small molecules

2026-08-11 | Autoimmune cholangiopathy presenting as a mimicker of hilar cholangiocarcinoma.

Autoimmune cholangiopathy can mimic cholangiocarcinoma. This video highlights the presentation and management of a patient with obstructive jaundice in the setting of a biliary stricture concerning for hilar cholangiocarcinoma who had resolution of her symptoms with steroids. A 49-year-old woman without autoimmune history presented with abdominal pain and jaundice and was found to have elevated liver enzymes (total bilirubin, 4.7 mg/dL; alkaline phosphatase, 405 U/L; aspartate aminotransferase, 174 U/L; and alanine aminotransferase, 530 U/L), a mass at the hepatic duct confluence, and a filling defect in the common bile duct on cross-sectional imaging. Serum carbohydrate antigen 19-9 (9 U/mL) and immunoglobulin G4 (IgG4)/IgG (7.2%) were normal. After multiple negative samples obtained by EUS/ERCP, including brushing, biopsy, and fluorescence in situ hybridization, she opted to trial systemic steroids for suspected autoimmune cholangiopathy. After 4 weeks of prednisone, an EUS/ERCP was performed and noted improvement in biliary duct dilatation, duct wall thickness, and stricture size. The periductal mass was not appreciated. Repeat cholangioscopy noted gross improvement in duct stenosis and neovascular changes. At 4-month follow-up, she remained clinically asymptomatic, with normal laboratory values and no radiographic evidence of a hilar mass or bile duct stricture. Autoimmune cholangiopathy can mimic cholangiocarcinoma and should be considered when the cytopathology result of hilar strictures is repeatedly negative.

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2026-08-05 | 192Ir brachytherapy combined with external beam radiotherapy and biliary stenting for unresectable hilar cholangiocarcinoma

Objective To evaluate the efficacy and safety of 192 Ir brachytherapy combined with external beam radiotherapy (EBRT) and biliary stenting in patients with unresectable hilar cholangiocarcinoma. Methodology Clinical data of 62 patients with unresectable hilar cholangiocarcinoma were retrospectively analyzed. All patients received concurrent chemoradiotherapy plus percutaneous biliary stenting. Among them, 32 patients ( 192 Ir group) additionally received 192 Ir brachytherapy, and 30 patients (EBRT group) received EBRT alone. Survival outcomes were analyzed using the Kaplan–Meier method. Results At 3 months after treatment, the objective response rate was 93.8% in the 192 Ir group and 70.0% in the EBRT group. Median progression-free survival was 11.2 months vs 8.6 months (P = 0.032), and median overall survival was 14.5 months vs 12.2 months (P = 0.361). Liver function parameters and CA19–9 levels decreased in both groups, with significantly lower levels in the 192 Ir group at 3 months. Adverse events were tolerable in both groups. Conclusion 192 Ir brachytherapy plus EBRT and biliary stenting may improve short-term tumor response and progression-free survival in unresectable hilar cholangiocarcinoma, with tolerable toxicity.

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2026-07-08 | Case Report: Making room for radicality: balancing liver reserve and oncologic clearance in hilar cholangiocarcinoma through portal vein embolisation

Hilar cholangiocarcinoma frequently necessitates extended hepatectomy to achieve oncological clearance, yet the risk of post-hepatectomy liver failure (PHLF) remains a critical concern when the future liver remnant (FLR) is inadequate. Over the last decade, strategies to induce FLR hypertrophy, including Portal Vein Embolization (PVE), Liver Venous Deprivation (LVD), and Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) have redefined the boundaries of resectability in patients with limited FLR. This report discusses a successful extended right hepatectomy enabled by PVE and explores the technical and physiological considerations of modern liver hypertrophy techniques for advanced hilar cholangiocarcinoma, highlighting three key aspects of contemporary hepatobiliary surgery: the physiological role of FLR optimization, the evolving hierarchy of liver hypertrophy strategies, and the intraoperative balance between oncologic radicality and preservation of functional liver reserve. We present a case of a 61-year-old male patient with minimal symptoms who was incidentally diagnosed with Bismuth-Corlette type IIIA hilar cholangiocarcinoma following detection of elevated serum carbohydrate antigen 19-9 (CA19-9) and cholestatic liver dysfunction. Multidisciplinary evaluation identified marginal FLR of 34%, prompting right PVE. Post-PVE volumetric assessment demonstrated robust hypertrophy with FLR increasing to 60.5%. The patient subsequently underwent open extended right hepatectomy with caudate lobectomy, complete bile duct excision, regional lymphadenectomy and Roux-en-Y hepaticojejunostomy reconstruction. The hypertrophied FLR enabled safe completion of extended resection without PHLF. This underscores the importance of preoperative PVE in converting a marginal FLR into an adequate physiological reserve, thereby enabling safe completion of extended hepatectomy for hilar cholangiocarcinoma without PHLF.

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2026-06-29 | Impact of Multimodal Oncological Therapy on Survival and Local Control in Unresectable Perihilar Cholangiocarcinoma.

This study aimed to evaluate the safety and effectiveness of targeted multimodal oncological therapy in patients with unresectable hilar cholangiocarcinoma (HCCA) presenting with obstructive jaundice, particularly those with the nodular-infiltrating morphological type. A total of 104 patients with Bismuth type III, nodular-infiltrating HCCA were analyzed. Fifty-two patients received percutaneous transhepatic biliary stenting (PTBS) combined with intraluminal 125I seed strand placement, percutaneous 125I seed implantation, and regional chemotherapy, whereas the remaining 52 patients received percutaneous transcatheter biliary drainage tube placement plus systemic chemotherapy. Overall survival (OS), progression-free survival (PFS), and biliary patency duration were compared between groups. Univariate and multivariate Cox regression analyses were performed to identify liver function biomarkers associated with prognosis. Intraluminal brachytherapy and percutaneous 125I seed implantation were successfully completed in all 52 patients in the multimodal treatment group. Compared with the drainage plus systemic chemotherapy group, patients receiving multimodal therapy had significantly longer median OS (22.0 vs. 10.0 months, p < 0.001), median PFS (14.1 vs. 5.9 months), and biliary patency duration (21.0 vs. 9.0 months, p < 0.001). Multivariate analysis showed that total bilirubin and albumin were independent prognostic factors for OS in patients treated with brachytherapy and regional chemotherapy. In the drainage plus systemic chemotherapy group, total bilirubin, albumin, and alkaline phosphatase were independently associated with OS. No serious complications, such as massive hemorrhage or bile leakage, were observed. Targeted multimodal oncological therapy may achieve durable local disease control, prolong biliary patency, and improve survival in patients with unresectable nodular-infiltrating HCCA accompanied by obstructive jaundice. Future studies should further consider tumor morphological characteristics and liver function biomarkers when refining treatment strategies and prognostic assessment.

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2026-06-04 | Case Report: Fatal mesenteric venous thrombosis and progressive bowel ischemia following right hemihepatectomy.

Mesenteric venous thrombosis (MVT) is an uncommon but potentially fatal complication following major hepatic resection. We report the case of a 62-year-old cirrhotic male with Hepatitis B who underwent an open right hemihepatectomy with Roux-en-Y reconstruction for a suspected Bismuth-Corlette Type 3A Klatskin tumour. On postoperative day (POD) 4, he developed refractory metabolic acidosis with profound hyperlactatemia, prompting urgent CT imaging and exploratory laparotomy which revealed extensive patchy small bowel ischaemia consistent with MVT. Serial laparotomies demonstrated relentless progression to total intestinal infarction despite maximal surgical and intensive care intervention and the patient succumbed to septic shock and multi-organ failure on POD 14. This case illustrates how the convergence of Virchow's triad in the post-hepatectomy cirrhotic patient, namely portal stasis exacerbated by inadequate fluid resuscitation, cirrhosis-mediated hypercoagulability and surgical endothelial injury can precipitate a rapidly fatal thrombotic cascade. It further highlights the dual clinical dilemma of diagnostic elusiveness as early imaging may be falsely negative and therapeutic paralysis where the perceived haemorrhagic risk of anticoagulation in a coagulopathic patient may delay the only intervention capable of halting thrombus propagation. This case underscores the imperative for heightened clinical vigilance, proactive hydration and a low threshold for repeat vascular imaging in cirrhotic patients undergoing major hepatectomy. Early anticoagulation tailored to the individual patient's risk profile should be carefully considered upon clinical suspicion of MVT, even in the setting of apparent coagulopathy.

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cell therapies

2026-06-22 | Outcomes of Liver Transplant Versus Partial Hepatectomy for Perihilar Cholangiocarcinoma Patients Requiring Arterial Reconstruction.

Liver resection (LR) and orthotopic liver transplantation (OLT) are therapeutic options for locally advanced perihilar cholangiocarcinoma (pCCA) requiring hepatic artery reconstruction (HAR). This study aimed to compare short- and long-term outcomes of LR and OLT. Outcomes were major vascular complications, 90-day mortality, overall survival (OS) and recurrence-free survival (RFS). A cohort of patients undergoing LR with HAR from 10 Western centres was compared with an OLT cohort comprising patients who received or did not receive neoadjuvant chemoradiotherapy (NACR). 109 patients, 60 LR and 49 OLT (22 OLT no-NACR and 27 OLT NACR) were included. LR patients were older and had fewer Bismuth type 4 tumours (38.3% vs. 69.4%, p = 0.009). Positive margins (49.2% vs. 6.5%, p < 0.001) and lymph nodes (54.2% vs. 32.4%, p = 0.058) were found more frequently in LR patients. No differences were found between LR and OLT in major (40% vs. 46.9%, p = 0.56) and vascular complications (23.3% vs. 28.6%, p = 0.66); NACR was an independent prognostic factor for vascular complications (OR 2.63, 95% CI 1.03-6.70, p = 0.043). 90-day mortality (15% for LR vs. 10.2% for OLT, p = 0.57) and 5-year OS (HR 0.68, 95% CI 0.40-1.17, p = 0.17) were similar. Median OS after LR versus OLT was higher but not significant (24 vs. 40 months, p = 0.13). OLT had better 5-year RFS (HR 0.52, 95% CI 0.29-0.96, p = 0.035) than LR. R1 resection (HR 2.07, 95% CI 1.03-4.18, p = 0.041) and perineural invasion (HR 3.64, 95% CI 1.09-12.16, p = 0.035) were independent prognostic factors for RFS. LR and OLT for locally advanced pCCA had similar rates of major complications and post-operative mortality, but NACR was associated with increased vascular complications. Survival was difficult to compare in the groups due to their heterogeneity, but OLT, especially with NACR, seems to give better results than LR.

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2026-05-12 | Short-type hydrophilic guidewire for reintervention after metal stents placement in malignant hilar biliary obstruction

The bilateral placement of self-expandable metal stents (SEMSs) is a widely accepted palliative treatment for unresectable malignant hilar biliary obstruction (MHBO), as adequate biliary drainage is associated with improved survival and prolonged stent patency [ 1 ]. Among the two major stenting methods, side-by-side and stent-in-stent (SIS), the SIS technique is often preferred because of its lower incidence of procedure-related adverse events, including pancreatitis [ 2 ] [ 3 ]. However, endoscopic reintervention for recurrent biliary obstruction after multiple SIS SEMS placements remains technically challenging [ 4 ]. Key steps in overcoming this challenge include selecting the SEMS mesh and inserting plastic stents (PSs) through the mesh with a guidewire (GW) support. While stiff GWs provide a strong support for PS insertion, their limited flexibility can impair maneuverability within the mesh and increase the risk of the PS tip being trapped in the mesh, potentially causing insertion difficulty or SEMS damage ([ Video 1 ]). In contrast, hydrophilic GWs offer greater flexibility and mesh selectivity, reducing PS–SEMS interference and facilitating smoother stent insertion. A 63-year-old man with unresectable hilar cholangiocarcinoma after the prior placement of three SEMSs using the SIS technique ([ Fig. 1 ]) was admitted for endoscopic reintervention. After selecting an appropriate SEMS mesh using a short-type hydrophilic GW (0.035-inch, 260-cm Radifocus; Terumo, Tokyo, Japan), gentle traction was applied to the GW to create a shaking motion, allowing the smooth insertion of a PS (Through & Pass Through the Mesh; Gadelius Medical, Tokyo, Japan) within the SEMS lumen ([ Fig. 2 ]). The “side-lock” technique, securing the GW alongside the elevator ([ Fig. 3 ]), facilitates stable device exchange, particularly when using a short-length GW. Finally, all PSs were inserted using a single GW ([ Video 1 ]). Fig. 1 The previous placement of three SEMSs for malignant hilar biliary obstruction using the SIS technique. SEMS, self-expandable metal stent; SIS, stent-in-stent. Fig. 2 a Selecting an appropriate SEMS mesh using a short-type hydrophilic GW. b The PS was navigated smoothly without the PS–SEMS interference or SEMS damage. GW, guidewire; PS, plastic stent; SEMS, self-expandable metal stent. Fig. 3 Comparison of center-lock and side-lock guidewire fixation mechanisms. Download Video Endoscopic reintervention using a short-type hydrophilic GW after the placement of SEMSs in malignant hilar biliary obstruction. GW, guidewire; SEMS, self-expandable metal stent.Video 1 A short-type hydrophilic GW combined with the “side-lock” technique enables safe and efficient reintervention after the SIS SEMS placement in MHBO. Endoscopy_UCTN_Code_CCL_1AZ_2AC Publication History Article published online: 12 May 2026 © 2026. 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

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2026-05-08 | Rewiring facilitation during inside plastic stent exchange in malignant hilar biliary obstruction

Endoscopic biliary drainage for malignant hilar biliary obstruction (MHBO) often requires multiple stents. Self-expandable metal stent (SEMS) deployment and subsequent replacement could be technically demanding [ 1 ]. Suprapapillary placement of inside plastic stents (iPSs) provides an alternative. iPSs might prevent recurrent biliary obstruction (RBO) by reducing duodenobiliary reflux, and they represent removable options in the case of stent dysfunction [ 2 ]. In unresectable MHBO, iPSs reportedly allow for time to RBO comparable to that of SEMSs after initial intervention [ 3 ] [ 4 ]. Moreover, scheduled iPS exchange could prevent cholangitis and reduce unplanned hospitalization [ 5 ]. However, during multiple iPS exchanges, guidewire access must be re-established in each targeted branch. Rewiring could be challenging in certain branches, e.g., the right posterior sectoral duct (RPSD), leading to a prolonged procedure time or technical failure. Herein, a unique rewiring technique for iPS exchange is described ([ Video 1 ]). Download Video Guidewire-assisted rewiring during inside plastic stent exchange in malignant hilar biliary obstruction: right posterior sectoral duct rewiring via the stent lumen, followed by stent removal while maintaining guidewire access.Video 1 A man in his 80s with unresectable hilar cholangiocarcinoma presented with RBO-related acute cholangitis 15 months after the initial stent placement. He had MHBO of bismuth type IIIa and three suprapapillary iPSs, i.e., a 7-Fr, 12-cm deep-angle stent in the RPSD, and two 7-Fr, 9-cm light-angle stents, displayed as one in the right anterior sectoral duct (RASD) and another in the left hepatic duct (LHD; [ Fig. 1 ]). First, the iPSs in the RASD and LHD were removed. Next, for the RPSD iPS, the thread was gently pulled using biopsy forceps until the distal end appeared at the major duodenal papilla, with the proximal end seated in the RPSD. A guidewire was advanced through the exposed stent lumen into the RPSD ([ Fig. 2 ]). The stent was removed while maintaining the guidewire in the RPSD using a snare-over-the-guidewire approach. Finally, guidewire access was established in the RASD and LHD, and all three iPSs were successfully exchanged ([ Fig. 3 ]). Fig. 1 The patient had MHBO of bismuth type IIIa and three suprapapillary inside plastic stents. MHBO, malignant hilar biliary obstruction. Fig. 2 A guidewire was advanced into the right posterior sectoral duct through the plastic stent. Fig. 3 All three inside plastic stents were successfully exchanged. Endoscopy_UCTN_Code_TTT_1AR_2AZ Publication History Article published online: 08 May 2026 © 2026. 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

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2025-11-17 | Improved liver transplant outcomes for patients with hilar cholangiocarcinoma following implementation of the MMAT-3 policy.

In 2019, the United Network for Organ Sharing (UNOS) policy for patients with hilar cholangiocarcinoma (hCCA) changed from granting a MELD exception score of 22 with 10% escalation every 3 months to a median MELD at transplant minus three (MMaT-3) without escalation, after completion of an approved neoadjuvant protocol. Using the UNOS registry, we compared waitlist and post-transplant outcomes in hCCA patients who received exception points in the pre-MMaT (October 1, 2015-November 15, 2018) and the MMaT eras (May 15, 2019-July 1, 2022). We also compared these outcomes to those of propensity-matched HCC patients. Our study demonstrated that the probability of liver transplant (LT) significantly increased in hCCA patients during the MMaT era. One-year LT probability rose from 56.0% to 73.6% ( p <0.001), and 3-year LT probability improved from 72.1% to 79.6% ( p <0.001). Furthermore, waitlist mortality also dropped, with 3-year waitlist mortality decreasing from 26.6% to 17.6% ( p =0.04). Post-transplant survival remained unchanged in both eras. Compared with HCC patients, hCCA patients in the pre-MMaT era had lower LT probability (1-year: 56.0% vs. 75.0%, 3-year: 72.1% vs. 82.1%; p <0.001) and higher waitlist mortality (3-year dropout: 26.6% vs. 13.1%; p <0.001). Conversely, in the MMaT era, hCCA patients had a similar LT probability to HCC patients. However, although significantly improved, waitlist mortality remained higher in hCCA patients compared with HCC patients (3-year dropout: 17.6% vs. 14.%; p =0.02). Under the MMaT policy, hCCA patients have improved access to LT with improved waitlist survival.

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2025-09-14 | Operative and Oncological Outcomes of Vascular Resection and Reconstruction for Perihilar Cholangiocarcinoma.

Hepatectomy with associated vascular resection and reconstruction (VR) is an option to increase the number of patients with locally advanced perihilar cholangiocarcinoma (pCCA) eligible for radical-intent surgery. This study aimed to assess the safety and oncological outcomes of VR in pCCA patients. Patients who underwent surgery for pCCA at 10 western centers were retrospectively reviewed and divided according to the performance of the VR. Primary outcomes were major morbidity, vascular morbidity, 90-day mortality, and overall survival (OS). A total of 1054 patients were included, of whom 259 (24.6%) underwent VR. Of these 259 patients, 199 (76.8 %) underwent portal vein reconstruction (PVR) only and 60 (23.2%) underwent hepatic artery reconstruction (HAR) with or without PVR. VR patients were younger (66 vs. 68 years; p = 0.011) and more frequently had Bismuth type 4 tumors (31.3% vs. 22.9%; p = 0.008). They more frequently underwent portal vein embolization (32.0% vs. 17.6%; p < 0.001), biliary drainage (84.9% vs. 77.3%; p = 0.008), and extended hepatectomy (56.8% vs. 37.1%; p < 0.001), with longer operative times (539 vs. 479 min; p < 0.001) and higher blood loss (1300 vs. 700 mL; p < 0.001). Positive resection margins were observed more frequently (45.7% vs. 35.2%; p = 0.003). Major complications (51.4% vs. 41.0%; p = 0.004), vascular complications (19.7% vs. 3.3%; p < 0.001), and mortality (16.2% vs. 10.6%; p = 0.02) were higher in VR patients. Median OS was 28.0 months for patients without VR versus 22.8 months for patients with VR (p = 0.18). Liver resection and VR in patients with locally advanced pCCA are associated with increased major and vascular morbidity but offer similar survival as patients not undergoing VR; therefore, VR should be considered in selected patients.

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oligonucleotides

2024-04-06 | MiR-380 inhibits the proliferation and invasion of cholangiocarcinoma cells by silencing LIS1

Abstract Background The objective of this study was to determine the role and regulatory mechanism of miR-380 in cholangiocarcinoma. Methods The TargetScan database and a dual-luciferase reporter assay system were used to determine if LIS1 was a target gene of miR-380. The Cell Counting Kit 8 assay, flow cytometry, and Transwell assay were used to detect the effects of miR-380 and LIS1 on the proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. Western blotting was used to determine the effect of miR-380 on MMP-2/p-AKT. Immunohistochemistry detected the regulatory effect of miR-380 on the expression of MMP-2/p-AKT/LIS1. Results Expression of miR-380 in cholangiocarcinoma was decreased but expression of LIS1 was increased. LIS1 was confirmed to be a target gene of miR-380. Transfection with miR-380 mimics inhibited the proliferation, S-phase arrest, and invasion of HCCC-9810/HuCCT1/QBC939 cells, and LIS1 reversed these inhibitory effects. miR-380 inhibitor promoted proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. si-LIS1 salvaged the promotive effect of miR-380 inhibitor. Overexpression of miR-380 inhibited expression of MMP-2/p-AKT/LIS1, but miR-380 inhibitor promoted their expression. Conclusion An imbalance of miR-380 expression is closely related to cholangiocarcinoma, and overexpression of miR-380 inhibits the expression of MMP-2/p-AKT by directly targeting LIS1.

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2023-11-14 | KLF4 suppresses the proliferation of perihilar cholangiocarcinoma by negatively regulating GDF15 and phosphorylating AKT.

Krüppel‑like factor 4 (KLF4) is a transcription factor which functions as a tumor suppressor or an oncogene in numerous types of solid tumors. However, its expression levels and function in perihilar cholangiocarcinoma (pCCA) have yet to be elucidated. In the present study, in order to investigate its roles in pCCA, reverse transcription‑quantitative PCR (RT‑qPCR), western blot analysis and immunohistochemistry were used to detect KLF4 expression in pCCA. The Chi‑squared test was used to analyze the associations between KLF4 and the clinicopathological features of patients with pCCA. Univariate and multivariate analyses were subsequently used to analyze the prognostic significance of KLF4. The tumor suppression of KLF4 was investigated for the purposes of illustrating its biological function both in vitro and in vivo. Furthermore, the association between KLF4 and growth/differentiation factor 15 (GDF15) was determined using pCCA tissue microarray (TMA) analysis and RT‑qPCR. The underlying molecular mechanisms between KLF4 and GDF15 were subsequently investigated in vitro. In pCCA tissues, KLF4 was found to be downregulated, and this was negatively associated with the histological grade and tumor size. The knockdown of KLF4 was also found to be a prognostic indicator of the poorer survival of patients with pCCA. Based on in vitro and in vivo analyses, KLF4 was found to suppress tumor progression and induce cell apoptosis. Furthermore, it was found that KLF4 executed its tumor suppressive effects via the regulation of the GDF15/AKT signaling pathway. Taken together, the findings of the present study demonstrate that KLF4 may be considered as an independent biomarker of a favorable prognosis of patients with pCCA, and the KLF4/GDF15/AKT signaling pathway may potentially be a novel molecular therapeutic target for patients with pCCA.

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2023-07-04 | Functional Mechanism of MicroRNA-25-3p in Hilar Cholangiocarcinoma Cell Proliferation and Migration Through Regulation of Dual Specificity Phosphatase 5.

Hilar cholangiocarcinoma (HCCA) is a highly aggressive biliary tract tumor. microRNAs (miRs) exert dual actions in various cancers. This paper seeks to expound on the functional mechanisms of miR-25-3p/dual specificity phosphatase 5 (DUSP5) in HCCA cell proliferation and migration. HCCA-related data were downloaded from GEO database to screen out differentially-expressed genes. The potential target miR (miR-25-3p) and its expression in HCCA were analyzed on Starbase. The binding relation between miR-25-3p and DUSP5 was confirmed by dual-luciferase assay. Levels of miR-25-3p and DUSP5 in FRH-0201 cells and HIBEpics were determined by RT-qPCR and Western blot. miR-25-3p and DUSP5 levels were intervened with to explore their effects on FRH-0201 cells. The apoptosis, proliferation, migration, and invasion of FRH-0201 cells were evaluated by TUNEL, CCK8, scratch healing, and Transwell assays. Flow cytometry was conducted to assess FRH-0201 cell cycle. Levels of cell cycle-related proteins were determined by Western blot. DUSP5 was weakly-expressed and miR-25-3p was highly-expressed in HCCA samples and cells. miR-25-3p targeted DUSP5. miR-25-3p suppressed FRH-0201 cell apoptosis and increased cell proliferation, migration, and invasion. DUSP5 overexpression partially abrogated miR-25-3p overexpression-exerted effects on FRH-0201 cells. miR-25-3p stimulated G1/S phase transition of FRH-0201 cells by targeting DUSP5. miR-25-3p regulated HCCA cell cycle and facilitated cell proliferation and migration by targeting DUSP5.

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2022-08-01 | Exosome-transmitted miR-3124-5p promotes cholangiocarcinoma development via targeting GDF11

Objective Cholangiocarcinoma (CHOL) is a deadly cancer worldwide with limited available therapies. The aim of this study was to investigate key exosomal miRNAs and their functions in CHOL development. Methods Serum exosomes were isolated from patients with CHOL and healthy controls, followed by miRNA sequencing for identifying differentially expressed miRNAs (DEMs) and their functions. Then, the expression of key DEMs was experimentally validated in exosomes from clinical CHOL patients and CHOL cells. The effects of overexpression of key DEMs on CHOL cell migration and proliferation were investigated. A key exosomal DEM miR-3124-5p was identified. The effects of overexpression or knockdown of exosomal miR-3124-5p on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were investigated. Moreover, the function of exosomal miR-3124-5p on tumor growth in vivo was explored. Results A total of 632 exosomal DEMs were identified between CHOL and control samples. Target genes of DEMs were significantly enriched in pathways, such as the p53 signaling pathway. miR-3124-5p was upregulated in serum exosomes from CHOL patients and exosomes from CHOL cells, and overexpression of miR-3124-5p promoted RBE cell migration and viability. Moreover, overexpression of exosomal miR-3124-5p promoted the proliferation, migration, and angiogenesis of HUVECs, while knockdown of miR-3124-5p had the opposite effect. miR-3124-5p could target growth differentiation factor 11 (GDF11) and downregulate GDF11 expression. Furthermore, exosomal miR-3124-5p promoted tumor growth in vivo . Conclusions Our findings revealed that exosome-encapsulated miR-3124-5p promoted the malignant progression of CHOL by targeting GDF11. Exosomal miR-3124-5p and GDF11 could be promising biomarkers or therapeutic targets for CHOL.

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2021-05-01 | LncRNA ST8SIA6-AS1 Promotes Cholangiocarcinoma Progression by Suppressing the miR-145-5p/MAL2 Axis

The tumor-promoting roles of ST8SIA6-AS1 and miR-145-5p have been found in several cancers, but their function in cholangiocarcinoma (CHOL) remains speculative. The purpose of this study was to examine the regulatory functions of the ST8SIA6-AS1/MAL2/miR-145-5p pathway in CHOL progression.RT-qPCR assay was used to detect ST8SIA6-AS1 expression in CHOL tissues and cell lines. Cell migration, apoptosis, invasion, and proliferation abilities were assessed by RIP, RNA pull-down, and luciferase assays. CCK-8, BrdU, transwell, and FITC assays to investigate the regulatory functions of ST8SIA6-AS1, miR-145-5p, and MAL2 function in CHOL cells.Findings revealed the enrichment of ST8SIA6-AS1 in CHOL tissues and cell lines. It was also found that ST8SIA6-AS1 facilitated cell growth and migration, but it reduced the apoptosis level of the CHOL cells. The results of experiments showed that ST8SIA6-AS1 sponged miR-145-5p, thereby allowing MAL2 to exert its biological function on CHOL cells.This research suggested that the ST8SIA6-AS1/miR-145-5p/MAL2 axis could enhance CHOL progression, which might be useful to improve the clinical outcomes of CHOL patients.

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antibodies

2026-07-17 | Perihilar cholangiocarcinoma: Expanding the role of liver transplantation in the era of multimodal therapy.

Perihilar cholangiocarcinoma (pCCA) accounts for approximately 50% of all cholangiocarcinomas and carries a dismal prognosis owing to late diagnosis and high post-resection recurrence rates. Over the past two decades, liver transplantation (LT) following neoadjuvant therapy according to the Mayo Criteria has yielded acceptable long-term survival in highly selected patients with unresectable pCCA, establishing LT as an established treatment option. Nevertheless, substantial challenges remain, including tumor progression on the waiting list, intolerance to neoadjuvant therapy, and postoperative complications from prior chemoradiation. Moreover, pCCA recurrence is closely linked to post-transplant immunosuppressive management, and minimizing long-term immunosuppression may be critical. This review analytically examines the current role of LT for pCCA, emphasizing patient selection, standardized neoadjuvant regimens, immunological considerations, and favorable prognostic factors. The emerging potential and risks of incorporating immune checkpoint inhibitors in the pre-transplant setting are also explored. By synthesizing available evidence, we aim to define the clinical contexts in which LT may confer durable benefit and to highlight the key obstacles limiting its broader application.

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2026-06-30 | Cholangiocarcinoma with metachronous urothelial malignancy as a rare manifestation of Lynch syndrome with no gastrointestinal tumour.

Lynch syndrome, an autosomal dominant disorder caused by defective DNA mismatch repair genes, is linked to early-onset colorectal, ovarian, gastric, urinary tract and, less commonly, small bowel, biliary and pancreatic cancers. We present a case of a man in his late 50s who presented with obstructive jaundice due to a biliary hilar mass with a history of urothelial malignancy requiring surgical intervention. Family history revealed colon cancer in mother and brother both below the age of 50 years. He underwent curative resection and reconstruction. Histopathology confirmed hilar cholangiocarcinoma. Due to suspicion of Lynch syndrome, microsatellite instability and mismatch repair gene mutation testing were performed, which confirmed loss of nuclear expression of MSH2/MSH6, hence confirming the diagnosis of Lynch syndrome. This enabled the decision to treat with immunotherapy for recurrence and also conduct family screening. In spite of the absence of colonic tumours, Lynch syndrome should be suspected in young patients with multiple tumours, particularly when supported by a relevant family history.

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2026-03-28 | Integrated Transcriptomic Analysis and Functional Validation Identify CNTN1 as a Novel Metastatic Driver in Hilar Cholangiocarcinoma.

Background: Hilar cholangiocarcinoma (HC) is a highly aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular drivers. This study aimed to systematically identify and functionally validate key genes and pathways driving HC pathogenesis. Methods: RNA sequencing (RNA-seq) was performed on paired primary HC tumors and matched adjacent non-tumorous tissues to identify differentially expressed genes (DEGs). Subsequent bioinformatic analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network construction, were conducted to characterize the functional landscape and identify hub genes. Transwell assays and orthotopic metastatic models were used to investigate the functions of Contactin-1 (CNTN1) in HC invasion in vitro and metastasis in vivo. Results: RNA-seq analysis identified 35 DEGs in HC, mainly involved in cell adhesion, cytoskeletal regulation, and axon development. PPI network analysis identified six hub genes, including CNTN1, NCAM1, PLP1, GPM6B, SLC1A3, and PMP2. Furthermore, we demonstrated that CNTN1, a neuronal membrane glycoprotein, was markedly up-regulated in HC at both mRNA and protein levels, and its elevated expression correlated with poor prognosis. Gain- and loss-of-function studies demonstrated that CNTN1 promotes HC cell invasion in vitro and metastasis in vivo. Mechanistically, CNTN1 exerts its pro-invasive effects by activating the PI3K-AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT). Conclusions: Our integrated analysis identifies CNTN1 as a critical oncogenic driver in HC, promoting metastasis through PI3K-AKT-mediated EMT. These findings nominate CNTN1 as a potential prognostic biomarker and therapeutic target in HC.

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2026-02-01 | Surufatinib plus anti‐PD‐1/PD‐L1 antibody as second‐line therapy for advanced biliary tract cancer: A single‐centre investigator‐initiated trial

Abstract Objective To explore the efficacy and safety of surufatinib in combination with anti‐PD‐1/PD‐L1 antibodies (with or without chemotherapy) in patients with advanced BTC after failure of first‐line treatment. Methods 24 patients with advanced BTC who failed first‐line treatment were admitted to our centre from March 2023 to August 2024 and treated with surufatinib combined with anti‐PD‐1/PD‐L1 antibodies (with or without chemotherapy). The primary endpoint was PFS, and the secondary endpoints were ORR, DCR, OS and safety indicators. Results There were 10 cases of intrahepatic cholangiocarcinoma, 5 cases of hilar cholangiocarcinoma, 2 cases of extrahepatic cholangiocarcinoma, and 7 cases of gallbladder cancer. There were 16 cases of combined chemotherapy and immunotherapy, and 8 cases of combined immunotherapy alone. The median PFS of all patients was 3.81 months (95%CI 2.46–4.50), the median OS was 10.48 months (95%CI 6.54–16.43), and the ORR was 20.8% (95%CI 7.1%–42.2%). The DCR was 54.2% (95%CI 32.8%–74.4%). Subgroup analysis showed that the median PFS of cholangiocarcinoma group was 3.81months (95%CI 2.07–4.50), while the median OS was 9.56months (95%CI 6.34–16.43). The median PFS of gallbladder cancer was 3.81 months (95%CI 2.07–4.50), while the OS was 11.11 months (95%CI 3.42–11.11). The median PFS in the combined chemotherapy plus immunization group was 3.91months (95%CI 2.46–5.16), and the median OS was 8.80 months (95%CI 6.34–16.34). The median PFS in the combined immunotherapy alone group was 3.22 months (95%CI 1.08–4.70), and the median OS was 10.48 months (95%CI 2.53–11.2). TRAE occurred in 15 cases (62.5%) which mainly including hypothyroidism, transaminase elevation and fatigue. While the incidence of grade 3 and above AE was 12.5% (3/24), mainly including leukopenia and thrombocytopenia. Conclusion Surufatinib combined with anti PD‐1/PD‐L1 antibodies was effective and tolerable in second‐line treatment of advanced BTC. It is worthy of further in‐depth exploration through multi‐centre and large‐sample clinical trials.

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2026-01-30 | Multimodal treatment and tumour biology-driven long-term survival in PSC-associated hilar cholangiocarcinoma: A case report.

Primary sclerosing cholangitis (PSC) is a recognised risk factor for hilar cholangiocarcinoma (hCCA). In selected patients, neoadjuvant chemoradiotherapy followed by liver transplantation provides the optimal chance of long-term survival. However, for the patient described in the present case report, at the time of the patient s treatment, the UK did not have an approved transplant programme for cholangiocarcinoma, and access to liver transplantation was limited, often necessitating upfront surgical resection despite its complexity and limited curative potential. The present study describes the case of a 52-year-old male patient with PSC who was diagnosed with hCCA and underwent an extended right hepatectomy. After 26 months, progressive liver dysfunction due to PSC-related cirrhosis prompted liver transplantation, which was approved following a lengthy appeals process. Over the following years, the patient developed metastases in the bowel, lungs and abdominal wall, all of which were successfully managed with surgical resections. He remained disease-free for 8 years following his initial diagnosis before developing intrahepatic recurrence. The tumour was HER2-positive, and the compassionate use of zanidatamab was initiated following progression on standard therapies. At the time of the writing of the present case report, the patient remained alive 101 months following this initial diagnosis. On the whole, the present case report highlights the potential impact of tumour biology and multimodal treatment in PSC-associated hCCA. The prolonged survival of the patient despite delayed transplant and metastatic recurrence suggests that PSC-related hCCA may follow a more indolent course compared to de novo cases. Future efforts are required to focus on tumour profiling and stratified therapeutic approaches to better guide treatment in this complex disease.

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2025-04-03 | A case of endovascular treatment for acute portal vein thrombosis following portal vein resection and hepatectomy for hilar cholangiocarcinoma.

Currently, portal vein (PV) resection is performed in 10%-40% of liver resections performed for hilar cholangiocarcinoma (HC). The defect is generally repaired with a patch of an autologous vein graft or end-to-end anastomosis after complete separation of the main PV trunk and the left PV. Postoperative PV thrombosis is a severe complication occurring in 2%-9% of patients requiring PV reconstruction. Here in, we presented a 55-year-old man with abdominal pain without hyperbilirubinaemia who was diagnosed with HC. The patient underwent right hepatectomy, extrahepatic biliary resection, and PV resection. The PV defect was repaired with autologous umbilical vein graft. Following the operation, acute PV thrombosis was encountered postoperative day 1. We conducted the treatment of the early acute PV thrombosis by intraportal tPA and PV stenting with endovascular approach.

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2024-07-17 | Impact of post-hepatectomy biliary leaks on long-term survival in different liver tumors: A single institute experience.

A postoperative biliary leak is one of the most morbid complications occurring after a liver resection, the long-term impact of which remains unknown. Retrospective analysis of consecutive liver resections performed from 1 January 2011 to 31 December 2021. Primary endpoint of disease-free survival (DFS) was compared between patients with and without a bile leak, stratifying for tumor type. Survival curves were plotted using Kaplan-Meier estimates, and differences between them were analyzed using the log-rank test. In toto, 862 patients were analyzed, and included 306 (35.5%) hepatocellular carcinomas, 212 (24.6%) metastatic colorectal cancers, and 111 (12.9%) cholangiocarcinomas (69 intrahepatic cholangiocarcinomas, 42 hilar cholangiocarcinomas). Occurrence of a bile leak was associated with significantly poorer DFS only in patients with cholangiocarcinoma (median DFS 9.9 months vs. 24.9 months, p = 0.013), and further analysis was restricted to this cohort. A Cox regression performed for factors associated with DFS detriment in patients with cholangiocarcinoma showed that apart from node positivity (hazard ratio [HR]: 2.482, p = 0.033) and margin positivity (HR: 2.65, p = 0.021), development of a bile leak was independently associated with worsening DFS on both univariate and multiple regression analyses (HR: 1.896, p = 0.033). Post-hepatectomy biliary leaks are associated with significantly poorer DFS only in patients with cholangiocarcinoma, but not in patients with hepatocellular carcinoma or metastatic colorectal cancer. Methods to mitigate this survival detriment need to be explored.

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2018-09-01 | Abstract: Multiple Anastomotic Thrombus Due to Decreased Anti-Thrombin Activity during Microvascular Anastomosis - Case Report

INTRODUCTION: With recent advances in microsurgical instruments and technique, microvascular anastomosis has become a universal surgical technique however, thrombosis still presents in a number of cases. Tension, twisting and compression to the anastomotic site are the main causes of thrombus however disorder of the coagulation fibrinolysis system also need to be considered. To date, only few reports exist regarding thrombosis caused by disorder of coagulant system in microvascular anastomosis. Here we report our three cases in which multiple thrombus formation occurred intraoperatively caused by decrease of anti-thrombin (AT) activity. CASE REPORTS: Case 1: A 70-year-old male presenting with an esophageal and intestinal fistula after gastric tube cancer were subjected to jejunal pull-up through ante-thoracic route and vascular augmentation to the jejunal artery and vein with the internal thoracic artery and vein was performed. During the operation, arterial thromboses occurred three time and venous thromboses occurred four time. Intraoperative examination showed AT activity decrease (50 %) and AT transfusion was performed. After transfusion, arterial or venous thrombosis was not observed. The intraoperative bleeding volume was 1100ml and the operation time was 12 hours 20 minutes. Case 2: A 77-year-old man presenting with a right hepatic artery injury during hepatectomy for hilar cholangiocarcinoma. Resection of injured artery followed by vascular anastomosis were performed however thrombosis was observed 3 times. Intraoperative blood test showed marked decreaseof AT activity (25 %) and AT transfusion was performed. Fourth arterial anastomosis was performed after AT transfusion and no further thrombosis was observed thereafter. Intraoperative bleeding volume was 403ml and operation time was 13 hours 23 minutes. Case 3: A 78-year-old man presenting with extensive left maxillary sinus carcinoma underwent left total maxillectomy, anterior and middle skull base resection, and subsequent free rectus abdominis myocutaneous flap reconstruction. During the operation, arterial thrombosis was observed 3 times in the microvascular anastomotic site. Intraoperative examination showed AT activity decrease (37 %) and AT transfusion was performed. Fourth arterial anastomosis was performed after AT transfusion and no further thrombosis was observed. Intraoperative bleeding volume was 1480ml and operation time was 18 hours 20 minutes. RESULTS: Thrombosis was not observed in any of three patients intraoperatively after the transfusion or postoperatively and no other complications were observed. DISCUSSION: AT deficiency was thought to be a main reason for the thromboses observed during the operation in all three cases. AT is synthesized in the liver and inhibits thrombus formation. It accounts for about 80 % of the thrombin inactivation in the blood, and is greatly related to the balance of the coagulation-fibrinolytic system. Various factors are thought to explain the decrease of AT activity observed in the cases presented; including hereditary AT deficiency, severe intraoperative blood loss, highly invasive operation, malnutrition and impaired liver function. It is necessary to consider AT deficiency in case repeated thrombosis developed intraoperatively.

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2018-07-10 | IGFBP7 is associated to prognosis and could suppress cell survival in cholangiocarcinoma

Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein and its expression was restrained in varied solid tumours, but there was no report about biological role of IGFBP7 in cholangiocarcinoma (CCA). Here, we found that high expression of IGFBP7 correlated to a better overall survival in CCA patients. To investigate the hypothetic antineoplastic activity of IGFBP7 in CCA, we induced overexpression of IGFBP7 in QBC939 and RBE cells, as well as knockdown in HCCC9810 cells. And the biological functions triggered by level changes of IGFBP7 were assessed, including proliferation, cell cycle distribution, apoptosis and invasion evaluation. Cell growth assessment showed that enhanced IGFBP7 expression significantly retarded proliferation rates of QBC939 and RBE cells while an enhancement was observed in IGFBP7-inhibited HCCC9810 cells. The inhibition of cell viability was induced via G2/M phase arrest and apoptosis. Both QBC939 and RBE cells possess highly invasive ability, and IGFBP7 overexpression attenuated their serious invasiveness by reversing their mesenchymal phenotype to endothelial signature. We next investigated the potential mechanism involving in IGFBP7-induced tumour suppression and found that increased expression of IGFBP7 resulted in decrease of IGF-IR, IRS-1 and phosphor-AKT protein levels, accompanied with elevation of phorsphor-p38MAPK. These results suggest that IGFBP7 might be related to CCA carcinogenesis and metastasis, which further implicates that IGFBP7 might become a prospective benchmark for CCA diagnosis and therapy.

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2010-07-01 | Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma

Epithelial-mesenchymal transition is an important mechanism behind initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of epithelial-mesenchymal transition in the progression of cholangiocarcinoma. Cholangiocarcinoma cell lines, CCKS-1 and TFK-1, were treated with transforming growth factor-beta1 (TGF-beta1), and the phenotypic changes and invasive activity were examined. Immunohistochemical analysis was performed using tissue sections of cholangiocarcinoma. In vitro, TGF-beta1 induced mesenchymal features in CCKS-1 and TFK-1 characterized by the reduction of E-cadherin and cytokeratin 19 expression and the induction of mesenchymal markers, such as vimentin and S100A4. TGF-beta1 also induced the nuclear expression of Snail, and the invasive activity was significantly increased in both cell lines. Studies using a mouse xenograft model showed that TGF-beta1 worsened the peritoneal dissemination of CCKS-1. All these changes by TGF-beta1 were inhibited by the simultaneous administration of soluble TGF-beta type II receptor. In vivo, six (16%) of 37 cholangiocarcinoma cases showed marked immunoreactivity of Snail in their nuclei. In these six cases, the immuno-expression of cytokeratin 19 was significantly reduced, and the expression of vimentin was significantly increased. The Snail expression significantly correlated with the lymph node metastasis and a poor survival rate of the patients. These results suggest that epithelial-mesenchymal transition induced by TGF-beta1/Snail activation is closely associated with the aggressive growth of cholangiocarcinoma, resulting in a poor prognosis.

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