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Background & Aims: Liver stiffness measurement (LSM) has been shown to adequately predict outcomes in patients with liver disease. However, the value of LSM as a predictor of disease progression in autoimmune hepatitis (AIH) remains to be determined. This study aimed to evaluate the role of LSM as a predictor of disease progression and decompensation of cirrhosis in patients with AIH. Methods: This multicentre cohort study included 439 patients with histologically confirmed AIH and at least one LSM during follow-up. The association between the first LSM performed at least 6 months after treatment initiation (baseline LSM [BLSM]) and cirrhosis development and poor outcomes (decompensation, liver transplantation, and/or liver-related death) was assessed using Cox regression and its discriminating capacity with a receiver-operating characteristic curve. Results: Most patients were female (n = 301, 70%), with a median age of 52 years. BLSM performed after a median of 2.18 (1.19-4.68) years had a median value of 6 kPa (4.5-8.5). At the time of BLSM, 332 (76%) patients had achieved a biochemical response and 57 (13%) had cirrhosis. During follow-up, eight patients (2%) presented with poor outcomes and 26 (7%) developed cirrhosis. BLSM was higher among patients with poor outcomes (13.5 kPa vs. 6 kPa; p

Introduction and Objectives: Different patterns of liver injury have been reported in association with the SARS-CoV-2 vaccines. The aim of this study was to describe a nationwide cohort of patients with SARS CoV-2 vaccine-induced liver injury, focusing on treatment and the evolution after further booster administration. Patients and Methods: multicentre, retrospective-prospective study, including subjects who developed abnormal liver tests within 90 days after administration of SARS-CoV-2 vaccination. Results: 47 cases were collected: 17 after prime dose and 30 after booster. Age was 57 years, 30 (63.8 %) were female, and 7 (14.9 %) had a history of prior autoimmune hepatitis (AIH). Most cases were non-severe, though 9 (19.1 %) developed acute liver injury or failure (ALF). Liver injury tended to be more severe in those presenting after a booster (p=0.084). Pattern of liver injury was hepatocellular (80.9 %), mixed (12.8 %) and 3 (6.4 %) cholestatic. Liver biopsy was performed on 33 patients; 29 showed findings of AIH. Forty-one (87.2 %) patients received immunosuppressants, mostly corticosteroids (35/41). One required liver transplantation and another died due to ALF. Immunosuppression was discontinued in 6/41 patients without later rebound. Twenty-five subjects received at least one booster and 7 (28.0 %) relapsed from the liver injury, but all were non-severe. Recurrence was less frequent among patients on immunosuppressants at booster administration (28.6 % vs. 88.9 %, p=0.007). Conclusions: SARS CoV-2 vaccine-induced liver injury is heterogeneous but mostly immune-mediated. Relapse of liver injury after re-exposure to vaccine is frequent (28.0 %) but mild. Immunosuppression at booster administration is associated with a lower risk of liver injury.

Introduction: Acute lymphoblastic leukemia (ALL) is a prevalent childhood cancer with high cure rate, but poses a significant medical challenge in adults and relapsed patients. Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype, with approximately half of cases characterized by CRLF2 overexpression and frequent concomitant IKZF1 deletions.Methods: To address the need for efficient, rapid, and cost-effective detection of CRLF2 alterations, we developed a novel RT-qPCR technique combining SYBR Green and highresolution melting analysis on a single plate.Results: The method successfully identified CRLF2 expression, P2RY8::CRLF2 fusions, and CRLF2 and JAK2 variants, achieving a 100% sensitivity and specificity. Application of this method across 61 samples revealed that 24.59% exhibited CRLF2 overexpression, predominantly driven by IGH::CRLF2 (73.33%). High Resolution Melting analysis unveiled concurrent CRLF2 or JAK2 variants in 8.19% of samples, as well as a dynamic nature of CRLF2 alterations during disease progression.Discussion: Overall, this approach provides an accurate identification of CRLF2 alterations, enabling improved diagnostic and facilitating therapeutic decision-making.

Gastrointestinal adverse events (GIAEs) are common in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Diarrhea is a prevalent event responsible for treatment interruptions and dosage modifications. Our study evaluates the role of baseline blood L-glutamine (L-Gln) levels in the prediction of gastrointestinal adverse events development early during treatment (eGIAE). Blood L-Gln was measured in 135 patients with advanced HCC prior to starting sorafenib. Any adverse events developed during therapy were registered in a prospective database. We used Mann–Whitney U and Fisher’s exact tests to compare quantitative or categorical variables, respectively, Kaplan–Meier method to analyze time to event variables, log-rank test for the survival functions and Cox regression models to estimate hazard ratios (HR). Fifteen per cent of patients developed eGIAE, with diarrhea as the most frequent one. Patients displaying the lowest L-Gln levels presented a significant higher risk of eGIAE, while those with the highest levels were protected from eGIAE and achieved better survival. Our study shows for the first time the association of baseline blood L-Gln levels with eGIAE development in HCC patients during sorafenib treatment. Low L-Gln concentrations might reflect a potentially compromised intestinal barrier that becomes clinically relevant early after treatment start.

Background: Cholangiocarcinoma (CCA) encompasses a heterogeneous group of malignant tumors with dismal prognosis and increasing incidence worldwide. Both late diagnosis due to the lack of early symptoms and the refractory nature of these tumors seriously compromise patients’ welfare and outcomes. Summary: During the last decade, immunotherapy and, more specifically, modulation of immune checkpoints-mediated signaling pathways have been under the spotlight in the field of oncology, emerging as a potential therapeutic approach for the treatment of several cancers, including CCA. Generally, high expression levels of immune checkpoints in patients with CCA have been associated with worse clinical outcomes, particularly with shorter overall survival and relapse-free survival. Thus, immune checkpoint inhibitors (ICIs), which mainly constitute different monoclonal antibodies, have been developed in order to hamper the immune checkpoint-mediated pathways. Interestingly, chemotherapy may increase the expression of immune checkpoints, while other therapeutic approaches such as ablative and targeted therapies may enhance their antitumor activity. In this sense, several clinical trials evaluated the safety and efficacy of ICIs for CCA, both as a monotherapy and in combination with other ICIs or loco-regional and systemic therapies. Additionally, many other clinical trials are currently ongoing and results are eagerly awaited. Here, we summarize the key aspects of immune checkpoint molecules as prognostic factors and therapeutic targets in CCA, highlighting the most recent advances in the field and future research directions. Key Messages: (1) Effective therapeutic approaches for CCA are urgently needed. (2) Expression levels of immune checkpoints in patients with CCA have been proposed to be related with clinical outcomes. (3) Combination of different ICIs may outperform the efficacy of ICI monotherapy for CCA treatment. (4) Recent studies point toward the combination of ICIs and other common therapies, especially chemotherapy, as a promising strategy for treatment of CCA patients.

Summary: The management of hepatocellular carcinoma (HCC) has evolved considerably over the last decade. Surveillance of cirrhotic patients and refinements to imaging techniques have enabled a relevant proportion of patients to be diagnosed at an early stage, when effective therapies are feasible. Resection, transplantation and ablation are all options in patients with early stage HCC. Thus, there is some controversy regarding which is the best treatment approach in challenging scenarios. There have also been major developments in locoregional therapies, particularly in intra-arterial approaches. Finally, the systemic treatment for HCC has changed dramatically following the demonstration of a survival benefit with sorafenib; there are currently several first-line (sorafenib and lenvatinib) and second-line (regorafenib, cabozantinib and ramucirumab) treatments that have shown a survival benefit. Expectations for immune checkpoint inhibitors are high, with the results of the ongoing phase III trials eagerly awaited. In this review we discuss some of the controversies in the management of HCC, focussing in particular on systemic therapy. Keywords: Hepatocelullar carcinoma, Diagnosis, Surgery, Liver transplantation, Locoregional therapy, Systemic therapy

This is an updated review of screening, early diagnosis and treatment of hepatocellular carcinoma, focusing on the advancements occurred in the last years and highlighting the challenges in clinical research. Hepatocellular carcinoma (HCC) is nowadays the sixth most frequent cancer worldwide with up to 740,000 new cases diagnosed each year, and it is the third most prevalent cause of cancer-related-death worldwide (1). This neoplasm usually appears linked to an underlying liver disease, being one of the most relevant causes of death in patients diagnosed of liver cirrhosis (2,3). In the last years, important advancements in terms of diagnosis, staging and treatment of HCC, improving the management and outcome of the disease, have been made (4-7). Despite the fact that these improvements have absolutely changed natural history of HCC, there are several areas that still need further advancements. The aim of this document is to discuss some controversial aspects, which in our opinion constitute real challenges in clinical research of HCC.