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Several noninvasive liver fibrosis tests have been developed and appear to predict the severity of fibrosis, possibly replacing invasive liver biopsy as a monitoring tool. 1 The fibrosis-4 (FIB-4) score originally was proposed to help assess liver fibrosis in patients with human immunodeficiency virus and hepatitis C virus co-infection. 1 FIB-4 has been used widely to monitor the severity of liver fibrosis, especially in patients with nonalcoholic fatty liver disease, 2 now termed metabolic dysfunction-associated steatotic liver disease (MASLD). 3 ., (Copyright © 2024. Published by Elsevier Inc.)

Objectives : To evaluate the long-term anatomical and functional prognosis of patients with retinal detachment (RD) secondary to acute retinal necrosis (ARN) treated with pars plana vitrectomy (PPV). Methods : This retrospective case series included 21 eyes from 21 patients with RD secondary to ARN. The study analyzed vitreous or aqueous biopsy results, the impact of antiviral therapy, time to retinal detachment, changes in visual acuity (VA), and anatomical and surgical outcomes. All cases underwent 23-gauge PPV with silicone oil tamponade, and an episcleral encircling band was used in 11 cases. All patients received systemic antiviral therapy at diagnosis. Results : Retinal reattachment was achieved in 91% of cases during follow-up, with an average follow-up period of 39.5 ± 36.8 months. The average time from ARN diagnosis to RD onset was 33.3 ± 27.5 days. VZV was detected in 10 eyes through PCR analysis. Significant differences in visual prognosis were found between macula-off and macula-on RD ( p = 0.048). Eyes with optic nerve head inflammation had worse final VA ( p = 0.010). No significant difference was observed between preoperative VA and VA at the end of follow-up ( p = 0.665). Conclusions : VZV was the primary virus associated with ARN-related RD. Early involvement of the macula and optic nerve in retinitis negatively impacted the final visual prognosis.

Background & Aims: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes., Methods: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared., Results: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22)., Conclusion: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup., Impacts and Implications: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality., Methods: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality., Results: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results., Conclusion: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Purpose: Blue sclera is a characteristic and common clinical sign of Osteogenesis Imperfecta (OI). However, there is currently no widely accepted, objective method for assessing and grading blue sclera in individuals with OI. To address this medical need, this study is aimed to design and validate a new method called 'BLUES' (BLUe Eye Sclera) to objectively identify and quantify the blue color in the sclera of patients affected by OI., Methods: Sixty-two patients affected by OI and 35 healthy controls were enrolled in the present prospective study, for a total of 194 eyes analyzed. In the 'BLUES' procedure, eye images from patients with OI and control subjects were analyzed to assess and grade the blue level of the sclera using Adobe Photoshop Software. The validation process then involved comparing the results obtained with the 'BLUES' procedure to the judgement of experienced ophthalmologists (JEO). A receiver-operating characteristic (ROC) curve analysis was used to examine the overall discriminatory power. The sensitivity and specificity levels and the Cohen's Kappa (K) indexes of 'BLUES' and 'JEO' were estimated versus the standard OI diagnosis. The K indexes of 'BLUES' versus 'JEO' were also evaluated., Results: The optimal cut-off point of the scleral blue peak was calculated at 17%. Our findings demonstrated a sensitivity of 89% (CI95%: 0.835-0.945) and specificity of 87% (CI95%: 0.791-0.949) for the 'BLUES' procedure with an agreement versus the diagnosis of OI of 0.747. In comparison, the sensitivity and specificity of 'JEO' ranged from 89 to 94% and 77% to 100%, respectively, with an agreement ranging from 0.663 to 0.871 with the diagnosis of OI. The agreement between 'BLUES 'and 'JEO' evaluations ranged from 0.613 to 0.734., Conclusions: Our findings demonstrated an 89% sensitivity and an impressive 87% specificity of our method to analyze the blue sclera in OI. The results indicated high agreement with disease diagnosis and were consistent with evaluations by experienced ophthalmologists. The 'BLUES' procedure appears to be a simple, reliable and objective method for effectively identify and quantify the blue color of the sclera in OI., (© 2024. The Author(s).)

We read with great interest the article by Cangir et al., "A CT-Based Radiomic Signature for the Differentiation of Pulmonary Hamartomas from Carcinoid Tumors", published on 5 February 2022 [...].

Background: GCSF may improve the prognosis of severe liver disease by promoting liver regeneration and immune restoration. Our Aim was to investigate its controversial efficacy in decompensated cirrhosis, acute alcoholic hepatitis (AAH), or acute-on-chronic liver failure (ACLF) through meta-analysis., Methods: Meta-analysis of proportions (random effect model) including 19 RCTs (1287 patients from 16 Asian and 3 European studies including 487 ACLF, 231 AAH and 569 cirrhotic patients) evaluating survival at day-28, day-90, 6 months, one year, and/or occurrence of sepsis as major outcomes., Results: In patients with decompensated cirrhosis, G-CSF administration was associated with a reduction in the weight-adjusted risk of mortality of 9% at day-90 (OR=0.33; 95%CI: 0.18-0.58; p = 0.0002), 16% at 6 months (OR=0.31; 95%CI: 0.15-0.62; p = 0.0009), 26% at one year (OR=0.21; 95%CI:0.12-0.38, p<0.0001) and a weight-adjusted 28% risk reduction for sepsis (OR=0.28; 95%CI: 0.16-0.49; p<0.0001). Only Asian studies were positive. In AAH, G-CSF was associated with an 18% reduction in weight-adjusted mortality risk at day-28 (OR=0.31; 95%CI:0.11-0.83, p = 0.021), 32% at day-90 (OR=0.20; 95%CI:0.09-0.46, p<0.0001) and a weight-adjusted 42% risk reduction for sepsis (OR=0.17; 95%CI: 0.08-0.38; p<0.0001). Only Asian studies, in which corticosteroids were not given systematically in case of severe AAH, were positive. In patients with ACLF, the results on mortality at day-28 were heterogeneous, and GCSF had no beneficial effect on sepsis or survival at day-90., Conclusion: G-CSF may be effective in patients with decompensated cirrhosis or AAH by reducing the occurrence of sepsis and mortality. Further meta-analyses of individual data, or new, powerful and methodologically flawless therapeutic trials, are warranted to confirm these results, which harbor wide divergences between Asian and European RCTs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

Purpose: Pulmonary hamartomas (HAs) and neuroendocrine neoplasms (NENs) are often impossible to discriminate using high-resolution computed tomography (CT) as they share morphologic features. This challenge makes differential diagnosis crucial as HAs are invariably benign, whereas NENs must be considered malignant, thus requiring them to be evaluated for surgical excision.Our aim was, therefore, to develop a simple method to discriminate between pulmonary "fat-poor" HAs and NENs using contrast-enhanced CT (CECT)., Materials and Methods: Between September 2015 and December 2021, 95 patients with a histologically proven diagnosis of lung NENs (74) and HAs (21) and who underwent a preoperative CECT scan were initially identified through a review of our pathologic and radiologic databases. Among these, 55 cases (18 HAs and 37 NENs), which have been studied with biphasic CECT, were ultimately selected and reviewed by 3 radiologists with different levels of experience, analyzing their morphologic and enhancement features.The enhancement analysis was performed by placing a region of interest within the lesion in noncontrast (NCp), postcontrast (PCp, 55 to 65 s after intravenous contrast injection), and delayed phases (Dp, 180 to 300 s). A subgroup of 35 patients who underwent 18FDG-PET/CT was evaluated in a secondary analysis., Results: HU values were significantly different between NENs and HAs in the PCp ( P <0.001). NCp and Dp attenuation values did not show significant differences in the 2 groups. Differences in values of HUs in PCp and Dp allowed to discriminate between NENs and HAs., Conclusion: Wash-out analysis, ΔHU (PCp-Dp), can perfectly discriminate pulmonary "fat-poor" HAs from NENs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies.

Background: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV +  cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study., Methods: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously., Discussion: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials., Trial Registration: NCT05528952., (© 2023. The Author(s).)

Dual-energy computed tomography (DECT) is one of the most promising technological innovations made in the field of imaging in recent years. Thanks to its ability to provide quantitative and reproducible data, and to improve radiologists' confidence, especially in the less experienced, its applications are increasing in number and variety. In thoracic diseases, DECT is able to provide well-known benefits, although many recent articles have sought to investigate new perspectives. This narrative review aims to provide the reader with an overview of the applications and advantages of DECT in thoracic diseases, focusing on the most recent innovations. The research process was conducted on the databases of Pubmed and Cochrane. The article is organized according to the anatomical district: the review will focus on pleural, lung parenchymal, breast, mediastinal, lymph nodes, vascular and skeletal applications of DECT. In conclusion, considering the new potential applications and the evidence reported in the latest papers, DECT is progressively entering the daily practice of radiologists, and by reading this simple narrative review, every radiologist will know the state of the art of DECT in thoracic diseases.

Background: Pleuroparenchymal Fibroelastosis (PPFE) is a rare disease that consists of elastofibrosis that involves the pleura and subpleural lung parenchyma; it is an unusual pulmonary disease with unique clinical, radiological and pathological characteristics. According to recent studies, PPFE may not be a definite disease but a form of chronic lung injury. The aim of this retrospective study is to determine the incidence and to evaluate the distribution, severity and progression of this radiological entity on high-resolution CT (HRCT) exams of the chest, performed in routine clinical practice. In total, 1514 HRCT exams performed in the period January 2016-June 2018 were analyzed. For each exam, the presence of PPFE was evaluated and a quantitative score was assigned (from 0 to 7 points, based on the maximum depth of fibrotic involvement of the parenchyma). When available, two exams with a time interval of at least 6 months were compared for each patient in order to evaluate progression (defined as the increase in the disease score). Patients were divided into different groups according to exposure and their associated diseases. Statistical analysis was performed by using the Wilcoxon test and Kruskal-Wallis test. Results: PPFE was detected in 174 out of 1514 patients (11.6%), with a mean score of 6.1 ± 3.9 (range 1-14). In 106 out of 174 patients (60.9%), a previous CT scan was available and an evolution of PPFE was detected in 19 of these (11.5%). Among these 19 patients with worsening PPFE, 4 had isolated PPFE that was associated with chronic exposure or connective tissue disorders, and the other 15 had an associated lung disease and/or a chronic exposure. In this group, it was found that the ventral segments of the upper lobes, fissures and apical segments of the lower lobes had a greater statistically significant involvement in the progression of the disease compared to the non-progressive group. In 16 of 174 patients (9.2%, 7 of which belonged to the radiological progression group) a biopsy through video-assisted thoracoscopic surgery or apicoectomy confirmed PPFE. Conclusion: PPFE-like lesions are not uncommon on HRCT exams in routine clinical practice, and are frequently found in patients with different forms of chronic lung injury. Further studies are necessary to explain why the disease progresses in some cases, while in most, it remains stationary over time.

Background and Aims: Endoscopic band legation (EBL) is an effective method for the prophylaxis of acute variceal bleeding (AVB). This procedure may be associated with several complications, particularly bleeding. Our analysis aimed to evaluate the risk of complications due to EBL in a cohort of patients who underwent EBL for the prophylaxis of variceal bleeding and the eventual presence of risk predictors. Patients and Methods: We retrospectively analysed data from consecutive patients who underwent EBL in a primary prophylaxis regimen. For all patients, simultaneously with EBL, we recorded the Child-Pugh and MELD score, platelet count and US features of portal hypertension. Results: We collected data from 431 patients who performed a total of 1028 EBLs. We recorded 86 events (8.4% of all procedures). Bleeding after EBL occurred 64 times (6.2% of all procedures), with the following distribution: intraprocedural bleeding in 4%; hematocystis formation in 17 cases (1.7%); 6 events (0.6%) of AVB due to post-EBL ulcers. None of these events presented a correlation with platelet count (84,235 ± 54,175 × 10 3 /mL vs. 77,804 ± 75,949 × 10 3 /mL; p = 0.70) or with the condition of severe thrombocitopenia established at PLT < 50,000/mmc (22.7% with PLT ≤ 50,000/mmc vs. 15.9% with PLT ≥ 50,000/mmc; p = 0.39). Our results showed a relationship between cumulative complications of EBL and Child-Pugh score (6.9 ± 1.6 vs. 6.5 ± 1.3; p = 0.043). Conclusions: EBL in cirrhotic patients is a safe procedure. The risk of adverse events depends on the severity of liver disease, without a relationship with platelet count.

Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes. However, it is a poorly understood complication, with no consensus for diagnosis. Therefore, HE is often underdiagnosed. Differential diagnosis may be cumbersome because of non-specific symptoms, such as confusion, cognitive disorders, the aetiological factors of cirrhosis and comorbidities, which are often observed in cirrhotic patients. Therefore, an overt or covert form of HE should be systematically investigated. Advice is provided to drive patient work-up. Effective treatments are available to prevent or treat HE bouts, but the issue of single or combination therapy has not been resolved. Transjugular intrahepatic portosystemic shunt (TIPS) placement largely improved the prognosis of cirrhotic patients, but HE occurrence of HE is often a fear, even when post-TIPS HE can be avoided by a careful selection of patients and preventive treatment. HE is an indication of liver transplantation. However, its reversibility post-transplantation and the consequences of transplantation in patients with other causes of neurological disorders remain controversial, which supports the performance of an extensive work-up in expert centres for this subset of patients. The present guidelines assist clinicians in the diagnosis of the overt or covert form of HE to implement curative and preventive treatments and clarify which patients require referral to expert centres for consideration for liver transplantation. These guidelines are very clinically oriented and address different frequent clinical issues to help physicians make bedside decisions., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: In the current setting of organ shortage, brain-dead liver donors with recent liver trauma (RLT) represent a potential pool of donors. Yet, data on feasibility and safety of liver transplantation (LT) using grafts with RLT are lacking., Methods: All liver grafts from brain-dead donors with RLT proposed for LT between 2010 and 2018 were identified from the nationwide CRISTAL registry of the Biomedicine Agency. The current study aimed at evaluating 1-y survival as the primary endpoint., Results: Among 11 073 LTs, 142 LTs (1.3%) using grafts with RLT were performed. These 142 LTs, including 23 split LTs, were performed from 131 donors (46.1%) of 284 donors with RLT proposed for LT. Transplanted grafts were procured from donors with lower liver enzymes levels ( P  < 0.001) and less advanced liver trauma according to the American Association for the Surgery of Trauma liver grading system ( P  < 0.001) compared with not transplanted grafts. Before allocation procedures, 20 (7%) of 284 donors underwent damage control intervention. During transplantation, specific liver trauma management was needed in 19 patients (13%), consisting of local hemostatic control (n = 15), partial hepatic resection on back-table (n = 3), or perihepatic packing (n = 1). Ninety-day mortality and severe morbidity rates were 8.5% (n = 12) and 29.5% (n = 42), respectively. One-year overall and graft survival rates were 85% and 81%, and corresponding 5-y rates were 77% and 72%, respectively., Conclusions: Using liver grafts from donors with RLT seems safe with acceptable long-term outcomes. All brain-dead patients with multiorgan trauma, including liver injury, should be considered for organ allocation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Methotrexate is a key component of the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis. Hepatotoxicity has long been a concern for prescribers envisaging long-term treatment with methotrexate for their patients. However, the putative liver toxicity of methotrexate should be evaluated in the context of advances in our knowledge of the pathogenesis and natural history of liver disease, especially non-alcoholic fatty liver disease (NAFLD). Notably, patients with NAFLD are at increased risk for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD. Understanding the mechanisms of acute hepatotoxicity can facilitate the interpretation of elevated concentrations of liver enzymes in this context. Liver fibrosis and the mechanisms of fibrogenesis also need to be considered in relation to chronic exposure to methotrexate. A number of non-invasive tests for liver fibrosis are available for use in patients with rheumatic disease, in addition to liver biopsy, which can be appropriate for particular individuals. On the basis of the available evidence, practical suggestions for pretreatment screening and long-term monitoring of methotrexate therapy can be made for patients who have (or are at risk for) chronic liver disease., (© 2022. Springer Nature Limited.)

Background: Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up., Methods: An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals., Results: A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child-Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed., Conclusions: DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective.

Introduction: Noninvasive criteria to predict the progression of low-risk esophageal varices (EV) in patients with compensated hepatitis C virus (HCV) cirrhosis after sustained virological response (SVR) by direct-acting antivirals (DAAs) are lacking. Our aim was to assess the diagnostic performance of Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) criteria for EV progression compared with elastography-based criteria (Baveno VI, Expanded Baveno VI, and Baveno VII-HCV criteria)., Methods: All consecutive patients observed at 3 referral centers with compensated HCV cirrhosis with or without F1 EV who achieved sustained virological response by DAAs were classified at last esophagogastroduodenoscopy (EGDS) as RESIST-HCV low risk (i.e., low probability of high-risk varices [HRV]) if platelets were >120 × 10 9 /L and serum albumin >3.6 g/dL or RESIST-HCV high risk (i.e., high probability of HRV) if platelets were <120 × 10 9 /L or serum albumin <3.6 g/dL. The primary outcome was the progression to HRV. The area under the receiver operating characteristic curve and decision curve analysis of noninvasive criteria were calculated., Results: The cohort consisted of 353 patients in Child-Pugh class A (mean age 67.2 years, 53.8% males). During a mean follow-up of 44.2 months, 34 patients (9.6%, 95% CI 6.7%-13.5%) developed HRV. At the last EGDS, 178 patients (50.4%) were RESIST-low risk, and 175 (49.6%) were RESIST-high risk. RESIST-HCV criteria showed the highest area under the receiver operating characteristic curve (0.70, 95% confidence interval 0.65-0.75), correctly sparing the highest number of EGDS (54.3%), with the lowest false-positive rate (45.7%), compared with elastography-based criteria. Decision curve analysis showed that RESIST-HCV had higher clinical utility than elastography-based criteria., Discussion: Biochemical-based RESIST-HCV criteria are useful to easily predict HRV development after HCV eradication by DAAs in patients with compensated cirrhosis and low-risk EV., (Copyright © 2022 by The American College of Gastroenterology.)

Refractory ascites (RA) is a frequent and life-threatening complication of cirrhosis. In selected patients with RA, transjugular intrahepatic portosystemic shunt (TIPS) placement and liver transplantation (LT) are currently considered the best therapeutic alternatives to repeated large volume paracentesis. In patients with a contraindication to TIPS or LT, the alfapump ® system (Sequana Medical, Ghent, Belgium) has been developed to reduce the need for iterative paracentesis, and consequently to improve the quality of life and nutritional status. We report here recent data on technical progress made since the first implantation, the efficacy and tolerance of the device, the position of the pump in the therapeutic arsenal for refractory ascites, and the grey areas that remain to be clarified regarding the optimal selection of patients who are potential candidates for this treatment., Competing Interests: Conflict-of-interest statement: Stirnimann G has received support for travel and meeting attendance, served as a speaker, and participated in Advisory Boards for Sequana Medical. There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Anastomotic biliary stricture (ABS) remains the most frequent complication after liver transplantation (LT). This study aimed to identify new anastomotic biliary stricture risk factors, with a specific focus on postoperative events. Additionally, ABS management and impact on patient and graft survival were assessed. Methods: All consecutive patients who underwent LT with duct-to-duct anastomosis between 2010 and 2019 were included. All patients who died within 90 days after LT due to non-ABS-related causes were excluded. Results: Among 240 patients, 65 (27.1%) developed ABS after a median time of 142 days (range, 13-1265). Median follow-up was 49 months (7-126). Upon multivariable analysis, donor BMI (OR=0.509, p = 0.037), post-LT CMV primoinfection (OR = 5.244, p < 0.001) or reactivation (OR = 2.421, p = 0.015) and the occurrence of post-LT anastomotic biliary fistula (OR = 2.691, p = 0.021) were associated with ABS. Anastomotic technical difficulty did not independently impact the risk of ABS (OR = 1.923, p = 0.051). First-line ABS treatment was systematically endoscopic (100%), and required a median of 2 (range, 1-11) procedures per patient. Repeat LT was not required in patients developing ABS. The occurrence of ABS was not associated with overall patient survival ( p = 0.912) nor graft survival ( p = 0.521). Conclusion: The risk of developing ABS after LT seems driven by the occurrence of postoperative events such as CMV infection and anastomotic fistula. In this regard, the role of CMV prophylaxis warrants further investigations., 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 Georges, Clerc, Turco, Di Martino, Paquette, Minello, Calame, Magnin, Vuitton, Weil-Verhoeven, Lakkis, Vanlemmens, Latournerie, Heyd and Doussot.)

Background and Aims: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients., Methods: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 μmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation» or « the occurrence of one or more parameters » among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival., Results: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1)., Conclusion: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To capture and monitor flu-like symptoms in relation to the clinical characteristics and the oncologic treatment of a large head and neck cancer (HNC) patient cohort during the Coronavirus disease 2019 (COVID-19) pandemic., Methods: Patients were monitored through by 2 rounds of interviews. Clinical characteristics of patients with no symptoms (group 0) and of those reporting ⩾1 (group A), ⩾3 (group B), or ⩾5 symptoms (group C) were analyzed. Patients with ⩾1 symptom at both interviews were defined as group A2., Results: Five hundred patients with HNC were analyzed. A higher frequency of patients with the following characteristics was observed in group A vs group 0: active treatment (40% vs 24%, p = 0.0002), gastrostomy (6% vs 2%, p = 0.027), recent active treatment (48% vs 29%, p < 0.0001), and higher number of concomitant medications ( p = 0.01). A lower median age was observed in group B vs group no-B (patients with fewer than three symptoms) (59 vs 63.55 years, p = 0.016) and in group A2 vs group no-A2 (patients without at least one symptom at both interviews) (56 vs 63 years, p = 0.021); patients in group B received more recent active treatment than those in group no-B and in group A2 vs those in group no-A2 ( p = 0.024 and 0.043, respectively); patients in group B had a lower body mass index than those in group no-B (22.4 vs 23.93 kg/m 2 , p = 0.0066)., Conclusions: This work is based on patient-reported symptoms and signs independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. In the future, these results might serve as a a benchmark for clinicians triaging and managing patients with HNC during infectious outbreaks involving flu-like symptoms.

Although coronary artery disease (CAD) and advanced liver fibrosis (AdLF) are commonly associated in patients with non-alcoholic fatty liver disease (NAFLD), the prevalence of AdLF and the diagnostic performance of non-invasive fibrosis tests (NITs) in CAD patients remains unknown. We aimed to prospectively screen for AdLF in patients with documented CAD using NITs and Fibroscan. High and intermediate zones of NITs were combined to define AdLF. AdLF was suspected whenever APRI ≥ 0.5, Forns index ≥ 4.2, NAFLD fibrosis score (NFS) ≥ -1.455/0.12 for age

Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of liver-related events (LREs). Here, we have assessed the ability of a composite score based on clinical features, metabolic comorbidities, and genetic variants to predict LREs. A total of 546 consecutive patients with NAFLD were recruited and stratified according to the fibrosis-4 (FIB-4) index. LREs were defined as occurrence of hepatocellular carcinoma or hepatic decompensation. Cox regression multivariate analysis was used to identify baseline variables associated with LREs. The UK Biobank was used as the validation cohort, and severe liver disease (incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation) was used as the outcome. LREs were experienced by 58 patients, only one of whom was in the cohort of patients with a FIB-4 score < 1.3. Multivariate Cox regression analysis of 229 patients with a FIB-4 score ≥ 1.3 highlighted clinical variables independently associated with the development of LREs, including older age, low platelet count, low albumin, low high-density lipoprotein cholesterol, certain genetic factors, and interactions between genetic factors and sex or diabetes. The area under the curve (AUC) for the model was 0.87 at 1, 3, and 5 years. Our novel Genetic and Metabolic Staging (GEMS) scoring system was derived from the Cox model linear predictor, ranked from 0 to 10, and categorized into five classes (0-5, 5-6, 6-7, 7-8, and 8-10). The risk of LREs increased from 4% in patients in the best class (GEMS score 0-5) to 91% in the worst (GEMS score 8-10). GEMS score was associated with incident severe liver disease in the study population (hazard ratio, 1.56; 95% confidence interval, 1.48-1.65; P < 0.001) as well as in the UK Biobank cohort where AUCs for prediction of severe liver disease at 1, 3, and 5 years were 0.70, 0.69, and 0.67, respectively. Conclusion: The novel GEMS scoring system has an adequate ability to predict the outcome of patients with NAFLD., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Liver fibrosis is the main predictor of events in patients with nonalcoholic fatty liver disease (NAFLD), 1 and its evolution is characterized by a nonlinear trend 2,3 mostly affected by metabolic risk factors, severity of liver inflammation and steatosis, and weight loss. 3 The rs738409 C>G common variant in PNPLA3 gene has been associated with severity of fibrosis and risk of liver-related events in NAFLD. 4,5 Noninvasive tests as Fibrosis-4 (FIB-4) and liver stiffness measurement (LSM) are useful to rule-out advanced fibrosis and they could be reliable to predict fibrosis progression. 2,6 We aimed to evaluate in patients with NAFLD whether PNPLA3 rs738409 C>G variant impacts on fibrosis progression, noninvasively assessed by FIB-4 and LSM., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: In the last years the Hepatitis C virus (HCV) infection was a relevant public health problem due to the large number of affected people worldwide and the impact on hepatic and extrahepatic complications. The availability of direct-acting antivirals (DAAs) and the very high rate of sustained virological response (SVR) after treatment has radically changed the course of HCV chronic infection., Evidence Acquisition: We searched PubMed for articles published between January 1, 1995, through December 31, 2020, in English language., Evidence Synthesis: Robust evidence showed a close link between HCV infection and development of cardiovascular disease (CVD), as result of the atherogenic effect of the virus., Conclusions: This review aimed to explore the evidence linking HCV infection with cardiovascular disease and to evaluate the impact of SVR after DAAs on cardiovascular complications.

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Background: In patients with autoimmune hepatitis (AIH), relapse rates between 25 and 100% after treatment withdrawal have been reported. The optimal strategy for immunosuppressive treatment withdrawal is controversial., Aim: To identify the predictive factors of histological remission and to assess the relapse rate after treatment withdrawal in AIH patients with prolonged biochemical response., Methods: Patients with AIH and sustained biochemical remission on first-line treatment were retrospectively included. Histological response was defined as complete regression of interface hepatitis and lobular necrosis and no or minimal portal inflammation and relapse as any elevation of serum aminotransferase or gammaglobulin/IgG levels., Results: Sixty-two patients were included. Forty-seven had a biopsy after a median biochemical response of 49.7 months. Twenty-five of them were histological responders. Independent predictors of histological remission were older age (OR = 1.1; CI 95%: 1.0; 1.2), mild-to-moderate fibrosis at diagnosis (OR = 8; CI: 1.4; 47.6) and aspartate aminotransferases < 0.6 × ULN (OR = 7.1; CI: 1.3; 36.7). Thirty-nine patients stopped therapy after a median biochemical response of 48.6 months. Twenty-four of them had a biopsy before treatment withdrawal: 21 were histological responders. The cumulative rate of relapse was 25% at 64 months., Conclusions: This study indicates that older age, mild-to-moderate fibrosis at diagnosis and serum aspartate aminotransferases in the lower range of normal are independent predictors of histological response in AIH with prolonged biochemical response. The relapse rate after treatment withdrawal may be limited to 25% at 64 months when patients are selected on the basis of prolonged biochemical remission and, when available, histological response.

Background & Aims: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated., Methods: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3-D0)/D0., Results: A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC = 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%., Conclusion: In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort., Lay Summary: The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required., Competing Interests: Conflict of interest EDM: nothing to disclose, AC: nothing to disclose, OC: nothing to disclose, OR: nothing to disclose, JMP: nothing to disclose, PHD: nothing to disclose, FA: nothing to disclose, CS: nothing to disclose, IOH: nothing to disclose, CD: nothing to disclose, AHB: nothing to disclose, SB: nothing to disclose, NG: nothing to disclose, GPP: nothing to disclose, CB: nothing to disclose, MB: nothing to disclose, HF: nothing to disclose, VdL: nothing to disclose, JD: nothing to disclose, FC: nothing to disclose, SR: nothing to disclose, MDG: nothing to disclose, OG: nothing to disclose, FD: nothing to disclose, PP: nothing to disclose, VDM: nothing to disclose, NR: nothing to disclose, PI: nothing to disclose, MS: nothing to disclose, PM: nothing to disclose, HA: nothing to disclose, DS: nothing to disclose, JCDV: nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

First reported in 1976, hepatic angiomyolipoma (HAML) is a rare mesenchymal liver tumor occurring mostly in middle-aged women. Diagnosis of the liver mass is often incidental on abdominal imaging due to the frequent absence of specific symptoms. Nearly 10% of HAMLs are associated with tuberous sclerosis complex. HAML contains variable proportions of blood vessels, smooth muscle cells and adipose tissue, which renders radiological diagnosis hazardous. Cells express positivity for HMB-45 and actin, thus these tumors are integrated into the group of perivascular epithelioid cell tumors. Typically, a HAML appears on magnetic resonance imaging (or computed tomography scan) as a hypervascular solid tumor with fatty areas and with washout, and can easily be misdiagnosed as other liver tumors, particularly hepatocellular carcinoma. The therapeutic strategy is not clearly defined, but surgical resection is indicated for symptomatic patients, for tumors showing an aggressive pattern ( i.e. , changes in size on imaging or high proliferation activity and atypical epithelioid pattern on liver biopsy), for large (> 5 cm) biopsy-proven HAML, and if doubts remain on imaging or histology. Conservative management may be justified in other conditions, since most cases follow a benign clinical course. In summary, the correct diagnosis of HAML is challenging on imaging and relies mainly on pathological findings., Competing Interests: Conflict-of-interest statement: No conflicts of interest exist., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Microvesicles (MVs) with procoagulant properties may favor liver parenchymal extinction, then cirrhosis-related complications and mortality. In a longitudinal cohort of cirrhotic patients, we measured plasma levels of platelet-derived MVs (PMVs), endothelial-derived MVs, and red blood cell-derived MVs, expressing phosphatidylserine (annexin V-positive [AV+]) or not, and evaluated their impact on Model for End-Stage Liver Disease (MELD) score and transplant-free survival., Methods: MVs were quantified using flow cytometry in plasma from 90 noninfected cirrhotic patients and 10 healthy volunteers matched for age and sex. Impact of plasma microvesicle levels on 6-month transplant-free survival was assessed using log-rank tests and logistic regression., Results: Microvesicle levels, mostly platelet-derived, were 2.5-fold higher in healthy volunteers compared with cirrhotic patients. Circulating small AV+ PMV levels were lower in cirrhotic patients (P = 0.014) and inversely correlated with MELD scores (R = -0.28; P = 0.0065). During 1-year follow-up, 8 patients died and 7 underwent liver transplantation. In the remaining patients, circulating microvesicle levels did not change significantly. Six-month transplant-free survival was lower in patients with low baseline small AV+ PMV levels (72.6% vs 96.2%; P = 0.0007). In multivariate analyses adjusted for age, ascites, esophageal varices, encephalopathy, clinical decompensation, total platelet counts, MELD score, and/or Child-Pugh C stage, patients with lower small AV+ PMV levels had a significant 5- to 8-fold higher risk of 6-month death or liver transplant. Other PMV levels did not impact on survival., Discussion: Decreased circulating small AV+ PMV levels are associated with significantly lower transplant-free survival in cirrhotic patients independently of MELD score and platelet counts., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background & Aims: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins., Methods: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61)., Results: Maximal cortisol secretion rate (CSR max ) was significantly decreased ( p  = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSR max was negatively correlated with CP score (r = -0.19, p  = 0.01). Free cortisol elimination rate was significantly ( p  = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min -1 ) compared with that in the CP ≤8 group (0.21 ± 0.21 min -1 ), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p  = 0.01). A significant correlation between CSR max and free cortisol elimination rate (r = 0.88, p <0.001) was observed., Conclusions: CSR max and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSR max estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis., Lay Summary: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis., Competing Interests: The authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details.

Background: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use., Aim: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients., Methods: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors., Results: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo., Conclusion: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background & Aims: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status., Methods: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014)., Results: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]., Conclusions: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs., Lay Summary: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction., Competing Interests: Conflict of interest Dr. Nahon has received honoraria from and/or consults for Abbvie, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen, MSD, Roche. He received research grants from Abbvie and Bristol-Myers Squibb. Dr. Pol consults for and has received grants from Bristol-Myers Squibb, Gilead, Roche, and MSD. He consults for Gilead, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Abbvie, Roche and MSD. Dr. Guyader has received honoraria and/or grants from Abbvie, Gilead, Janssen and MSD. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Disturbances in fatty acid (FA) metabolism have been reported in cirrhosis, but the role of FAs in the development of hepatocellular carcinoma (HCC) is still unclear. Biomarkers are a promising means to explore the associations between exogenous intake or endogenous production of FAs and cancer risk., Aim: To estimate the relationship between fatty acid content in erythrocyte membranes and HCC risk in cirrhotic patients METHODS: The "CiRCE" case-control study recruited cirrhotic patients from six French hospitals between 2008 and 2012. Cases were cirrhotic patients with HCC (n = 349); controls were cirrhotic patients without HCC at inclusion (n = 550). FA composition of phospholipids in erythrocyte membranes was determined by high performance gas chromatography. Odds ratios for HCC risk according to FA concentrations were estimated with multivariable logistic regression., Results: HCC patients were older and more often men (P < 0.001). In both groups, saturated FAs represented more than 39% of all FAs in erythrocyte membranes, mono-unsaturated FAs around 14%, and polyunsaturated FAs around 46%. High levels of C15:0 + C17:0, C20:1 n-9, C18:2 n-6 and C20:2 n-6 were associated with higher risk of HCC. The levels of C18:0 and C20:4 n-6 were lower in HCC cases than in controls., Conclusions: The FA composition of erythrocyte membranes differed according to the presence of HCC with higher levels of saturated FAs, linoleic and eicosadienoic acids, and lower levels of stearic and arachidonic acids. These alterations may reflect particular dietary patterns and/or altered FA metabolism. Further investigations are warranted., (© 2020 John Wiley & Sons Ltd.)

Quali-quantitative analyses of anthocyanins and non-anthocyanin phenolic compounds performed with the use of liquid chromatography coupled with high resolution mass spectrometry, were evaluated in juice of pomegranate fruits ('Dente di Cavallo'), in relation to different light exposures (North, South, West and East). A total of 16 compounds were identified, including phenolic acids, flavonoids, hydrolysable tannins, and anthocyanins, known for their health-promoting effects. Striking differences were observed about the total phenolic content, which was high in juices from fruits with east- and north-facing position, while it was lower in juices facing south. The greatest contents of total flavonoids and anthocyanins were recorded in fruit juices with southern exposure; however, there are no great differences in the content in phenolic acids. Tannins were mainly synthesized in fruit juices with West exposure. The results showed that the position within the tree had no significant effects on color juice, however, it significantly ( p < 0.05) affected data on fruit weight, soluble sugars and juice yield. Remarkable synergies existed among polyphenols and phytochemicals in pomegranate juice, but collecting fruits with different solar exposure could enhance different health benefits, i.e., the juices with higher polyphenols content could have more anticancer effect or those with higher tannins content could have more antimicrobial effect.

Background: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naïve patients, with non-severe fibrosis., Methods: HCV mono-infected and treatment naïve patients with non-severe fibrosis (Fibroscan ® <9.5 kPa and Fibrotest ®  < 0.59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non-1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12)., Findings: Mean age was 54 ± 13 years, 31% were men and viral load was higher than 800.000 IU/mL in 70 of 112 patients (63%). Using Fibroscan ® , 100 had F0-1 fibrosis score. FIB-4 lower than 1.45 and APRI less than 1 was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance-associated substitution). Then, modified intention-to-treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow-up week 24., Interpretation: Naïve patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for 8 weeks., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: The reported hepatotoxicity of methotrexate underlines the need for a repeated non-invasive and reliable evaluation of liver fibrosis. We estimated, using a non-invasive strategy, the prevalence of significant liver fibrosis in patients treated by methotrexate and the predictors of significant fibrosis (fibrosis≥F2)., Methods: Fibrosis was prospectively evaluated using 9 non-invasive tests in consecutive patients with psoriasis, rheumatoid arthritis, or Crohn's disease. Significant fibrosis was assessed without liver biopsy by defining a "specific method" (result given by the majority of the tests) and a "sensitive method" (at least one test indicating a stage≥F2)., Results: One hundred and thirty-one patients (66 Psoriasis, 40 rheumatoid arthritis, and 25 Crohn's disease) were enrolled, including 83 receiving methotrexate. Seven tests were performed on average per patient, with a complete concordance in 75% of cases. Fibroscan® was interpretable in only 61% of patients. The best performances (AUROC>0.9) for predicting significant fibrosis were obtained by tests dedicated to steatohepatitis (FibroMeter NAFLD, NFS and FPI). The prevalence of fibrosis≥F2 according to the "specific" or the "sensitive" assessment of fibrosis was 10% and 28%, respectively. Methotrexate exposure did not influence the fibrosis stage. Factors independently associated with significant fibrosis according our "sensitive method" were age, male gender, and metabolic syndrome., Conclusion: We provided a non-invasive approach for identifying liver fibrosis≥F2 by using 8 biochemical tests and Fibroscan®. In this population, the risk of significant fibrosis was related to age, male gender, and presence of metabolic syndrome, but was not influenced by methotrexate., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background & Aims: Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy., Methods: We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (<50 IU/mL) 12 weeks after the end of treatment (SVR) or an undetectable level of HBV DNA. The primary aims were to validate the Baveno VI guidelines for screening and surveillance of EV in patients with compensated cirrhosis and to study the effects of an SVR on the progression of PHT., Results: A total of 200 patients achieved an SVR (22.4%) (94 patients with HCV infection, 98 patients with HBV infection, and 8 patients with both); 80 of these patients had favorable Baveno VI status and none had VNT. Progression of PHT was studied in 548 patients; during a follow-up period of 61.2 months (interquartile range, 39.5-80.6 months), 105 of these patients (19.1%) had progression of PHT. Lack of an SVR and grade 1 EV were independently associated with progression of PHT. At the time of PHT progression, all patients had unfavorable Baveno VI status. Achieving favorable Baveno VI status after an SVR was associated with the absence of PHT progression. Favorable Baveno VI status and SVR were independently associated with survival., Conclusions: In an analysis of data from a large cohort of patients with HBV- or HCV-associated cirrhosis in France, we validated the Baveno VI guidelines on screening and surveillance of PHT, even for patients who achieved a sustained response to antiviral therapy., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)