Adenosquamous carcinoma (ASC) with the presence of a sarcomatous component is exceptionally uncommon in intrahepatic cholangiocarcinoma (iCCA). We report a case of hepatic ASC with rhabdoid transformation, one variation of sarcomatous change. A 72-year-old man was admitted to our hospital after being diagnosed with a 45 mm-diameter neoplastic lesion in the right hepatic duct on abdominal computed tomography. Laboratory findings showed increases in AST, ALT, ALP, gamma-GT, CA19-9 and DUPAN-II. The patient then underwent an extended right hepatectomy. Histopathologically, the tumor was composed of an ASC component within an abundant fibrous stroma and a sarcomatoid carcinoma component. By immunohistochemistry, keratin 7 and keratin 19 were expressed by all tumor cells. Expression of keratin 5/6, p40 and p63 was restricted to the squamous component. The sarcomatoid component was immunoreactive for vimentin with no loss of INI1 expression. This component also showed a loss of membranous E-cadherin expression and a reduction of membranous β-catenin expression. Staining for desmin, myoglobin and HepPar1 was negative in any tumor cells. The patient died of liver failure 3 months after surgery. This report aims to provide a better understanding of the clinicopathological characteristics and disease progression of the rare variants of iCCA to aid diagnosis and treatment.

A comprehensive review of 45-year trends in intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) in the United States has not been published. Given their rising incidence, our study aimed to analyze trends in incidence and survival, comparing ICC and ECC.

We extracted a 45-year dataset (1975-2020) from the Surveillance, Epidemiology, and End Results database. Age-adjusted incidence rates were calculated using SEERStat®. Annual Percent Change (APC) was estimated via weighted least squares. Relative survival (1- and 5-year) was calculated using the Ederer II method and compared across sexes and races.

A significant rise in ICC and ECC incidence was observed in both sexes (APC 3.71 for ICC vs. 6.16 for ECC; P<0.001). In females, ECC incidence increased more than ICC (APC 5.96 vs. 4.09, P<0.05), whereas males showed a fluctuating ECC trend and a steady ICC rise. Survival rates significantly improved across all races and sexes (P<0.05). ICC survival rose from 17.45% to 41.41% (1-year) and 2.83% to 10.99% (5-year), while ECC increased from 30.33% to 41.12% (1-year) and 5.96% to 10.44% (5-year). Among white and other-race females, ECC showed less improvement than ICC. Black individuals lacked statistically significant data.

Our study highlights disparities in ICC and ECC incidence, with higher rates in males, but better survival for ECC in males and ICC in females. The underrepresentation of Black individuals warrants further study to explore contributing factors such as risk, access to care, and treatment.

The plasma lipidome and immune cells are instrumental in shaping the health profile of an organism, and their influence on diseases is profound. However, the intricate interactions between cholangiocarcinoma (CCA) and these physiological components have yet to be comprehensively explored. Employing Mendelian randomization (MR), our study delved into the causal links among immune cells, the lipidome, and CCA. The research design meticulously considered both the direct associations and the mediating roles of immune cells within the complex interplay between the lipidome and CCA. Our analysis uncovered significant correlations between the levels of Sphingomyelin (d34:1), Phosphatidylcholine (0-16:0, 22:5) and Sterol ester (27:1/16:0) and CCA. Moreover, we have pinpointed various immune cells that play a mediating role in the impact of the lipidome on CCA. For example, Sphingomyelin (d34:1) can impact CCA through the IgD on IgD+ CD38- unswitched memory (unsw mem) B cell (B cell panel), IgD on unsw mem (B cell panel) and Naive CD4+ %CD4+ (maturation stages of T cell). The proportion of mediating effects further sheds light on the intricate interplay among the lipidome, immune cells, and their cumulative influence on CCA. Our study illuminates the intricate relationship among the lipidome, immune cells, and CCA. These findings suggest that the lipidome could serve as a promising and potentially effective therapeutic target in the treatment of CCA.

Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition.

This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1,000 mg/m2; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples.

Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo.

In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

Cholangiocarcinoma (CCA) is a diverse group of epithelial malignant tumors arising from the biliary tract, characterized by high molecular heterogeneity. It is classified into intrahepatic (iCCA) and extrahepatic CCA (eCCA) based on the location of the primary tumor. CCA accounts for approximately 15% of all primary liver cancers, with iCCA comprising 10-20% of all CCAs. iCCA is especially known for its characteristic aggressiveness and refractoriness, leading to poor prognosis. Despite the increasing global incidence and mortality rates, surgery remains the only available standard treatment approach for a subset (25%) of patients with early-stage, resectable iCCA. The paucity of effective systemic medical therapies restricts therapeutic options for patients with advanced or metastatic iCCA. In the past decade, advances in the understanding of the molecular complexity of these tumors have provided fruitful insights for the identification of promising new druggable targets and the development of feasible therapeutic strategies that may improve treatment outcomes for patients with iCCA. In this review, we aim to highlight critical up-to-date studies and medicinal chemistry aspects, focusing on novel targeted approaches utilizing promising candidates for molecular targeted therapy in iCCA. These candidates include aberrations in isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR), B-Raf proto-oncogene (BRAF), neurotrophic tyrosine receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1). Furthermore, this review provides an overview of potential inhibitors aimed at overcoming acquired drug resistance in these actionable targets for iCCA.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer characterized by a poor prognosis. Despite Zinc finger proteins (ZNFs) importance in tumor development and progression, it is unknown how dysregulated ZNF263 contributes to intrahepatic cholangiocarcinoma. This study aimed to determine whether ZNF263 plays an oncogenic role in ICC progression. The microarray of tumor tissues from clinical intrahepatic cholangiocarcinoma was immunohistochemically analyzed for ZNF263. Based on plate colony formation, CCK8, and tumor xenograft models, ZNF263 was assessed for its biological function. Mechanistically, CUT&Tag, RNA-seq, CHIP-PCR, Dual luciferase reporter assay, Western blotting, transmission electron microscopy (TEM), and immunohistochemical staining were employed. ZNF263 expression was elevated in intrahepatic cholangiocarcinoma tissues compared to nontumor tissues, which negatively impacted patient outcomes. Notably, ZNF263 overexpression promoted ICC cells proliferation via enhancing autophagy, whereas ZNF263 knockdown inhibited ICC cells proliferation. Furthermore, ZNF263 binds to the enhancer region of ULK1 and mediates its expression. ULK1 over-expressing ameliorated ZNF263 knockdown-induced inhibition of CRC proliferation. By activating the ULK1-autophagy axis, ZNF263 promotes proliferation of ICC and is potentially a prognostic or therapeutic target of ICC.

Intrahepatic cholangiocarcinoma (ICC) arises from the epithelial cells of the bile ducts present inside the liver parenchyma and is associated with an overall poor prognosis due to advanced disease stage at the time of diagnosis. We used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database to determine ICC-related mortality patterns in the United States from 1999 till 2020.

Age-adjusted mortality rates (AAMR) and crude mortality rates (CMR) were extracted from the CDC WONDER database. Annual percentage change (APC) was calculated using Joinpoint regression.

Our analysis of ICC-related deaths revealed a consistent upwards trend from 1999 to 2020 in the United States (APC: 3.59, 95% CI: 3.34 to 3.83, p < 0.05). AAMR remained higher in males (1.7, 95% CI: 1.6 to 1.7) than females in (1.3, 95% CI: 1.3 to 1.3). Upon stratification by geographical distribution, we observed the highest mortality rate in the Northeast region (AAMR: 1.6, 95% CI: 1 to 2) and urban areas (1.4, 95% CI: 1.3 to 1.5). The highest ICC-related AAMR was observed in Hawaii, Rhode Island, and Washington, with mortality rates being twice as high as states at the lower end of the spectrum, including Mississippi and Arkansas. Non-Hispanic Asian or Pacific Islanders exhibited the highest AAMR (1.9, 95% CI: 1.9 to 2) as compared to other racial groups, and adults aged ≥ 85 years exhibited the highest CMR (11.2, 95% CI: 10.3 to 12.1).

The rise in ICC-related deaths from 1999 to 2020 is concerning, with the AAMRs observed to be the highest in males, non-Hispanic Asian or Pacific Islanders, adults aged ≥ 85 years and residents of the Northeast region, urban areas, and Hawaii. Efforts must be directed towards vulnerable populations to decrease ICC-related mortality.

Cholangiocarcinoma (CCA) is a rare neoplasm, with high mortality, originating in the bile ducts. Its incidence is higher in Eastern countries due to the endemic prevalence of liver parasites. Factors such as metabolic syndrome, smoking, and pro-inflammatory conditions are also linked to the disease. Clinical features include asthenia, abdominal pain, cholestasis, and increased serum levels of CEA and CA19-9.

The aim of this study was to evaluate CCA prevalence, survival, and potential prognostic and therapeutic implications in a patient cohort and assess correlations with clinical laboratory data and possible associated risk factors.

This is a retrospective study of the clinical and histological data of patients diagnosed with CCA at Santa Casa de Misericórdia in Porto Alegre, Brazil, between 2016 and 2021.

There was a 56% prevalence of CCA in women, with intrahepatic localization in 55.4% of cases and unifocality in 85.6% of patients. The mean age of the patients was 63 years (26-89 years), with a mean tumor size of 5.5 cm. The median survival time was 7 months (0 to >50). CA19-9 was altered in 81% of patients, whereas GOT/GPT was altered in 62.5% and gamma-glutamyl transferase/alkaline phosphatase/bilirubin in 69.1% of patients. Mortality was higher among patients with extrahepatic CCA.

Risk factors such as smoking, cholecystectomy, cirrhosis, intrahepatic lithiasis, and transplantation should be considered individually by the attending physician for radiological monitoring and incidental discovery of the neoplasm. Lack of timely identification by the attending physician can delay diagnosis, increasing mortality.

We present a genome assembly from a specimen of Opisthorchis viverrini (liver fluke; Platyhelminthes; Trematoda; Opisthorchiida; Opisthorchiidae). The genome sequence has a total length of 627.20 megabases. Most of the assembly (97.89%) is scaffolded into 6 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 18.04 kilobases in length.

Despite a biologically established causative role of viral hepatitis (VH), i.e. HBV and HCV infections, on intrahepatic cholangiocarcinoma (ICC), only few large Western cohorts exploring the association between VH and ICC development are available. The prognostic significance of VH in ICC is debated, and no data are available regarding a predictive role for standard first-line CT (CT1), consisting of gemcitabine +/- platinoids. VH-positivity definition is often clinically incomplete and inconsistent among studies. Five different VH conditions, based on laboratory and anamnestic data, were investigated in a multicentric retrospective cohort of advanced ICC cases. Depending on the specific VH condition considered, 139-194 of 472 ICC cases could be categorized according to the presence of the mentioned VH conditions. VH prevalence ranged from 9.3 to 25.3%. No VH condition showed an impact on survival, although a non-significant worse outcome was observed for some HBV-related conditions. HCV-related conditions were associated to lower pre-CT1 biomarkers of inflammation, markedly higher disease control, and numerically longer time-to-progression with CT1. No benefit on time-to-progression was demonstrated for the addition of platinoids to gemcitabine in VH-positive patients (HR 0.77, CI95% 0.41-1.45), at least in HBV-related cases. These findings are clinically relevant and deserve further investigation.

Intrahepatic cholangiocarcinoma (ICC) is the second most frequent primary liver malignancy after hepatocellular carcinoma. Contemporary mortality trends due to ICC are largely unknown. We aim to examine the temporal trends of ICC-related deaths among older adults in the United States from 1999 to 2022.

We utilised the Centers for Disease Control and Prevention Wide-Ranging, Online Data for Epidemiologic Research (CDC WONDER) database, which provides information from death certificates of all US residents according to the International Classification of Diseases, Tenth Revision (ICD-10).

Between 1999 and 2022, there were 90 996 deaths attributed to ICC among individuals aged 65 and older. Overall, there is an increasing trend in ICC mortality; the total AAMR increased from 5.6 in 1999 to 14.3 in 2022 with an annual increase of 3.3%. Males had consistently higher AAMR than females across all years. For males, AAMR initially increased by 2.9% annually from 1999 to 2015, and since then, the rate has accelerated to a 3.9% annual increase. Conversely, females experienced a steady annual increase of 3.4% in AAMR from 1999 to 2022. When stratified by race, AAMR was highest among the Non-Hispanic (NH) Asian population, followed by Hispanic or Latino, NH Whites and NH Blacks. In brief, the AAMR has increased for all races; however, the NH Black population has experienced the greatest rise in AAMR during the study duration (APC: 4.0%; 95% CI, 3.5 to 4.8). Large metropolitan areas had a higher overall AAMR than small/medium metropolitan and non-metropolitan areas, though the rate of increase was comparable across all regions. States within the top 90th percentile of ICC-related deaths included Minnesota, Alaska, District of Columbia, Wisconsin, Massachusetts and Rhode Island.

Over the past two decades, there has been a consistent rise in mortality rates associated with intrahepatic cholangiocarcinoma in the United States. This upward trajectory underscores the imperative for additional research aimed at comprehending and delineating the underlying risk factors driving this increase.

Mass-forming intrahepatic cholangiocarcinoma (MF-ICC) is the second most common primary liver cancer and liver resection offers the best chance of possible cure. This study aimed to assess treatment outcomes and prognostic factors for long-term survival in patients who underwent curative-intent liver resection.

A retrospective analysis was conducted on prospectively collected data from patients with MF-ICC managed at the Royal North Shore/North Shore Private Hospital from January 1998 to October 2023. Baseline, peri-operative and long-term outcomes have been analysed, including an overall survival (OS) and disease-free survival (DFS) analysis.

During the 25-year study period, 47 patients underwent curative-intent liver resection for primary MF-ICC at a median age of 70 years. The median OS was 36 months, with a 5-year OS of 33%. Multiple liver tumours (HR = 2.84; 95% CI = 1.24-6.48; P = 0.013) and a positive resection margin (HR = 2.46; 95% CI = 1.10-5.52; P = 0.029) were identified as independent predictors of poor long-term OS. Recurrence occurred in 62% of patients after a median DFS of 16 months, with poor tumour differentiation (HR = 3.93; 95% CI = 1.62-9.54; P = 0.002) and elevated tumour markers (HR = 3.47; 95% CI = 1.53-7.87; P = 0.003) as independent predictors of poor DFS.

Liver resection can offer a significant chance for prolonged survival in a highly selected population of patients with MF-ICC. However, the surgical challenges inherent in treating this rare disease are evident, emphasizing the need for a multimodal approach and continued exploration of additional therapies to enhance personalized treatment strategies.

Liver resection plus lymphadenectomy is essential to ensure precise staging in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate the influence of the clinical status of lymph nodes on the survival outcomes in ICC patients.

Between January 2015 and December 2020, consecutive patients diagnosed with ICC who underwent liver resection plus lymphadenectomy were enrolled. Clinical assessment of lymph node status included positron emission tomography/computed tomography examination by radiologists pre-operatively, alongside intraoperative abdominal examination by the surgical team. Retrospective collection and analysis of clinical information alongside survival data were performed to assess outcomes.

The study included a total of 359 patients, with 291 (81.0%) and 151 (42.1%) displaying clinically and pathologically positive lymph nodes, respectively. The clinical assessment method had a sensitivity of 81.2% and a specificity of 54.3%. Following a median follow-up period of 32 months, the overall survival (OS) rates at 1, 3, and 5 years were 69.1%, 50.6%, and 41.2%, respectively, while the disease-free survival (DFS) rates were 60.7%, 42.8%, and 40.1%, respectively, across the cohort. Patients who had clinically positive but pathologically negative lymph nodes recorded the highest median OS (52 months) and median DFS (32 months). Conversely, those who were clinically negative but pathologically positive experienced the lowest median OS (16 months) and median DFS (8 months).

The current approach to clinically assessing lymph node status in ICC has a significant rate of false positives. Patients with clinically positive but pathologically negative lymph nodes exhibit the most favourable survival outcomes.

Cholangiocarcinoma (CCA) represents a global health challenge, with rising incidence and mortality rates. This study aimed to elucidate the clinical course and practices of CCA in Latin America.

This observational cohort study investigated individuals diagnosed with CCA between 2010 and 2023 at five referral centres across Latin America. Demographic, biochemical, and clinical data were analysed.

A total of 309 patients were enrolled, demonstrating a balanced distribution of CCA subtypes (intrahepatic, perihilar, and distal), with Hispanics and Caucasians as the predominant ethnic groups, followed by Africans. Major risk factors identified included age, diabetes, obesity, MASLD, bile duct stones, and cholecystitis. Disparities in overweight/obesity prevalence were noted among CCA subtypes and ethnicities, with higher rates in extrahepatic CCA and among Hispanics and Caucasians. At diagnosis, 72% of patients had ECOG-PS scores of 0-1, with disease presentations ranging from localized (47%) to locally advanced (19%) and metastatic (34%). Patients who did not receive any anti-cancer therapy exhibited a median survival of 2.3 months. Survival rates significantly improved across treatment modalities, with surgery yielding the longest (34 months), followed by chemotherapy (8 months). Notably, Africans presented with worse ECOG-PS scores and more advanced disease, while Hispanics were less frequently treated with chemotherapy for advanced disease, contributing to lower survival rates (8.3 and 6 months, respectively) compared to Caucasians (12.6 months).

The high prevalence of late-stage CCA diagnosis in Latin America, particularly among individuals of African ethnicity, coupled with a significant proportion of Hispanic patients not receiving chemotherapy, underscores the dismal prognosis for these patients. These findings reveal structural challenges in cancer screening and healthcare access among diverse ethnic backgrounds and lower socioeconomic statuses in the region. Urgent measures are needed, including the identification of preventable risk factors, raising awareness among high-risk populations, and establishing equitable health coverage to address these disparities.

European Union's Horizon 2020 R&I Program, Incyte Bioscience International Sàrl, and European Association for the Study of the Liver (EASL).

Systemic chemotherapy (SC) stands the only first-line treatment for advanced intrahepatic cholangiocarcinoma (iCCA) for the past few decades. Immune checkpoint inhibitors (ICIs) have been proved to provide additional benefit in disease control. However, oncological outcome of iCCA remains poor and awaits further improvement with new treatment modalities. Promising results have been observed in lenvatinib plus pembrolizumab (Len-P) as a second-line therapy in iCCA. This study aimed to explore the safety and efficacy of Len-P as a first-line therapy for iCCA patients in real-world clinical practice.

We retrospectively enrolled 133 patients with advanced iCCA who received Len-P or SC between May 2019 and May 2023. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were compared between the two groups.

There were 72 patients and 61 patients in the Len-P and SC groups, respectively. The median OS for the Len-P and SC groups was 16.3 and 17.8 months, respectively. The median PFS for the Len-P and SC groups was 8.9 and 11.4 months, respectively. There was no significant difference in ORR and DCR between the Len-P and SC groups (ORR: 22.2% vs. 23%; P=0.92; DCR: 69.4% vs. 77%; P=0.58). Additionally, the overall incidence of AEs was lower in the Len-P group than SC group. Low inflammation-based scores were indicative of favorable outcomes in patients undergoing Len-P therapy.

This study demonstrated that Len-P is promising for the treatment of advanced ICC, with highly improved safety. It emerges as a viable treatment alternative for advanced iCCA. Inflammation-based scores show potential utility in identifying individuals likely to benefit from Len-P therapy.

The assessment of tumor-infiltrating lymphocytes (TILs) has led to the development of various immunotherapies beyond their predictive potential in gastrointestinal malignancies. However, the clinicopathologic and prognostic values of TILs have yet to be well elucidated in distal extrahepatic bile duct carcinoma (DBDC).

We evaluated stromal TILs (sTILs) and intraepithelial TILs (iTILs) in 405 surgically resected DBDCs to analyze their correlations with overall survival (OS) and recurrence-free survival (RFS) and with clinicopathologic parameters according to the eighth edition of the American Joint Committee on Cancer scheme.

High levels of sTIL density (sTILHigh; >5%) and iTIL count (iTILHigh; >3) were found in 245 (61%) and 74 cases (18%), respectively. sTILHigh was more commonly found in larger tumors (P = 0.048) diffusely involving both intra- and extrapancreatic bile ducts (P = 0.013), in tumors with lower T category (P = 0.002), and in tumors without pancreatic (P = 0.003) or duodenal invasion (P < 0.001). iTILHigh was associated with tumors with papillary or nodular growth pattern (P < 0.001) without perineural invasion (P = 0.006). Both sTILHigh and iTILHigh significantly predicted better OS (P = 0.009 and 0.036, respectively) and RFS (P = 0.003 and 0.026, respectively). sTIL consistently provided prognostic predictability in OS, even when tested with different quantitative cut-offs and prognostically stratified OS (P = 0.006) and RFS (P = 0.005) on multivariate analysis. The survival benefit of sTILHigh persisted regardless of the stage in both OS (P = 0.010 for lower stages I and II and P = 0.001 for higher stages III and IV) and RFS (P = 0.004 and 0.025 for lower- and higher-stage tumors, respectively).

sTILs were superior to iTILs in predicting survival, and it was shown to be a strong prognosticator for DBDC patients regardless of the stage. The utility of sTILs may extend beyond prognostication to aid in predicting therapeutic responses in DBDC patients.

Biliary tract cancer (BTC) is a rare and aggressive malignancy that is anatomically classified as gallbladder cancer (GBC), extra- and intra-hepatic cholangiocarcinoma (eCCA and iCCA) and ampullary cancer (AC). BTC is often diagnosed at an advanced stage when treatment options are limited and patients have a poor prognosis, so the identification of new drug targets is of critical importance. BTC is molecularly diverse and harbours different therapeutically actionable biomarkers, including mouse double minute 2 homolog (MDM2), which is currently being investigated as a drug target. The aim of this targeted review was to evaluate and synthesise evidence on the epidemiology of BTC and its subtypes in different geographic regions and on the frequency of MDM2 amplifications in BTC tumours. Epidemiological studies (N = 33) consistently demonstrated high incidence rates in South and Central Asia for BTC overall (up to 9.00/100,000) and for all subtypes, with much lower rates in Europe and the US. Among the different types of BTC, the highest global incidence was observed for CCA, mainly driven by iCCA (1.4/100,000), followed by GBC (1.2/100,000) and AC (0.18-0.93 per 100,000). Studies of MDM2 in BTC (N = 19) demonstrated variable frequency of MDM2 amplification according to subtype, with consistently high MDM2 amplification rates in GBC (up to 17.5%), and lower rates in CCA (up to 4.4%). The results from this literature review highlight the geographic heterogeneity of BTC and the need for standardised clinicopathologic assessment and reporting to allow cross-study comparisons.

Chronic liver disease is a known risk factor for cholangiocarcinoma (CCA), but the proportion of people with CCA who have concurrent chronic liver disease is unclear. We aimed to evaluate the prevalence of chronic liver diseases in people with CCA.

In this single-arm meta-analysis, we searched MEDLINE and EMBASE from inception to August 10, 2024, for articles in English containing data for CCA with and without chronic liver diseases. Data were pooled to obtain the prevalence of different chronic liver diseases, with further stratification by geographical location and tumor location.

In total, 118,068 individuals diagnosed with CCA were included, of whom 16,771 had chronic liver diseases. A pooled analysis of 109 studies determined that the prevalence of chronic liver disease was 25.23% (95% confidence interval [CI], 20.82%-30.23%; I2 = 99.0%), and 10.21% (7.75%-13.35%; I2 = 98.6%) of CCA patients had cirrhosis. Chronic liver diseases were associated more with intrahepatic CCAs, compared with extrahepatic CCAs (relative risk, 2.46; 95% CI, 2.37-2.55; P < .0001). This was observed across all etiologies of liver disease, except for primary sclerosing cholangitis, which was associated with extrahepatic CCAs (relative risk, 0.49; 95% CI, 0.43-0.57; P < .0001).

Around 1 in 4 people with CCA have chronic liver diseases, and 1 in 10 have cirrhosis.

This study aims to investigate the interplay between tumor-associated endothelial cells (TECs) and immune cells within the tumor microenvironment (TME) and its impact on tumor prognosis. We conducted single-cell RNA sequencing (scRNA-seq) of tumor, normal, and lymph node tissues obtained from intrahepatic cholangiocarcinoma (ICC) patients to reveal the role of TECs in tumor angiogenesis and their significant heterogeneity. Meanwhile, we identified genes highly expressed in TECs and constructed TEC signatures (TEC.Sig). Next, we calculated TEC scores of samples based on TEC.Sig. Patients with higher TEC scores exhibited a higher frequency of KRAS mutations, which was associated with increased infiltration of neutrophils and immature dendritic cells (iDCs), and decreased numbers of natural killer (NK), CD4 + T, and CD8 + T effector memory (Tem) cells, indicating an inflammation-dominated immunosuppressive phenotype. In contrast, BAP1 mutations and CXCL12 overexpression showed a contrasting trend. Spatial transcriptomics analysis and histological experiments further confirmed that TECs interacted with various tumor-killing immune cells through the CXCL12/CXCR4 axis. Multiple tumor immunotherapy datasets confirmed that the TEC.Sig could predict patient responses to immunotherapy. The TEC score is a promising and reliable biomarker for predicting genetic mutations and prognosis in ICC patients. Enhancing the regulation of the CXCL12/CXCR4 signaling pathway may represent a potential novel therapeutic target for ICC treatment.

This research was intended to compare the clinical efficacy of hepatic arterial infusion chemotherapy (HAIC) in conjunction with lenvatinib and PD1 inhibitors to first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma(ICC). The research enrolled advanced ICC patients who underwent HAIC plus lenvatinib and PD1 inhibitor(n = 51) or first-line systemic chemotherapy(cisplatin + gemcitabine, n = 39) between July 2020 to January 2023 in Zhongshan People's Hospital.Their clinical outcomes were assessed through measurement of parameters encompassing objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), median progression-free survival (mPFS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). In accordance with the RECIST1.1, the ORR in the HAIC + L + P and SC groups was 43.1% and 20.5%, while the DCR was 90.2% and 69.2%, respectively (P = 0.04 and = 0.02, respectively). The change in the maximum diameter of intrahepatic target lesions in patients before and after treatment and the diameter of intrahepatic tumors in the HAIC + L + P group were sharply smaller versus the SC group ( P < 0.001). The HAIC + L + P group had prolonged mOS (16.8 months vs. 11.0 months, P = 0.01) and mPFS (12.0 months vs. 6.9 months, P < 0.01) in comparison with the SC group. Compared to first-line systemic chemotherapy(cisplatin + gemcitabine), HAIC plus lenvatinib and PD-1 inhibitors contributes to improvement of tumor response and prolongation of OS and PFS in advanced ICC patients.

Cholangiocarcinoma (CCA) is a highly malignant, rapidly progressing tumor of the bile duct. Owing to its chemoresistance, it always has an extremely poor prognosis. Therefore, detailed elucidation of the mechanisms of chemoresistance and identification of therapeutic targets are still needed.

We analyzed the expression of MBD2 (Methyl-CpG-binding domain 2) in CCA and normal bile duct tissues using the public database and immunohistochemistry (IHC). The roles of MBD2 in CCA cell proliferation, migration, and chemoresistance ability were validated through CCK-8, plate cloning assay, wound healing assays and xenograft mouse model. In addition, we constructed a primary CCA mouse model to further confirm the effect of MBD2. RNA-seq and co-IP-MS were used to identify the mechanisms by how MBD2 leads to chemoresistance.

MBD2 was upregulated in CCA. It promoted the proliferation, migration and chemoresistance of CCA cells. Mechanistically, MBD2 directly interacted with WDR5, bound to the promoter of ABCB1, promoted the trimethylation of H3K4 in this region through KMT2A, and activated the expression of ABCB1. Knocking down WDR5 or KMT2A blocked the transcriptional activation of ABCB1 by MBD2. The molecular inhibitor MM-102 targeted the interaction of WDR5 with KMT2A. MM-102 inhibited the expression of ABCB1 in CCA cells and decreased the chemoresistance of CCA to cisplatin.

MBD2 promotes the progression and chemoresistance of CCA through interactions with WDR5. MM-102 can effectively block this process and increase the sensitivity of CCA to cisplatin.

Intrahepatic cholangiocarcinoma (iCC) is an aggressive tumor, usually detected at an advanced stage. Our aim was to investigate the potential of body composition analysis (BCA) derived from presurgical staging computed tomography (CT) in predicting perisurgical complications.

In this retrospective cohort study, we enrolled 86 patients who underwent CT imaging prior to liver surgery. Cox and logistic regression were performed to assess risk factors for prolonged hospital and intensive care unit (ICU) stays, as well as the occurrence of various complications. BCA parameters served as covariates besides conventional risk factors.

Postoperative complications after resection of iCC significantly prolonged the overall length of hospitalization (p < .001). Presence of sarcopenia was associated with longer ICU stays. Complications were common, with 62.5% classified as Clavien-Dindo grade IIIa or lower and 37.5% as more severe. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were identified as risk factors for complications, including bile leakage (in 24 cases, p = .025), pleural effusions (in 26 cases, p = .025), and intra-abdominal abscess formation (in 24 cases, p = .043). SAT was associated with severe complications requiring interventional therapy, whereas VAT was correlated with abscess formation. Despite normal prevalence of obesity (22%), body mass index (BMI) did not have an impact on the development of perioperative complications.

BCA is a useful tool for preoperative risk stratification in patients with iCC and is superior to BMI assessment. Increased SAT and VAT were associated with the risk of perisurgical complications, prolonging hospitalization. Therefore, BCA derived from routine staging CT should be considered in the preoperative assessment of patients with iCC.

Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment.

We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated.

We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway.

Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA.

Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.

Epithelial splicing regulatory protein 1 (ESRP1) regulates tumor progression and metastasis through the epithelial‒mesenchymal transition by interacting with zinc finger E-box binding 1 (ZEB1) and CD44 in cancers. However, the role of ESRP1 in intrahepatic cholangiocarcinoma (iCCA) remains unclear.

Three iCCA cell lines (HuCCT-1, SSP-25, and KKU-100) were analyzed using small interfering RNA to investigate the molecular biological functions of ESRP1 and ZEB1. The association between clinicopathological features and the expression of ESRP1 and ZEB1 in iCCA tissues was analyzed immunohistochemically. Proteomic analysis was performed to identify molecules related to ESRP1 expression.

ESRP1 expression was upregulated in HuCCT-1 and SSP-25 cells. Cell migration and invasion were enhanced, and the expression of ZEB1 and CD44s (CD44 standard) isoforms were upregulated in the ESRP1 silencing cells. Moreover, ESRP1 silencing increased the expression of N-cadherin and vimentin, indicating the presence of mesenchymal properties. Conversely, ZEB1 silencing increased the expression of ESRP1 and CD44v (CD44 variant) isoforms. Immunohistochemical analysis revealed that a lower ESRP1-to-ZEB1 expression ratio was associated with poor recurrence-free survival in patients with iCCA. Flotillin 2, a lipid raft marker related to epithelial‒mesenchymal transition, was identified as a protein related to the interactive feedback loop in proteomic analysis.

ESRP1 suppresses tumor progression in iCCA by interacting with ZEB1 and CD44 to regulate epithelial‒mesenchymal transition.

Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.

The efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) and conventional TACE (c-TACE) in the treatment of patients with unresectable intrahepatic cholangiocarcinoma (ICC) remained controversial. Therefore, we aimed to compare the efficacy and safety between c-TACE and DEB-TACE among patients with ICC.

Between June 10, 2016 and November 19, 2022, consecutive patients with pathological diagnoses of ICC were divided into the DEB-TACE group and the c-TACE group based on the type of TACE treatment they received. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) between the two groups. Propensity score matching (PSM) was used to balance the characteristics between the c-TACE group and the DEB-TACE group.

A total of 132 patients were included in this study, with 64 patients in the c-TACE group and 68 patients in the DEB-TACE group. The median OS for c-TACE and DEB-TACE was 5 and 12 months, respectively. The objective response rate (ORR) for c-TACE and DEB-TACE was 0 % and 66.2 %, respectively; the disease control rate (DCR) was 37.5 % and 91.2 %. There were no significant differences between c-TACE and DEB-TACE among adverse effects at 3 months after treatment (P > 0.05). The results remained consistent after PSM. The Cox regression demonstrated that the DEB-TACE was an independent protective factor for OS.

Patients in the DEB-TACE group had longer OS and higher ORR and DCR than those in the c-TACE group, but no significant difference was observed between the two groups regarding adverse effects.

Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer with poor survival especially when it spreads. The histopathology of its rare intraductal papillary neoplasm of the bile duct type (IPNB) characteristically shows cancer cells originating within the confined bile duct space. These cells eventually invade and infiltrate the nearby liver tissues, making it a good model to study the mechanism of local invasion, which is the earliest step of metastasis. To discover potential suppressor genes of local invasion in ICC, we analyzed the somatic mutation profiles and performed clonal evolution analyses of the 11 pairs of macrodissected locally invasive IPNB tissues (LI-IPNB) and IPNB tissues without local invasion from the same patients. We identified a protein-truncating variant in an E3 ubiquitin ligase, RNF213 (c.6967C>T; p.Gln2323X; chr17: 78,319,102 [hg19], exon 29), as the most common protein-truncating variant event in LI-IPNB samples (4/11 patients). Knockdown of RNF213 in HuCCT1 and YSCCC cells showed increased migration and invasion, and reduced vasculogenic mimicry but maintained normal proliferation. Transcriptomic analysis of the RNF213-knockdown vs control cells was then performed in the HuCCT1, YSCCC, and KKU-100 cells. Gene ontology enrichment analysis of the common differentially expressed genes revealed significantly altered cytokine and oxidoreductase-oxidizing metal ion activities, as confirmed by Western blotting. Gene Set Enrichment Analysis identified the most enriched pathways being oxidative phosphorylation, fatty acid metabolism, reactive oxygen species, adipogenesis, and angiogenesis. In sum, loss-of-function mutation of RNF213 is a common genetic alteration in LI-IPNB tissues. RNF213 knockdown leads to increased migration and invasion of ICC cells, potentially through malfunctions of the pathways related to inflammation and energy metabolisms.

Routine blood tests are prognostic tests for patients with cholangiocarcinoma. New drug regimens may produce a median overall survival of 2 years or more.

This single practice, IRB-approved, phase II trial examines prognostic tests, Kaplan-Meier survival, and univariate Cox regression analyses. Eligibility requires: intent-to-treat; signed consent; advanced measurable intrahepatic cholangiocarcinoma, with or without resistance to the test drugs; any adult age; performance status 0-2; and expected survival of ≥ 6 weeks. Biweekly treatment, with 1/3 of standard dosages in mg/M2, includes: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hours; Leucovorin 180; Irinotecan 80; and on day 2, Oxaliplatin 40. On progression, drugs are added on day 2: first, Docetaxel 25 precedes Oxaliplatin, with or without Mitomycin C 6 after Oxaliplatin. The next sequential additions are day 1, Cetuximab 400 total mg, then 200 mg weekly, and then Bevacizumab 10 mg/kg is substituted for Cetuximab (FDA IND# 119005).

For 35 patients, 19 with 1-2 lines of prior therapy, resistant tumors, and 16 no prior therapy, survival at 24-months is ≥ 72 and ≥ 58%, respectively. For 14 patients aged ≥ 70 years, ≥ 63% survive 24 months, P = 0.28. Validated tests that predict ≤ 6-month survivals find median survival times of 17-months through > 2-years when compared to patients with favorable tests: Neutrophils lymphocyte ratio > 3.0, HR = 6.54, P < 6.4x10-3; absolute neutrophil count > 8000/μl, HR = 4.95, P < 6.5x10-3; serum albumin < 3.5 g/dl, HR = 4.10, P < 0.03; and lymphocyte monocyte ratio< 2.1, HR = 1.6, P = 0.50. Overall, the 76 (60-90)% of patients with 0-2 out of 4 high risk tests survive ≥ 24 months, (P = 7.1x10-3). Treatments produce neither hospitalization, neutropenic fever, severe enteritis, nor severe neuropathies.

Two-year survival is replicable and predictable. Findings warrant phase III validation tests of sequential regimens, re-challenge with recombination, low dosages, and blood tests that are associated with lethal mechanisms that impair response and survival.

Altered lipid metabolism is a common hallmark of various cancers, including intrahepatic cholangiocarcinoma (ICC), a highly lethal carcinoma that lacks effective treatment options. To elucidate the lipid metabolism changes in ICC, we coupled the expression of the firefly luciferase gene (FFL) to AKT1 (AKT-FFL) via an IRES linker, and then hydrodynamically injected mice with AKT-FFL and Notch1 intracellular cytoplasmic domain (NICD) to establish a luciferase-positive ICC model. This model not only enabled us to monitor and quantify tumor growth by injecting the mice with luciferin, but also allowed us to assess the fatty acid uptake rate by injecting the mice with free fatty acid luciferin (FFA-Luc). The ICC model exhibited robust uptake of exogenous fatty acids compared with the HCC model induced by AKT-FFL/ neuroblastoma Ras (Ras). Lipidomics analysis showed a dramatically higher level of fatty acid in ICC, further supporting the increased fatty acids uptake. Mechanistic studies identified FATP5 as the predominant mediator of fatty acid uptake required for ICC growth using Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5. Our study discovered a novel therapeutic target for the treatment of ICC and shed light on the contributions of lipid metabolism to ICC development.

This study provides the first in vivo evidence that FATP5 is a potential therapeutic target for treating ICC.