Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child–Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy.

Introduction: Proton pump inhibitors (PPIs) are one of the most prescribed classes of drugs worldwide as a first-line treatment of acid-related disorders. Although adverse effects are rare and rapidly reversible after a short exposure, concerns have been recently raised about a greater toxicity on cardiovascular health after a longer exposure, especially when combined with clopidogrel. We aimed to evaluate the safety of long-term PPI use on cardiovascular health in patients with known atheromatous cardiovascular disease. Methods: A literature search was conducted in the PubMed, Embase, and Cochrane Library databases and grey literature in April 2022. Articles published between 2014 and 2022 were considered relevant if they were designed as randomized controlled trials (RCTs) that included post hoc analyses or prospective observational studies and if they investigated clinical cardiovascular outcomes associated with PPI use for 6 months or more in patients suffering from cardiovascular disease requiring antiplatelet agent therapy and/or coronary angioplasty. Statistical analyses were performed using RevMan 5.4 software (Computer program, the Cochrane Collaboration, 2020, London, UK). The risk of bias was assessed using the Cochrane risk-of-bias tool for the RCTs and the Newcastle–Ottawa scale for the observational studies. Results: A total of 10 full-text articles involving 53,302 patients were included. Substantial heterogeneity was found among the 10 included studies. The primary analysis showed no significant differences between the PPI group and the control group for the risks of major adverse cardiovascular events (MACEs), all-cause death (ACD), or target vessel revascularization (TVR) using a random-effects model (OR 1.15, 95% CI 0.98–1.35, p = 0.08, I² = 73%; OR 1.24, 95% CI 0.94–1.65, p = 0.13, I² = 63%; and OR 1.19, 95% CI 0.76–1.87, p = 0.45, I² = 61%, respectively). The primary analysis yielded similar results for the risks of myocardial infarction (MI), stroke, and cardiovascular death (CVD) using a fixed-effects model (OR 0.98, 95% CI 0.88–1.09, p = 0.66, I² = 0%; OR 1.02, 95% CI 0.90–1.17, p = 0.73, I² = 0%; and OR 1.04, 95% CI 0.94–1.16, p = 0.44, I² = 35%, respectively). Likewise, a subgroup analysis based on eight randomized controlled trials failed to identify any association between PPI use and the risks of MACEs, MI, stroke, TVR, ACD, or CVD using a fixed-effects model (overall pooled OR 1.01, 95% CI 0.96–1.06; p = 0.66; I² = 0%). The pulled data from the two included observational studies (OS) demonstrated a significantly increased risk of MACEs in the PPI group (OR 1.42, 95% CI [1.29–1.57], p <0.001; I² = 0%). In another subgroup analysis, no evidence of an increased risk of adverse cardiovascular events in the co-therapy PPI/clopidogrel versus clopidogrel alone groups was found with the exception of the risk of ACD (OR 1.50, 95% CI 1.23–1.82, p = 0.001, I² = 0%). Nevertheless, after performing a sensitivity analysis reaching heterogeneity I² = 0%, the co-prescription of PPIs and clopidogrel was at increased risk of MACEs (p < 0.001), CVD (p = 0.008), and TVR (p < 0.001) but remained statistically non-significant for the risk of MI (p = 0.11). Conclusions: The overall results of this meta-analysis showed that long-term PPI use was not associated with an increased risk of adverse cardiovascular events. However, inconsistent results were found for combined PPI/clopidogrel therapy. These results should be considered with caution in light of the significant heterogeneity, the limited number of included studies, and the lack of adjustment for potential confounders.

The management of bile duct injuries (BDIs) involves endoscopic and radiologic interventions, with surgery reserved for complex cases [1]. We present two cases of BDI managed with endoscopic ultrasound-guided hepaticoduodenostomy (EUS-HDS). Case 1: A 77-year-old patient underwent a cholecystectomy complicated by an injury to the common bile duct. A surgical choledochoduodenostomy was performed. One year later, the patient developed cholestasis due to a strictured anastomosis. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous biliary drainage failed to traverse the anastomosis. EUS-hepaticogastrostomy was performed. Two weeks later, a nasobiliary catheter through the hepaticogastrostomy was used to distend the common hepatic duct (CHD) with normal saline. Linear EUS, from the duodenal bulb, enabled CHD puncture. A guidewire was advanced into the hepatic duct, followed by insertion of a 6-Fr cystotome and a 4-cm covered biliary stent ([Video 1]). No complications occurred. The stent was later replaced with double-pigtail stents, exchanged every three months, over one year. Case 2: A 75-year-old patient had a BDI (Strasberg D) during cholecystectomy, managed with surgical hepaticoduodenal anastomosis. Six months later, cholestasis and dilation of right hepatic ducts (RHDs) were noted ([Fig. 1]). During endoscopic retrograde cholangiopancreatography, cannulation of the surgical anastomosis revealed exclusive drainage of the left hepatic ducts. A percutaneous drain with cholangioscopic assistance also failed to traverse the anastomosis. The RHDs were likely excluded. A percutaneous drain was placed for RHD distension. Under EUS guidance, the RHDs were punctured with a 19G needle. The hepaticoduodenal tract was dilated with a cystotome and a 6-mm balloon. Two double-pigtail stents were subsequently placed through the hepatobiliary tract orifice and exchanged every three months for one year ([Fig. 2]). We presented two cases of successful bile duct reconstruction using EUS-HDS after failed endoscopic and percutaneous interventions. This technique offers a minimally invasive alternative to surgical reconstruction in complex BDI. Larger series are still needed to assess the role of EUS-HDS in this indication. Endoscopy_UCTN_Code_TTT_1AQ_2AZ Article published online: 09 September 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/). Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Aims Zenker's diverticulum usually presents in the elderly population with symptoms of dysphagia. The endoscopic diverticulotomy can be performed using either cap or diverticuloscope assistance. The abandonment of the diverticuloscope for the treatment of diverticula allows to perform a complete septotomy of the diverticular wall in particular in the case of large diverticula (greater than 5 cm). The aim of this study was to evaluate the safety and feasibility of complete septotomy in the setting of large Zenker's diverticula. Methods We conducted a retrospective analysis that included all patients who had endoscopic septotomy for large Zenker diverticulum (greater than 5 cm) between January 2014 and November 2020. The procedure was performed under general anesthesia using a gastroscope with a cap assistance. The complete incision of the diverticulum septum was achieved using a Dual or TT knife, until complete effacement of the diverticulum. The short and medium term clinical results were collected. The clinical success rate was defined as the absence of regurgitation or dysphagia-like symptoms. Results 105 patients have been treated endoscopically for Zenker's diverticulum. Twelve patients had large diverticula. The mean size of the diverticula was 6+/- 1.15 cm. The clinical success rate was 100% and the complication rate was 8%. After a median follow-up of 12.5 months, the clinical success rate was 92% in ITT and 100% in per protocol. Conclusions Complete endoscopic septotomy seems to be an interesting approach for the treatment of large diverticula with a high clinical success rate and low rate of morbidity. Publication Date: 14 April 2022 (online) © 2022. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany