competing Interests: The authors report the following conflicts of interest related to the present work: Francesco Tovoli: consultant for Bayer and LaForce Guerbet. Fabio Marra: consultant for Bayer, Ipsen, and Eisai and received travel support from Bayer., (Copyright © 2021 by S. Karger AG, Basel.)

Background and Aims: Patients with autoimmune atrophic gastritis (AAG) often complain of acid reflux symptoms, despite the evidence of hypo-achlorhydria. Rome IV criteria are used to define functional esophageal disorders. Our aim was to characterize gastroesophageal reflux disease (GERD) phenotypes in patients with AAG., Methods: Between 2017-2018, 172 AAG patients were evaluated at Gastro-Oncology outpatient clinic of University of Padua. Of them, 38 patients with reflux symptoms underwent high-resolution manometry (HRM) and multichannel intraluminal impedance-pH monitoring (MII-pH). Seventy-six AAG consecutive patients asymptomatic for gastroesophageal reflux were selected as age and gender matched controls. Serum biomarkers (pepsinogens, gastrin-17 and Helicobacter pylori antibodies), upper endoscopy, histology and clinical data were compared., Results: Out of 38/172 (22%) AAG patients with reflux symptoms, 2/38 had a GERD diagnosis based on abnormal esophageal acid exposure and 6/38 had a major motility disorder (i.e. outflow obstruction). Among the 30/38 patients with normal endoscopic findings, 9/30 had reflux hypersensitivity, 19 functional heartburn, 1 functional globus, 1 functional chest pain according to the Rome IV criteria. Antral atrophy, advanced corpus atrophy and OLGA stage were more frequent in controls than in reflux patients (p=0.01, p=0.031, p=0.01, respectively). No differences were found for serum biomarkers and symptom presentation. Most of the patients received proton pump inhibitors (PPIs) treatment (87%), with a minority (34%) reporting clinical benefit., Conclusions: Reflux symptoms are relatively common in AAG patients, but a firm diagnosis of GERD is rare (5%), whereas most of the patients have a functional disorder. PPI treatment is mostly clinical ineffective and should not be largely indicated.

Hyper-functional platelets are being proposed as a potential therapeutic target in multiple cancers. Whether this can be considered in patients with cirrhosis and hepatocellular carcinoma (HCC) is unknown as their platelet function has not yet been investigated. We evaluated platelet function in cirrhosis patients with HCC. Patients with cirrhosis with and without HCC were prospectively recruited. Platelet aggregation, a marker of platelet function, was assessed by impedance aggregometry with adenosine diphosphate (ADP), arachidonic acid (ASPI), and thrombin (TRAP) stimulation. Plasmatic levels of Von Willebrand factor antigen (VWF) were also determined. One-hundred patients were recruited (50 cirrhotics with and 50 without HCC). Cirrhosis severity by Child class and platelet count were comparable between cirrhotics with and without HCC. Cirrhotics with HCC had higher ADP- (45 vs. 28; p < 0.001), ASPI- (47 vs. 28; p < 0.001), and TRAP- (85 vs. 75; p = 0.01) induced platelet aggregation than cirrhotics without HCC, all indicative of platelet hyper-function. The relatively increased platelet aggregation in patients with HCC was confirmed after adjusting the analysis for platelet count/severity of thrombocytopenia. Levels of VWF were higher in patients with vs. without HCC (348 vs. 267; p = 0.006), particularly in compensated cirrhosis. In patients with cirrhosis, HCC is associated with increased platelet aggregation and higher VWF. The clinical implications of these findings deserve further investigation.

Background and Aims: Epidemiology of hepatocellular carcinoma (HCC) is changing in most areas of the world. This study aimed at updating the changing scenario of aetiology, clinical presentation, management and prognosis of HCC in Italy during the last 15 years., Methods: Retrospective analysis of the Italian Liver Cancer (ITA.LI.CA) database included 6034 HCC patients managed in 23 centres from 2004 to 2018. Patients were divided into three groups according to the date of cancer diagnosis (2004-2008, 2009-2013 and 2014-2018)., Results: The main results were: (i) a progressive patient ageing; (ii) a progressive increase of non-viral cases and, particularly, of 'metabolic' and 'metabolic + alcohol' HCCs; (iii) a slightly decline of cases diagnosed under surveillance, but with an incremental use of the semiannual schedule; (iv) a favourable cancer stage migration; (v) an increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) an improved overall survival (adjusted for the lead time in surveyed patients) in the last calendar period, particularly in viral patients; (viii) a large gap between the number of potential candidates (according to oncologic criteria and age) to liver transplant and that of transplanted patients., Conclusions: During the last 15 years several aspects of HCC scenario have changed, as well as its management. The improvement in patient survival observed in the last period was likely because of a larger use of thermal ablation with respect to the less effective alcohol injection and to an improved management of intermediate stage patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hepatocellular carcinoma prognosis depends on both liver and tumor determinants, especially on maximum tumor diameter, multifocality, and presence of portal vein thrombosis, despite apparently complete tumor removal by resection or liver transplantation., Aims: To examine parameters of hepatocellular carcinoma aggressiveness as tumor size increases., Methods: A large hepatocellular carcinoma database was examined for trends in serum alpha-fetoprotein and the percentage of patients with macroscopic portal vein thrombosis or tumor multifocality., Results: A total of 13,016 hepatocellular carcinoma patients were identified having full tumor and survival data. Of these, 76.56% were male and 23.44% were female, with a median age of 64.4 years. We found that as the maximum tumor diameter increased, there was a significant trend for increased alpha-fetoprotein levels ( P <0.001) and an increased percentage of patients with either portal vein thrombosis or tumor multifocality, each P <0.0001. Furthermore, the increases of both alpha-fetoprotein and portal vein thrombosis were proportionately greater than the related maximum tumor diameter increases. These trends of increased alpha-fetoprotein, portal vein thrombosis, and multifocality with increasing maximum tumor diameter had non-linear patterns. Within alpha-fetoprotein and multifocality trends, there were identifiable sub-trends associated with specific maximum tumor diameter ranges., Conclusions: The greater fold-increases in alpha-fetoprotein and portal vein thrombosis compared with increases in maximum tumor diameter imply that hepatocellular carcinoma characteristics may change with increasing size to a more aggressive phenotype, suggesting that follow-up tumor sampling might be useful, in addition to baseline tumor sampling, for optimal therapeutic choices to be made.

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 (<5 years, SS group). The association between surveillance and LS was adjusted for confounders by multivariable logistic regression analysis. Survival of surveilled patients was presented both as observed and corrected for the lead-time bias, and the comparison of survival between surveillance and no surveillance groups was also performed after balancing the baseline characteristics with inverse probability weights (IPW)., Results: LS patients were more frequently diagnosed under surveillance ( 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.

Background: Hepatocellular carcinoma (HCC) factors, especially maximum tumor diameter (MTD), tumor multifocality, portal vein thrombosis (PVT), and serum alpha-fetoprotein (AFP), influence survival., Aim: To examine patterns of tumor factors in large HCC patients., Methods: A database of large HCC patients was examined., Results: A multiple Cox proportional hazard model on death identified low serum albumin levels and the presence of PVT and multifocality, with each having a hazard ratio ≥2.0. All combinations of these three parameters were examined in relation to survival. Using univariate Cox analysis, the combination of albumin >3.5 g/dL and the absence of both PVT and multifocality had the best survival rate, while all combinations that included the presence of PVT had poor survival and hazard ratios. We identified four clinical phenotypes, each with a distinct median survival: patients with or without PVT or multifocality plus serum albumin ≥3.5 (g/dL), with each subgroup displaying high (≥100 IU/mL) or low (<100 IU/mL) blood AFP levels. Across a range of MTDs, we identified only two significant trends, blood AFP and platelets., Conclusions: Patients with large HCCs have distinct phenotypes and survival, as identified by the combination of PVT, multifocality, and blood albumin levels.

Background & Aims: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, monofocal hepatocellular carcinoma (HCC) is classified as early (BCLC A) irrespective of its size, even though controversies still exist regarding staging and treatment of large tumours. We aimed at evaluating the appropriate staging and treatment for large (>5 cm) monofocal (HCC)., Methods: From the Italian Liver Cancer database, we selected 924 patients with small early monofocal HCC (2-5 cm; SEM-HCC), 163 patients with larger tumours (>5 cm; LEM-HCC) and 1048 intermediate stage patients (BCLC B)., Results: LEM-HCC patients had a worse overall survival (OS) than SEM-HCC (31.0 vs 49.0 months; P < .0001), and this was confirmed at multivariate analysis (HR 1.63, 95% CI 1.29-2.05; P < .0001). The small difference in OS between LEM-HCC and BCLC B patients (31.0 vs 27.0 months; P = .03) disappeared in the multivariate model (HR 0.98, 95% CI 0.77-1.25; P = .89). In all monofocal tumours, treatment was the strongest independent predictor of survival, with a progressively decreasing survival benefit moving from "curative" to "palliative" therapies. The survival of resected patients with LEM-HCC was significantly shorter than that of SEM-HCC (44.0 vs 78.0 months; P = .002), but liver resection provided the highest survival benefit in both groups compared to other treatments., Conclusions: Monofocal HCC larger than 5 cm should not be staged as BCLC A and either a different staging system or a different subgrouping of patients (e.g. BCLC AB) should be used. Liver resection, if feasible, remains the recommended treatment for all these patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aim: Autoimmune atrophic gastritis (AAG) is characterized by a variable spectrum of gastric and extra-gastric symptoms and has been associated with other autoimmune diseases. It is still unknown whether AAG patients have a higher risk of coeliac disease (CeD) or of any other particular duodenal histological damage. Our study aimed at evaluating the duodenal histological findings and the risk of CeD in patients with AAG, with and without other concurrent autoimmune diseases., Methods: We retrospectively collected all the histological findings of the adult patients undergoing upper gastrointestinal endoscopy with concurrent duodenal and gastric biopsies at our gastroenterology unit between 2015 and 2018 and who were regularly followed up at our centre. Date of endoscopy evaluation, endoscopy indication, data on previous CeD diagnosis and on other autoimmune-associated diseases, and a description of histological diagnosis were recorded., Results: Of the 2,423 evaluated endoscopies, 209 patients had an AAG diagnosis (8.6%). One hundred thirty-nine patients, aged 57.4 (standard deviation 13.2) years, were regularly followed up at our centre and were included. Of them, 4 subjects had a previous diagnosis of CeD and one had CeD diagnosis at index endoscopy. Additionally, 8 patients had an isolated increase of intraepithelial lymphocytes (IELs, 6%) and 2 villous atrophy with a normal IEL count. The risk of CeD in AAG was not modulated by the presence of other concurrent autoimmune diseases., Conclusions: We support the screening of all AAG patients with CeD autoantibodies. Findings of isolated IEL or villous atrophy are not exclusively related to CeD., (© 2020 S. Karger AG, Basel.)

The physiological role of autophagy in the progression of liver diseases is still debated. To understand the clinical relevance of autophagy in primary e secondary hepatic tumors, we analyzed the expression of mTOR (mammalian target of rapamycin), a key regulator of autophagy; Raptor (regulatory-associated protein of mTOR); ULK1 (Unc-51 like kinase 1) determinant in the autophagy initiation; LC3 (microtubule-associated protein 1A/1B-light chain 3), a specific marker of autophagosomes; and p62, a selective autophagy receptor. Samples from subjects with chronic hepatitis (n.58), cirrhosis (n.12), hepatocellular carcinoma (HCC, n.56), metastases (n.48) from colorectal cancer and hyperplasia or gallbladder stones (n.7), the latter considered as controls, were examined. Gene expression analysis was carried out in n.213 tissues by absolute q-PCR, while protein expression by Western Blot in n.191 lysates, including tumoral, surrounding tumoral and normal tissues. Nonparametric statistical tests were used for comparing expression levels in the above-mentioned groups. Subgroup analysis was performed considering viral infection and chemotherapy treatment. The mTOR transcriptional level was significantly lower in metastases compared to HCC (P = 0.0001). p-mTOR(Ser2448) and LC3II/LC3I protein levels were significantly higher in metastases compared to HCC (P = 0.008 and P<0.0001, respectively). ULK(Ser757) levels were significantly higher in HCC compared to metastases (P = 0.0002) while the HCV- and HBV- related HCC showed the highest p62 levels. Chemotherapy induced a down-regulation of the p-mTOR(Ser2448) in metastases and in non-tumor surrounding tissues in treated patients compared to untreated (P = 0.001 and P = 0.005, respectively). Conclusions: the different expression of proteins considered, owning their interaction and diverse tissue microenvironment, indicate an impairment of the autophagy flux in primary liver tumors that is critical for the promotion of tumorigenesis process and a coexistence of autophagy inhibition and activation mechanisms in secondary liver tumors. Differences in mTOR and LC3 transcripts emerged in tumor-free tissues, therefore particular attention should be considered in selecting the control group., Competing Interests: The authors have declared that no competing interests exist.

Treatment allocation is extremely complex in patients with hepatocellular carcinoma (HCC) because this neoplasm arises, in most cases, in patients with cirrhosis and additional comorbidities. The "stage hierarchy" approach, which involves linking each stage (or substage) of the disease to a specific treatment, has become the main proposed treatment strategy for the clinical management of HCC, particularly in the West. The Barcelona Clinic Liver Cancer (BCLC) scheme serves as the main example of the application of this strategy. In an attempt to increase the plasticity of the "stage hierarchy" approach as well as its adaptability to the requirements of real-world clinical practice, the latest versions of European and American guidelines have introduced certain relevant elements of flexibility, which were not intrinsic to the original BCLC scheme. These elements are as follows: the "treatment stage migration" strategy, which allows moving to another treatment (generally the one that is associated with the subsequent stage) if the approach linked with the current stage proves to be unfeasible, and the "treatment stage alternative" approach, which proposes further therapeutic options for each BCLC-defined stage. In regard to most of the solid cancers, another potential strategy is to consider the treatment decision to be hierarchically dictated by the efficacy of each therapy with complete or partial independence from the tumor stage. This concept of "therapeutic hierarchy" has been historically endorsed by the Asia-Pacific treatment algorithm as well as by the recent Italian multisociety guidelines. The present review provides a critical analysis of the different conceptual approaches to HCC management, highlighting their advantages and disadvantages and focusing on the remarkable differences between the stage-guided and the hierarchical strategies., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Faecal microbiota transplantation (FMT) is a reasonable therapeutic option for the treatment of Clostridioides difficile infection (CDI) recurrent and refractory (RCDI) to therapy, but little evidence on the long-term impact of this therapy is currently available in the literature. The aim of this study was to evaluate the efficacy and safety of FMT in recurrent and refractory CDI and the modifications of the recipient's gut microbiota in the medium-long term., Methods: This prospective study collects the clinical and laboratory data of RCDI patients treated with FMT by colonoscopy from February 2016 to October 2019. Stool samples for metagenomic analysis were collected pre-FMT at 1 week and at 6 and 12-24 months post-FMT., Results: In the study period, 20 FMT procedures were performed on 19 patients. Overall, FMT was effective in 85% of treated patients. No serious adverse event was recorded. In the medium- to long-term follow up, a newly diagnosed case of collagenous colitis was observed. Post-FMT, significant changes in microbiota were observed, characterised by the transition from a low- to a greater-diversity profile. Therefore, FMT restores eubiosis and maintains it over time., Conclusion: FMT is a safe and effective treatment option in RCDI patients. This procedure induces profound microbiota changes that explain its high clinical efficacy., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Immunotherapy has been recently approved for gastric (GC) and gastroesophageal-junction adenocarcinomas (GEC), and PD-L1 immunohistochemical evaluation represents a promising predictive biomarker in this oncological setting. A series of 125 gastroesophageal dysplastic lesions (52 low-grade, 73 high-grade) was investigated for PD-L1 and DNA mismatch repair proteins status. PD-L1 was positive (combined positive score (CPS) ≥ 1) in 48 (31.0%) dysplastic lesions. A higher prevalence of PD-L1-positive cases was observed among esophageal specimens compared with gastric ones (p = 0.0003), in high-grade and adenocarcinoma samples in comparison with low-grade dysplasia (p < 0.0001), and in lesions with mismatch repair deficiency (p = 0.028). For 30 dysplastic samples, a synchronous matched invasive lesion (GC = 15, GEC = 15) was available and tested for PD-L1 expression; a discordant PD-L1 status was observed in 12/30 (40%) cases. A relatively high prevalence in PD-L1 positivity was observed among gastroesophageal dysplastic lesions and this should be taken into consideration for future therapeutic strategies based on this biomarker.

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.

Beyond the small intestine, coeliac disease (CeD) may affect other gastrointestinal tracts, including the stomach. However, various studies have reported conflicting results regarding the association between CeD and gastric manifestations. The aim of this study was to analyze the existing literature on gastric involvement in CeD. A literature search was conducted in bibliographic databases of Embase, PubMed, Scopus, and Web of Science. Studies reporting the association between CeD and gastric disorders were examined in detail and are fully described in the review. Both in children and adults, a strong correlation between lymphocytic gastritis and CeD was found at CeD diagnosis, and lymphocytic gastritis seemed to improve on a gluten-free diet. Most of the literature described a lower risk of gastritis related to Helicobacter pylori infection in CeD subjects compared to controls. However, due to the discordance among studies in terms of study design and population, a clear association could not be determined. Finally, the relationship between CeD and reflux or dyspepsia has yet to be defined, as well as the association between CeD and autoimmune gastritis. CeD appears to be a multiform entity associated with different gastric disorders with a different degree of relationship. Thus, gastric biopsies should be routinely taken during upper endoscopy in CeD patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The main intent of secondary prevention strategies for Barrett's esophagus (BE) patients relies in the prompt identification of patients with dysplasia (or intra-epithelial neoplasia; IEN) and early-stage adenocarcinoma (Barrett's adenocarcinoma; BAc). Despite the adequate characterization of the molecular landscape characterizing Barrett's carcinogenesis, no tissue and/or circulating biomarker has been approved for clinical use. A series of 25 serum samples (12 BE, 5 HG-IEN and 8 BAc) were analyzed for comprehensive miRNA profiling and ten miRNAs were found to be significantly dysregulated. In particular seven were upregulated (i.e. miR-92a-3p, miR-151a-5p, miR-362-3p, miR-345-3p, miR-619-3p, miR-1260b, and miR-1276) and three downregulated (i.e. miR-381-3p, miR-502-3p, and miR-3615) in HG-IEN/BAc samples in comparison to non-dysplastic BE. All the identified miRNAs showed significant ROC curves in discriminating among groups with AUC values range of 0.75-0.83. Validation of the results were performed by droplet digital PCR in two out of three tested miRNAs. To understand the cellular source of circulating miR-92a-3p, we analyzed its expression in endoscopy biopsy samples by both qRT-PCR and ISH analyses. As observed in serum samples, miR-92a-3p was over-expressed in HG-IEN/BAc samples in comparison to naïve esophageal squamous mucosa and BE and was mainly localized within the epithelial cells, supporting neoplastic cells as the main source of the circulating miRNA. Our data further demonstrated that circulating miRNAs are a promising mini-invasive diagnostic tool in the secondary follow-up and management of BE patients. Larger multi-Institutional studies should validate and investigate the most adequate miRNAs profile in discriminating BE patients in specific risk classes., Competing Interests: Declaration of Competing Interest The other authors have no competing interests to declare related to the presented data., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Sustained virological response (SVR) after interferon-based therapy is associated with improvement of insulin resistance (IR) in HCV-infected patients. Few data are available in the direct-acting antivirals (DAAs) era, especially in cirrhotic patients. We prospectively evaluated the long-term effect of DAAs on IR. Patients treated with DAAs between May 2015 and December 2016 in 3 tertiary care centres were recruited. Patients with diabetes were excluded. Biochemical and virological data were collected at baseline, 12/24/48 weeks (W) after the end of therapy (EOT). Presence of IR was defined by a 'homeostasis model assessment index for IR' [HOMA-IR])> 2.5. Liver fibroscan was performed at baseline, at 24/48W after EOT. Hundred and thirty-eight patients were enrolled (mean age 58 years, M/F 85/53, GT1 61%, 68.8% cirrhotic). Sixty-eight patients (94/138) had IR. Patients with IR had significantly higher stiffness than patients without it (23 ± 12 vs 15 ± 8; P < .0001). SVR12 was achieved in 135 (98%) patients, and 124 (90%) patients reached the 48W post-EOT. At this time point, the percentage of patients with IR significantly decreased to 49% (P = 0,01). HOMA-IR was significantly lower than baseline (1.8 vs 3; P < .001), and this was related to a significant reduction of insulin level (11.7 ± 6.3 vs 16.4 ± 8.3). High BMI was associated with a significantly lower probability of achieving a non-IR status at 24W (P = .05) and 48W (P = .03).In conclusion, SVR following DAAs led to a significant reduction of IR, even in patients with cirrhosis. Nevertheless, IR can persist after the achievement of SVR, especially in patients with high BMI., (© 2019 John Wiley & Sons Ltd.)

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., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Videolaparoscopic (VL) microwave ablation (MWA) is not included in most of the international guidelines as a therapeutic option for hepatocellular carcinoma (HCC). Aim of this study was to assess the safety of VL MWA in patients with HCC for whom resection or percutaneous ablation is unsuitable., Methods: A retrospective analysis was performed on a prospective database of patients with HCC treated with VL MWA at our institution from 2009 to 2016. Patient demographics, operational characteristics, and complications were recorded. Statistical analysis was performed to identify safety profile, overall survival and recurrence rate., Results: A total of 815 VL MWA were performed in 674 patients with a mean age of 64 years. Patients had a mean Model for End-stage Liver Disease score of 10 (±3); 32.8% were Child B, 44.1% Barcelona Clinic Liver Cancer B-C. Perioperative mortality was 0.4%. Overall morbidity was 30.8%, with Dindo-Clavien complications ≥3 in 2%. The median length of stay was 2 days. In 43.1% VL MWA was the first-line therapy. Overall 1-, 3-, and 5-year survival rates were 81.9%, 54.9%, and 35.9%., Conclusions: The present is the largest series of VL ablation and the bigger number of patients with HCC treated with MW reported nowadays. It confirms the safety of a minimally invasive procedure for patients with HCC when resection or percutaneous ablation is not feasible., (© 2019 Wiley Periodicals, Inc.)

Objectives: This study aimed to evaluate trends in hospitalizations and outcomes of acute pancreatitis (AP) according to first admitting hospital unit and hospital volumes., Methods: Hospital discharge records of patients with AP admitted in the Veneto Region (Northeast Italy) during the period 2001-2015 were examined., Results: A total of 23,389 patients (54% males; mean age, 62.2 years; standard deviation, 19.3 years) were admitted for AP. Both hospitalization (32.4 to 29.5/100,000 inhabitants per year; P < 0.05) and in-hospital mortality (1.41 to 0.79/100,000 inhabitants per year; P < 0.05) decreased over the study period. Case fatality rate was altogether 3.2%. The percentages of patients admitted in surgery, nongastroenterology medical units, gastroenterology, and intensive care were 52%, 30%, 16%, and 2%, respectively. Fewer fatalities were observed in gastroenterology units (1.7%) compared with nongastroenterology medical units (4.3%; odds ratio, 0.37; 95% confidence interval, 0.28-0.49) and surgical units (2.7%; odds ratio, 0.61; 95% confidence interval, 0.47-0.80). Fatalities decreased progressively with increasing hospital volumes from 3.7% to 2.9% (P < 0.05)., Conclusion: In the Veneto Region, both hospitalizations and in-hospital mortality for AP significantly decreased over the last 15 years. Case fatality rate was lowest for patients admitted in gastroenterology units.

Background: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients., Patients and Methods: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival., Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT = 0.19 (0.18-0.20); RES = 0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT = 0.58 (0.55-0.61); SOR = 0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage., Conclusion: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Claudin-18 (CLDN18) is a highly specific tight junction protein of the gastric mucosa. An isoform of CLDN18, the Claudin 18.2, has recently emerged as an innovative drug target for metastatic gastric cancer., Methods: We investigated the immunohistochemical profile of CLDN18, p53, p16, E-cadherin, MSH2, MSH6, MLH1, PSM2, HER2, and PDL-1 in a large series of 523 primary gastric carcinomas (GCs; n = 408) and gastro-oesophageal carcinomas (GECs; n = 115) and 135 matched and synchronous nodal metastases. The status of HER2 and EBER by means of chromogenic in situ hybridisation (CISH) was also evaluated., Results: High membranous CLDN18 expression was present in 150/510 (29.4%) primary cases and in 45/132 (34.1%) metastases. An abnormal expression (i.e. nuclear and/or cytoplasmic) was observed in 115 (22.5%) primary cases and in 33 (25.0%) metastases. A 38.8% of the cases showed significant CLDN18 intratumoural variability among the different tissue microarray cores obtained from the same tumour. Positive membrane CLDN18 expression was statistically associated with non-antral GCs (p = 0.016), Lauren diffuse type (p = 0.009), and with EBV-associated cancers (p < 0.001)., Conclusions: CLDN18 is frequently expressed in gastric and gastro-oesophageal cancers; further studies should investigate the prognostic significance of CLDN18 heterogeneity in order to implement its test into clinical practice.

Competing Interests: None