Patients with malignant hilar biliary obstruction typically present with painless jaundice. They commonly have perihilar cholangiocarcinoma (pCCA), but also intrahepatic cholangiocarcinoma, gallbladder cancer, and metastases to the liver hilum can present with hilar biliary obstruction. Endoscopic biliary drainage is the standard of care in most centers. Many patients develop drainage-related complications after endoscopic biliary drainage for malignant hilar biliary obstruction, in particular cholangitis, resulting in reinterventions, clinical deterioration and a high mortality rate. Primary percutaneous stenting (PPS) aims to avoid bacterial contamination and reduce drainage-related complications. The aim of this randomized controlled trial is to compare PPS with endoscopic biliary drainage in patients with unresectable malignant hilar biliary obstruction.

This multicenter phase 3 randomized controlled trial (TESLA RCT) will recruit 148 patients with unresectable malignant hilar biliary obstruction in six Dutch tertiary academic referral centers. Diagnosis of malignant hilar biliary obstruction is pathologically confirmed or determined as very likely by the multidisciplinary team. In the intervention arm, patients undergo primary percutaneous stenting with uncovered self-expandable metal stents without crossing the ampulla and without leaving an external drain. In the control arm patients undergo endoscopic biliary drainage according to international guidelines. The primary endpoint is major complications within 90 days after randomization. Secondary outcomes include technical success, reintervention rates, decrease of bilirubin levels, eligibility for palliative systemic treatment, quality of life, and overall survival.

The multicenter TESLA RCT compares primary percutaneous stenting with endoscopic biliary drainage in patients with unresectable malignant hilar biliary obstruction. First patient was randomized on August 9, 2023.

Netherlands Trial Register (NL-OMON53463), registered on May 12, 2023, and Clinicaltrials.gov (NCT06671418), registered on November 1, 2024.

Cholangiocarcinoma (CCA) is the most common malignant tumor of the bile ducts. Due to its anatomical location, growth pattern, and lack of clear diagnostic criteria, it presents diagnostic challenges. Exploring its occurrence and development to find early markers and treatment targets is of great significance.

To determine whether Mucin 3A (MUC3A) can regulate the occurrence and development of cholangiocarcinoma cells and its mechanism, we compared the expression levels of MUC3A between intrahepatic biliary epithelial cells and cholangiocarcinoma cells and constructed stable transfections of KONC (transfection negative control group) and MUC3A-KO1 and KO2 (transfection MUC3A knockout vectors) lentivirus in CCA cell lines. We investigated the effect of MUC3A on the proliferative capacity of cholangiocarcinoma cells using the CCK-8 assay and colony formation assay. The regulatory effect of MUC3A on the cell cycle of cholangiocarcinoma cells was examined using flow cytometry. The impact of MUC3A on the invasion and migration of cholangiocarcinoma cells was observed through scratch and Transwell assays. Additionally, the mechanism by which MUC3A regulates proliferation and metastasis of cholangiocarcinoma was explored using Western blot.

MUC3A is highly expressed in cholangiocarcinoma. MUC3A promotes the proliferation of cholangiocarcinoma cells by regulating the cell cycle. Additionally, MUC3A enhances the invasion and migration of cholangiocarcinoma cells by regulating the epithelial-mesenchymal transition. Furthermore, MUC3A regulates the proliferation and metastasis of cholangiocarcinoma cells through the ERK signaling pathway.

This study demonstrates that MUC3A regulates the proliferation and metastasis of cholangiocarcinoma cells through the ERK signaling pathway.

The impact of age on the causes of death (CODs) in patients with early-stage intrahepatic cholangiocarcinoma (ICC) who had undergone surgery was analyzed in this study.

A total of 1555 patients (885 in the older group and 670 in the younger group) were included in this study. Before and after applying inverse probability of treatment weighting (IPTW), the different CODs in the 2 groups were further investigated. Additionally, 7 different machine learning models were used as predictive tools to identify key variables, aiming to evaluate the therapeutic outcome in early ICC patients undergoing surgery.

Before (5.92 vs. 4.08 years, P < 0.001) and after (6.00 vs. 4.08 years, P < 0.001) IPTW, the younger group consistently showed longer overall survival (OS) compared with the older group. Before IPTW, there were no significant differences in cholangiocarcinoma-related deaths (CRDs, P = 0.7) and secondary malignant neoplasms (SMNs, P = 0.78) between the 2 groups. However, the younger group had a lower cumulative incidence of cardiovascular disease (CVD, P = 0.006) and other causes (P < 0.001) compared with the older group. After IPTW, there were no differences between the 2 groups in CRDs (P = 0.2), SMNs (P = 0.7), and CVD (P = 0.1). However, the younger group had a lower cumulative incidence of other CODs compared with the older group (P < 0.001). The random forest (RF) model showed the highest C-index of 0.703. Time-dependent variable importance bar plots showed that age was the most important factor affecting the 2-, 4-, and 6-year survival, followed by stage and size.

Our study confirmed that younger patients have longer OS compared with older patients. Further analysis of the CODs indicated that older patients are more likely to die from CVDs. The RF model demonstrated the best predictive performance and identified age as the most important factor affecting OS in early ICC patients undergoing surgery.

The prognostic factors for overall survival (OS) in perihilar cholangiocarcinoma (pCCA) included resection margin (RM) and lymph node metastases (LNM). Nevertheless, the advantage associated with a negative RM in patients with LNM remains unresolved.

The study retrospectively analyzed patients with pCCA underwent curative-intent resection between October 2013 and December 2018. The evaluation of the OS was conducted based on the presence of LNM and the status of RM.

Of the 167 resected pCCA patients, 87 (52.1 ​%) were LNM negative, and 80 (47.9 ​%) were LNM positive. Of the 87 LNM-negative patients, 68 (78.2 ​%) were R0 resections, and 19 (21.8 ​%) were R1 resections. In LNM-negative patients, the OS was longer in the R0 resection than the R1 resection group (median survival time (MST) of 32.1 vs 15.7 months, respectively; p ​< ​0.001). Of the 80 LNM-positive patients, 35 were R0 resections and 45 were R1 resections. Among patients with LNM positivity, the OS rates were similar between the groups who underwent R1 resection and R0 resection (MST of 8.4 vs 8.0 months, respectively; p ​= ​0.109).

In patients with pCCA, the RM status was the most important prognostic factor for LNM-negative patients. However, there was no impact in LNM-positive patients.

Laparoscopic resection (LR) of perihilar cholangiocarcinoma (pCCA) is still in the exploratory stage due to its exacting technical requirements, and its feasibility remains controversial. The objective of this study was to compare the short- and long-term outcomes of LR and open resection (OR) of pCCA.

This study analyzed the data of pCCA patients who underwent LR or OR from January 2012 to January 2020 at Southwest Hospital. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were used to balance the baseline characteristics between the LR and OR groups. The short- and long-term outcomes were compared between the LR and OR groups.

Forty-five patients in the LR group and 243 in the OR group were analyzed. After IPTW and PSM, the amount of intraoperative blood loss, incidence of surgical site infections (SSIs), length of stay (LOS), and number of perioperative blood transfusions (PBTs) were significantly lower in the LR group than in the OR group (after IPTW: P<0.001, P=0.009, P=0.01, P<0.001 respectively; after PSM: P<0.001, P=0.003, P=0.03, P=0.04 respectively). Only after IPTW was the 30-day mortality rate significantly lower in the LR group than in the OR group (P=0.005). There was no significant difference in overall survival (OS) or recurrence-free survival (RFS) between the two groups after IPTW or PSM.

LR of pCCA is an achievable procedure whose long-term outcomes are similar to those of OR, and LR outperforms OR in short-term outcomes such as intraoperative blood loss, SSI, LOS, 30-day mortality, and PBTs. It is believed that it is safe and feasible to treat pCCA with LR after rigorous patient selection.

Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous malignancy arising from the epithelial cells of the biliary tract. The limitations of the current methods in the diagnosis of CCA highlight the urgent need for new, accurate tools for early cancer detection, better prognostication and patient monitoring. Liquid biopsy (LB) is a modern and non-invasive technique comprising a diverse group of methodologies aiming to detect tumour biomarkers from body fluids. These biomarkers include circulating tumour cells, cell-free DNA, circulating tumour DNA, RNA and extracellular vesicles. The aim of this review is to explore the current and potential future applications of LB in CCA management, with a focus on diagnosis, prognostication and monitoring. We examine both its significant potential and the inevitable limitations associated with this technology. We conclude that LB holds considerable promise, but further research is necessary to fully integrate it into precision oncology for CCA.

The prognostic value of the resection margin (RM) status and the efficacy of adjuvant therapy (AT) in distal cholangiocarcinoma (CCC) are unclear. RM status appears particularly impactful in lymph node-negative distal CCC, representing early-stage disease. The prognostic value of RM status was investigated, and subpopulations of patients with lymph node-negative distal CCC who might benefit from AT were identified. Overall, 139 patients with distal CCC who underwent surgical resection between March 2006 and December 2023 were analyzed. RM status was categorized as wide (>5 mm) in 65 patients (46.8%), close (≤5 mm) in 32 patients (23.0%), or positive in 42 patients (30.2%). AT was administered to 48 patients (34.5%). Patients with close or positive RMs achieved significantly lower locoregional control (LRC) than those with wide RMs. However, overall survival (OS) did not differ across the three RM groups. The impact of RM status was more evident in patients not receiving AT. Patients with wide RMs exhibited better 3-year LRC, progression-free survival (PFS), and OS rates (79.0%, 66.5%, and 69.1%, respectively) than those with close (21.7%, 15.7%, and 34.4%) or positive RMs (44.3%, 25.3%, and 50.2%, respectively). No significant differences were found between close and positive RM groups. AT appears to have improved LRC and PFS in patients with close or positive RMs but not in those with wide RMs. Close RMs were associated with poor outcomes comparable to those with positive RMs. These results indicate that achieving adequate RM width is crucial for improving survival. Moreover, AT may improve survival when adequate RMs cannot be achieved. Nonetheless, larger studies are needed to validate these findings.

IL-22 plays a pivotal role in the processes of inflammation and tissue healing., but its role in cholangiocarcinoma (CCA) remains unclear. our study explored the IL-22/IL-22R1 pathway and its impact on CCA progression through the ERK1/2 signaling cascade.

To determine the mechanism of the IL-22/IL-22R1 pathway in CCA and provide new directions for its clinical treatment.

IL-22R1 expression was assessed in human and rat CCA tissues utilizing immunohistochemical techniques, Western blot analysis, and quantitative reverse transcription PCR. The impact of IL-22 on CCA cells was assessed in vitro via tests for proliferation, migration, invasion, and apoptosis assays. The rat models of thioacetamide-induced CCA and subcutaneous xenografts in nude mice were used to assess the in vivo effects. ERK1/2 inhibitors were applied to elucidate the mechanistic role of the pathway.

IL-22R1 was overexpressed in CCA cell lines and tissues. IL-22 treatment increased the phosphorylation of ERK1/2, promoting tumor cell proliferation, migration, invasion, and resistance to apoptosis. ERK1/2 inhibition considerably reversed these effects both in vitro and in vivo.

The IL-22/IL-22R1 axis promotes CCA progression by activating ERK1/2 signaling. Targeting this pathway with ERK1/2 inhibitors offers potential therapeutic strategies for CCA.

Resection outcomes for perihilar cholangiocarcinoma differ between Western and Eastern centres, but reasons behind these disparities remain unclear. This study aimed to compare current outcomes between a Western and an Eastern expert centre to identify prognostic factors.

Patients who underwent hepatobiliary resection for perihilar cholangiocarcinoma between 2010 and 2022 at Karolinska University Hospital (Stockholm, Sweden) and Cancer Institute Hospital (Tokyo, Japan) were retrospectively included. Primary outcome was overall survival. Secondary outcomes were disease-free survival, postoperative complications and 90-day mortality rate.

Two hundred and forty-nine patients were included (Cancer Institute Hospital n = 159, Karolinska n = 90). Median overall survival was 20.4 months at Karolinska and 52.0 months at Cancer Institute Hospital (P < 0.001). Median disease-free survival was 11.9 months at Karolinska and 32.4 months at Cancer Institute Hospital (P < 0.001). Advanced tumours, ASA class ≥III, poor differentiation and radial margin positivity were more common in the Western cohort. Treatment centre, T-status, N1-status, resection side, R1-status, age and carbohydrate antigen 19-9 were prognostic for overall survival. The Eastern cohort had a lower rate of postoperative complications (24.5%) and a lower mortality rate (2.5%) compared with the Western cohort (51.1% and 10.0%).

Advanced tumour stage and radial margin positivity contributed to poor long-term survival in the Western cohort. A higher burden of co-morbidity and a higher rate of extended resections with smaller remnant liver volume influenced the Western postoperative mortality rate.

This study aimed to assess the feasibility and safety of performing cholangiopancreatoscopy-assisted endoscopic mucosal resection (CA-EMR) for biliopancreatic intraductal lesions.

Special electrocautery snares and injection needles that can pass through the working channel of a single-operator cholangiopancreatoscope were developed. Between November 2023 and April 2024, we performed CA-EMR for two patients with gallbladder polyps, one patient with a neoplastic lesion in the common bile duct (CBD), and one patient with a neoplastic lesion in the main pancreatic duct. The technical success rate and adverse events were recorded.

All four CA-EMR procedures were performed successfully. Postoperative pathology revealed inflammatory gallbladder polyps in two patients, low grade intraepithelial neoplasia of the CBD in one patient, and intraductal papillary mucinous neoplasm (IPMN) in one patient. The patient with IPMN experienced mild postoperative pancreatitis and recovered after conservative treatment. No adverse events were encountered in the other three CA-EMR procedures.

This study preliminarily confirmed the feasibility and safety of CA-EMR for treating biliopancreatic intraductal lesions.

Despite complete resection, the recurrence rate of biliary tract cancer (BTC) remains high, leading to poor prognosis. Postoperative adjuvant chemotherapy (ACT) following radical resection may substantially reduce the recurrence risk by eradicating micrometastatic lesions. However, the benefits of postoperative ACT and the optimal ACT strategy are still unclear for BTC. The objectives of this study are to evaluate the prognostic value of ACT and compare the effectiveness of different ACTs among BTC patients after curative resection.

A comprehensive literature search was conducted across PubMed, Cochrane Library, Web of Science, and EMBASE databases to identify randomized controlled trials (RCTs) comparing the benefits of ACT versus no intervention or other ACTs in BTC patients after curative resection. A random-effects network meta-analysis was performed to compare overall survival (OS) and relapse-free survival (RFS). The quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation framework.

Eight RCTs comprising 1803 patients were included in the meta-analysis. ACT was associated with significant improvements in 5-year all-cause mortality [four RCTs, hazard rate (HR) 0.93; 95% confidence interval (CI), 0.87-1.00, marginally significant; low-certainty evidence], RFS (five RCTs, HR 0.87; 95% CI, 0.78-0.98; moderate-certainty evidence), and OS (7 studies, HR 0.85; 95% CI, 0.75-0.96; low-certainty evidence) compared with observation. ACT had significantly better survival benefits on patients with negative margins (R0), lymph node-positive (N+), and tumor node metastasis classification (TNM) stage I/II ( P < 0.05). Further network meta-analysis demonstrated that fluorouracil-based ACT was significantly inferior to gemcitabine-based ACT (HR 1.20; 95% CI, 1.10-1.25) in improving RFS. However, both were superior to observation ( P < 0.05). No statistical difference in OS was observed between gemcitabine-based and fluorouracil-based chemotherapy (HR 1.00; 95% CI, 0.86-1.20). In subgroup analysis, fluorouracil-based ACT but not gemcitabine-based ACT achieved significantly better OS benefits on patients with N+ (HR 0.67; 95% CI, 0.52-0.86) and R0 (HR 0.69; 95% CI, 0.54-0.88).

Compared with observation, ACT should be routinely recommended to improve survival outcomes in BTC patients after curative resection, especially for those with R0, N+, and TNM stage I/II. Gemcitabine-based ACT performed better than other chemotherapies in improving RFS. This network meta-analysis provides precise information for determining the best adjuvant treatment for resected BTC. Further thorough and high-quality RCTs are needed.

Currently, no practical definition of potentially resectable, borderline or unresectable perihilar cholangiocarcinoma (pCCA) is available. Aim of this study was to define criteria to categorize patients for use in a future neoadjuvant or induction therapy study.

Using the modified DELPHI method, hepatobiliary surgeons from all tertiary referral centers in the Netherlands were invited to participate in this study. During five online meetings, predefined factors determining resectability and additional factors regarding surgical resectability and operability were discussed.

The five online meetings resulted in 52 statements. After two surveys, consensus was reached in 63% of the questions. The main consensus included a definition regarding potential resectability. 1) Clearly resectable: no vascular involvement (≤90°) of the future liver remnant (FLR) and expected feasibility of radical biliary resection. 2) Clearly unresectable: non-reconstructable venous and/or arterial involvement of the FLR or no feasible radical biliary resection. 3) Borderline resectable: all patients between clearly resectable and clearly unresectable disease.

This DELPHI study resulted in a practical and applicable resectability, or more accurate, an explorability classification, which can be used to categorize patients for use in future neoadjuvant therapy studies.

Multimorbidity is characterized by the presence of at least 3 chronic diseases with a prevalence of more than 50% of patients over 60 years old. The Charlson comorbidity index (CCI) enables a description of the severity of the multimorbidity and also provides a correlation with the postoperative outcome after liver resection. According to this, multimorbid patients are at increased risk of morbidity and mortality after liver resection, mostly due to postoperative liver failure. In particular, open major liver resection with biliary reconstruction and primary liver tumors linked to metabolic associated fatty liver disease (MAFLD) pose an increased risk for multimorbid patients. In contrast, minimally invasive resection leads to a clear reduction in postoperative morbidity and mortality. Preconditioning of the liver and the implementation of perioperative strategies according to the enhanced recovery after surgery (ERAS) concept can also lead to an improvement of the postoperative outcome.

Despite recent medical advancements, surgery for hilar cholangiocarcinoma is associated with high complication and mortality rates. This may be partly attributed to the absence of established preoperative liver evaluation criteria for safe surgery. This study aimed to propose a reliable indicator for safe and well-planned management of major hepatectomy with extrahepatic bile duct resection.

We included 150 patients who underwent major hepatectomy with extrahepatic bile duct resection between 2013 and 2021 in Japan. The risk factors for post-hepatectomy liver failure (PHLF) were retrospectively analyzed.

PHLF was observed in 24 (16.0 %) patients who underwent major hepatectomy with extrahepatic bile duct resection. In the multivariate analysis, the identified risk factors for PHLF were the ratio of future remnant liver volume to total liver volume (FRLV/TLV) ≤ 42 % and indocyanine green clearance fraction of the future remnant liver (ICGK-F) ≤ 0.07. Patients with these two factors were significantly associated with PHLF compared with those with either one or none of the risk factors (60.0 % vs 15.1 % and 8.1 %, respectively).

The combinational use of ICGK-F and FRLV/TLV is useful for preoperative liver function assessment with a safety margin to avoid PHLF and postoperative mortality in hepatectomy for hilar cholangiocarcinoma.

Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and <10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how 'resectable' disease is defined - molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.

Cholangiocarcinoma is a challenging malignancy with limited responses to conventional therapies, particularly immune checkpoint inhibitor therapy. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are key components of the tumor microenvironment (TME) and have been implicated in the immune response to cancer. However, the role and difference of TLSs and TILs in patients with cholangiocarcinoma remains unclear. This study elucidates their contributions to the TME.

We examined 16 tumor samples from a single-arm, phase II trial of nivolumab plus modified gemcitabine and S-1 and various datasets. Immunohistochemistry and RNA sequencing were employed to assess TLSs and TILs presence and activity. Differential gene expression and signature of immune cell composition were examined by GeoMx Digital Spatial Profiler and Cancer Transcriptome Altas analysis.

TLS-positive (N=7) patients demonstrated significantly better immunotherapy outcomes compared with TLS-negative (N=9) patients, including higher objective response rates (71% vs 0%) and disease control rates (100% vs 67%). The presence of TLSs correlated with improved progression-free and overall survival (p=0.03). TLSs were associated with "inflamed" tumors characterized by substantial immune infiltration, particularly involving T and B cells. Gene expression analyses identified significant upregulation of B cell-related genes in TLSs. Additionally, TLSs exhibited higher properties of memory B cells and myeloid dendritic cells but lower levels of innate immune cells compared with TILs. T cells within TLSs showed elevated expression of precursor-exhausted-related genes and lower cytotoxicity signature. Furthermore, TILs in TLS-positive tumors had higher levels of exhaustion signatures compared with TILs in TLS-negative tumors. Clinical data corroborated these findings, with higher PD-L1 and LAG-3 expression in TLS-positive tumors.

Our findings revealed that TILs in TLS-positive tumors have more exhausted T cell signature and PD-1 and LAG-3 protein expression in CCA which support our clinical finding. TLSs can predict favorable immunotherapy responses in patients with cholangiocarcinoma, highlighting their potential as a biomarker and therapeutic target to enhance treatment efficacy.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy that arises from second-order biliary epithelial cells. Its incidence is gradually increasing worldwide. Well-known risk factors have been described, although in many cases, they are not identifiable. Treatment options are continuously expanding, but the prognosis of iCCA remains dismal. R0 liver resection remains the only curative treatment, but only a limited number of patients can benefit from it. Frequently, major hepatectomies are needed to completely remove the tumour. This could contraindicate surgery or increase postoperative morbidity in patients with chronic liver disease and small remnant liver volume. In cases of anticipated inadequate future liver remnant, regenerative techniques may be used to expand resectability. The role and extent of lymphadenectomy in iCCA are still matters of debate. Improvements in iCCA diagnosis and better understanding of genetic profiles might lead to optimized surgical approaches and drug therapies. The role of neoadjuvant and adjuvant therapies is broadening, gaining more and more acceptance in clinical practice. Combining surgery with locoregional therapies and novel drugs, such as checkpoint-inhibitors and molecular-targeted molecules, might improve treatment options and survival rates. Liver transplantation, after very poor initial results, is now receiving attention for the treatment of patients with unresectable very early iCCA (i.e. <2 cm) in cirrhotic livers, showing survival outcomes comparable to those of hepatocellular carcinoma. Ongoing prospective protocols are testing the efficacy of liver transplantation for patients with unresectable, advanced tumours confined to the liver, with sustained response to neoadjuvant treatment. In such a continuously changing landscape, the aim of our work is to review the state-of-the-art in the surgical and medical treatment of iCCA.

Intrahepatic cholangiocarcinoma (ICC) is a common primary hepatic tumors with a 5-year survival rate of less than 20%. Therefore, it is crucial to elucidate the molecular mechanisms of ICC. Recently, the advance of high-throughput chromosome conformation capture (Hi-C) technology help us look insight into the three-dimensional (3D) genome structure variation during tumorigenesis. However, its function in ICC pathogenesis remained unclear.

Hi-C and RNA-sequencing were applied to analyze 3D genome structures and gene expression in ICC and adjacent noncancerous hepatic tissue (ANHT). Furthermore, the dysregulated genes due to 3D genome changes were validated via quantitative real-time PCR and immunohistochemistry.

Primarily, the intrachromosomal interactions of chr1, chr2, chr3, and chr11 and the interchromosomal interactions of chr1-chr10, chr13-chr21, chr16-chr19, and chr19-chr22 were also significantly distinct between ANHT and ICC, which may potentially contribute to the activation of cell migration and invasion via the upregulation of WNT10A, EpCAM, S100A3/A6, and MAPK12. Interestingly, 56 compartment regions from 23 chromosomes underwent A to B or B to A transitions during ICC oncogenesis, which attenuated the complement pathway through the downregulation of C8A/C8B, F7, F10, and F13B. Notably, topologically associated domain (TAD) rearrangements were identified in the region containing HOPX (chr4: 57,514,154-57,522,688) and ACVR1 (chr2:158,592,958-158,732,374) in ICC, which may contribute to the hijacking of remote enhancers that were previously outside the TAD and increased expression of HOPX and ACVR1.

This study reveals relationship between 3D genome structural variations and gene dysregulation during ICC tumorigenesis, indicating the molecular mechanisms and potential biomarkers.

Perihilar cholangiocarcinoma presents unique challenges in perioperative management, requiring a comprehensive approach to optimize patient outcomes.

This case study focuses on the multidisciplinary management and innovative interventions performed in the perioperative care of a patient with hilar cholangiocarcinoma.

A comprehensive assessment and treatment strategy involving neoadjuvant therapy and interventional radiology techniques were implemented. Neoadjuvant chemotherapy was administered to reduce tumor size and improve resectability. The crucial role of interventional radiology in managing postoperative complications is highlighted, particularly in the case of massive pulmonary embolism.

The neoadjuvant therapy successfully reduced tumor size, enabling an R0 surgical resection. Additionally, interventional radiology interventions, such as percutaneous pharmaco-mechanical thrombectomy, effectively addressed the life-threatening complication of massive pulmonary embolism.

This article highlights the importance of a collaborative, multidisciplinary approach in managing complex oncological surgeries, especially regarding the hospital's rescue capacity for severe postoperative complications. Emergent management with interventional radiology had a central role in resolving life-threatening complications.

Cholangiocarcinoma (CCA) is a malignant biliary system tumor and the second most common primary hepatic neoplasm, following hepatocellular carcinoma. CCA still has an extremely high unfavorable prognosis, regardless of type and location, and complete surgical resection remains the only curative therapeutic option; however, due to the underhanded onset and rapid progression of CCA, most patients present with advanced stages at first diagnosis, with only 30 to 60% of CCA patients eligible for surgery. Recent innovations in medical imaging combined with the use of radiomics and artificial intelligence (AI) can lead to improvements in the early detection, characterization, and pre-treatment staging of these tumors, guiding clinicians to make personalized therapeutic strategies. The aim of this review is to provide an overview of how radiological features of CCA can be analyzed through radiomics and with the help of AI for many different purposes, such as differential diagnosis, the prediction of lymph node metastasis, the defining of prognostic groups, and the prediction of early recurrence. The combination of radiomics with AI has immense potential. Still, its effectiveness in practice is yet to be validated by prospective multicentric studies that would allow for the development of standardized radiomics models.

Recent research indicates a role of gut microbiota in development and progression of life-threatening diseases such as cancer. Carcinomas of the biliary ducts, the so-called cholangiocarcinomas, are known for their aggressive tumor biology, implying poor prognosis of affected patients. An impact of the gut microbiota on cholangiocarcinoma development and progression is plausible due to the enterohepatic circulation and is therefore the subject of scientific debate, however evidence is still lacking. This review aimed to discuss the suitability of complex cell culture models to investigate the role of gut microbiota in cholangiocarcinoma progression.

Clinical research in this area is challenging due to poor comparability of patients and feasibility reasons, which is why translational models are needed to understand the basis of tumor progression in cholangiocarcinoma. A promising approach to investigate the influence of gut microbiota could be an organoid model. Organoids are 3D cell models cultivated in a modifiable and controlled condition, which can be grown from tumor tissue. 3D cell models are able to imitate physiological and pathological processes in the human body and thus contribute to a better understanding of health and disease.

The use of complex cell cultures such as organoids and organoid co-cultures might be powerful and valuable tools to study not only the growth behavior and growth of cholangiocarcinoma cells, but also the interaction with the tumor microenvironment and with components of the gut microbiota.

Major hepatectomy is the mainstay of curative-intent resection for perihilar cholangiocarcinoma (pCCA) patients. Textbook outcomes in liver surgery (TOLS) are a new composite parameter for evaluating the short-term outcomes of surgery; however, their association with overall survival (OS) is unknown. Therefore, this study aimed to investigate the association between TOLS and OS in pCCA patients following major hepatectomy.

Consecutive pCCA patients who underwent major hepatectomy between 2014 and 2020 at 5 hospitals were included in this analysis. TOLS were defined as no intraoperative grade ≥2 incidents, no postoperative grade B/C bile leakage, no postoperative grade B/C liver failure, no postoperative major morbidity, no readmission within 90 days due to surgery-related major morbidity, no mortality within 90 days after hospital discharge, and R0 resection. The Kaplan-Meier method was used to compare OS rates between patients who achieved TOLS and those who did not. Cox regression analysis was used to identify independent risk factors for poor OS.

In total, 399 patients were included in this study, 214 (53.6%) of whom achieved TOLS. After excluding patients who died within 90 days, the 5-year OS rate of patients who achieved TOLS was significantly greater than that of patients who did not achieve TOLS (5-year OS rate: 26.2% vs. 17.3%, p = 0.001). TOLS were independently associated with OS for pCCA patients following major hepatectomy.

TOLS were achieved in approximately half of the pCCA patients following major hepatectomy, and the patients who achieved TOLS had better survival.

This article outlines the systematic radiological approach preoperative evaluation of perihilar cholangiocarcinoma (pCCA) using CT and MRI to provide key information regarding the suitability for curative surgical resection. It discusses older classification systems (Bismuth-Corlette, Memorial Sloan Kettering Cancer Center T staging) and follows the Korean Society of Abdominal Radiology 2019 consensus recommendations for step-by-step assessment. The correlation between radiological, surgical, and pathological findings is illustrated through a pictorial review of pathologically proven cases. Benign and malignant mimics of pCCA are included to provide a comprehensive overview.

This study aimed to determine the prognostic survival impact of preoperative carbohydrate CA19-9 levels in resectable cholangiocarcinoma.

PubMed, Web of Science, Cochrane, and Embase databases were searched for articles published through April 28, 2023. The relationship between preoperative serum carbohydrate antigen 19-9 and the prognosis of patients with resectable cholangiocarcinoma was analyzed. Heterogeneity between studies was assessed by means of the I2 statistic. We also performed subgroup analyses based on anatomical site of the tumor, geographic region, time of occurrence, and different levels of CA19-9. A random effects model was performed to express effect sizes as Hazard Ratio (HR) with 95% confidence intervals (CIs).

A total of 60 original studies were eligible for inclusion, with a total of 15,031 patients with all sites, including 9014 males. The overall Hazard Ratio for all studies was 1.90 (95% CI 1.74-2.07, p < 0.001, Z = 14.59). Publication bias was suggested by the Begg's test (p = 0.014 < 0.05), and the overall HR was 1.66 (95% CI 1.53-1.80, p < 0.001, Z = 12.027) after the trim-and-filling method. Subgroup analyses showed that intrahepatic cholangiocarcinoma (HR = 2.00, 95% CI 1.79-2.23), extrahepatic cholangiocarcinoma (HR = 1.65, 95% CI 1.49-1.82), hilar cholangiocarcinoma (HR = 1. 82, 95% CI 1.60-2.07), and distal cholangiocarcinoma (HR = 1.66, 95% CI 1.27-2.15) were predicted to be linked with prognosis. Elevated CA19-9 levels were associated with an increased risk of death.

This meta-analysis showed that elevated CA19-9 levels were correlated with a poor prognosis in cholangiocarcinoma. In future, more distal and hilar cholangiocarcinoma should be included in statistical studies to improve the accuracy of our conclusions.

Cholangiocarcinoma is one of the most lethal human cancers, and chemotherapy failure is a major cause of recurrence and poor prognosis. We previously demonstrated that miR-200 family members are downregulated in clinical samples of cholangiocarcinoma and inhibit cholangiocarcinoma tumorigenesis and metastasis. However, the role of differentially expressed miR-200b-3p in 5-fluorouracil chemosensitivity remains unclear. Here, we examined how miR-200b-3p modulates 5-fluorouracil chemosensitivity in cholangiocarcinoma. We observed that miR-200b-3p was associated with 5-fluorouracil sensitivity in cholangiocarcinoma and increased 5-fluorouracil-induced mitochondrial apoptosis in cholangiocarcinoma cells. Mechanistically, miR-200b-3p suppressed autophagy in cholangiocarcinoma cells to mediate 5-fluorouracil sensitivity. Further, we identified KLF4 as an essential target of miR-200b-3p in cholangiocarcinoma. Notably, the miR-200b-3p/KLF4/autophagy pathway augmented the chemosensitivity of cholangiocarcinoma cells to 5-fluorouracil. Our findings underscore the key role of miR-200b-3p in chemosensitivity to 5-fluorouracil and highlight the miR-200b-3p/KLF4/autophagy axis as a potential therapeutic target for cholangiocarcinoma.

Background: We assessed the efficacy of evaluating palliative resection (R1/R2 resection), photodynamic therapy (PDT), and biliary stenting (stent) alone in the treatment of advanced cholangiocarcinoma using a reticulated meta-analysis. Methods: A systematical retrieval in PubMed, Web of Science, and the Cochrane Library was performed for relative literature on the effects of PDT, palliative resection, and simple biliary stenting in the treatment of advanced cholangiocarcinoma. A literature search updated to January 30, 2024, was performed. Newcastle-Ottawa Scale and Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) tools were used to assess the methodological quality of the included studies, and Addis-1.16 0.6 software for reticulated meta-analysis. Results: The results showed that PDT and palliative resection were superior to biliary stenting alone in improving 1-, 2-, and 3-year survivals, and the incidence of cholangitis. The relative effectiveness of PDT, palliative resection, and biliary stent placement alone in improving survival was as follows: PDT, palliative resection, and biliary stent placement alone. Conclusion: There is no significant difference between PDT and palliative resection in improving patient survival time, and PDT does not increase the incidence of cholangitis.

Traditional chemotherapy and immunotherapy-based systemic treatments for locally advanced or metastatic cholangiocarcinoma have been associated with poor clinical outcomes driven partly by molecular heterogeneity promoting early treatment resistance and a higher toxicity profile associated with these regimens. Few patients are eligible for upfront surgical resection and clinical studies have been traditionally difficult to conduct due to the orphan nature of this disease. However, increasing use of genomic profiling in clinical practice have led to active investigations of aberrant albeit promising mechanistic therapeutic targets such as IDH-1, FGFRs, BRAFV600E, HER-2 and NTRK. This review article aims to highlight the complex genomic landscape of this difficult-to-treat disease, followed by a discussion of evidence-based biological mechanisms that can be actioned using targeted agents. We explore the clinical rationale behind a targeted therapeutic strategy, the role of liquid biopsies in guiding clinical decisions and future treatment pathways for cholangiocarcinoma management. We also discuss the challenges and opportunities originating from recent clinical trials evaluating targeted treatments and our own institutional experience at UCLH that have aimed to address some of these biological complexities and have translated into improved patient outcomes via effective molecularly driven patient selection strategies. We also provide perspectives on emerging novel, next generation targeted inhibitors overcoming treatment resistance to previous targeted agents with demonstrated clinical value in a challenging patient population.

We examined the relation between several fibrotic markers reflecting liver parenchymal injury and conventional liver function or surgical outcomes in 67 patients with cholangiocarcinoma who underwent biliary drainage for obstructive jaundice followed by surgical resection.

We examined conventional clinicopathological factors, six hepatic fibrosis parameters, including platelet count, hyaluronic acid, Mac-2 binding protein glycosylation isomer (M2BPGi), type IV collagen 7S, aspartate aminotransferase-to-platelet ratio index (APRI), and FIB-4 index before hepatectomy, and surgical outcomes or long-term prognosis.

Obstructive jaundice was observed in 57% of the patients, a history of biliary diseases in 7.5%, and chronic hepatic injuries in 17.9%. M2BPGi was significantly higher in patients with obstructive jaundice as the primary sign (p <0.05), the FIB-4 index was significantly correlated with patient age (p <0.01), and serum hyaluronic acid and T4C7 levels were significantly increased in distal cholangiocarcinoma (CC). No markers were associated with the histological hepatic fibrotic index, tumor-related factors, or postoperative morbidities. Tumor relapse was observed in 37% of patients, and cancer-related death was observed in 25%. A higher FIB-4 index was significantly associated with shorter cancer-free survival (p <0.05). Cox multivariate analysis showed that bilirubin levels, poor histological cancer differentiation, and absence of fibrotic markers were associated with cancer-free, cancer-specific overall, and overall survival.

Although a sufficient relation exists between these markers and elastographic or histological fibrotic indexes, the clinical significance of measuring conventional fibrotic markers might no longer be necessary in future studies.

Background/Objectives: Biliary tract cancers (BTCs) are aggressive neoplasms with limited therapeutic options. The amount of prospective evidence is poor, and limited data are available on the impact of treatment sequencing on survival. Here we report a real-world experience of patients with advanced BTC treated with at least three lines of therapy. We evaluated the impact of sequential treatments, and we further compared the efficacy of Gemcitabine/Cisplatin (GemCis) and mFOLFOX to other first- and second-line chemotherapy regimens, respectively. Methods: Data on 60 patients with locally advanced or metastatic BTC under the care of a single Italian referral hospital and treated with at least three lines of chemotherapy were retrospectively collected. Data from 56 patients were included in the analysis. Survival analyses were performed using R software (v1.2.5042). Results: We compared the outcomes of patients treated according to the "standard" pre-immunotherapy sequence (GemCis and mFOLFOX in the first and second lines, respectively) versus those treated with all other combinations ("control" group). Our analysis did not show significant survival differences between the two groups. However, it should be noted that we selected long-survival patients by including only those who received at least three or more lines of chemotherapy. Focusing on the first-line setting, no significant differences in both mPFS and mOS emerged by comparing GemCis versus other doublets (mainly Gemcitabine/Oxaliplatin). Similarly, mPFS and mOS from second-line treatment did not statistically differ between patients treated with mFOLFOX versus those treated with other regimens (71% chemotherapy doublets). Conclusions: Our series provides real-world outcomes of patients with advanced BTC before the approval of immunotherapy. Even considering the monocentric and retrospective design, our study represents one of the first analyses on the impact of sequential treatment strategies in patients with BTC.

Treatment of perihilar cholangiocarcinoma (PHCC) and intrahepatic cholangiocarcinoma (IHCC) is a challenging issue. We aimed to investigate the clinical characteristics of both tumors and the outcome of our treatment policy.

We retrospectively analyzed data of 117 patients who were diagnosed with PHCC or IHCC between January 2007 and September 2023. Postoperative outcomes and the effects of prognostic factors on overall survival (OS) were investigated.

Surgical resection was performed on 47 patients (PHCC, n = 33 and IHCC, n = 14). Preoperative biliary drainage was applied in 32 of 33 cases with PHCC and 2 of 14 cases with IHCC. The mortality rate was 8.5% (n = 4). The complication rate was 68.1%. The R0 resection rate was 73% in PHCC. The mean OS time of PHCC cases that underwent R0 resection was 26.5 ± 24.8 months. The mean OS time of patients who underwent resection for IHCC was 28.7 ± 35.5 months. The OS was poorly affected by high CA19-9 levels (≥37 U/mL) (P = .005), the presence of lymphovascular invasion (P = .049), positive surgical margins after resection (P < .001), and the development of postoperative acute renal failure (P = .078). The OS of patients receiving adjuvant chemotherapy was significantly longer (P = .071). CA19-9 levels of more than 37 U/mL (P = .027) and positive surgical margin (P < .001) were independent factors for poor OS.

Surgical resection is the mainstay of multidisciplinary treatment for PHCC and IHCC. In advanced stages of IHCC, the combination of loco-regional therapies and repeat surgery, along with the enhanced efficacy of systemic chemotherapy, plays a significant role in a patient's survival.

Induction treatment may be beneficial in patients with unresectable locally advanced perihilar cholangiocarcinoma (LAPCCA). Prospective studies are currently lacking. This study aimed to assess the feasibility and efficacy of gemcitabine and cisplatin as induction treatment in patients with unresectable LAPCCA.

In this prospective single-center registration study, consecutive patients with unresectable LAPCCA who received induction treatment with gemcitabine and cisplatin in an intent to downsize the tumor to allow for resection were included. The primary outcomes were resection rate and overall survival.

Overall, 265 patients with perihilar cholangiocarcinoma were screened between January 2020 and June 2023, of whom 23 patients (9%) with unresectable LAPCCA met the eligibility criteria. Eight patients (35%) became eligible for resection, of whom six ultimately underwent resection (resection rate, 26% (11-42%)). Two out of 23 patients (9%) experienced adverse events grade≥3, forcing one to stop induction treatment. Compared to baseline, CA19.9 levels decreased by 42% (95 % CI, -65 to -5%; P = 0.039) and 8% (-44 to 112%; P = 0.80) at the first and second restaging, respectively. Tumor size did not significantly decrease after chemotherapy. Median overall survival was 27 months (18-36), with 40 (24-56) in the resected and 19 (13-26) in the unresected group (P = 0.127).

Patients with LAPCCA frequently tolerate induction gemcitabine-cisplatin, leading to a 26% resection rate with 40 months overall survival. These findings support routine re-staging after three to six cycles of palliative treatment, and lay the groundwork for future prospective trials in this patient group.

Cholangiocarcinoma (CCA) presents a formidable therapeutic challenge due to its extensive heterogeneity and plasticity, which inevitably lead to acquired resistance to current treatments. However, recent evidence suggests that acquired drug resistance is associated with a fitness cost resulting from the myriad of acquired alterations under the selective pressure of the primary treatment. Consequently, CCA patients with acquired resistance are more susceptible to alternative therapies that are ineffective as monotherapies. This phenomenon, termed "acquired vulnerability," has garnered significant interest in drug development, as the acquired alterations could potentially be exploited therapeutically. This review elucidates the modes of acquired vulnerability, methods for identifying and exploiting acquired vulnerabilities in cancer (particularly in CCA), and strategies to enhance the clinical efficacy of drug combinations by leveraging the principle of acquired vulnerability. Identifying acquired vulnerabilities may pave the way for novel drug combinations to effectively treat highly heterogeneous and adaptable malignancies such as CCA.

In cases of perihilar focal liver lesions, distinguishing between benign strictures and malignancies is critical to prevent unnecessary surgery. Although the use of contrast-enhanced CT or MRI in combination with clinical and laboratory findings can aid in diagnosis, histologic examination is often necessary. Histologic specimens can be obtained through various techniques, including ERCP-guided brush cytology or intraductal biopsy, cholangioscopy-directed biopsy or endoscopic ultrasound (EUS). However, these methods have been associated with suboptimal sensitivity and specificity, sometimes leading to inconclusive results. Therefore, ultrasound-guided percutaneous biopsy (US-guided PB) may play a crucial role, but data is lacking for perihilar lesions. The objective of our study was to assess the technical feasibility and safety of US-guided PB for perihilar lesions.

We included 20 consecutive patients who underwent US-guided PB of perihilar liver lesions that were not suitable for surgery between June 2018 and October 2023.

All samples were obtained using a Menghini needle 20G and were adequate for histological examination, with a mean diameter of 12.3 mm (range 3-40 mm). Out of the 20 patients, 11 were diagnosed with malignancy while the remaining 9 had inflammatory or fibrotic tissue samples. No adverse events related to the procedure were reported.

US-guided PB of perihilar liver lesions is a valuable and safe diagnostic approach to consider for patients who are not suitable for surgery.

Periampullary malignancies are uncommon and encompass a wide variety of tumors. Early and accurate biopsy-proven diagnosis is important because different malignancy subtypes warrant different management and treatment plans. We present a unique and rare case of periampullary lymphoma, initially presenting as acute pancreatitis.

Resection of perihilar cholangiocarcinoma (pCCA) is a complex procedure with a high risk of postoperative mortality and early disease recurrence. The objective of this study was to compare patient characteristics and overall survival (OS) between pCCA patients who underwent an R1 resection and patients with localized pCCA who received palliative systemic chemotherapy.

Patients with a diagnosis of pCCA between 1997-2021 were identified from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) registry. pCCA patients who underwent an R1 resection were compared with patients with localized pCCA (i.e., nonmetastatic) who were ineligible for surgical resection and received palliative systemic chemotherapy. The primary outcome was OS.

Overall, 146 patients in the R1 resection group and 92 patients in the palliative chemotherapy group were included. The palliative chemotherapy group more often underwent biliary drainage (95% vs. 66%, p < 0.001) and had more vascular encasement on imaging (70% vs. 49%, p = 0.012) and CA 19.9 was more frequently >200 IU/L (64 vs. 45%, p = 0.046). Median OS was comparable between both groups (17.1 vs. 16 months, p = 0.06). Overall survival at 5 years after diagnosis was 20.0% with R1 resection and 2.2% with chemotherapy. Type of treatment (i.e., R1 resection or palliative chemotherapy) was not an independent predictor of OS (hazard ratio 0.76, 95% confidence interval 0.55-1.07).

Palliative systemic chemotherapy should be considered instead of resection in patients with a high risk of both R1 resection and postoperative mortality.