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The digestive tract represents the most complex interface of an organism with its biotope. Food may be contaminated by pathogens and toxicants while an abundant and complex microbiota strives in the gut lumen. The organism must defend itself against potentially noxious biotic or abiotic stresses while preserving its microbiota, provided it plays a beneficial role. The presence of intestinal viruses adds another layer of complexity. Starting from a differential sensitivity of two lines from the same Drosophila wild-type strain to ingested Pseudomonas aeruginosa , we report here that the presence of Nora virus in the gut epithelium promotes the sensitivity to this bacterial pathogen as well as to an ingested oxidizing xenobiotic. The genotype, age, nature of the ingested food and to a limited extent the microbiota are relevant parameters that influence the effects of Nora virus on host fitness. Mechanistically, we detect the initial presence of viral proteins essentially in progenitor cells. Upon stress such as infection, exposure to xenobiotics, aging or feeding on a rich-food diet, the virus is then detected in enterocytes, which correlates with a disruption of the intestinal barrier function in aged flies. Finally, we show that the virus proliferates only when ISCs are induced to divide and that blocking either enterocyte apoptosis or JAK/STAT-driven ISC division leads to a drastically reduced Nora virus titer. In conclusion, it is important to check that experimental strains are devoid of intestinal viruses when monitoring survival/life span of fly lines or when investigating the homeostasis of the intestinal epithelium as these viruses can constitute significant confounding factors.

Objective: Evaluation of prognostic factors is crucial in patients with endometrial cancer for optimal treatment planning and prognosis assessment. This study proposes a deep learning pipeline for tumor and uterus segmentation from magnetic resonance imaging (MRI) images to predict deep myometrial invasion and cervical stroma invasion and thus assist clinicians in pre-operative workups., Methods: Two experts consensually reviewed the MRIs and assessed myometrial invasion and cervical stromal invasion as per the International Federation of Gynecology and Obstetrics staging classification, to compare the diagnostic performance of the model with the radiologic consensus. The deep learning method was trained using sagittal T2-weighted images from 142 patients and tested with a 3-fold stratified test with 36 patients in each fold. Our solution is based on a segmentation module, which employed a 2-stage pipeline for efficient uterus in the whole MRI volume and then tumor segmentation in the uterus predicted region of interest., Results: A total of 178 patients were included. For deep myometrial invasion prediction, the model achieved an average balanced test accuracy over 3-folds of 0.702, while experts reached an average accuracy of 0.769. For cervical stroma invasion prediction, our model demonstrated an average balanced accuracy of 0.721 on the 3-fold test set, while experts achieved an average balanced accuracy of 0.859. Additionally, the accuracy rates for uterus and tumor segmentation, measured by the Dice score, were 0.847 and 0.579 respectively., Conclusion: Despite the current challenges posed by variations in data, class imbalance, and the presence of artifacts, our fully automatic approach holds great promise in supporting in pre-operative staging. Moreover, it demonstrated a robust capability to segment key regions of interest, specifically the uterus and tumors, highlighting the positive impact our solution can bring to health care imaging., Competing Interests: Declaration of Competing Interests None declared., (Copyright © 2024 European Society of Gynaecological Oncology and the International Gynecologic Cancer Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Background: Spontaneous idiopathic liver hemorrhage (SILH) is a rare life-threatening condition occurring without a clear and specific etiology. A systematic review was performed to provide guidelines for the perioperative management of patients affected by SILH. A case report was also included., Methods: A systematic search of the last 24-year literature was conducted and the manuscript was structured following point-by-point the PRISMA guidelines., Results: After an initial selection of 6995 titles, 15 articles were considered for the final qualitative analysis (n = 22 patients, including the present report). Conservative treatment was chosen in 12 cases (54.5%) with stable clinical conditions, while 9 patients (40.9%) required a primary operative approach for emergency presentation at diagnosis. Direct liver resection was the preferred surgical treatment (n = 6), mostly major hepatectomies (n = 4). Hepatic arterial embolization was performed as the primary operative approach in three patients, followed by emergency laparotomy during the same hospitalization because of rebleeding in one case. Contrast-enhanced CT scan was the gold standard for diagnosis (n = 19)., Conclusions: Conservative treatment of SILH is mainly based on stable clinical conditions and may be considered even in case of a limited arterial blush found on imaging. The absence of underlying hepatic or systemic disorders seems to correlate with favorable outcomes and no mortality., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Objective: To issue recommendations for reduced energy consumption in controlled environment zones (CEZ) in operating theaters and interventional sectors., Design: A committee bringing together seven experts from the SFAR, AFC, SF2H, ASPEC and SOFCOT was convened by CERES. A conflict-of-interest statement was developed at the beginning of the process and enforced throughout the elaboration of the reference document. The experts received no financing from any company commercializing a healthcare product (medicine or medical device). The committee was called upon to follow and respect the GRADE® (grading of recommendations assessment, development and evaluation) method to evaluate quality of the factual data on which the recommendations were based., Methods: We analyzed the relevant literature and formulated the recommendations in accordance with the GRADE® methodology by identifying three different fields. Each question was formulated in accordance with the PICO (patients, intervention, comparison, outcome) format., Results: The experts' attempts at synthesis and application of the GRADE® method led to 16 recommendations. In cases where GRADE® method could not be applied, the recommendations were formulated as expert advice., Conclusion: Once strong agreement among the experts had been reached, we formulated 15 recommendations for decreased energy consumption and reduced environmental impact in the controlled environment zones of operating theaters and interventional sectors., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as an oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic colorectal cancer and colitis-associated cancer (CAC). CAC is one of the most severe complications of chronic inflammatory bowel disease (IBD), but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL levels in patients with IBD and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from patients with late-stage ulcerative colitis compared with controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, which facilitates IL-22-mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Furthermore, CAIX associates with and stabilizes MASTL in response to IL-22 stimulation. NEW & NOTEWORTHY MASTL is upregulated in colorectal cancer; however, its role in colitis and colitis-associated cancer is poorly understood. This study is the first to draw a link between MASTL and IL-22, a proinflammatory/intestinal epithelial recovery-promoting cytokine that is also implicated in colon tumorigenesis. We propose that IL-22 increases MASTL protein stability by promoting its association with CAIX potentially via AKT signaling to promote cell survival and proliferation.

Background: Hyperspectral imaging (HSI), combined with machine learning, can help to identify characteristic tissue signatures enabling automatic tissue recognition during surgery. This study aims to develop the first HSI-based automatic abdominal tissue recognition with human data in a prospective bi-center setting., Methods: Data were collected from patients undergoing elective open abdominal surgery at two international tertiary referral hospitals from September 2020 to June 2021. HS images were captured at various time points throughout the surgical procedure. Resulting RGB images were annotated with 13 distinct organ labels. Convolutional Neural Networks (CNNs) were employed for the analysis, with both external and internal validation settings utilized., Results: A total of 169 patients were included, 73 (43.2%) from Strasbourg and 96 (56.8%) from Verona. The internal validation within centers combined patients from both centers into a single cohort, randomly allocated to the training (127 patients, 75.1%, 585 images) and test sets (42 patients, 24.9%, 181 images). This validation setting showed the best performance. The highest true positive rate was achieved for the skin (100%) and the liver (97%). Misclassifications included tissues with a similar embryological origin (omentum and mesentery: 32%) or with overlaying boundaries (liver and hepatic ligament: 22%). The median DICE score for ten tissue classes exceeded 80%., Conclusion: To improve automatic surgical scene segmentation and to drive clinical translation, multicenter accurate HSI datasets are essential, but further work is needed to quantify the clinical value of HSI. HSI might be included in a new omics science, namely surgical optomics, which uses light to extract quantifiable tissue features during surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the last decade tight junction proteins exposed at the surface of liver or cancer cells have been uncovered as mediators of liver disease biology: Claudin-1 and Occludin are host factors for hepatitis C virus entry and Claudin-1 has been identified as a driver for liver fibrosis and hepatocellular carcinoma (HCC). Moreover, Claudins have emerged as therapeutic targets for liver disease and HCC. CLDN1 expression is upregulated in liver fibrosis and HCC. Monoclonal antibodies (mAbs) targeting Claudin-1 have completed preclinical proof-of-concept studies for treatment of liver fibrosis and HCC and are currently in clinical development for advanced liver fibrosis. Claudin-6 overexpression is associated with an HCC aggressive phenotype and treatment resistance. Claudin-6 mAbs or chimeric antigen receptor-T cells therapies are currently being clinically investigated for Claudin-6 overexpressing tumors. In conclusion, targeting Claudin proteins offers a novel clinical opportunity for the treatment of patients with advanced liver fibrosis and HCC., Competing Interests: Inserm, the University of Strasbourg, Strasbourg University Hospitals, and the Institut Hospitalo-Universitaire have filed patents and patent applications: US62/153,727 (Clinical gene signature–based human cell culture model and uses thereof; inventors: T.F.B.), US13/119,233 (anti-Claudin-1 antibodies for the inhibition of hepatitis C virus infection; T.F.B.), US15/979,609 PCT/EP2016/055942 (anti-Claudin-1 monoclonal antibodies for the prevention and treatment of HCC; T.F.B.), US16/086,934 PCT/EP2017/056703 (humanized anti-Claudin 1 antibodies and uses thereof; T.F.B.), and PCT/EP2020/081941 (Anti–Claudin 1 monoclonal antibodies for the prevention and treatment of fibrotic disease; T.F.B., N.R., A.S.) which have all been licensed to Alentis Therapeutics, Basel. T.F.B. is the founder, owns shares and serves as a consultant for Alentis. Any potential conflict of interest is managed independently by the SATT Conectus and Inserm Transfert for the authors of the University of Strasbourg and Inserm., (Thieme. All rights reserved.)

Objective: The aim of this systematic review and meta-analysis is to identify current robotic assistance systems for percutaneous liver ablations, compare approaches, and determine how to achieve standardization of procedural concepts for optimized ablation outcomes., Background: Image-guided surgical approaches are increasingly common. Assistance by navigation and robotic systems allows to optimize procedural accuracy, with the aim to consistently obtain adequate ablation volumes., Methods: Several databases (PubMed/MEDLINE, ProQuest, Science Direct, Research Rabbit, and IEEE Xplore) were systematically searched for robotic preclinical and clinical percutaneous liver ablation studies, and relevant original manuscripts were included according to the Preferred Reporting items for Systematic Reviews and Meta-Analyses guidelines. The endpoints were the type of device, insertion technique (freehand or robotic), planning, execution, and confirmation of the procedure. A meta-analysis was performed, including comparative studies of freehand and robotic techniques in terms of radiation dose, accuracy, and Euclidean error., Results: The inclusion criteria were met by 33/755 studies. There were 24 robotic devices reported for percutaneous liver surgery. The most used were the MAXIO robot (8/33; 24.2%), Zerobot, and AcuBot (each 2/33, 6.1%). The most common tracking system was optical (25/33, 75.8%). In the meta-analysis, the robotic approach was superior to the freehand technique in terms of individual radiation (0.5582, 95% confidence interval [CI] = 0.0167-1.0996, dose-length product range 79-2216 mGy.cm), accuracy (0.6260, 95% CI = 0.1423-1.1097), and Euclidean error (0.8189, 95% CI = -0.1020 to 1.7399)., Conclusions: Robotic assistance in percutaneous ablation for liver tumors achieves superior results and reduces errors compared with manual applicator insertion. Standardization of concepts and reporting is necessary and suggested to facilitate the comparison of the different parameters used to measure liver ablation results. The increasing use of image-guided surgery has encouraged robotic assistance for percutaneous liver ablations. This systematic review analyzed 33 studies and identified 24 robotic devices, with optical tracking prevailing. The meta-analysis favored robotic assessment, showing increased accuracy and reduced errors compared with freehand technique, emphasizing the need for conceptual standardization., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Left-sided or segmental portal hypertension (SPHT) is a rare entity, most often associated with pancreatic disease or antecedent pancreatic surgery. The starting point is splenic vein obstruction secondary to local inflammation or, less often, extrinsic compression. SPHT leads to splenomegaly and development of collateral porto-systemic venous circulation. SPHT should be suspected in patients with pancreatic history who present with episodic upper gastrointestinal bleeding and splenomegaly with normal liver function tests. The most common clinical presentation is major upper gastrointestinal bleeding secondary to rupture of esophageal and/or gastric varices. At the present time, there are no management recommendations for SPHT, particularly when the patient is asymptomatic. In patients with upper gastro-intestinal bleeding, hemostasis can be obtained either by medical or interventional means according to patient status and available resources. For symptomatic patients, splenectomy is the reference treatment. Recently, less invasive, radiologic procedures, such as splenic artery embolization, have been developed as an alternative to surgery. Additionally, sonography-guided endoscopic hemostasis can also be envisioned, leading to the diagnosis and treatment of the lesion by elastic band ligation or by glue injection into the varices during the same procedure. The goal of this article is to describe the pathophysiological mechanisms behind SPHT and its clinical manifestations and treatment, based on a review of the literature. Because of the absence of recommendations for the management of SPHT, we propose a decisional algorithm for the management of SPHT based on the literature., (Copyright © 2023. Published by Elsevier Masson SAS.)

Background: Combined hepatocholangiocarcinoma is a rare cancer with a grim prognosis composed of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma morphologic patterns in the same tumor. The aim of this multicenter, international cohort study was to compare the oncologic outcomes after surgery of combined hepatocholangiocarcinoma to hepatocellular carcinoma and intrahepatic cholangiocarcinoma., Methods: Patients treated by surgery for combined hepatocholangiocarcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma from 2000 to 2021 from multicenter international databases were analyzed retrospectively. Patients with combined hepatocholangiocarcinoma (cases) were compared with 2 control groups of hepatocellular carcinoma or intrahepatic cholangiocarcinoma, sequentially matched using a propensity score based on 8 preoperative characteristics. Overall and disease-free survival were compared, and predictors of mortality and recurrence were analyzed with Cox regression after propensity score matching., Results: During the study period, 3,196 patients were included. Propensity score adjustment and 2 sequential matching processes produced a new cohort (n = 244) comprising 3 balanced groups was obtained (combined hepatocholangiocarcinoma = 56, intrahepatic cholangiocarcinoma = 66, and hepatocellular carcinoma = 122). Kaplan-Meier overall survival estimations at 1, 3, and 5 years were 67%, 45%, and 28% for combined hepatocholangiocarcinoma, 92%, 75%, and 55% for hepatocellular carcinoma, and 86%, 53%, and 42% for the intrahepatic cholangiocarcinoma group, respectively (P = .0014). Estimations of disease-free survival at 1, 3, and 5 years were 51%, 25%, and 17% for combined hepatocholangiocarcinoma, 63%, 35%, and 26% for the hepatocellular carcinoma group, and 51%, 31%, and 28% for the intrahepatic cholangiocarcinoma group, respectively (P = .19). Predictors of mortality were combined hepatocholangiocarcinoma subtype, metabolic syndrome, preoperative tumor markers alpha-fetoprotein and carbohydrate antigen 19-9, and satellite nodules, and recurrence was associated with satellite nodules rather than cancer subtype., Conclusion: Despite data limitations, overall survival among patients with combined hepatocholangiocarcinoma was worse than both groups and closer intrahepatic cholangiocarcinoma, whereas disease-free survival was similar among the 3 groups. Future research on immunophenotypic profiling may hold more promise than traditional nonmodifiable clinical characteristics (as found in this study) in predicting recurrence or response to salvage treatments., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this issue, Lehmann et al. addresses the high infection risk in liver transplantation by examining the gut microbiome in a patient cohort. By uncovering a predictive role of the microbiome for the clinical course, the study unravels the gut microbiome as a guidepost for infection risk in liver transplantation., Competing Interests: Declaration of interests T.F.B. is founder, shareholder, and advisor of Alentis Therapeutics. T.F.B. has received grant support from Janssen, Aligos, and Alentis Therapeutics. T.F.B. is an inventor on approved patents and patent applications on monoclonal antibodies for treatment of fibrosis and cancer filed by Inserm, University of Strasbourg, and Alentis Therapeutics; patent applications for the use of prognostic liver gene signatures for discovery of liver disease therapeutics filed by Inserm, the University of Strasbourg, and Mount Sinai Hospital; and a patent application of epigenetics signatures to predict cancer risk in patients with liver disease filed by Inserm, the University of Strasbourg, IHU, and UTSW Dallas., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Liver resection is the mainstay for a curative treatment for patients with resectable hepatocellular carcinoma (HCC), also in elderly population. Despite this, the evaluation of patient condition, liver function and extent of disease remains a demanding process with the aim to reduce postoperative morbidity and mortality., Aim: To identify new perioperative risk factors that could be associated with higher 90- and 180-d mortality in elderly patients eligible for liver resection for HCC considering traditional perioperative risk scores and to develop a risk score., Methods: A multicentric, retrospective study was performed by reviewing the medical records of patients aged 70 years or older who electively underwent liver resection for HCC; several independent variables correlated with death from all causes at 90 and 180 d were studied. The coefficients of Cox regression proportional-hazards model for six-month mortality were rounded to the nearest integer to assign risk factors' weights and derive the scoring algorithm., Results: Multivariate analysis found variables (American Society of Anesthesiology score, high rate of comorbidities, Mayo end stage liver disease score and size of biggest lesion) that had independent correlations with increased 90- and 180-d mortality. A clinical risk score was developed with survival profiles., Conclusion: This score can aid in stratifying this population in order to assess who can benefit from surgical treatment in terms of postoperative mortality., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.

Aims: Training programs are essential to introduce new methods for bile duct clearance. Visual examination via cholangioscopy is ideal to diagnose and treat biliary tract diseases such as cancer and choledocholithiasis. However, surgeons rarely use cholangioscopes. Specific training is required to master laparoscopic and percutaneous cholangioscopy. This study aims to assess skill acquisition and retention during cholangioscopy training in the Image-Guided Therapies Masterclass., Methods: This prospective study enrolled 17 physicians undergoing training in interventional treatments of biliary diseases. A novel disposable cholangioscope and access kit were used with a biliary tract model including two simulated common bile duct (CBD) stones. The curriculum required visualization of all critical structures before removal of one stone with a Dormia basket. After informed consent, demographic data and time to exercise completion were recorded on each of two subsequent training days. Task-specific questions were measured at the completion of training using a Likert scale (strongly disagree to strongly agree, 1-5 points)., Results: All participants successfully completed the task (6F/11 M, age 36 ± 5 years; 13 surgeons, 4 interventional radiologists; median experience with percutaneous procedures 2 years, range 0-20). Significant improvement in mean task completion time was observed (day 1: 172 ± 59 s, day 2: 89 ± 45 s; P < 0.0001). All task-specific questions were answered with a median rating of 5/5: "The platform facilitates cholangioscopy" and "This training method accelerates gain in proficiency and is useful for residents/fellows" (IQR 5-5), "This platform is useful to measure the proficiency level" and "There is an application for simulation in percutaneous surgery training" (IQR 4.5-5), "The platform is user-friendly" and "The model quality recreates realistic scenarios" (IQR 4-5)., Conclusion: Cholangioscopic bile duct exploration and stone retrieval were achieved by all participants using a dedicated training program and physical simulator. Significant skill progress was observed during 2 days of dedicated training., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available., (© 2023. Springer Nature Limited.)

Background: A preoperative surgical strategy before hepatectomy for hepatocellular carcinoma is fundamental to minimize postoperative morbidity and mortality and to reach the best oncologic outcomes. Preoperative 3D reconstruction models may help to better choose the type of procedure to perform and possibly change the initially established plan based on conventional 2D imaging., Methods: A non-randomized multicenter prospective trial with 136 patients presenting with a resectable hepatocellular carcinoma who underwent open or minimally invasive liver resection. Measurement was based on the modification rate analysis between conventional 2D imaging (named "Plan A") and 3D model analysis ("Plan B"), and from Plan B to the final procedure performed (named "Plan C")., Results: The modification rate from Plan B to Plan C (18%) was less frequent than the modification from Plan A to Plan B (35%) (OR = 0.32 [0.15; 0.64]). Concerning secondary objectives, resection margins were underestimated in Plan B as compared to Plan C (-3.10 mm [-5.04; -1.15])., Conclusion: Preoperative 3D imaging is associated with a better prediction of the performed surgical procedure for liver resections in HCC, as compared to classical 2D imaging., (Copyright © 2022. Published by Elsevier Ltd.)

Background & Aims: Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored., Methods: Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC., Results: Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment., Conclusions: Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC., Impact and Implications: Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the diagnostic performance and inter-reader agreement of the CT-based v2019 versus v2005 Bosniak classification systems for risk stratification of cystic renal lesions (CRL)., Methods: This retrospective study included adult patients with CRL identified on CT scan between 2005 and 2018. The reference standard was histopathology or a minimum 4-year imaging follow-up. The studies were reviewed independently by five readers (three senior, two junior), blinded to pathology results and imaging follow-up, who assigned Bosniak categories based on the 2005 and 2019 versions. Diagnostic performance of v2005 and v2019 Bosniak classifications for distinguishing benign from malignant lesions was calculated by dichotomizing CRL into the potential for ablative therapy (III-IV) or conservative management (I-IIF). Inter-reader agreement was calculated using Light's Kappa., Results: One hundred thirty-nine patients with 149 CRL (33 malignant) were included. v2005 and v2019 Bosniak classifications achieved similar diagnostic performance with a sensitivity of 91% vs 91% and a specificity of 89% vs 88%, respectively. Inter-reader agreement for overall Bosniak category assignment was substantial for v2005 (κ = 0.78) and v2019 (κ = 0.75) between senior readers but decreased for v2019 when the Bosniak classification was dichotomized to conservative management (I-IIF) or ablative therapy (III-IV) (0.80 vs 0.71, respectively). For v2019, wall thickness was the morphological feature with the poorest inter-reader agreement (κ = 0.43 and 0.18 for senior and junior readers, respectively)., Conclusion: No significant improvement in diagnostic performance and inter-reader agreement was shown between v2005 and v2019. The observed decrease in inter-reader agreement in v2019 when dichotomized according to management strategy may reflect the more stringent morphological criteria., Key Points: • Versions 2005 and 2019 Bosniak classifications achieved similar diagnostic performance, but the specificity of higher risk categories (III and IV) was not increased while one malignant lesion was downgraded to v2019 Bosniak category II (i.e., not subjected to further follow-up). • Inter-reader agreement was similar between v2005 and v2019 but moderately decreased for v2019 when the Bosniak classification was dichotomized according to the potential need for ablative therapies (I-II-IIF vs III-IV)., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Minimally invasive surgery (MIS), including laparoscopic and robotic approaches, is widely adopted in elective digestive surgery, but selectively used for surgical emergencies. The present position paper summarizes the available evidence concerning the learning curve to achieve proficiency in emergency MIS and provides five expert opinion statements, which may form the basis for developing standardized curricula and training programs in emergency MIS., Methods: This position paper was conducted according to the World Society of Emergency Surgery methodology. A steering committee and an international expert panel were involved in the critical appraisal of the literature and the development of the consensus statements., Results: Thirteen studies regarding the learning curve in emergency MIS were selected. All but one study considered laparoscopic appendectomy. Only one study reported on emergency robotic surgery. In most of the studies, proficiency was achieved after an average of 30 procedures (range: 20-107) depending on the initial surgeon's experience. High heterogeneity was noted in the way the learning curve was assessed. The experts claim that further studies investigating learning curve processes in emergency MIS are needed. The emergency surgeon curriculum should include a progressive and adequate training based on simulation, supervised clinical practice (proctoring), and surgical fellowships. The results should be evaluated by adopting a credentialing system to ensure quality standards. Surgical proficiency should be maintained with a minimum caseload and constantly evaluated. Moreover, the training process should involve the entire surgical team to facilitate the surgeon's proficiency., Conclusions: Limited evidence exists concerning the learning process in laparoscopic and robotic emergency surgery. The proposed statements should be seen as a preliminary guide for the surgical community while stressing the need for further research., (© 2023. The Author(s).)

Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient's liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Ischemia-reperfusion injury during major hepatic resections is associated with high rates of post-operative complications and liver failure. Real-time intra-operative detection of liver dysfunction could provide great insight into clinical outcomes. In the present study, we demonstrate the intra-operative application of a novel optical technology, hyperspectral imaging (HSI), to predict short-term post-operative outcomes after major hepatectomy. We considered fifteen consecutive patients undergoing major hepatic resection for malignant liver lesions from January 2020 to June 2021. HSI measures included tissue water index (TWI), organ hemoglobin index (OHI), tissue oxygenation (StO 2 %), and near infrared (NIR). Pre-operative, intra-operative, and post-operative serum and clinical outcomes were collected. NIR values were higher in unhealthy liver tissue ( p = 0.003). StO 2 % negatively correlated with post-operative serum ALT values ( r = -0.602), while ΔStO 2 % positively correlated with ALP ( r = 0.594). TWI significantly correlated with post-operative reintervention and OHI with post-operative sepsis and liver failure. In conclusion, the HSI imaging system is accurate and precise in translating from pre-clinical to human studies in this first clinical trial. HSI indices are related to serum and outcome metrics. Further experimental and clinical studies are necessary to determine clinical value of this technology.

Purpose: The purpose of this study was to identify abdominal computed tomography (CT) features associated with underlying malignancy in patients with mesenteric panniculitis (MP)., Materials and Methods: This single-institution retrospective longitudinal cohort study included patients with MP and a minimum 1-year abdominopelvic CT follow-up or 2-year clinical follow-up after initial abdominopelvic CT examination. Two radiologists, blinded to patients' medical records, conjointly reviewed CT-based features of MP. Electronic medical records were reviewed for newly diagnosed malignancies with the following specific details: type (lymphoproliferative disease or solid malignancy), location (possible mesenteric drainage or distant), stage, time to diagnosis. An expert panel of three radiologists and one hemato-oncologist, who were blinded to the initial CT-based MP features, assessed the probability of association between MP and malignancy based on the malignancy characteristics., Results: From 2006 to 2016, 444 patients with MP were included. There were 272 men and 172 women, with a median age of 64 years (age range: 25-89); the median overall follow-up was 36 months (IQR: 22, 60; range: 12-170). A total of 34 (8%) patients had a diagnosis of a new malignancy; 5 (1%) were considered possibly related to the MP, all being low-grade B-cell non-Hodgkin lymphomas. CT features associated with the presence of an underlying malignancy were the presence of an MP soft-tissue nodule with a short axis >10 mm (P < 0.0001) or lymphadenopathy in another abdominopelvic region (P < 0.0001). Associating these two features resulted in high diagnostic performance (sensitivity 100%; [95% CI: 57-100]; specificity 99% [95% CI: 98-100]). All related malignancies were identified., Conclusion: Further workup to rule out an underlying malignancy is only necessary in the presence of an MP soft-tissue nodule >10 mm or associated abdominopelvic lymphadenopathy., Competing Interests: Conflict of Interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2022 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1 + dendritic cells and dysfunctional CD8 + T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

Introduction: Significant hepatocellular carcinoma (HCC) risk persists after chronic hepatitis C (CHC) cure. Preclinical studies have shown that erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has an antiviral activity and HCC chemopreventive effect. Erlotinib is metabolized in the liver, and its safety in patients with CHC is unknown. This study aimed to assess the safety and antiviral activity of erlotinib in patients with CHC., Methods: In this investigator-initiated dose-escalation phase Ib prospective randomized double-blind placebo-controlled study, noncirrhotic hepatitis C virus (HCV) patients received placebo or erlotinib (50 or 100 mg/d) for 14 days with a placebo-erlotinib ratio of 1:3. Primary end points were safety and viral load reduction at the end of treatment (EOT). The secondary end point was viral load reduction 14 days after EOT., Results: This study analyzed data of 3 patients receiving placebo, 3 patients receiving erlotinib 50 mg/d, and 3 patients receiving erlotinib 100 mg/d. One grade 3 adverse event was reported in the placebo group (liver enzymes elevation), leading to treatment discontinuation and patient replacement, and 1 in the erlotinib 100 mg/d group (pericarditis), which was not considered to be treatment-related. Grade 2 skin rash was observed in 1 erlotinib 100 mg/d patient. No significant HCV-RNA level reduction was noted during treatment, but 2 of the 3 patients in the erlotinib 100 mg/d group showed a decrease of >0.5 log HCV-RNA 14 days after EOT., Discussion: Erlotinib demonstrated to be safe in noncirrhotic CHC patients. An antiviral activity at 100 mg/d confirms a functional role of EGFR as an HCV host factor in patients. These results provide perspectives to further study erlotinib as an HCC chemopreventive agent in patients with CHC., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Chronic liver diseases, resulting from chronic injuries of various causes, lead to cirrhosis with life-threatening complications including liver failure, portal hypertension, hepatocellular carcinoma. A key unmet medical need is robust non-invasive biomarkers to predict patient outcome, stratify patients for risk of disease progression and monitor response to emerging therapies. Quantitative imaging biomarkers have already been developed, for instance, liver elastography for staging fibrosis or proton density fat fraction on magnetic resonance imaging for liver steatosis. Yet, major improvements, in the field of image acquisition and analysis, are still required to be able to accurately characterize the liver parenchyma, monitor its changes and predict any pejorative evolution across disease progression. Artificial intelligence has the potential to augment the exploitation of massive multi-parametric data to extract valuable information and achieve precision medicine. Machine learning algorithms have been developed to assess non-invasively certain histological characteristics of chronic liver diseases, including fibrosis and steatosis. Although still at an early stage of development, artificial intelligence-based imaging biomarkers provide novel opportunities to predict the risk of progression from early-stage chronic liver diseases toward cirrhosis-related complications, with the ultimate perspective of precision medicine. This review provides an overview of emerging quantitative imaging techniques and the application of artificial intelligence for biomarker discovery in chronic liver disease., (© 2022. Asian Pacific Association for the Study of the Liver.)

Objective: To distinguish benign from malignant cystic renal lesions (CRL) using a contrast-enhanced CT-based radiomics model and a clinical decision algorithm., Methods: This dual-center retrospective study included patients over 18 years old with CRL between 2005 and 2018. The reference standard was histopathology or 4-year imaging follow-up. Training and testing datasets were acquired from two institutions. Quantitative 3D radiomics analyses were performed on nephrographic phase CT images. Ten-fold cross-validated LASSO regression was applied to the training dataset to identify the most discriminative features. A logistic regression model was trained to classify malignancy and tested on the independent dataset. Reported metrics included areas under the receiver operating characteristic curves (AUC) and balanced accuracy. Decision curve analysis for stratifying patients for surgery was performed in the testing dataset. A decision algorithm was built by combining consensus radiological readings of Bosniak categories and radiomics-based risks., Results: A total of 149 CRL (139 patients; 65 years [56-72]) were included in the training dataset-35 Bosniak(B)-IIF (8.6% malignancy), 23 B-III (43.5%), and 23 B-IV (87.0%)-and 50 CRL (46 patients; 61 years [51-68]) in the testing dataset-12 B-IIF (8.3%), 10 B-III (60.0%), and 9 B-IV (100%). The machine learning model achieved high diagnostic performance in predicting malignancy in the testing dataset (AUC = 0.96; balanced accuracy = 94%). There was a net benefit across threshold probabilities in using the clinical decision algorithm over management guidelines based on Bosniak categories., Conclusion: CT-based radiomics modeling accurately distinguished benign from malignant CRL, outperforming the Bosniak classification. The decision algorithm best stratified lesions for surgery and active surveillance., Key Points: • The radiomics model achieved excellent diagnostic performance in identifying malignant cystic renal lesions in an independent testing dataset (AUC = 0.96). • The machine learning-enhanced decision algorithm outperformed the management guidelines based on the Bosniak classification for stratifying patients to surgical ablation or active surveillance., (© 2021. The Author(s), under exclusive licence to European Society of Radiology.)

Background and Aims: Coronavirus disease 2019 (COVID-19) is a serious public health issue that became rapidly pandemic. Liver injury and comorbidities, including metabolic syndrome, are associated with severe forms of the disease. This study sought to investigate liver injury, clinical features, and risk factors in patients with mild, moderate, and severe COVID-19., Methods: We retrospectively included all consecutive patients hospitalized with laboratory-confirmed COVID-19 between February, 22 and May 15, 2020 at the emergency rooms of a French tertiary hospital. Medical history, symptoms, biological and imaging data were collected., Results: Among the 1381 hospitalizations for COVID-19, 719 patients underwent liver tests on admission and 496 (68.9%) patients displayed abnormal liver tests. Aspartate aminotransferase was most commonly abnormal in 57% of cases, followed by gamma-glutamyl transferase, alanine aminotransferase, albumin, alkaline phosphatase, and total bilirubin in 56.5%, 35.9%, 18.4%, 11.4%, and 5.8%. The presence of hepatocellular type more than 2xULN was associated with a higher risk of hospitalization and a worse course of severe disease (odd ratio [OR] 5.599; 95%CI: 1.27-23.86; p = 0.021; OR 3.404; 95% CI: 2.12-5.47; p < 0.001, respectively). A higher NAFLD fibrosis score was associated with a higher risk of hospitalization (OR 1.754; 95%CI: 1.27-2.43, p < 0.001). In multivariate analyses, patients with high fibrosis-4 index had a 3-fold greater risk of severe disease (p < 0.001)., Conclusion: Abnormal liver tests are common in patients with COVID-19 and could predict the outcome. Patients with non-alcoholic fatty liver disease and liver fibrosis are at higher risk of progressing to severe COVID-19., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background & Aims: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression., Methods: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122)., Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients., Conclusion: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Portal hypertension (PH) is one of the most severe complications of chronic liver diseases. It is defined as an increase in pressure in the portal venous system which results in a portosystemic gradient >5 mmHg. In the western world, cirrhosis is the most frequent cause of PH, mainly due to nonalcoholic fatty liver disease and alcoholic liver disease. Patients with PH have esophageal varices in 68-73% of cases, portal hypertensive gastropathy in 51-73% and hyperplastic polyps (HPs) in 0.9-2%. Recent studies have shown that HPs found in PH patients are different from classical HPs. They constitute a new entity called portal hypertensive polyps (PHPs). The main difference between sporadic HPs and PHP is the presence of larger and more numerous vascular capillaries in the lamina propria. The clinical course of PHPs is unknown. Their physiopathology seems different from HPs: the increased congestion caused by higher portal pressure in the stomach may induce capillaries proliferation and neoangiogenesis. PHPs may be responsible for symptoms, such as pyloric obstruction, iron deficiency and anemia. Their prevalence in portal hypertensive and cirrhotic patients is from 1% to 8%. PHPs can be single or numerous, in the antrum or the gastric corpus. Their size ranges from 2 to 3 cm. PHPs seem to disappear or shrink with the treatment of PH. They should be resected in case of symptom and if >10 mm, after Helicobacter pylori eradication if present. However, their recurrence is frequent (40-79%), thus surveillance endoscopy is mandatory, at the same time as esophageal varices., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)