Hepatobiliary Research Articles

Influence of Perineural (Pn), Lymphangio (L) and Vascular (V) Invasion on Survival after Resection of Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma is a rare malignancy of the biliary tract, for which surgery remains the treatment of choice. However, even after radical resection, the prognosis is poor. In addition to tumor size, depth of invasion and nodal/metastatic status, the TNM classification includes additional parameters such as perineural (Pn), lymphangio (L) and vascular (V) invasion. The prognostic impact of these factors is not yet fully understood. The aim of this study was to investigate the influence of these parameters on overall survival after resection of perihilar cholangiocarcinoma. Data from all patients who underwent surgical exploration for perihilar cholangiocarcinoma between January 2013 and December 2023 were included into an institutional database. The impact of perineural, lymphangio and vascular invasion on overall survival was analyzed. Over the 11-year period, a total of 214 patients underwent surgical exploration for perihilar cholangiocarcinoma. Curative intended resection was possible in 168 patients (78.5%). Perineural invasion, lymphangio invasion and vascular invasion were present in 79.2%, in 17.3% and in 14.3% of patients, respectively. Cross tabulation revealed a significant association between the presence of L1 and V1 (p = 0.006). There was also a significant association of Pn1, L1, and V1 with R-status (p = 0.010; p = 0.006 and p ≤ 0.001). While V1 was associated with significantly worse overall survival across the entire cohort, Pn1 alone showed only a tendency towards worse overall survival without reaching statistical significance. In Bismuth type IV, both L1 and V1, but not Pn1, were significantly associated with worse overall survival (p = 0.001; p = 0.017 and p = 0.065). Perineural invasion is very common in perihilar cholangiocarcinoma. Although Pn1 was associated with a tendency toward worse survival, it did not reach statistical significance. In contrast, vascular invasion significantly worsened overall survival in the entire cohort, and lymphangio invasion was linked to worse overall survival in Bismuth type IV tumors. The combination of perineural invasion with positivity of more than one additional factor (either L or V) was also associated with worse overall survival. In patients with Bismuth type IV, these pathological markers appeared to have even greater prognostic relevance.

Anatomical Evaluation of the Biliary System of Living Liver Donors using Pre-Operative Non-Enhanced MRCP in Comparison to Intra-Operative Cholangiogram

Anatomical Evaluation of the Biliary System of Living Liver Donors using Pre-Operative Non-Enhanced MRCP in Comparison to Intra-Operative Cholangiogram

Endoscopic or combined management of post-surgical biliary leaks: a two-center recent experience.

Post-surgical biliary leaks (PSBL) are one of the most prevalent and significant adverse events emerging after liver or biliary tract surgeries. Endoscopic retrograde cholangiopancreatography (ERCP) alone or combined with another approach (Rendez Vous) as treatment of PSBL obtains optimal outcomes due to the possibility of modifying the resistances in the biliary tree. A retrospective double-center study was conducted in two tertiary centers. Consecutive patients who underwent at least one attempt of PSBL correction by ERCP or Rendez Vous procedure between January 2018 and August 2023 were included. The primary outcome was overall endoscopic clinical success. In contrast, the secondary outcomes were hospital stay exceeding five days and endoscopic clinical success with the first endoscopic procedure at the tertiary center. Both univariate and multivariate analyses were used to assess outcomes. 65 patients were included. Patients with one or multiple) leaks had more possibility to achieve the endoscopic clinical success compared to those affected by the association of leaks and stricture (96% vs 67%, p value 0.005). Leaks occurring in the main biliary duct had less probability (67%) to achieve the overall endoscopic clinical success compared to those in the end-to-end anastomosis (90%), in the resection plane or biliary stump (96%) or first or secondary order biliary branches (100%, p value 0.038). A leak-bridging stent positioning had more probability of achieving the endoscopic clinical success than a not leak-bridging stent (91% vs 53%, p value 0.005). ERCP and Rendez Vous procedures are safe and effective for treating PSBL, regardless of the type of preceding surgery, even if technical or clinical success was not achieved on the first attempt. A stent should be placed, if feasible, leak-bridging to enhance treatment efficacy.

Cultured Bacteria Isolated from Primary Sclerosing Cholangitis Patient Bile Induce Inflammation and Cell Death.

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammation and progressive fibrosis of the biliary tree. The pathogenesis of PSC remains poorly understood, and there are no effective therapeutic options. Previous studies have observed associations between changes in the colonic and biliary microbiome and PSC. We aimed to determine whether bacterial isolates cultured from PSC patient bile induced disease-associated phenotypes in cells. Bile was collected from PSC patients (n=10) by endoscopic retrograde cholangiography and from non-PSC controls (n=3) undergoing cholecystectomies. Biliary bacteria were cultured anaerobically, and 50 colonies per sample were identified by 16S rRNA sequencing. The effects of supernatants from seven PSC-associated bacterial strains on cellular phenotypes were characterized using human colonic (Caco-2), hepatic (HepG2), and biliary (EGI-1) cells. No bacteria were isolated from non-PSC controls, while bacteria were cultured from most PSC patients. The PSC bile microbiomes exhibited reduced diversity compared to the gut or oral cavity, with one or two bacterial strains predominating. Overall, PSC-associated bacteria produced factors that were cytotoxic to hepatic and biliary cells. Enterococcus faecalis , and to a lesser extent Veillonella parvula , induced epithelial permeability, while Escherichia coli, Fusobacterium necrophorum , and Klebsiella pneumoniae induced inflammatory cytokines in biliary cells. Our data suggest that bacteria cultured from PSC bile induce cellular changes that may contribute to PSC disease pathogenesis. Enterococcus may promote intestinal permeability, facilitating bacterial migration to the biliary tree. Once there, Escherichia, Fusobacterium and Klebsiella , may cause inflammation and damage in biliary and liver cells.

Injection of carbon dioxide instead of iodinated contrast to display the common bile duct during endoscopic retrograde cholangiopancreatography.

Common bile duct (CBD) stones are usually caused by biliary tract infection, biliary stricture, duodenal peripapillary diverticulum, Oddis sphincter dysfunction, and so on. Treatment is preferably with endoscopic retrograde cholangiopancreatography (ERCP), where an iodine-containing contrast agent is injected into the CBD to display the stone under fluoroscopy and then to confirm complete removal of the stone(s). We described a 65-year-old woman with CBD stones who had undergone cardiac pacemaker implantation and was allergic to iodinated contrast media. We performed ERCP + lithotomy + stent implantation under local anesthesia, with injection of carbon dioxide instead of iodinated contrast into the CBD, and successfully visualized the stones under fluoroscopy and then confirmed complete removal of them. The patient was generally in good condition without complications. Thus, we have demonstrated in this case report that carbon dioxide can be used as a safe, economical, and effective alternative to iodinated contrast agent during ERCP.

Interplay of Cardiometabolic Syndrome and Biliary Tract Cancer: A Comprehensive Analysis with Gender-Specific Insights.

BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC.

Integration of circulating tumor DNA in biliary tract cancer: the emerging landscape

Integration of circulating tumor DNA in biliary tract cancer: the emerging landscape

Altering Trends in Pathological Spectrum of Cholecystectomy Specimen: Time to be More Vigilant

Abstract Background: Gall bladder cancer is a rare, most common and aggressive malignancy of the biliary tree, accounting for 80%–90% of biliary tract cancers. Gallstones are one of the major causes of the development of cholecystitis and long-term malignancy in developing countries. Cholecystectomy specimens have a great value in documenting various entities with clinical significance. Early detection is the most important step in improving the prognosis of gall bladder carcinoma (GBC) screening. Aim: Clinico- pathological spectrum of cholecystectomy specimen and Incidence of malignancy and its precursor lesion with gallstones. Patient and Methods: We conducted a retrospective analysis of all gall bladder specimens (cholecystectomy, laparoscopic, open or radical) from the period of January 2019–January 2022, including demographic data of the patients such as age and sex. Additional findings, such as the presence of gallstones, cholesterolosis, gastric or intestinal metaplasia, dysplasia and histopathological type of GBC, were documented. Results: A total of 1221 gall bladder specimens were received, with a higher female preponderance and a female-to-male ratio of 2.6:1. The mean age of presentation was 45 years. The most common histopathological diagnosis made was chronic cholecystitis (97%), and malignant cases accounted for 3% of the total cases. Conclusions: The high propensity of GBC with non-cholelithiasis cases, more than half of cases with metaplasia and increased incidence of adenosquamous carcinoma indicate a high burden of tumours, alerting the clinician as well as the pathologist.

Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab.

Biliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer ( NCT04057365 ). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials.

Durvalumab Plus Chemotherapy for Advanced Biliary Tract Cancer Treatment: Insights from the TOPAZ-1 Trial

Durvalumab Plus Chemotherapy for Advanced Biliary Tract Cancer Treatment: Insights from the TOPAZ-1 Trial

Usefulness of multigene liquid biopsy of bile for identifying driver genes of biliary duct cancers.

Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

Sex disparities in global burden of gallbladder and biliary tract cancer: analysis of Global Burden of Disease study from 2010 to 2019.

The global burden of gallbladder and biliary tract cancer (GBTC) has been on the rise, making it a major public health concern. We aim to comprehensively analyze sex disparities in the temporal trends of GBTC incidence, mortality, and disability-adjusted life years (DALYs) regionally and globally from 2010 to 2019. Age-standardized rates of GBTC incidence, death, and DALYs were analyzed utilizing the Global Burden of Disease study 2019. From 2010 to 2019, the estimated annual percent change (APC) of the age-standardized incidence rates (ASIRs) and age-standardized disability-adjusted life years (ASDALYs) due to GBTC globally decreased in both sexes (males, APC: -0.80%; APC: -1.00%) and (females, APC: -0.89%; APC: -0.96%). At the same time, age-standardized death rates (ASDRs) decreased only in males (APC: -0.82%) and remained stable in females. By regions, ASIRs and ASDR increased in both sexes only in Southeast Asia (SEA) but decreased in the other regions. All regions had decreased ASDALYs except for an increase in ASDALYs for females only in the SEA region (APC: 0.41%), and males have a stable trend. Our study reveals substantial geographic variance in the burden of GBTC, specifically in the SEA region. Therefore, localized interventional methodologies must be undertaken to effectively address this global burden from GBTC.

Different biliary tract cancers, same operation: Importance of cancer origin in patients with hilar-invading tumors.

For patients with biliary tract cancer involving the hepatic hilum, major hepatic resection with extrahepatic bile duct resection may be required. In addition to perihilar cholangiocarcinoma (PHCC), the same extent of surgery is used in advanced gallbladder cancer (GBC) and intrahepatic cholangiocarcinoma (IHCC) with hilar involvement. Few studies compare prognostic factors and long-term outcomes across tumor types. This study compared risk characteristics and outcomes after surgery in all subtypes of biliary tract cancer with hilar involvement. Patients with biliary tract cancer with hilar involvement undergoing major liver resection and extrahepatic bile duct resection between 2011 and 2021 at a single center were retrospectively analyzed. The primary postoperative outcome was overall survival. Secondary outcomes were recurrence-free survival and postoperative complications. Survival analysis was performed with Cox regression analysis and Kaplan-Meier method. One-hundred and eight patients were included. Seventy-three (67%) had PHCC, 24 (22%) had GBC, and 11 (10%) had IHCC. Hilar-invading IHCC and GBC had more adverse histopathological factors like lymph node positivity (p = 0.021), higher number of positive nodes (p = 0.043), and larger tumor size (p < 0.001) compared with PHCC. Peritoneal invasion and lymph node positivity were significant independent predictors for survival (p = 0.011 and p = 0.004, respectively). Median overall survival was 29 months for PHCC, 22 months for GBC and 21 months for IHCC (p = 0.53). IHCC tended to recur earlier (p = 0.046) than GBC and PHCC (6, 15, and 18 months, respectively). Patients with biliary tract cancer with hilar involvement undergoing major liver resection and resection of extrahepatic bile ducts had similar overall survival regardless of subtype, while IHCC recurred earlier. Peritoneal cancer invasion was common in all subtypes, including PHCC, and was an independent prognostic factor. This finding may support routine reporting of peritoneal invasion-status in resected biliary tract cancer.

Role of Inflammation and Motility Disorders in the Development, Course and Consequences of Functional Gastrointestinal and Biliary Tract Diseases (Literature Review and Expert Panel Resolution)

Aim: to present the results of the Expert Panel with a discussion of modern concepts of the pathogenesis of functional gastrointestinal diseases and the possibilities of multitarget therapy with trimebutine. Key points. Low-grade inflammation can be considered as a morphological substrate of functional diseases with an increase in activated mastocytes and eosinophils, T-helpers 2 and T-helpers 17 in the gastrointestinal mucosa. In the development in the content of visceral hypersensitivity, the functional connection between mastocytes and TRPV1-positive sensory endings of the vagus nerve is of great importance. Proinflammatory cytokines and matrix metalloproteinases can enter the systemic circulation, provoking the development of systemic manifestations. Increased levels of proinflammatory cytokines are supported by altered intestinal permeability and microbiota. Functional diseases are believed to modify the symptoms and course of concomitant organic diseases of the gastrointestinal tract (for example, functional diseases of the biliary tract may contribute to the development of cholelithiasis, pancreatitis). The peripheral μ-, κ- and δ-receptor agonist trimebutine (Trimedat®) regulates the production of enterohormones, modulates motility throughout the gastrointestinal tract and normalizes visceral sensitivity. The effectiveness of trimebutine in the treatment of functional disorders has been shown in various studies. Trimebutine helps reduce the production of proinflammatory cytokines, including interleukin-6. Conclusion. In the treatment of functional diseases of the gastrointestinal tract, trimebutine can be considered as a multitarget agent, since the drug helps to normalize motility, reduces the degree of visceral hypersensitivity, exhibits anti-inflammatory and neuroregenerative effects, and can also increase the effectiveness of treatment of concomitant diseases.

Functional Disorders of the Biliary Tract and Cholelithiasis: Analysis of a Possible Relationship

Aim: Diagnostic criteria for functional disorders of the biliary tract are presented in the materials of the Rome IV consensus, as well as expert councils of Russian and foreign specialists. Episodes of functional biliary pain are caused by a violation of bile outflow through the cystic duct and sphincter of Oddi. It has been suggested that there is a “biliary continuum” in which in some patients’ biliary dysfunction is transformed into cholelithiasis. Key points. Lithogenic bile is considered as the pathophysiological basis for the development of biliary dyskinesia and cholelithiasis. Lithogenic bile provokes inflammation of low grades in the mucous membrane of the biliary tract, decreased contractility of the gallbladder and impaired relaxation of the biliary sphincters, impaired physiological response to cholecystokinin. Changes in motility of the biliary tract may be associated with the influence of hydrophobic bile salts and impaired eicosanoid metabolism. Hyperplasia of the epithelium and muscle layer, hypersecretion of mucin and cholesterol precipitation further impair the outflow of bile. Experimental data and some clinical observations indicate the possibility of transformation of biliary dysfunction into cholelithiasis. Dysfunction of the sphincter of Oddi is one of the possible consequences of cholecystectomy and, in fact, acts as a variant of postcholecystectomy syndrome. The basis for the treatment of biliary dysfunctions are antispasmodics of different classes, which can be combined with ursodeoxycholic acid. The biliary tract-selective antispasmodic hymecromone has shown high effectiveness in relieving biliary pain, which also has a moderate choleretic effect and the ability to prevent the crystallization of cholesterol in bile and can be used both for functional diseases and for cholelithiasis. The domestic drug hymecromone “Odecromone” entered the pharmaceutical market. Conclusion. There is no doubt that the relevance of further study of the patterns of development of biliary dysfunctions and GI is obvious. The study of this problem will contribute to the development of effective preventive approaches, including in the field of nutraceuticals.

Aberrant Expression of Pneumocytic Markers (TTF-1 and Napsin-A) in Biliary Duct and Gallbladder Adenocarcinomas; A Potential Diagnostic Pitfall.

Cholangiocarcinomas and gallbladder carcinomas are epithelial tumours with biliary differentiation. On histology and immunohistochemistry, they resemble adenocarcinomas and possess overlapping immunohistochemical profiles. Diagnosing these tumours is best done using appropriate imaging and clinical features with compatible immunohistochemistry. Immuno-staining for thyroid transcription factor-1 (TTF-1) and novel aspartic proteinase of pepsin A (Napsin-A) is believed to be specific for primary pulmonary adenocarcinomas. We herein report uncommon instances of strong and diffuse expression of these markers in two examples of adenocarcinomas arising from the bile duct and gallbladder. A review of the literature and a summary of similar studies relating to aberrant TTF-1 and Napsin-A expression in biliary tract adenocarcinomas are presented.

The spectrum of pathogens and their resistance in patients with malignant liver and biliary tract tumors with biliary obstruction after extensive liver resections

The spectrum of pathogens and their resistance in patients with malignant liver and biliary tract tumors with biliary obstruction after extensive liver resections

Detecting Cholangiocarcinoma in the Setting of Primary Sclerosing Cholangitis: Is Biliary Tract Fluorescence InSitu Hybridization Helpful?

Biliary brushing cytology (BB) to detect cholangiocarcinoma (CCA) is integral in the surveillance of patients with primary sclerosing cholangitis (PSC). Since reactive changes can mimic carcinoma, indeterminant results are frequent. Fluorescence insitu hybridization (FISH) using the UroVysion probe set has been advocated to enhance the detection of CCA. This study evaluates the performance of FISH for detecting CCA in patients with and without PSC. A query of our pathology database for atypical and suspicious BB with concurrent FISH results was performed from 2014 to 2021. FISH (using UroVysion probe set containing centromere enumeration probes to chromosomes 3, 7, and 17) was positive if at least 5 cells demonstrated polysomy. Electronic medical records were reviewed to identify patients with PSC and CCA. CCA was confirmed by pathology or clinical impression. Of the 65 patients (103 BB) in the PSC cohort, 59 patients (94 BB) without CCA and 6 patients (9 BB) with CCA were identified. 33 non-PSC patients (41 BB) with CCA were included for comparison. Positive FISH was highest in non-PSC patients with CCA (10/41 BB, 24%). Positive FISH was seen in both PSC with (1/9 BB, 11%) and without (2/94 BB, 2%) CCA. FISH positivity was lower than expected and was positive in PSC patients without CCA. These results question the clinical utility of FISH for CCA surveillance in PSC patients.

Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer

BackgroundLenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC).MethodsPatients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety.ResultsA total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2–20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2–26.9) and 6.1 (95% CI: 4.9–7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil–lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported.ConclusionAnti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

Exceptional sustained long-term complete response to Tepotinib in a MET-amplified advanced intrahepatic biliary tract cancer failing Durvalumab plusCisplatin and Gemcitabine.

Biliary tract cancers (BTCs) are a diverse group of malignancies with varied genetic backgrounds. The prevalence of intrahepatic cholangiocarcinoma (iCC) is increasing, particularly in Western countries. Despite advancements in treatments, the prognosis for BTC remains poor. Recent molecular profiling has revealed that up to 40% of iCC cases have targetable genetic alterations. MET amplification, although rare, presents a significant target for therapy. A 25-year-old female with a history of ulcerative colitis presented with shoulder pain and a positron emission tomography-computed tomography (PET-CT) scan revealed an enlarged liver and multiple metastases. Histopathological analysis diagnosed poorly differentiated adenocarcinoma. First-line therapy with Cisplatin, Gemcitabine, and Durvalumab resulted in disease progression. Molecular profiling identified a TP53 mutation and MET amplification. Based on these findings, Tepotinib was initiated. Tepotinib treatment led to a significant reduction in tumor size and normalization of CA 19-9 levels within 2 months, achieving a complete metabolic remission lasting up to 17 months. The treatment was well tolerated with minimal side effects. MET-amplified BTCs are exceedingly rare, and evidence for targeted treatment is limited. This case demonstrates the efficacy of Tepotinib in a young patient with MET-amplified iCC, showing a long-term response and suggesting a potential new standard treatment option for this molecularly defined entity. This case also highlights the aggressive nature of MET-amplified tumors and the need for targeted second-line therapies. Tepotinib showed remarkable efficacy in treating MET-amplified intrahepatic cholangiocarcinoma, underscoring the importance of molecular profiling in BTCs and suggesting a potential new therapeutic approach for this rare cancer subtype.