Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in the gallbladder, help the absorption/processing of lipids, and modulate host inflammatory responses and gut microbiota (GM) composition. The latter is the new “actor” that links the GI tract and liver in NAFLD pathogenesis. In fact, the discovery and mechanistic characterization of hepatic and intestinal farnesoid X receptor (FXR) shed new light on the gut–liver axis. We conducted a search on the main medical databases for original articles, reviews, meta-analyses of randomized clinical trials, and case series using the following keywords, their acronyms, and their associations: farnesoid X receptor, bile acids metabolism, gut microbiota, dysbiosis, and liver steatosis. Findings on the synthesis, metabolism, and conjugation processes of BAs, and their action on FXR, change the understanding of NAFLD physiopathology. In detail, BAs act as ligands to several FXRs with GM modulation. On the other hand, the BAs pool is modulated by GM, thus, regulating FXRs functioning in the frame of liver fat deposition and fibrosis development. In conclusion, BAs passed from their role of simple lipid absorption and metabolism agents to messengers between the gut and liver, modulated by GM.

Cholangiocarcinoma (CCA) is an aggressive neoplasia with an increasing incidence and mortality. It is characterized by a strong desmoplastic stroma surrounding cancer cells. Cancer-associated fibroblasts (CAFs) are the main cell type of CCA stroma and they have an important role in modulating cancer microenvironments. CAFs originate from multiple lines of cells and mainly consist of fibroblasts and alpha-smooth muscle actin (α-SMA) positive myofibroblast-like cells. The continuous cross-talking between CCA cells and desmoplastic stroma is permitted by CAF biochemical signals, which modulate a number of pathways. Stromal cell-derived factor-1 expression increases CAF recruitment to the tumor reactive stroma and influences apoptotic pathways. The Bcl-2 family protein enhances susceptibility to CAF apoptosis and PDGFRβ induces fibroblast migration and stimulates tumor lymphangiogenesis. Many factors related to CAFs may influence CCA prognosis. For instance, a better prognosis is associated with IL-33 expression and low stromal IL-6 (whose secretion is stimulated by microRNA). In contrast, a worst prognosis is given by the expression of PDGF-D, podoplanin, SDF-1, α-SMA high expression, and periostin. The maturity phenotype has a prognostic relevance too. New therapeutic strategies involving CAFs are currently under study. Promising results are obtained with anti-PlGF therapy, nintedanib (BIBF1120), navitoclax, IPI-926, resveratrol, and controlled hyperthermia.

Endoscopic resection can be challenging for large nonpedunculated colorectal polyps (LNPCPs) around the appendiceal orifice. Factors predicting failure of endoscopic mucosal resection (EMR) include deep invasion of the appendiceal orifice and >50% involvement of the appendiceal orifice. In contrast, patients with a previous appendectomy are often able to undergo complete resection using EMR for LNPCPs that completely cover the prior appendiceal orifice [1]. Unfortunately, it is often difficult to tell upfront which of these factors is present in a given LNPCP. Other options include full-thickness resection, which carries a 25% risk of acute appendicitis and is not suitable for large lesions [2]. Surgery may also be considered, but an extended appendectomy is often insufficient for lesions extending into the cecum. More extensive surgery, such as ileocecal resection or right hemicolectomy, carry significant risks, including 20% morbidity and 0.5% mortality [3]. This case series ([Video 1]) demonstrates endoscopic submucosal dissection (ESD) for peri-appendiceal LNPCPs showing type 3a, 1, and 3 lesions according to Toyonaga’s classification [3]. Other studies have described the ESD technique for LNPCPs of the appendiceal orifice using both traction-assisted and nontraction methods [3] [4] [5]. However, none have described a combined approach using multipoint traction with saline immersion. In this case series, multipoint traction, using a multiband system ([Fig. 1]), is applied to lift the appendix and expose the submucosal plane between the appendiceal mucosa and muscularis propria ([Video 1]) for precise dissection. Saline immersion is used intermittently to improve visualization and access to the dissection plane ([Fig. 2]). In contrast to EMR, even lesions with deep invasion into the appendiceal orifice can be fully resected using this ESD-based technique as the caudal appendiceal margin can be visualized and the depth of mucosal incision within the appendix completely controlled. Furthermore, lesions fully encircling the orifice can also be completely removed. In conclusion, using traction-assisted ESD with intermittent saline immersion, the skilled practitioner can avoid the pitfalls of EMR while avoiding the excess risks of full-thickness resection and laparoscopic surgery. Endoscopy_UCTN_Code_TTT_1AQ_2AD_3AD Article published online: 20 February 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

Unresectable extrahepatic cholangiocarcinoma remains a challenging malignancy with limited therapeutic options and poor prognosis. In this setting, effective and durable biliary drainage is crucial to prevent cholangitis, allow timely initiation and maintenance of systemic therapy, and ultimately improve survival. Endobiliary radiofrequency ablation (RFA) has emerged as a promising adjunct to biliary stenting, aimed at delaying tumor ingrowth and prolonging stent patency through localized thermal ablation of malignant tissue. Several studies have reported longer stent patency and, in some cases, improved survival with RFA plus stenting compared with stenting alone. However, the literature remains heterogeneous, and recent high-quality trials have yielded conflicting results, highlighting the need for further standardization of technique and patient selection. This narrative review summarizes the current evidence on the role of endobiliary RFA in unresectable cholangiocarcinoma, with particular emphasis on mechanism of action, endoscopic technique and oncologic outcomes.

Endobiliary radiofrequency ablation (RFA) has emerged as a promising adjunct to biliary stenting in the palliative management of unresectable extrahepatic cholangiocarcinoma. By generating localized thermal injury through a high-frequency alternating current (400–500 kHz) delivered via an intraductal electrode, RFA induces coagulative necrosis of malignant tissue, aiming to delay tumor ingrowth, maintain ductal patency, and improve quality of life. The procedure can be performed during endoscopic retrograde cholangiopancreatography or percutaneously, using bipolar probes advanced over a guidewire under fluoroscopic control. Technical success depends on adequate positioning of the electrodes within the stricture, correct energy settings (7–10 W for 60–120 s), and appropriate stent selection. Preclinical studies demonstrated controlled necrosis extending through the bile-duct wall, while clinical investigations have evaluated its impact on outcomes. Early retrospective series and several randomized controlled trials showed that RFA combined with stenting prolongs stent patency and, in selected subgroups, improves survival compared with stenting alone, without increasing the overall rate of complications. Meta-analyses have confirmed a consistent benefit in stent function and a moderate survival advantage, particularly in distal malignant strictures, although results remain heterogeneous due to differences in technique, patient selection, and stent type. The most frequent adverse events are cholangitis, pancreatitis, and acute cholecystitis. Overall, endobiliary RFA is a safe, technically feasible, and clinically relevant option to enhance biliary drainage in advanced cholangiocarcinoma. Standardization of procedural parameters and prospective trials are still needed to better define its therapeutic role and identify patients most likely to benefit.