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Simple Summary: Inter-alpha-trypsin inhibitor-5 (ITIH5), a class II tumor suppressor gene, encodes a protein that is lost during tumor progression in many solid cancers. Unexpectedly, however, ITIH5 is significantly upregulated in cholangiocarcinoma (CCA), making it a potential liquid biopsy marker for early CCA detection, as recently shown. Indeed, CCA is the first tumor entity described in which ITIH5 is upregulated rather than downregulated in the tumor compared to normal tissue. In our study, we demonstrate that CCAs with abundant ITIH5 protein expression have favorable survival, a low UICC stage and the absence of perineural invasion. The re-expression of ITIH5 impairs the colony growth of cholangiocarcinoma cell lines. Although ITIH5 is upregulated in the tumor, it retains its tumor-suppressive function in CCA, similar to other tumor entities such as breast cancer and pancreatic cancer, where it is downregulated. Thus, ITIH5 may have both diagnostic and prognostic biomarker potential in CCA. The mechanisms of ITIH5 upregulation, particularly in intrahepatic CCAs, during oncogenic transformation remain unclear, but their elucidation could improve future CCA therapies. Background: Cholangiocarcinoma (CCA) are aggressive bile duct cancers with a poor prognosis for which there are only few established prognostic biomarkers and molecular targets available. The gene ITIH5, a known class II tumor suppressor gene (C2TSG), encodes a secreted protein of the extracellular matrix mediating tumor suppressive properties. Recently, it was surprisingly found that the ITIH5 protein is specifically upregulated in CCAs and that ITIH5 detection in blood could be an excellent liquid biopsy marker for indicating the presence of a CCA tumor in a patient. We therefore investigated whether patients with CCAs with abundant versus low ITIH5 protein expression also differ in their prognosis. Methods: To clarify this question, a large CCA cohort (n = 175) was examined using immunohistochemistry on a tissue microarray (TMA). Results: Abundant ITIH5 expression in CCA was associated with favorable survival, a low UICC stage and the absence of perineural invasion (PNI). Conclusions: ITIH5 has biomarker potential not only for the early detection of CCA from blood-based liquid biopsies but also as a prognostic tissue biomarker for risk stratification. Our results suggest that the upregulation of ITIH5 is particularly abundant in intrahepatic CCAs (iCCA). The mechanisms mediating the strong initial upregulation of ITIH5 during the oncogenic transformation of bile duct cells are still unclear. [ABSTRACT FROM AUTHOR]

Background: Metabolomics is an emerging field that quantifies numerous metabolites systematically aiming to determine the metabolites corresponding to each biological phenotype and then provide an analysis of the mechanisms involved. Bile acids (as an organic metabolites) are synthesized in the liver from cholesterol and could be used as indicator of hepatobiliary impairment. However, the role of these bile acids in the pathogenesis of cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) is still unclear. Therefore, the current study aimed to use serum bile acid profiles potential diagnostic biomarkers for early detection of cholangiocarcinoma and differentiating it from hepatocellular carcinoma. Subjects and methods: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/ MS) analytical method was used for the measurement of bile acids in the serum of patients with hepatocellular carcinoma (n = 35), cholangiocarcinoma (n = 35), and control group (n = 35) to determine role as markers for differentiation between hepatocellular carcinoma and cholangiocarcinoma. Results: This study revealed that there was a significant increase in all 14 bile acids in both HCC and CCA compared to control. Also, there was significant increase in LCA, TCA, GDCA, and GCA in cholangiocarcinoma (CCA) compared to HCC with AUC 0.775, 0.825, 0.797, and 0.831 respectively with highest sensitivity and specificity for GCA (82% and 74%, respectively) for differentiation between the two types of cancers. Conclusion: Determination of the serum bile acids pattern using UPLC/MS/MS may help to differentiate between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) especially GCA which may be a good biomarker for differentiation between two types of liver cancers. [ABSTRACT FROM AUTHOR]

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Long-term live cell imaging requires sophisticated and fully automated commercial-stage incubators equipped with specified inverted microscopes to regulate temperature, CO2 content, and humidity. In this study, we present a CO2-free on-stage incubator specifically designed for use across various cell culture platforms, enabling live cell imaging applications. A simple and transparent incubator was fabricated from acrylic sheets to be easily placed on the stages of most inverted microscopes. We successfully performed live-cell imaging of cholangiocarcinoma (CCA) cells and HeLa cell dynamics in both 2D and 3D microenvironments over three days. We also analyzed directed cell migration under high serum induction within a microfluidic device. Interesting phenomena such as "whole-colony migration", "novel type of collective cell migration" and "colony formation during cell and colony migration" are reported here for the first time, to the best of our knowledge. These phenomena may improve our understanding of the nature of cell migration and cancer metastasis. [ABSTRACT FROM AUTHOR]

We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 inhibition affects global protein acetylation, using genetic knockdown and pharmacological inhibition with an ACC1 inhibitor ND-646 as models. Both ACC1 knockdown and ACC1-inhibitor-treated cells displayed the hyperacetylation of proteins, accompanied by impaired growth and migration. The immunoprecipitation of hyperacetylated proteins using the anti-acetylated lysine antibody, followed by tandem mass spectrometry, identified three potential verification candidates, namely POTE ankyrin domain family member E, peroxisomal biogenesis factor 1, and heat shock protein 90 beta (HSP90B). HSP90 acetylation was the candidate selected for the verification of protein acetylation. To establish the effects of protein hyperacetylation, treatment with suberoylanilide hydroxamic acid (SAHA), a lysine deacetylase inhibitor, was conducted, and this served as an independent model. Decreased tumor growth but increased acetylated protein levels were observed in ACC1-KD xenograft tumors. Hyperacetylated-alleviated cell growth and migration were consistently observed in the SAHA-treated models. The molecular linkage between protein hyperacetylation and the AKT/GSK3β/Snail pathway was demonstrated. This study highlighted the importance of protein acetylation in CCA progression, suggesting that ACC1 and KDAC are potential targets for CCA treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Metabolomics is an emerging field that quantifies numerous metabolites systematically aiming to determine the metabolites corresponding to each biological phenotype and then provide an analysis of the mechanisms involved. Bile acids (as an organic metabolites) are synthesized in the liver from cholesterol and could be used as indicator of hepatobiliary impairment. However, the role of these bile acids in the pathogenesis of cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) is still unclear. Therefore, the current study aimed to use serum bile acid profiles potential diagnostic biomarkers for early detection of cholangiocarcinoma and differentiating it from hepatocellular carcinoma. Subjects and methods Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/ MS) analytical method was used for the measurement of bile acids in the serum of patients with hepatocellular carcinoma (n = 35), cholangiocarcinoma (n = 35), and control group (n = 35) to determine role as markers for differentiation between hepatocellular carcinoma and cholangiocarcinoma. Results This study revealed that there was a significant increase in all 14 bile acids in both HCC and CCA compared to control. Also, there was significant increase in LCA, TCA, GDCA, and GCA in cholangiocarcinoma (CCA) compared to HCC with AUC 0.775, 0.825, 0.797, and 0.831 respectively with highest sensitivity and specificity for GCA (82% and 74%, respectively) for differentiation between the two types of cancers. Conclusion Determination of the serum bile acids pattern using UPLC/MS/MS may help to differentiate between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) especially GCA which may be a good biomarker for differentiation between two types of liver cancers.

Significant advancements in our understanding and clinical treatment of cholangiocarcinoma (CCA) have been achieved over the past 5 years. Groundbreaking studies have illuminated the immune landscape and pathological characteristics of the tumor microenvironment in CCA. The development of immune- and metabolism-based classification systems has enabled a nuanced exploration of the tumor microenvironment and the origins of CCA, facilitating a detailed understanding of tumor progression modulation. Despite these insights, targeted therapies have not yet yielded satisfactory clinical results, highlighting the urgent need for innovative therapeutic strategies. This review delineates the complexity and heterogeneity of CCA, examines the current landscape of therapeutic strategies and clinical trials, and delves into the resistance mechanisms underlying targeted therapies. Finally, from a single-cell and spatial transcriptomic perspective, we address the challenge of therapy resistance, discussing emerging mechanisms and potential strategies to overcome this barrier and enhance treatment efficacy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and commonly associated with hepatic fibrosis or cirrhosis. This study aims to establish a rat model mimicking the progression from liver fibrosis to cirrhosis and subsequently to HCC using thioacetamide (TAA). We utilized male Lewis rats, treating them with intra-peritoneal injections of TAA. These rats received bi-weekly injections of either 200 mg/kg TAA or saline (as a control) over a period of 34 weeks. The development of cirrhosis and hepatocarcinogenesis was monitored through histopathological examinations, biochemical markers, and immunohistochemical analyses. Our results demonstrated that chronic TAA administration induced cirrhosis aggressive cholangiocarcinoma in addition to well-differentiated HCC, providing a model for early-stage, stage and a mixed liver cancer phenotype. This model is characterized by increased fibrosis, altered liver architecture, and increased hepatocyte proliferation. Biochemical analyses revealed significant alterations in liver function markers, including elevated alpha-fetoprotein (AFP) levels, without affecting kidney function or causing significant weight loss or mortality in rats. This TAA-induced cirrhosis and mixed HCC rat model successfully replicates the clinical progression of human HCC, particularly in terms of liver function impairment and early-stage liver cancer characteristics. It serves as a valuable tool for future research on the mechanisms of antitumor drugs in tumor initiation and development.

Cholangiocarcinoma (CCA), a highly aggressive primary liver cancer arising from the bile duct epithelium, represents a substantial proportion of hepatobiliary malignancies, posing formidable challenges in diagnosis and treatment. Notably, the global incidence of intrahepatic CCA has seen a rise, necessitating a critical examination of diagnostic and management strategies, especially due to presence of close imaging mimics such as hepatocellular carcinoma (HCC) and combined hepatocellular carcinoma–cholangiocarcinoma (cHCC–CCA). Hence, it is imperative to understand the role of various imaging modalities such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), elucidating their strengths, and limitations in diagnostic precision and staging accuracy. Beyond conventional approaches, there is emerging significance of functional imaging tools including positron emission tomography (PET)–CT and diffusion-weighted (DW)-MRI, providing pivotal insights into diagnosis, therapeutic assessment, and prognostic evaluation. This comprehensive review explores the risk factors, classification, clinical features, and role of imaging in the holistic spectrum of diagnosis, staging, management, and restaging for CCA, hence serving as a valuable resource for radiologists evaluating CCA. [ABSTRACT FROM AUTHOR]

Long-term live cell imaging requires sophisticated and fully automated commercial-stage incubators equipped with specified inverted microscopes to regulate temperature, CO2 content, and humidity. In this study, we present a CO2-free on-stage incubator specifically designed for use across various cell culture platforms, enabling live cell imaging applications. A simple and transparent incubator was fabricated from acrylic sheets to be easily placed on the stages of most inverted microscopes. We successfully performed live-cell imaging of cholangiocarcinoma (CCA) cells and HeLa cell dynamics in both 2D and 3D microenvironments over three days. We also analyzed directed cell migration under high serum induction within a microfluidic device. Interesting phenomena such as “whole-colony migration”, “novel type of collective cell migration” and “colony formation during cell and colony migration” are reported here for the first time, to the best of our knowledge. These phenomena may improve our understanding of the nature of cell migration and cancer metastasis.

We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 inhibition affects global protein acetylation, using genetic knockdown and pharmacological inhibition with an ACC1 inhibitor ND-646 as models. Both ACC1 knockdown and ACC1-inhibitor-treated cells displayed the hyperacetylation of proteins, accompanied by impaired growth and migration. The immunoprecipitation of hyperacetylated proteins using the anti-acetylated lysine antibody, followed by tandem mass spectrometry, identified three potential verification candidates, namely POTE ankyrin domain family member E, peroxisomal biogenesis factor 1, and heat shock protein 90 beta (HSP90B). HSP90 acetylation was the candidate selected for the verification of protein acetylation. To establish the effects of protein hyperacetylation, treatment with suberoylanilide hydroxamic acid (SAHA), a lysine deacetylase inhibitor, was conducted, and this served as an independent model. Decreased tumor growth but increased acetylated protein levels were observed in ACC1-KD xenograft tumors. Hyperacetylated-alleviated cell growth and migration were consistently observed in the SAHA-treated models. The molecular linkage between protein hyperacetylation and the AKT/GSK3β/Snail pathway was demonstrated. This study highlighted the importance of protein acetylation in CCA progression, suggesting that ACC1 and KDAC are potential targets for CCA treatment.

Cholangiocarcinoma, classified as intrahepatic, perihilar, and extrahepatic, is considered a deadly malignancy of the hepatobiliary system. Most cases of cholangiocarcinoma are asymptomatic. Therefore, early detection of cholangiocarcinoma is significant but still challenging. The routine screening of a tumor lacks specificity and accuracy. With the application of AI, high-risk patients can be easily found by analyzing their clinical characteristics, serum biomarkers, and medical images. Moreover, AI can be used to predict the prognosis including recurrence risk and metastasis. Although they have some limitations, AI algorithms will still significantly improve many aspects of cholangiocarcinoma in the medical field with the development of computing power and technology. [ABSTRACT FROM AUTHOR]

Patients with cholangiocarcinoma (CCA) with lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, the underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation of PDGF-BB in CAFs derived from patients with CCA with LMN (LN+CAFs). Clinically, the expression of CAFPDGF-BB correlated with poor prognosis and increased LMN in patients with CCA, while CAF-secreted PDGFBB enhanced lymphatic endothelial cell (LEC)-mediated lymphangiogenesis and promoted the trans-LEC migration ability of tumor cells. Co-injection of LN+CAFs and cancer cells increased tumor growth and LMN in vivo. Mechanistically, CAF-derived PDGF-BB activated its receptor PDGFR-β and its downstream ERK1/2-JNK signaling pathways in LECs to promote lymphoangiogenesis, while it also upregulated the PDGFR-β-GSK-P65-mediated tumor cell migration. Finally, targeting PDGF-BB/PDGFR-β or the GSK-P65 signaling axis prohibited CAF-mediated popliteal lymphatic metastasis (PLM) in vivo. Overall, our findings revealed that CAFs promote tumor growth and LMN via a paracrine network, identifying a promising therapeutic target for patients with advanced CCA. [ABSTRACT FROM AUTHOR]

Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Biliary cancers are rare, and few reported cases of brain metastases from primary biliary cancers exist, especially describing patients in the United States. This report assesses the proportion and incidence of brain metastases arising from primary biliary cancers [cholangiocarcinoma (CCA) and gallbladder cancer] at Stanford University and the University of California, San Francisco, describes clinical characteristics, and provides a case series. METHODS: We queried 3 clinical databases at Stanford and the University of California, San Francisco to retrospectively identify and review the charts of 15 patients with brain metastases from primary biliary cancers occurring between 1990 to 2020. RESULTS: Among patients with brain metastases analyzed at Stanford (3,585), 6 had a primary biliary cancer, representing 0.17% of all brain metastases. Among biliary cancer patients at the University of California, San Francisco (1,055), 9 had brain metastases, representing an incidence in biliary cancer of 0.85%. A total of 15 biliary cancer patients with brain metastases were identified at the two institutions. Thirteen out of 15 patients (86.7%, 95% CI: 59.5-98.3) were female. The median overall survival from primary biliary cancer diagnosis was 214 days (95% CI: 71.69-336.82 days) and subsequent OS from the time of brain metastasis diagnosis was 57 days (95% CI: 13.43-120.64 days). Death within 90 days of brain metastasis diagnosis occurred in 66.67% of patients (95% CI: 38.38-88.17). CONCLUSIONS: Brain metastases from primary biliary cancers are rare, with limited survival once diagnosed. This report can aid health care providers in caring for patients with brain metastases from primary biliary cancers.

This article is an editorial that discusses the potential benefits of using inflammatory markers in the diagnosis, prognosis, and treatment response prediction of liver cancers, specifically hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The authors highlight the importance of accurate pre-intervention prognostication and personalized treatment approaches for liver cancer patients. They also discuss various studies that have investigated the role of inflammatory markers, such as serum markers, gene signatures, and inflammation-based scores, in predicting HCC recurrence, survival, and treatment outcomes. Additionally, the article mentions the potential use of immune checkpoint inhibitors and tyrosine kinase inhibitors in combination with transcatheter arterial embolization (TACE) for unresectable HCC. The authors conclude that identifying reliable prognostic inflammatory markers is crucial for improving outcomes in liver cancer patients. [Extracted from the article]

Introduction: Systemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank. Methods: Expression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a highthroughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts. Results: Three preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordanceindex of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells. Discussion: In conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells. [ABSTRACT FROM AUTHOR]

Objectives: Plumbagin has been displayed on growth inhibition in several cancer cells; however, the anticancer effects of plumbagin on cholangiocarcinoma (CCA) cell are still less information. This article will explore the potential anticancer effects and underlying mechanisms of plumbagin on CCA cells. Materials and Methods: Two types of CCA cell, including KKU-100 with slow growth and migration and KKU-M452 with rapid growth and migration, were treated with plumbagin and measured the growth inhibition and migratory suppression by sulforhodamine B, colony formation, acridine orange/ethidium bromide staining, wound healing, and Matrigel migration. Apoptosis induction, reactive oxygen species (ROS) formation, and mitochondrial function were analyzed by the flow cytometric method. Results: To compare the plumbagin effects on two types of CCA cells, the data indicated that plumbagin strongly reduced cell proliferation in a concentration- and time-dependent manner. At 72 h, IC50 values were 1.11 ± 0.12 µM for KKU-100 and 2.52 ± 0.40 µM for KKU-M452 cells, with inhibition of the cell cycle in the G0/G1 phase for KKU-100 and the G2/M phase for KKU-M452, respectively. Moreover, plumbagin decreased cell migration in both CCA cells in a dose-dependent manner. Furthermore, late apoptosis was significantly induced after treatment with plumbagin. Mechanistically, plumbagin increased ROS along with decreased mitochondrial function in CCA cells. Finally, the position of 5-hydroxy on the naphthoquinone ring of plumbagin was in a good position to form an H-bond with the amino group for all caspase 3, cytochrome C, and p21 binding sites, and these data indicated that plumbagin suppressed CCA cells via modulation of these proteins. Conclusion: Plumbagin strongly suppresses cell viability and stimulates apoptosis in CCA cells via induction of ROS and inhibition of mitochondrial function. [ABSTRACT FROM AUTHOR]

Objectives: The difficulties in the early detection consequent to the lack of sensitive biomarkers render patients with cholangiocarcinoma (CCA) to have poor outcomes. Recently, sensitive and specific volatile organic compounds (VOCs) were identified in several cancers. However, the VOC profiles in CCA are not well-studied. Thus, we investigated the VOC profiles in exhaled breath of CCA patients and controls. Methods: We prospectively collected exhaled breath samples from 30 consecutive patients newly diagnosed with CCA and 30 controls who did not have CCA (seven had benign biliary strictures and 23 had other medical conditions). Exhaled VOCs were identified using gas chromatography mass spectrometry Triple Quadrupoles system. Analysis of the significant differences in VOCs between cases and controls was conducted using supervised multivariate regression analysis. Further validation was performed for these VOCs in another cohort of 18 CCA patients and 22 controls. Results: Levels of six compounds were significantly different between CCA patients and controls, namely, acetone, isopropyl alcohol, dimethyl sulfide, 1,4-pentadiene, allyl methyl sulfide, and N,N-dimethylacetamide. Acetone and dimethyl sulfide were independently associated with CCA as demonstrated in the multivariate analysis. Using the cut-off value of 8.59 × 107 arbitrary unit (AU), acetone had a sensitivity and specificity of 82.1% and 75.8%, respectively, with an area under the receiving operator curve (AUROC) of 0.85 for the CCA diagnosis. Acetone level was also significantly different between cases and controls in the validation cohort. Using the same cut-off value, the sensitivity, specificity, and AUROC was 59.1%, 66.7%, and 0.85, respectively. Conclusion: Breath analysis may potentially be useful for CCA diagnosis. A cohort of patients with early-stage CCA in further studies is needed to confirm the ability of exhaled VOCs for the early detection of CCA.

Background: Cholangiocarcinoma (CCA) is a silent tumor with a high mortality rate due to the difficulty of early diagnosis and prediction of recurrence even after timely surgery. Serologic cancer biomarkers have been used in clinical practice, but their low specificity and sensitivity have been problematic. In this study, we aimed to identify CCA-specific glycan epitopes that can be used for diagnosis and to elucidate the mechanisms by which glycosylation is altered with tumor progression. Methods: The serum of patients with various cancers was fractioned into membrane-bound and soluble components using serial ultracentrifugation. Lectin blotting was conducted to evaluate glycosylation. Proteins having altered glycosylation were identified using proteomic analysis and further confirmed using immunoblotting analysis. We performed HPLC, gene analysis, real-time cargo tracking, and immunohistochemistry to determine the origin of CCA glycosylation and its underlying mechanisms. Extracellular vesicles (EV) were isolated from the sera of 62 patients with CCA at different clinical stages and inflammatory conditions and used for glycan analysis to assess their clinical significance. Results: The results reveal that glycosylation patterns between soluble and membrane-bound fractions differ significantly even when obtained from the same donor. Notably, glycans with a1-3/4 fucose and b1-6GlcNAc branched structures increase specifically in membrane-bound fractions of CCA. Mechanically, it is primarily due to b-haptoglobin (b-Hp) originating from CCA expressing fucosyltransferase-3/4 (FUT 3/4) and N-acetylglucosaminyltransferase-V (MGAT5). Newly synthesized b-Hp is loaded into EVs in early endosomes via a KFERQ-like motif and then secreted from CCA cells to induce tumor progression. In contrast, b-Hp expressed by hepatocytes is secreted in a soluble form that does not affect CCA progression. Moreover, evaluation of EV glycosylation in CCA patients shows that fucosylation level of EV-Hp gradually increases with tumor progression and decreases markedly when the tumors are eliminated by surgery. Conclusion: This study suggests that terminal fucosylation of Hp in cancerderived exosomes can be a novel glycan marker for diagnosis and prognosis of CCA. These findings highlight the potential of glycan analysis in different fractions of serum for biomarker discover for other diseases. Further research is needed to understand the role of fucosylated EVs on CCA progression. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CCA) is a malignant disease of the epithelial cells of the intrahepatic and extrahepatic bile ducts. This review focuses on various aspects of cholangiocarcinoma such as its associated causes, treatment criteria, and more. Methods: Although it remains a rare malignancy and is the second most common primary malignancy of the liver, the incidence is increasing, especially the incidence of intrahepatic CCA. Several studies suggested that surgery is not only solution; recently, reported targeted drugs may have the potential to become an alternative option. Results: This review provides an overview of the current scenario of targeted therapies for CCA, which were tabulated with their current status and it also included its associated causes and its treatment criteria. Conclusion: Because of its rarity and complexity, surgery remains the preferred treatment in resectable patients. Howerver, the studies suggested that the recently reported drugs may have the potential to be an alternative option for the treatment of CCA and related complications. In addition, this review will certainly benefit the community and researcher for further investigation. [ABSTRACT FROM AUTHOR]

IntroductionSystemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank.MethodsExpression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a high-throughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts.ResultsThree preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordance-index of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells.DiscussionIn conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells.

Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.

Cholangiocarcinoma (CCA) are the second most common primary liver tumors and carry a dismal prognosis. Chemosaturation with percutaneous hepatic perfusion (PHP) is a palliative, intra-arterial therapeutic approach that provides a high dose chemotherapy of the liver with reduced systemic exposure. Aim of this retrospective, monocentric study was to analyze PHP as a palliative treatment for unresectable CCA. Toxicity, adverse events and complications were classified using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1). Median overall survival (mOS), median progression-free survival (mPFS) and hepatic mPFS (mhPFS) were computed using Kaplan–Meier estimation. In total 17 patients were treated with 42 PHP between 10/2014 and 09/2020. No significant complications occurred during the interventions. mOS was 27.6 (interquartile range (IQR) 16.5–37) months from first diagnosis and 9.9 (IQR 3.8–21) months from first PHP. mPFS was 4 (IQR 2–7) and mhPFS was 4 (IQR 3–10) months. ORR was 25% and DCR 75%. Significant, but transient hematotoxicity was frequent with grade 3/4 thrombopenia after 50%, leukopenia after 26% and anaemia after 21% of the interventions. An increase of transaminases (AST increase after 21% and ALT increase after 14% of the PHP) developed more often than a deterioration of the liver synthesis capacity. Salvage treatment with PHP has the potential to prolong life in selected patients with unresectable, refractory cholangiocarcinoma. The interventional procedure is safe. Post-interventional toxicity is frequent but manageable. [ABSTRACT FROM AUTHOR]

Patients with cholangiocarcinoma (CCA) often have an unfavorable prognosis because of its insidious nature, low resectability rate, and poor response to anticancer drugs and radiotherapy, which makes early detection and treatment difficult. At present, CCA has a five-year overall survival rate (OS) of only 5%, despite advances in therapies. New an increasing number of evidence suggests that nanoplatforms may play a crucial role in enhancing the pharmacological effects and in reducing both short- and long-term side effects of cancer treatment. This document reviews the advantages and shortcomings of nanoparticles such as liposomes, polymeric nanoparticle，inorganic nanoparticle, nano-metals and nano-alloys, carbon dots, nano-micelles, dendrimer, nano-capsule, bio-Nanomaterials in the diagnosis and treatment of CCA and discuss the current challenges in of nanoplatforms for CCA.

Background and aimIndeterminate biliary stricture (IBS) is a frequently encountered clinical problem. In this study, we aimed to highlight the clinical characteristics, risk factors and diagnostic outcomes of patients presented with indeterminate biliary stricture.MethodA Retrospective multicenter study included all patients diagnosed with IBS in the participating centers between 2017 and 2021. Data regarding IBS such as presentations, patient characteristics, diagnostic and therapeutic modalities were collected from the patients' records and then were analyzed.ResultsData of 315 patients with IBS were retrospectively collected from 7 medical centers with mean age: 62.6 ± 11 years, females: 40.3% and smokers: 44.8%. For diagnosing stricture; Magnetic resonance imaging/Magnetic resonance cholangiopancreatography (MRI/MRCP) was the most frequently requested imaging modality in all patients, Contrast enhanced computerized tomography (CECT) in 85% and endoscopic ultrasound (EUS) in 23.8%. Tissue diagnosis of cholangiocarcinoma was achieved in 14% only. The used therapeutic modalities were endoscopic retrograde cholangiopancreatography (ERCP)/stenting in 70.5%, percutaneous trans-hepatic biliary drainage (PTD): 17.8%, EUS guided drainage: 0.3%, and surgical resection in 8%. The most frequent type of strictures was distal stricture in 181 patients, perihilar in 128 and intrahepatic in 6. Distal strictures had significant male predominance, with higher role for EUS for diagnosis and higher role for ERCP/stenting for drainage, while in the perihilar strictures, there was higher role for CECT and MRI/MRCP for diagnosis and more frequent use of PTD for drainage.ConclusionIndeterminate biliary stricture is a challenging clinical problem with lack of tissue diagnosis in most of cases mandates an urgent consensus diagnostic and treatment guidelines.

Purpose: Cholangiocarcinoma (CCA) is a cancer of the biliary system, including intrahepatic and extrahepatic cholangiocarcinoma, and is highly aggressive. C-type lectins family member 3b (CLEC3B) is a Ca 2+ binding transmembrane protein with different biological functions in a variety of cancers. The objective of this study was to explore the biological function of CLEC3B in CCA., Methods: The CLEC3B gene was identified using the TCGA database and survival analysis of the cholangiocarcinoma clinical cohort. The expression CLEC3B cholangiocarcinoma and correlation with prognosis was investigated in our patient cohort. The effects of CLEC3B on proliferation, apoptosis, migration and invasion were verified in QBC939 and HUCCT1 cells. The effect of CLEC3B on the tumor formation was proved by xenograft tumor model in nude mice. The signaling pathway of CLEC3B in regulating CCA progression was further analyzed RNA sequencing and western blot., Results: CLEC3B was decreased in the cholangiocarcinoma in the database. The mRNA and protein expression level of CLEC3B were significantly lower and correlated with poor overall survival in cholangiocarcinoma of our patient cohort. In vitro experiments proved that overexpression of CLEC3B can inhibit proliferation, migration and invasion in bile duct cancer cells. The CLEC3B was correlated with epithelial-mesenchymal transition and apoptosis. The calcium could promote the biological function of CLEC3B. The vivo study indicated that CLEC3B inhibited tumor formation. RNA sequencing indicating CLEC3B may transduce signal through e Wnt/β-catenin signaling pathway., Conclusions: The CLEC3B inhibits cellular proliferation and migration of cholangiocarcinoma through the Wnt/β-catenin pathway., Competing Interests: The authors declare there are no competing interests., (©2024 Wu et al.)

Hepatobiliary malignancies (HBMs), primarily hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), share the common traits of having a generally poor prognosis, late presentation, and high symptom burden related to both the disease process itself and underlying poor liver function. The incidences of both malignancies have been rising in recent decades for unclear reasons. Curative options remain limited given the general aggressive disease course despite advances in diagnosis, therapies, and surgery. Early integration of palliative care into the routine care of patients with HBMs is an essential, but underutilized, component of care to improve the functional and symptomatic quality of the lives of patients and their families. While formal guidelines for its integration are currently lacking, palliative care can and should be provided in parallel to disease specific care at any stage to address the physical, emotional, and spiritual needs of patients with HBMs. In this review, the special needs of this patient population are examined ranging from early symptom management at the time of diagnosis all the way through to end-oflife care. Key barriers that prevent the early provision of palliative care for patients with HBMs are identified and discussed and recommendations provided on how to improve early integration.

The tumor immune microenvironment significantly affects tumor progression, metastasis, and clinical therapy. Its basic cell components include tumor-associated endothelial cells, fibroblasts, and macrophages, all of which constitute the tumor stroma and microvascular network. However, the functions of tumor stromal cells have not yet been fully elucidated. The three-dimensional (3D) model created by 3D bioprinting is an efficient way to illustrate cellular interactions in vitro. However, 3D bioprinted model has not been used to explore the effects of stromal cells on cholangiocarcinoma cells. In this study, we fabricated 3D bioprinted models with tumor cells and stromal cells. Compared with cells cultured in two-dimensional (2D) environment, cells in 3D bioprinted models exhibited better proliferation, higher expression of tumor-related genes, and drug resistance. The existence of stromal cells promoted tumor cell activity in 3D models. Our study shows that 3D bioprinting of an immune microenvironment is an effective way to study the effects of stromal cells on cholangiocarcinoma cells. [ABSTRACT FROM AUTHOR]

Background: The systemic immune-inflammation index (SII) is a significant prognostic factor for neoplastic diseases. However, the prognostic value of SII in patients with cholangiocarcinoma (CCA) remains unclear. This meta-analysis aimed to investigate the prognostic value of preoperative SII in patients with CCA. Method: We systematically searched for relevant studies in PubMed, Scopus, EMBASE, Web of Science, PROSPERO, and Cochrane Library databases up to March 22, 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the association between SII and survival outcomes, including overall survival (OS) and recurrence-free survival. Results: Five studies with 1402 patients were included in this meta-analysis to determine the prognostic value of preoperative SII. The results showed that a higher SII was associated with poor OS in patients with CCA who underwent invasive surgery (HR=1.916; 95% CI, 1.5662.343; Z=6.329; P<0.001). The results were reliable in the subgroup analysis according to country, age, sample size, SII cutoff values, and treatment methods. Conclusions: A high preoperative SII appears to be an effective and practical method for monitoring survival in patients with CCA. Systematic Review Registration: International Platform of Registered Systematic. Review and Meta-Analysis Protocols (INPLASY), identifier INPLASY202240015. [ABSTRACT FROM AUTHOR]

The co-delivery of multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a monodisperse mesoporous silica nanoparticle (mSiO2) is prepared and functionalized into high-efficiency loaded Lenvatinib and Bufalin for targeted delivery to Cholangiocarcinoma (CCA). mSiO2 was synthesized on solid silica nanoparticles by oil–water interface method, and highly monodisperse mSiO2 with uniform morphology was obtained. mSiO2 was then sequentially modified by polyethylene glycol (PEG) and the targeting molecule folic acid (FA). mSiO2-FA was designed as co-delivery system for Lenvatinib (Le) and Bufalin (Bu) to increase drug availability and highly target tumor cells. Compared with unfunctionalized mSiO2, mSiO2-FA can more efficiently enter human CCA cell lines (9810 cells) and enhance intracellular drug delivery. Moreover, drug-loaded mSiO2-FA (Le/Bu@mSiO2-FA) significantly inhibited the viability, migration and invasion of 9810 cells. In vivo, the nanocomplex significantly reduced the tumor load in CCA tumor-bearing mouse models compared to Le or Bu alone. The current work provides a useful strategy for highly targeted and multidrug-resistance reversal therapy for CCA. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA), or biliary tract cancer, has a poor prognosis. The median survival time among patients with CCA is under 2 years from diagnosis, and the global 5-year survival rate is only 10%. First-line therapy with chemotherapeutic agents, gemcitabine plus cisplatin, has traditionally been used to treat unresectable advanced CCA. In recent years, precision medicine has become a mainstream cancer treatment due to innovative next-generation sequencing technology. Several genetic alterations, including mutations, gene fusions, and copy number variations, have been found in CCA. In this review, we summarized the current understanding of genetic profiling in CCA and targeted therapy in CCA. Owing to the high heterogeneity of CCA, tumor microenvironmental factors, and the complexity of tumor biology, only pemigatinib, infigratinib, ivosidenib, larotrbctinib, and entrectinib are currently approved for the treatment of CCA patients with fibroblast growth factor receptor 2 gene (FGFR2) fusion, isocitrate dehydrogenase gene (IDH1) mutation, and neurotrophin receptor tyrosine kinase gene (NRTK) fusion, respectively. Additional targeted therapies, including other FGFR2 inhibitors, PI3K/AKT/mTOR inhibitors, and BRAF-directed targeted therapy, have been discussed for the management of CCA, and immune checkpoint inhibitors, particularly pembrolizumab, can be administered to patients with high microsatellite instability tumors. There is a further need for improvement in precision medicine therapies in the treatment of CCA and discuss the approved and potential targeted therapies for CCA. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is one of the most difficult to treat cancers, and its nature of being largely refractory to most, if not all, current treatments results in generally poor prognosis and high mortality. Efficacious alternative therapies that can be used ubiquitously are urgently needed. Using acquired vulnerability screening, we observed that CCA cells that reprofile and proliferate under CDK4/6 inhibition became vulnerable to ribosomal biogenesis stress and hypersensitive to the anti-ribosome chemotherapy oxaliplatin. CCA cells overexpress the oncogenic ribosomal protein RPL29 under CDK4/6 inhibition in a manner that correlated with CDK4/6 inhibitor resistance. Depletion of RPL29 by small interfering RNAs (siRNAs) restored the sensitivity of CCA cells to CDK4/6 inhibition. Oxaliplatin treatment suppressed the RPL29 expression in the CDK4/6 inhibitor treated CCA cells and triggered RPL5/11-MDM2-dependent p53 activation and cancer apoptosis. In addition, we found that combination treatment with oxaliplatin and the CDK4/6 inhibitor palbociclib synergistically inhibited both parental and CDK4/6 inhibitor-resistant CCA, and prevented the emergence of CDK4/6 and oxaliplatin-resistant CCA. This drug combination also exerted suppressive and apoptosis effects on CCA in the in vitro 3-dimensional culture, patient-derived organoid, and in vivo xenograft CCA models. These results suggest the combination of the CDK4/6 inhibitor palbociclib and the anti-ribosome drug oxaliplatin as a potentially promising treatment for cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy, however, it is difficult to diagnose and treat, and only a few patients with CCA are suitable for surgery. Iodine-125 (I-125) is an effective treatment for cancer, but the molecular mechanisms underlying the effects of I-125 differ among different cancers. This study aimed to explore the effects of I-125 on CCA cell activity and determine the possible mechanisms of action of I-125 in this type of cancer. CCA cell proliferation, cycling, apoptosis, autophagy, and endoplasmic reticulum (ER) stress were determined after irradiation of CCA cells with I-125 seeds. The effects of I-125 on autophagy and ER stress in three CCA cell lines were evaluated using western blotting, while the effects of I-125 on apoptosis and autophagy in QBC939 cells treated with si-Beclin1 or si-PERK, respectively, were assessed using flow cytometry. I-125 suppressed cell viability and induced cell cycle G2/M-phase arrest in three CCA cell lines (QBC939, TFK-1, HuCCT1). I-125 induced apoptosis, autophagy, and ER stress by altering the expression levels of some related proteins in each of the three CCA cell lines. Furthermore, autophagy inhibition (treatment with si-Beclin1) increased expression of apoptosis-related proteins (cleaved-PARP and cleaved-caspase-3, Bax/Bcl2) in QBC939 cells irradiated with I-125 seeds, while ER stress inhibition (with si-PERK) suppressed the expression of autophagy-related proteins (LC3-I, LC3-II, p62). Therefore, I-125 induces ER stress, thereby activating protective autophagy in CCA cells through the PERK signaling pathway. Combined inhibition of ER stress and autophagy signaling may increase the killing effect of I-125 on cancer cells and serve as a new auxiliary method in I-125 radiotherapy. [ABSTRACT FROM AUTHOR]

Major hepatectomy for perihilar and intrahepatic cholangiocarcinoma (CCA) is often associated with a significant intraoperative blood loss and the requirement for perioperative transfusion of blood products. The aim of this study was to investigate the oncological impact of fresh frozen plasma (FFP) transfusion during hospitalization in patients undergoing hepatectomy for CCA as adverse effects have been described in other malignancies. Patients undergoing hepatectomy for CCA from 2010 to 2019 at a single institution were eligible for this study. Survival analysis was carried out according to Kaplan-Meier and the associations of cancer-specific (CSS) and recurrence-free survival (RFS) with in-hospital application of FFP and other clinico-pathological characteristics were assessed using Cox regression models. Perioperatively deceased patients were excluded from the analysis. A total of 219 CCA patients were included in this survival analysis of which 53.0% (116/219) received FFP during hospitalization. Patients receiving in-hospital FFP showed a median CCS of 33 months (3-year-CSS = 46%, 5-year-CSS = 29%) compared to 83 months (3-year-CSS = 55%, 5-year-CSS = 53%) in patients who did not receive in-hospital FFP (p = 0.006 log rank). Further, in-hospital FFP was identified as an independent predictor of oncological outcome in multivariable analysis (CSS: HR = 1.71, p = 0.016; RFS: HR = 1.89, p = 0.003). In a large European cohort of patients, in-hospital transfusion of FFP was identified as a novel independent prognostic marker in CCA patients undergoing curative-intent liver surgery. A restrictive transfusion policy is therefore recommended to improve long-term outcome in these patients. [ABSTRACT FROM AUTHOR]

Cholangiocarcinomas (CCAs) are tumors that arise from the cholangiocytes. Although some genes have been shown with important roles in pathological process, interactions or cross-talks among different RNAs are important to understand the detailed molecular mechanisms in cancer development, especially discussing cross-talks among isomiRs and other RNAs. Herein, to characterize crucial genes in CCA, the protein expression profile was performed to survey potential crucial mRNAs and related non-coding RNAs (ncRNAs) in mRNA-ncRNA network, mainly including miRNAs/isomiRs and lncRNAs. Deregulated mRNAs were firstly obtained if consistent expression patterns were found at protein and mRNA levels, and related miRNAs/isomiRs were screened according to regulatory relationships. Diverse isomiRs from a given miRNA locus also contributed to interactions between the small RNAs and target mRNAs, and miRNAs were further used to survey related lncRNAs to expand the interactions. Thus, several groups of RNAs were constructed as candidate competitive endogenous RNA (ceRNA) networks. Finally, we found that RAB11FIP1:miR-101-3p:MIR3142HG may be a potential ceRNA network, and the interactions among them may be more complex due to variety of isomiRs. Simultaneously, RAB11FIP1 and miR-194-5p were also detected other related lncRNAs (FBXL19-AS1, SNHG1 and PVT1) that may be crucial in coding-non-coding RNA regulatory network. Our results show that diverse isomiRs with sequence and expression heterogeneities contribute to ceRNA regulatory network that may have crucial roles in CCA, which will expand our understanding of interactions among diverse RNAs and their contributions in cancer development.

Cholangiocarcinoma (CCA) is one of the most difficult to treat cancers, and its nature of being largely refractory to most, if not all, current treatments results in generally poor prognosis and high mortality. Efficacious alternative therapies that can be used ubiquitously are urgently needed. Using acquired vulnerability screening, we observed that CCA cells that reprofile and proliferate under CDK4/6 inhibition became vulnerable to ribosomal biogenesis stress and hypersensitive to the anti-ribosome chemotherapy oxaliplatin. CCA cells overexpress the oncogenic ribosomal protein RPL29 under CDK4/6 inhibition in a manner that correlated with CDK4/6 inhibitor resistance. Depletion of RPL29 by small interfering RNAs (siRNAs) restored the sensitivity of CCA cells to CDK4/6 inhibition. Oxaliplatin treatment suppressed the RPL29 expression in the CDK4/6 inhibitor treated CCA cells and triggered RPL5/11-MDM2-dependent p53 activation and cancer apoptosis. In addition, we found that combination treatment with oxaliplatin and the CDK4/6 inhibitor palbociclib synergistically inhibited both parental and CDK4/6 inhibitor-resistant CCA, and prevented the emergence of CDK4/6 and oxaliplatin-resistant CCA. This drug combination also exerted suppressive and apoptosis effects on CCA in the in vitro 3-dimensional culture, patient-derived organoid, and in vivo xenograft CCA models. These results suggest the combination of the CDK4/6 inhibitor palbociclib and the anti-ribosome drug oxaliplatin as a potentially promising treatment for cholangiocarcinoma.

Cholangiocarcinomas (CCA) are uncommon malignant tumours and are classified as intrahepatic, perihilar, or distal, depending on where they arise within the biliary epithelium. Surgery is still the only curative treatment, yet diagnosis is often made too late for this to be a viable option. For patients with locally advanced (unresectable), metastatic, or recurrent CCA, guidelines recommend palliative first-line chemotherapy with platinum compounds plus gemcitabine. However, the benefits are limited, with median overall survival being below 1 year, and there is an urgent need for novel, more effective treatment options. Next-generation sequencing has revealed information about the genetic makeup of the CCA subtypes and CCA, especially intrahepatic, rank among tumours with the highest rate of potentially actionable gene alterations. A number of next-generation sequencing platforms are now commercially available, opening up the possibility for routine molecular testing at the time of diagnosis to allow a more personalised, targeted treatment approach. However, despite the availability of these platforms, barriers to their use remain, including issues with reimbursement in some countries. Several clinical trials have been completed or are underway in CCA, investigating treatments directed against potentially actionable targets, such as FGFR2, IDH, NTRK, BRAF, and HER2. Some of these treatments are showing promising efficacy. Alongside, or before, initiating standard chemotherapy, efforts should be made to identify specific targets in all patients via molecular testing and treat eligible patients accordingly or enrol them in appropriate clinical trials.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterised by chronic inflammation and fibro-obliteration of the intrahepatic and/or extrahepatic bile ducts. It is associated with numerous hepatobiliary complications including an increased risk of malignancy (in particular, cholangiocarcinoma) and biliary tract stone formation. The evaluation of biliary strictures in patients with PSC is especially challenging, with imaging and endoscopic methods having only modest sensitivity for the diagnosis of cholangiocarcinoma, and treatment of biliary strictures poses a similarly significant clinical challenge. In recent years, peroral cholangioscopy has evolved technologically and increased in popularity as an endoscopic tool that can provide direct intraductal visualisation and facilitate therapeutic manipulation of the biliary tract. However, the indications for and effectiveness of its use in patients with PSC remain uncertain, with only a few studies performed on this small but important subset of patients. In this review, the authors discuss the available data regarding the use of peroral cholangioscopy in patients with PSC, with a focus on its use in the evaluation and management of biliary strictures and stones.

Gemcitabine and cisplatin serve as appropriate treatments for patients with cholangiocarcinoma (CCA). Our previous study using histoculture drug response assay (HDRA), demonstrated individual response patterns to gemcitabine and cisplatin. The current study aimed to identify predictive biomarkers for gemcitabine and cisplatin sensitivity in tissues and sera from patients with CCA using metabolomics. Metabolic signatures of patients with CCA were correlated with their HDRA response patterns. The tissue metabolic signatures of patients with CCA revealed the inversion of the TCA cycle that is evident with increased levels of citrate and amino acid backbones as TCA cycle intermediates, and glucose which corresponds to cancer stem cell (CSC) properties. The protein expression levels of CSC markers were examined on tissues and showed the significantly inverse association with the responses of patients to cisplatin. Moreover, the elevation of ethanol level was observed in gemcitabine- and cisplatin-sensitive group. In serum, a lower level of glucose but a higher level of methylguanidine was observed in the gemcitabine-responders as non-invasive predictive biomarker for gemcitabine sensitivity. Collectively, our findings indicate that these metabolites may serve as the predictive biomarkers in clinical practice which not only predict the chemotherapy response in patients with CCA but also minimize the adverse effect from chemotherapy.

Significant advancements in our understanding and clinical treatment of cholangiocarcinoma (CCA) have been achieved over the past 5 years. Groundbreaking studies have illuminated the immune landscape and pathological characteristics of the tumor microenvironment in CCA. The development of immune- and metabolism-based classification systems has enabled a nuanced exploration of the tumor microenvironment and the origins of CCA, facilitating a detailed understanding of tumor progression modulation. Despite these insights, targeted therapies have not yet yielded satisfactory clinical results, highlighting the urgent need for innovative therapeutic strategies. This review delineates the complexity and heterogeneity of CCA, examines the current landscape of therapeutic strategies and clinical trials, and delves into the resistance mechanisms underlying targeted therapies. Finally, from a single-cell and spatial transcriptomic perspective, we address the challenge of therapy resistance, discussing emerging mechanisms and potential strategies to overcome this barrier and enhance treatment efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Liu, Cao and Chen.)

Background: Diabetes mellitus (DM) is associated with the increased risk of development and the advancement of cholangiocarcinoma (CCA). High glucose levels were previously shown for upregulating interleukin-1β (IL-1β) in CCA cells with unclear functions. The present study, thus, aimed to investigate molecular mechanisms linking DM to CCA progression, with IL-1β hypothesized as a communicating cytokine., Methods: CCA cells were cultured in media with normal (5.6 mM) or high (25 mM) glucose, resembling euglycemia and hyperglycemia, respectively. Expressions of IL-1β and IL-1 receptor (IL-1R) in CCA tissues from patients with and without DM were examined using immunohistochemistry. Functional analyses of IL-1β were performed using siRNA and recombinant human IL-1R antagonist (rhIL-1RA), in which Western blots investigated the knockdown efficacy. BALB/c Rag-2 -/- Jak3 -/- (BRJ) mice were implanted with CCA xenografts to investigate hyperglycemia's effects on CCA growth and the anti-tumor effects of IL-1RA., Results: CCA tumors from patients with hyperglycemia showed significantly higher IL-1β expression than those from non-DM patients, while IL-1β was positively correlated with fasting blood glucose (FBG) levels. CCA cells cultured in high glucose showed increased IL-1β expression, resulting in increased proliferation rates. Suppressing IL-1β signaling by si-IL-1β or rhIL-1RA significantly reduced CCA cell proliferation in vitro . Anakinra, a synthetic IL-1RA, also exerted significant anti-tumor effects in vivo and significantly reversed the effects of hyperglycemia-induced growth in CCA xenografts., Conclusions: IL-1β plays a crucial role in CCA progression in a high-glucose environment. Targeting IL-1β might, then, help improve therapeutic outcomes of CCA in patients with DM and hyperglycemia., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-8/coif). C.S. received research grant for Young Talented Scholars, National Research Council of Thailand (No. N41A640108). K.K. and C.S. received the Invitation Research Grant of Faculty of Medicine, Khon Kaen University (No. IN66069). K.K. received scholarship from the Development and Promotion of Science and Technology Talents Project (DPST), and the Institute for the Promotion of Teaching Science and Technology of Thailand for the graduate study. The other authors have no conflicts of interest to declare., (2024 Translational Gastroenterology and Hepatology. All rights reserved.)

Background: Cholangiocarcinoma (CCA), a highly lethal tumor of the hepatobiliary system originating from bile duct epithelium, can be divided into the intrahepatic, hilar, and extrahepatic types. Due to its insidious onset and atypical early clinical symptoms, the overall prognosis is poor. One of the important factors contributing to the poor prognosis of CCA is the occurrence of perineural invasion (PNI), but the specific mechanisms regarding how it contributes to the occurrence of PNI are still unclear. The main purpose of this study is to explore the molecular mechanism leading to the occurrence of PNI and provide new ideas for clinical treatment., Methods: CCA cell lines and Schwann cells (SCs) were stimulated to observe the changes in cell behavior. SCs cocultured with tumor supernatant and SCs cultured in normal medium were subjected to transcriptome sequencing to screen the significantly upregulated genes. Following this, the two types of tumor cells were cultured with SC supernatant, and the changes in behavior of the tumor cells were observed. Nonobese diabetic-severe combined immunodeficiency disease (NOD-SCID) mice were injected with cell suspension supplemented with nerve growth factor (NGF) via the sciatic nerve. Four weeks later, the mice were euthanized and the tumor sections were removed and stained., Results: Nerve invasion by tumor cells was common in CCA tissues. SCs were observed in tumor tissues, and the number of SCs in tumor tissues and the degree of PNI were much higher than were those in normal tissues or tissues without PNI. The overall survival time was shorter in patients with CCA with PNI than in patients without PNI. SCs were enriched in CCA tissues, indicating the presence of PNI and associated with poor prognosis in CCA patients. CCA was found to promote NGF secretion from SCs in vitro . After the addition of exogenous NGF in CCA cell culture medium, the proliferation activity and migration ability of CCA cells were significantly increased, suggesting that SCs can promote the proliferation and migration of CCA through the secretion of NGF. NGF, in turn, was observed to promote epithelial-mesenchymal transition in CCA through tropomyosin receptor kinase A (TrkA), thus promoting its progression. Tumor growth in mice shows that NGF can promote PNI in CCA., Conclusions: In CCA, tumor cells can promote the secretion of NGF by SCs, which promotes the progression of CCA and PNI by binding to its high-affinity receptor TrkA, leading to poor prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-309/coif). N.T. has served as a consultant for Helsinn, TEMPUS, Astrazeneca, Genentech, Exelixis. The other authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Anomalies of the inferior vena cava (IVC) are often discovered incidentally, yet they pose significant challenges in both diagnosis and treatment. This study discusses a case of a 50-year-old female with situs inversus and well-differentiated cholangiocarcinoma, emphasizing the rarity and complexity involved. Imaging studies confirmed the presence of dextrocardia, abdominal situs inversus, and an interrupted IVC with continuation to the azygos vein. A thorough understanding of IVC embryology is crucial, as it helps explain the pathogenesis of such anomalies, which arise from disturbances in the embryonic venous system leading to various anatomical variations. Managing an interrupted IVC is critical due to the potential for vascular complications, highlighting the need for preoperative awareness. This study underlines the importance of recognizing and properly managing these rare vascular anomalies to improve patient care., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Castillo Reina et al.)

Cholangiocarcinoma (CCA) is the most common malignant tumor of the biliary system with a very poor prognosis. The human microbiome, which is the sum of the genetic information of human microorganisms, plays an important role in regulating the digestion, absorption, immune response, and metabolism of the host. Increasing evidence indicates a close relationship between CCA and the human microbiome. Specific alterations occur in the human microbiome of patients with CCA. Therefore, in this review, we aimed to summarize the recent evidence on dysbiosis in the human microbiome of CCA. Then, we generalized the effect of Helicobacter pylori on CCA. Additionally, the potential mechanism of human microbial dysbiosis promoted the progress of CCA, and its precancerous disease was also explored. Furthermore, the possibility of the human microbiome as a diagnostic and therapeutic target of CCA was discussed. [ABSTRACT FROM AUTHOR]