Hepatitis C virus (HCV) infection is a risk factor of intrahepatic cholangiocarcinoma (ICC). However, the impact of HCV infection control status on prognosis after surgery for ICCs is still unclear.

This multicenter retrospective study included patients who underwent curative resection for ICCs. The sera of 56 patients tested positive for anti-HCV antibody and negative for hepatitis B surface antigen (HCV group). Additionally, the sera of 358 patients tested negative for anti-HCV antibody and hepatitis B surface antigen (NBNC group). In the HCV group, 33 of 56 patients achieved sustained virologic response (SVR) for HCV (SVR group), whereas 23 patients did not (non-SVR group). To investigate the prognostic impact of HCV infection control status in the whole study cohort and in patients with solitary ICC without lymph node metastasis (StN0 study cohort), the postoperative prognosis of the SVR, non-SVR, and NBNC groups was compared.

In the whole study cohort, there were no significant differences in terms of recurrence-free survival (RFS) or overall survival among the three groups. Based on the multivariate Cox regression analysis, non-SVR was an independent unfavorable prognostic factor of RFS. In the StN0 study cohort, the non-SVR group had a significantly lower RFS than the NBNC and SVR groups. Based on the multivariate analysis, non-SVR was an independent unfavorable prognostic factor of RFS.

The achievement of SVR for HCV infection in patients with HCV infection-related ICCs is associated with a better RFS after surgery for HCV-related ICCs, particularly solitary ICC without lymph node metastasis.

To examine incidence trends and patterns for early- and late-onset liver cancer.

Liver and intrahepatic bile duct (IBD) cancers diagnosed between 2000 and 2019 were acquired from 22 SEER registries. Variables included early-onset (20-49) vs. late-onset (50+), anatomic subsite, histologic type (hepatocellular carcinoma [HCC] and IBD cholangiocarcinoma [ICC]), sex, and race/ethnicity. Age-standardized incidence rates were calculated using SEER*Stat. Jointpoint regression analysis was employed to estimate the annual percent change (APC) and the average APC (AAPC) with pairwise comparisons for trend by sex and by race/ethnicity stratified by age and subsite.

Liver cancer incidence decreased among early-onset (AAPC [95% CI] - 2.39 [- 2.74, - 2.07]) but increased among late-onset patients (2.85 [2.71, 3.01]), primarily driven by HCC (3.60 [3.50, 3.71]). IBD incidence increased for both ages with ICC incidence annually increasing 7.92% (6.84, 9.26) for early-onset and 6.32% (5.46, 8.86) for late-onset patients. Early-onset liver cancer displayed comparable trends across racial/ethnic groups; however, late-onset liver cancer showed more variation, particularly among American Indian/Alaska Native/Asian Pacific Islander (AI/AN/API) populations, which experienced a significant decrease in incidence, thereby narrowing the gap with other racial/ethnic groups. For IBD, an identical pattern of early-onset IBD among non-Hispanic Blacks (NHBs) compared to Hispanics was showed with coincidence test p = 0.1522, and a parallel pattern was observed among late-onset patients for both sexes (p = 0.5087).

Late-onset HCC continues to rise, except for NHB and AI/AN/API, where incidence rates have started to decrease over the past 4-5 years. Early and late-onset ICC incidence continues to increase across all racial/ethnic groups.

To study hepatobiliary expert ultrasound (US) in a cohort of suspected primary intrahepatic lithiasis (IHL) and to compare these findings with MRI/MRCP data.

All patients with a diagnosis of primary-IHL based upon biological and, or, clinical symptoms who underwent US between 2008 and 2023 were retrospectively enrolled in two tertiary hepatobiliary centers. Clinical characteristics, available genetic and radiological features (expert US and MRCP) were recorded. Data were compared for the presence of comet-tail images or stones on US, between US and MRCP features and between imaging and patients' genetic status. Statistical analyses were performed with R software environment version 4.2.1, by univariate and multivariate analysis.

A total of 112 primary-IHL patients were included (mean age 43 years old ±14 and 55% women). US identified primary-IHL in 92/112 (82%) patients including intrahepatic biliary comet-tail in 82/112 (73%) and stones in 51/112 (46%). Among these, 66/112 (68%) had both US and MRCP. Lithiasis was identified in 60/76 US (79%) and 44/76 MRCP (58%). MRCP showed only stones in 22/76, 29%. Genetic testing was performed in 66/112 (58%) patients. Thirty-two (49%) of these patients had pathogenic ABCB4/MDR3 gene variants, 14/66 (21%) other pathogenic variants and 5/66 (5%) had unknown significant variants. No genetic abnormalities were found in 19/66 (29%). A multivariate logistic model with the comet-tail sign as an outcome showed that there was a significant negative correlation between other pathogenic genetic variants and the comet-tail phenotype (P-value = 0.049).

US, and not MRCP, should be the primary diagnostic tool in suspected primary-IHL patients.

The tumor microenvironment has shown abilities to influence the progression and prognosis of intrahepatic cholangiocarcinoma (iCCA). However, little is known about the effect of IgG4+ plasma cells in iCCA.

We stained IgG4+plasma cells by immunohistochemistry and performed Kaplan-Meier survival analysis to detect the prognostic value. We also stained CD3, CD4, CD8 and Foxp3 positive T cells to explore its associations with IgG4+plasma cells.

We found that tumor infiltrated IgG4+plasma cells were associated with poor prognosis of iCCA, rather than IgG4+plasma cells in adjacent liver tissue. The number of IgG4+plasma cells was associated with CD8+ T cells. We divided the iCCA patients into 3 groups by IgG4+plasma cells to CD8+ T cells ratio. The group I (IgG4-/CD8+) had the best prognosis. The group II (IgG4-/CD8- or IgG4+/CD8+) and group III (IgG4+/CD8-) were independent risk factors of recurrence-free survival (HR = 1.69, group II; HR = 2.11, group III) and overall survival (HR = 1.76, group II; HR = 2.38, group III) compared with group I.

We examined the distribution of IgG4+ plasma cells in iCCA and discovered its prognostic utility when combined with CD8+ T cell distribution in iCCA.

The purpose of this review is to summarize the current knowledge of cholangiocarcinoma molecular biology and to suggest a framework for implementation of next-generation sequencing in all stages of liver transplantation. This is timely as recent guidelines recommend increased use of these technologies with promising results.

The main themes covered here address germline and somatic genetic alterations recently discovered in cholangiocarcinoma, particularly those associated with prognosis and treatment responses, and nascent efforts to translate these into contemporary practice in the peri-liver transplantation period.

Early efforts to translate molecular profiling to cholangiocarcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking is a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care with the ambition of increasing the number of patients eligible for liver transplantation and improving their long-term outcomes.

Cholangiocarcinoma (CCA) is an extremely malignant and aggressive primary liver tumor that has become increasingly prevalent in recent years. Unfortunately, the prognosis for patients diagnosed with CCA remains exceptionally poor. Currently, the primary treatment options include surgery and chemotherapy. However, the effectiveness of postoperative chemotherapy is limited, characterized by a brief duration of remission and high rates of recurrence and metastasis, resulting in minimal survival benefits for patients. Therefore, there is an urgent need to develop new therapeutic strategies that are both safer and more effective. In recent years, as oncology research has progressed, Claudin 18.2 (CLDN18.2)-targeted therapy has emerged, showing promise for improving the survival of patients with CLDN18.2-positive cancers. Studies suggest that combining new agents targeting CLDN18.2 with standard cytotoxic therapies offers significant survival benefits in CLDN18.2-positive solid tumors, which is expected to provide a more effective treatment option for patients with advanced cholangiocarcinoma. While existing immune checkpoints or therapeutic targets have limitations, such as low positivity rates and minimal absolute improvement in patient survival time, drugs that target FGFR, IDH, and Her-2, along with antiangiogenic agents, have shown promise for patients with advanced malignancies affecting the bile ducts. Therefore, exploring these novel therapeutic strategies may yield new insights for precision treatment of cholangiocarcinoma in the future. This review aims to focus on the potential application of CLDN18.2 in treating solid tumors, particularly cholangiocarcinoma, to systematically summarize research progress related to this target and thoroughly examine its value in diagnosing, treating, and assessing the prognosis of cholangiocarcinoma.

Cholangiocarcinoma (CCA), a malignancy of the bile ducts, presents a significant health burden with a notably high prevalence in Northeast Thailand, where its incidence ratio is 85 per 100,000 population per year. The prognosis for CCA patients remains poor, particularly for proximal tumors, with a dismal 5-year survival rate of just 10%. The challenge in managing CCA is exacerbated by its typically late detection, contributing to a high mortality rate. Current screening methods, such as ultrasound, are insufficient, as many CCA patients do not exhibit prior symptoms or detectable liver fluke (Opisthorchis viverrini : OV) infections, underscoring the urgent need for alternative early detection methods.

In this study, we introduce a novel approach utilizing surface-enhanced Raman spectroscopy (SERS) combined with near-lossless signal compression via discrete wavelet transform (DWT) together with 2D CNN for the first time. Hamster serums of different stages were collected as the data set. DWT was employed for feature extraction, enabling the capture of the entire SERS spectrum, unlike traditional methods like PCA and LDA, which focus only on specific peaks. These features were used to train a 2D convolutional neural network (2D CNN), which is particularly robust against translation, rotation, and scaling, thus effectively addressing the SERS peak shifting issues. We validated our approach using gold-standard histology, and notably, our method could detect CCA at an early stage. The ability to identify CCA at the early stage significantly improves the chances of successful intervention and patient outcomes.

Our results demonstrate that our method, combining SERS with extremely compact wavelet feature extraction and 2D CNN, outperformed other approaches (PCA + SVM, PCA + 1D CNN, PCA + 2D CNN, LDA + SVM, and DWT + 1D CNN), achieving performance of 95.1% accuracy, 95.08% sensitivity, 98.4% specificity, and an area under the curve (AUC) of 95%. The trained model was further deployed on a server and mobile application interface, paving the way for future field experiments in rural areas and home-use potential point-of-care services.

Cholangiocarcinoma (CCA) is a unifying title granted to epithelial adenocarcinomas specific to the bile ducts making up 10-25% of all hepatobiliary malignancies. CCA is more appropriately classified based on anatomic site of origin within the biliary tract into intrahepatic cholangiocarcinoma (iCCA), peri-hilar (pCCA) cholangiocarcinoma, and distal cholangiocarcinoma (dCCA). Intrahepatic cholangiocarcinoma makes up 10-20% of CCA and originates within and/or proximal to the second order bile ducts. The incidence of iCCA has been rising overtime with up to 1.26 per 100,000 persons, per year in the United States and up to 3.3 per 100, 000 persons, per year affected globally. Risk factors include chronic hepatic inflammation secondary to viral hepatitis, alcohol/NASH cirrhosis, biliary cystic lesions, and endemic causes, among other less common genetic drivers. Given its rarity, the recognition and diagnosis of cholangiocarcinoma, iCCA specifically, remains challenging resulting in delays in treatment initiation or any treatment at all. Median overall survival (mOS) for iCCA remains low. Early diagnosis, and stage-based treatment approaches have evolved and are associated with improved survival. To this goal, a multi-disciplinary treatment approach has been demonstrated to improve patient outcomes by providing expert evaluation as it pertains to an accurate imaging and histologic diagnosis, staging, radiologic and surgical review for resectability, operative expertise, post operative care, as well as comprehensive knowledge and implementation of systemic/targeted or liver directed therapies. Here, we discuss the central role of imaging in the diagnosis of intrahepatic cholangiocarcinoma to implement a comprehensive treatment plan that frequently involves multiple disciplines to achieve the best outcome for each patient.

Cancer disparities are well-established across measures of cancer incidence and mortality. Cholangiocarcinoma, a common hepatic malignancy, is no exception to these inequities. Globally and within the United States, Asian, Hispanic, and Indigenous peoples of the Americas, Alaskan Natives, and Pacific Islander populations experience higher incidence rates of cholangiocarcinoma. These same groups and non-Hispanic Black individuals simultaneously experience lower disease-specific survival, highlighting the role of social factors in cholangiocarcinoma outcome inequities. Higher age-standardized death rates from cholangiocarcinoma are associated with a lower social determinant index (SDI) in Andean Latin America, Southern Latin America, and Central sub-Saharan Africa. SDI, which evaluates education, fertility, and income, can be used to model the social determinants of health (SDOH). The SDOH also affect cholangiocarcinoma survival in the United States as factors such as migratory status, insurance status, and geographic location can cause treatment delays and worsened outcomes. Despite these inequities, limited research exists on the topic of disparities in cholangiocarcinoma when compared with other malignancies, and clinical trial under-representation remains a significant concern. Representing diverse populations in cholangiocarcinoma clinical trials is exceedingly important as populations with the highest incidence are simultaneously under-represented in clinical trials. Diversity in clinical trial enrollment and research regarding cholangiocarcinoma is needed to create robust databases and biobanks that can be used to develop targeted treatments and guidelines. In addition, risk factors, including parasitic infections, infectious diseases, and environmental exposures, are associated with cholangiocarcinoma but vary by global region, highlighting the need to study unique risk factors for cholangiocarcinoma across diverse populations. Without research that represents the populations that suffer most from this cancer, incidence and mortality inequities will continue to have a disproportionate burden.

Biliary tract cancer (BTC) is becoming more common worldwide, with geographic differences in incidence and risk factors. In Europe, BTC may be associated with primary sclerosing cholangitis, lithiasis, and liver cirrhosis, but is more frequently observed as a sporadic disease. BTC increasingly affects patients under 60 years, resulting in a significant social and economic burden. Early diagnosis remains challenging due to vague symptoms in 50% of patients with BTC, and lack of specific biomarkers, resulting in late presentation and poor prognosis. The identification of patients at increased risk and reliable biomarkers require collaborative efforts to make faster progress. This Series paper highlights the disparities in access to diagnostic tools and multidisciplinary care in Europe, particularly in economically disadvantaged regions, while identifying priority areas for improvement. Addressing these inequities requires harmonised guidelines, accelerated pathways to curative treatments, and improved awareness among healthcare professionals and the public. Multidisciplinary teams (MDTs) are crucial for the diagnosis of BTC and for improving patient outcomes, yet inconsistencies exist in their implementation not only between different countries, but also between different centres within a country. Collaboration and standardisation of diagnostic and treatment protocols across Europe are essential to effectively address the management of patients with BTC.

Biliary tract cancer (BTC) is a rare but highly aggressive malignancy that includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, and gallbladder cancer (GBC). While BTC has a low global incidence, its regional variations are notable. Among nations, Korea has the second-highest incidence of BTC globally, with the highest mortality rate worldwide, underscoring the need for a deeper understanding of this cancer. Liver fluke infection and hepatitis B virus infection are key risk factors unique to Korea, contributing to regional differences in BTC incidence. Additionally, genomic alterations in Korean patients with BTC differ from those in other populations, including lower frequencies of IDH1 mutations and FGFR2 fusions in ICC and a higher prevalence of ERBB2 amplification in GBC. Recognizing the clinical significance of these alterations, ivosidenib and pemigatinib have been approved in Korea for BTC patients with IDH1 mutations and FGFR2 fusions, respectively. This review explores the epidemiology, risk factors, and molecular features of BTC, along with corresponding targeted therapies. Furthermore, we compare the unique characteristics of BTC in Korea with global data to inform future research and clinical practice.

Obstructive sleep apnea (OSA) has been associated with an increased risk of cancer in various organs. OSA is also linked to chronic inflammation in the biliary tract and pancreas, a well-established risk factor for carcinogenesis in these organs. However, its relationship with biliary tract and pancreatic cancers remains unclear and has been rarely investigated. Therefore, we aimed to evaluate whether OSA serves as an independent risk factor for these malignancies by analyzing a nationwide healthcare claims database in South Korea.

A retrospective cohort study was conducted using the Korean National Health Insurance Service (KNHIS) database. Adults aged ≥20 years who were newly diagnosed with OSA (ICD-10: G47.30) between 2007 and 2014 were identified and propensity score-matched (1:5) with controls based on age, sex, and comorbidities. Individuals with pre-existing cancer diagnoses were excluded. The primary endpoints were the incidence of overall cancer, biliary tract cancer (C23-C24), and pancreatic cancer (C25). Cox proportional hazards regression models were used to calculate hazard ratios (HRs), adjusting for demographic and clinical factors.

A total of 1,191,444 individuals were included, comprising 198,574 patients diagnosed with OSA and 992,870 matched controls. OSA was associated with an increased overall cancer incidence (HR, 1.132; 95% confidence interval [CI], 1.097-1.169); however, it was not significantly associated with pancreatic cancer (HR, 0.941; 95% CI, 0.823-1.072) or biliary tract cancer (HR, 0.931; 95% CI, 0.751-1.142). Subgroup analyses stratified by sex and age revealed no statistically significant associations across these groups.

Our findings do not support OSA as an independent risk factor for biliary tract or pancreatic cancers.

Cholangiocarcinoma, a malignancy originating from the bile ducts, poses significant treatment challenges due to its typically late diagnosis and limited therapeutic options. However, recent advances in molecular genetics enable more personalized treatment approaches. A notable breakthrough in this context is the identification of isocitrate dehydrogenase (IDH) mutations, particularly IDH1 and IDH2, which occur in a subset of cholangiocarcinoma patients. Those with IDH1/2 mutations may benefit from targeted therapies. For instance, Ivosidenib, an IDH1 inhibitor, has shown efficacy in clinical trials, offering a new therapeutic option for patients with IDH1-mutant cholangiocarcinoma. Developing and implementing standardized protocols for testing and reporting mutation status are crucial for consistency and accuracy in clinical practice. Both the Idylla™ IDH1-2 Mutation Assay Kit as a FastTrack method and Next-Generation Sequencing (NGS) panels play critical roles in molecular characterization of cholangiocarcinoma.

Under this aspect, a set of cholangiocarcinomas was tested using the Idylla™ platform regarding the respective recommended guidelines and standards of DIN EN ISO:17020 and DIN EN ISO:15198.

Overall, 25 clinically diagnosed intrahepatic cholangiocarcinomas or Adeno-CUPs were analyzed. IDH1/2 mutations were identified in 68% (17/25) of cases using both methods, with high concordance between NGS and Idylla™ results. Discrepancies were observed in two samples, where Idylla™ detected no mutations, but NGS reported IDH1 and IDH2 mutations, respectively.

IdyllaTM offers a rapid, user-friendly, and specific method for detecting IDH1/2 mutations, ideal for immediate clinical needs. NGS, while more time-consuming and costly, provides comprehensive genetic profiles valuable for personalized medicine and research. The choice between these methods should be guided by the clinical context, resource availability, and individual patient needs. For routine diagnostics, we recommend an algorithmic approach starting with the FastTrack method followed by NGS for wildtype cases.

To analyze the research hotspots and potential of Artificial Intelligence (AI) in cholangiocarcinoma (CCA) through visualization.

A comprehensive search of publications on the application of AI in CCA from January 1, 2014, to December 31, 2023, within the Web of Science Core Collection, was conducted, and citation information was extracted. CiteSpace 6.2.R6 was used for the visualization analysis of citation information.

A total of 736 publications were included in this study. Early research primarily focused on traditional treatment methods and care strategies for CCA, but since 2019, there has been a significant shift towards the development and optimization of AI algorithms and their application in early cancer diagnosis and treatment decision-making. China emerged as the country with the highest volume of publications, while Khon Kaen University in Thailand was the academic institution with the highest number of publications. A core group of authors involved in a dense network of international collaboration was identified. HEPATOLOGY was found to be the most influential journal in the field. The disciplinary development pattern in this domain exhibits the characteristic of multiple disciplines intersecting and integrating.

The current research hotspots primarily revolve around three directions: AI in the diagnosis and classification of CCA, AI in the preoperative assessment of cancer metastasis risk in CCA, and AI in the prediction of postoperative recurrence in CCA. The complementarity and interdependence among different AI applications will facilitate future applications of AI in the CCA field.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant neoplasm. Certain histologic features and the tumor microenvironment may impact disease progression. We aim to characterize the clinicopathologic features of ICC to identify prognostic factors. A total of 50 surgically resected ICC (partial or transplant) cases were analyzed. The cohort included 26 men and 24 women with a median age of 62 years. Eighteen (36%) cases were multifocal ICC with a mean largest tumor size of 6.5 cm. Neoadjuvant and adjuvant chemotherapy was done in eight (16%) and 33 (66%) patients, respectively. Histologically, 42 (84%) were small duct type, seven (14%) large duct type, and one mixed (2%). Thirty (60%) cases showed lymphovascular invasion (LVI) and 11 (22%) with perineural invasion (PNI). Twenty-eight (56%) cases demonstrated dense intratumoral hyaline fibrosis and 18 (36%) with tumor necrosis, each ≥ 10% tumor volume. On follow-up, 35 (70%) patients died of disease after a median disease-specific survival (DSS) of 21 months. Univariate analysis revealed that hyaline fibrosis and adjuvant chemotherapy were associated with better DSS, while tumor size, multifocality, necrosis, and peritumoral neutrophil to lymphocyte ratio were associated with worse DSS. In contrast, age, sex, small vs. large duct types, LVI, and individual inflammatory cell counts were not significant prognostic factors. In summary, ICC is a heterogeneous malignancy with variable clinical courses associated with tumor burden, histology, and microenvironment. Targeting specific components within the tumor microenvironments may be a promising approach for treatment in the future.

There is concern about the risk of cholangiocarcinoma mortality (CCA) among U.S. veterans who deployed to the Vietnam War theater. A variety of risk factors potentially related to Vietnam deployment may be associated with an increased risk of mortality from CCA. This study assessed the risk of CCA mortality among all Vietnam War era veterans, the first study to do so.

The Vietnam Era Veterans Mortality Study is a retrospective mortality study of all 2.5 million veterans who served in Vietnam and Southeast Asia (theater) and the 7.3 million veterans who served elsewhere during the Vietnam War (non-theater). Mortality was followed from 1979 to 2019. Hazard ratios (HRs) calculated from Cox proportional hazards models, adjusted for sex and age, compared CCA mortality risk between theater and non-theater veterans overall and by branch of service. Branch specific crude rates of CCA were also compared between theater and non-theater veterans.

There were 2410 and 6502 CCA deaths among all theater and non-theater veterans respectively. Overall, there was no increased CCA mortality risk among theater versus non-theater veterans after adjusting for sex and age (hazard ratio, (HR: 1.00, 95 % CI: 0.95-1.04). When stratified by branch, the crude HRs for CCA were no different between branch-theater status groups except in non-theater Marines who had lower risk. A monotonic increase in crude rates for CCA mortality was observed in both theater and non-theater over forty years of follow-up.

There was no increased risk of CCA mortality in theater versus non-theater U.S. Vietnam War veterans, an important and new finding. This study lacked data on environmental exposures and behavioral factors that would further inform analyses of CCA risk. Identification of Vietnam era veterans' specific risk factors for CCA would require alternate methods and data which do not exist.

Cholangiocarcinoma (CCA) represents a heterogenous set of malignancies arising from the biliary tract. Classification of CCA subdivides tumours into intrahepatic (iCCA) and extrahepatic (eCCA), with eCCA further categorised as perihilar (pCCA) and distal (dCCA) lesions. Tumour subtypes show distinct epidemiological, genetic and clinical characteristics. Global incidence and mortality are rising, with the highest rates seen in Asian populations compared to the West. There has been a divergence in recent mortality trends observed between CCA subtypes, with rising rates of iCCA seen compared with eCCA. There are several drivers for these differing trends, including specific risk factors, misclassification of CCA subtypes and variation in diagnosis and surveillance. Risk factors for CCA can be divided into hepatobiliary, extra-hepatic and environmental, with hepatobiliary diseases conferring the largest risk. Surgery represents the only curative treatment for CCA, but can only be offered to early-stage candidates who are otherwise fit; the majority of patients are therefore treated with chemotherapy and, recently, immunotherapy. Due to late-stage presentation of disease, prognosis is poor, with 5-year survival <20%.

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

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

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

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

Accumulating evidence has demonstrated that Keratin18 (KRT18) functions as a pivotal gene in the progression of various cancers. However, its role in cholangiocarcinoma (CCA) remains unexplored. Our study elucidated the biological functions and underlying mechanisms of KRT18 in CCA. Bioinformatic databases were used to identify potential miRNAs and lncRNAs. The cellular localization of KRT18 and lncRNA HCG18 was examined through subcellular fractionation. Expression levels of genes were assessed by qRT-PCR, while protein levels were measured via western blot. Cell viability was analyzed using CCK-8 assays. Colony formation and EdU assays assessed cell proliferation, and sphere formation assays evaluated stem cell properties. The interactions between HCG18, miR-194-5p, and KRT18 were explored through RNA immunoprecipitation, RNA pulldown, and luciferase reporter assays. A xenograft tumor model was conducted to evaluate the in vivo function. In CCA tissues and cell lines, KRT18 expression was elevated. Functionally, silencing KRT18 reduced cell proliferation and stemness and inhibited cell cycle. Mechanistically, miR-194-5p directly targeted KRT18. HCG18, which was upregulated in CCA, interacted with miR-194-5p. Overexpression of KRT18 negated the effects of HCG18 suppression on CCA cell proliferation and stemness. Activation of MAPK signaling reversed the antitumor effects of KRT18 downregulation on CCA in vitro. Moreover, HCG18 was found to activate MAPK signaling through the miR-194-5p/KRT18 pathway. The in vivo assay demonstrated that HCG18 knockdown inhibited tumor growth by the miR-194-5p/KRT18/MAPK axis. HCG18 can promote cell proliferation and stem cell characteristics in CCA through the miR-194-5p/KRT18/MAPK signaling.

Choledochal cysts (CCs) are cystic dilations of intrahepatic and/or extrahepatic bile ducts. Around 80% of CCs are diagnosed within the first decade of life. These complex clinical entities are extremely rare, especially in the Western population. CCs are frequently classified according to the Todani classification. CCs may be asymptomatic or present as acute pancreatitis and/or cholangitis, biliary obstruction, or malignancy. Therefore, the diagnosis relies primarily on abdominal imaging modalities, mainly magnetic resonance cholangiopancreatography. Management is tailored based on the cyst morphology and the patient's clinical characteristics, with surveillance, surgery, and interventional endoscopy being the most frequent management options. While the surgical approach is the most frequently employed, type III CCs (also known as choledochocele) are frequently managed endoscopically, and novel endoscopic, minimally invasive treatment options are rapidly emerging.

This study explored the causal relationships among primary sclerosing cholangitis (PSC), ulcerative colitis (UC), and hepatobiliary cancer (HBC) by using bidirectional two-sample, two-step Mendelian randomization (MR) analysis. Genetic variants associated with PSC and UC from the FinnGen research database were used for instrumental variable-based analyses. Mediation analyses were conducted to examine the role of PSC and UC in HBC risk. The findings revealed a causal effect of genetic predisposition to UC on PSC risk (inverse-variance-weighted [IVW] analysis odds ratio [OR] 1.145, p < 0.001), whereas no reverse causality was observed. Although UC showed no direct causal effect on HBC risk, genetic susceptibility to PSC significantly increased the risk of HBC (IVW analysis OR = 1.855, p < 0.001). Mediation analysis further identified PSC as a significant mediator amplifying the causal effect of UC on HBC risk (effect size = 0.083). These results established a causal link between genetic susceptibility to UC and increased risk of PSC, and highlighted the critical role of PSC in mediating the impact of UC on HBC risk.

Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis. Bile duct and peribiliary changes related to CCA may present on ultrasound (US) findings. This study aims to evaluate US findings that could be used as predictors for developing CCA through our surveillance program in an endemic area of Thailand.

The study population was 4,337 villagers in Northern Thailand with a 5-year abdominal US surveillance. Patient demographics data and ultrasound findings of calcifications/granulomas, periductal fibrosis, and diffuse bile duct dilatation were included. A logistic regression model was used to determine significant predictors.

There were 4,225 people included with an average age of 45.49±7.66 years. Prevalence of calcifications/granulomas, periductal fibrosis, and diffuse bile duct dilatation detected on baseline sonographic surveillance was 11.7%, 20.5%, and 11.3%, respectively. The univariate analysis for significant predictors for CCA include age (Relative Risk; RR = 1.12), family history of CCA (RR = 2.29), periductal fibrosis (RR=2.38), and diffuse bile duct dilatation  (RR = 7.59). The multivariate analysis the independent predictors were age (RR = 1.12), family history of CCA (RR = 1.92), and diffuse bile duct dilatation (RR = 5.94), respectively.

The sonographic predictor for CCA surveillance in endemic areas is diffuse bile duct dilatation.  Age and family history of CCA are also helpful clinical markers.

Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus are the three important liver flukes, infecting approximately 25 million people worldwide. Despite the reporting of the carcinogenesis of these liver flukes, the comprehensive and systematic analysis of the pathogenicity of these parasites in hepatobiliary system is still not sufficient. We conducted a thorough systematic review and search for published articles in MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure databases until early 2024. Cohort studies, case-control studies, and cross-sectional studies associated with C. sinensis, O. viverrini, or O. felineus infection were selected. Pooled risk ratio (RR), odds ratio (OR) and their 95 % confidence intervals (95 % CIs) were calculated to assess the risk of hepatobiliary complications due to these liver fluke infections. From a total of 6488 articles, 22 eligible studies and 34,367 participants were included for review. Our results showed C. sinensis, O. viverrini, and O. felineus infections were significantly associated with cholangiocarcinoma, with an overall OR of 4.24 (95 % CI: 3.33-5.39, P < 0.00001) and an overall RR of 10.43 (95 % CI: 2.90-37.47, P = 0.0003). The ORs for the association between cholangiocarcinoma and C. sinensis and O. viverrini infection were 4.49 (95 % CI:3.43-5.87, P < 0.00001) and 3.69 (95 % CI: 2.07-6.55, P < 0.00001) respectively. For the association between cholelithiasis and C. sinensis infection, the OR was 6.46 (95 % CI: 5.15-8.11, P < 0.00001). C. sinensis infection increased the risk of cholecystitis and cirrhosis, with the RR of 21.02 (95 % CI: 17.27-25.58) and an overall RR of 8.77 (95 % CI: 6.79-11.33, P < 0.00001) respectively. C. sinensis infection was also significantly associated with fatty liver, with an overall OR of 2.46 (95 % CI: 1.79-3.37, P < 0.00001). This comprehensive study, reviewing the largest dataset to date, provided an overall risk of hepatobiliary complications due to Clonorchis and Opisthorchis infections, and aids more systematic understanding for the pathogenicity of Opisthorchiidae family parasites.

Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established.

Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway.

Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non-canonical NF-κB signalling pathway.

Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target.

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.

Thailand has the world's highest prevalence of cholangiocarcinoma (CCA), especially in the endemic area of liver fluke Opisthorchis viverrini infection. However, other regions of Thailand still have relatively high CCA prevalence.

We aimed to determine CCA risk factors in areas not endemic for OV infection.

A case--control study was performed at a referral center during December 2016-December 2017. We collected blood samples and information from CCA patients and identified them as cases. The control group comprised patients who visited a gastrointestinal clinic for colorectal cancer screening colonoscopy. Logistic regression analysis was used to determine risk factors for CCA.

Of 138 participants, O. viverrini infection rate was higher in the case than in the control group (57.1% vs. 36.1%, P = 0.023). Male, O. viverrini infection, smoking, alcohol consumption, and biliary tract diseases were independent risk factors, whereas diabetes, obesity, and cirrhosis were not associated with CCA. By age and sex-adjusted analysis, chronic biliary tract diseases, especially choledochal cysts and smoking, were risk factors for CCA, with adjusted odds ratio (aOR) of 12.7 (95% confidence interval [CI]: 1.4-116.9) and 3.8 (95% CI: 1.3-11.8), respectively, while O. viverrini infection became insignificant risk for CCA (aOR 1.8, 95% CI: 0.8-4.1).

In contrast with endemic areas for O. viverrini infection, chronic biliary tract diseases and smoking are major risk factors, whereas O. viverrini infection has trivial contribution to the development of CCA.

Cancer ranks as the second leading cause of mortality worldwide, prompting extensive investigations into factors contributing to its development. Among these factors, genetic variations, known as genotypic polymorphisms, have been identified as significant influencers in the susceptibility to various types of cancer. Recent research has focused on exploring the connection between polymorphisms in the Long Non-coding RNA HOTAIR and cancer risk. However, the results from these studies have been inconsistent, leading to ambiguity and controversy. To address this uncertainty, we conducted a systematic analysis by gathering relevant studies from PubMed, EMBASE, and Google Scholar. Specifically, we focused on three well-studied polymorphisms within the HOTAIR lncRNA (HOTAIR rs920778 C > T, HOTAIR rs1899663 G > T, HOTAIR rs4759314 A > G) and their association with cancer risk. Our meta-analysis included data from 48 case-control studies involving 42,321 cases and 54,137 controls. The results of our updated meta-analysis revealed a significant correlation between HOTAIR rs1899663 G > T and HOTAIR rs4759314 A > G polymorphisms and overall cancer risk, particularly in the homozygous and recessive genetic models. Subgroup analysis further revealed that these associations were notably pronounced in the Asian population but not observed in the Iranian population. Furthermore, our findings underscore the potential of HOTAIR polymorphisms as diagnostic markers for overall cancer risk, particularly in gynecological cancers, precisely, HOTAIR rs1899663 G > T polymorphism in breast cancer. In conclusion, our systematic analysis provides compelling evidence that Long Non-coding RNA HOTAIR polymorphisms are linked to cancer risk, particularly in certain populations and cancer types, suggesting their potential clinical relevance as diagnostic indicators.

Biliary tract cancers (BTC) are rare and aggressive malignancies originating from intrahepatic and extrahepatic bile ducts and the gallbladder. Surgery is the only curative option, but due to late-stage diagnosis, is frequently not feasible, leaving chemotherapy as the primary treatment. Radiotherapy (RT) can be an effective alternative for patients with unresectable, non-metastatic BTC despite the generally poor prognosis and significant variability. To help manage patients with unresectable BTC who receive RT, we aimed to identify prognostic markers that could aid in predicting overall survival (OS).

A retrospective cohort study was conducted at the University of Pennsylvania, involving seventy-eight patients with unresectable BTC treated with definitive intent RT. Comprehensive demographic, clinical, and treatment-related data were extracted from the electronic medical records. Univariate and multivariate Cox regressions were employed to identify predictors of OS after RT. A biomarker model was developed for refined survival prediction.

The cohort primarily comprised patients with good performance status without significant hepatic dysfunction at presentation. The predominant treatment approach involved hypofractionated RT or concurrent 5FU-based chemoRT. Median OS after RT was 12.3 months, and 20 patients (15.6%) experienced local progression with a median time of 30.1 months. Univariate and multivariate analyses identified CA19-9 (above median) and higher albumin-bilirubin (ALBI) grades at presentation as significant predictors of poor OS. Median OS after RT was 24 months for patients with no risk factors and 6.3 months for those with both.

Our study demonstrates generally poor but significantly heterogeneous OS in patients with unresectable BTC treated with RT. We have developed a biomarker model based on CA19-9 and ALBI grade at presentation that can distinguish sub-populations with markedly diverse prognoses. This model can aid the clinical management of this challenging disease.

Cholangiocarcinomas are aggressive cancers originating in the bile ducts, classified based on their location as intrahepatic, perihilar, or distal, and often present with symptoms such as jaundice, abdominal pain, and weight loss. Hepatorenal syndrome, a severe complication of liver failure that impairs kidney function and worsens prognosis, further complicates the management of these tumors. We present the case of a 49-year-old Caucasian male who initially sought treatment for jaundice and associated symptoms, including severe itching, gray-colored stools, and fatigue. His medical history, including recent gastric sleeve surgery, obesity, and smoking, along with symptoms of weight loss and increased leg swelling, initially obscured the severity of his condition. Diagnostic imaging and laboratory tests eventually revealed intrahepatic cholangiocarcinoma complicated by acute kidney injury (AKI) and hepatorenal syndrome. Despite the poor prognosis of hepatorenal syndrome, which typically requires liver transplantation for a definitive cure, the patient chose aggressive treatment following stabilization of his renal function. This case highlights the importance of a thorough diagnostic approach in patients presenting with jaundice and vague symptoms, especially as the incidence of cholangiocarcinoma rises, particularly among younger populations. Early and accurate diagnosis, combined with prompt intervention, is crucial for improving patient outcomes in this challenging clinical scenario.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with biliary tract cancer (BTC), published in late 2022 were adapted in December 2023, according to established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with BTC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with BTC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Taiwan Oncology Society (TOS). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different regions of Asia. Drug access and reimbursement in the different regions of Asia are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with BTC across the different countries and regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices and molecular profiling, as well as age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different countries.