Hepatobiliary malignancies encompass a spectrum of invasive carcinomas arising in the liver [hepatocellular carcinoma (HCC), bile ducts [intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (EHC)] and the gallbladder. These malignancies represent a growing global health burden, with rising incidence and mortality rates and their overall prognosis remains poor because many patients present with advanced unresectable disease at diagnosis. In recent years, significant advancements in understanding HCC immunogenicity have reshaped the therapeutic scenario of advanced HCC with the immunotherapy revolutionizing the current HCC treatment landscape and patients' prognosis. Moreover, the addition of immunotherapy to chemotherapy has recently established a new standard of care first-line treatment for patients with biliary tract cancers (BTCs) who had historically few therapeutic options. Currently, immunotherapy and immune checkpoint inhibitor (ICI)-based regimens stand as a valuable and practice-changing options in both HCC and BTC management. The mounting recent evidence supporting immunotherapy's survival benefit demands clinicians to stay updated with a rapidly evolving treatment landscape as well as gain knowledge about patient selection, response rate compared with other systemic treatments and immune-mediated adverse events (imAEs) management. A panel of international Experts, comprising hepatologists and oncologists, gathered to explore the challenges in effectively integrating immunotherapy in routine clinical practice. The aim of this review is to present the Experts' insights to inform treatment choice in HCC and BTC with a special emphasis on the role of currently available ICI-based therapies in shifting treatment paradigms and potentially reversing the natural course of these two deadly malignancies.

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.

Claudins are key components of tight junctions, essential for maintaining cellular adhesion, regulating intercellular molecule transport, and preserving cell polarity. Altered claudin expression can lead to tight junction dysfunction, potentially disrupting signaling pathways and contributing to the development of epithelial cancers. This study aims to explore the understudied role of CLDN18.2 in intrahepatic cholangiocarcinoma and its relationship with clinical outcomes. We analyzed tissue samples from 182 patients who underwent curative surgery for intrahepatic cholangiocarcinoma. Our research examined the relationship between CLDN18.2 expression and various clinical factors, including patient characteristics, pathological findings, and survival metrics such as overall survival (OS), disease-free survival (DFS), metastasis-free survival (MeFS), and local recurrence-free survival (LRFS). Overexpression of CLDN18.2 showed significant associations with R1 resection (p = 0.032) and advanced T stage (p = 0.043). Univariate analysis revealed that high CLDN18.2 expression was correlated with poorer OS (p = 0.0002), DFS (p < 0.0001), LRFS (p < 0.0001), and MeFS (p < 0.0001). Multivariate analysis further confirmed that high CLDN18.2 expression was independently associated with worse OS (p = 0.015), DFS (p < 0.001), LRFS (p < 0.001), and MeFS (p < 0.001). Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.

Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. It explores their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, it introduces available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discusses the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.

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.

Intrahepatic cholangiocarcinoma (iCCA) presents in two clinically distinct subtypes: large duct (LD-iCCA) and small duct (SD-iCCA). These subtypes exhibit significant molecular, genetic, and histopathological differences that impact patient prognosis and treatment responsiveness. This review advocates for a subtype-specific approach to iCCA research and clinical management, including tailored therapeutic strategies that consider distinct genetic profiles and tumor microenvironments. Current therapeutic approaches hold promise, yet efficacy varies by subtype. Additionally, subtype-specific molecular diagnostics, including DNA methylation-based classifiers and transcriptomic sequencing, have shown potential in refining iCCA subclassification, thereby guiding precision medicine efforts. This article outlines existing clinical trials, key research trajectories, and future directions for developing more effective subtype-adapted therapies for iCCA.

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.

Intrahepatic cholangiocarcinoma (ICC), a malignancy originating from the epithelial cells of bile ducts, has shown a notable rise in its incidence over the years. It ranks as the second most frequent primary liver cancer after hepatocellular carcinoma. This study investigates how independent prognostic factors, specifically, age and tumor stage, interact to impact mortality in ICC patients. Furthermore, it examines the clinical features, survival rates, and prognostic indicators of ICC cases diagnosed between 2010 and 2017.

Using data from 5083 patients obtained from the Surveillance, Epidemiology, and End Results (SEER) database, this study evaluated demographic and clinical factors alongside overall mortality (OM) and cancer-specific mortality (CSM). Variables achieving a p-value below 0.1 in univariate Cox regression analysis were incorporated into multivariate Cox regression models to identify independent prognostic factors. Hazard ratios (HRs) exceeding 1 were interpreted as markers of poor prognosis. Additionally, this study explored the interaction between age and tumor stage in shaping survival outcomes.

The multivariate Cox proportional hazards analysis indicated higher OM in males (HR = 1.19, 95% CI: 1.12-1.26, p < 0.01) and residents of metropolitan counties with populations exceeding 250,000 (HR = 1.15, 95% CI: 1.01-1.31, p < 0.05). Conversely, lower OM was observed in individuals aged 40-59 years (HR = 0.58, 95% CI: 0.38-0.89, p < 0.05), those aged 60-79 years (HR = 0.65, 95% CI: 0.43-0.98, p < 0.05), and patients who received radiation therapy (HR = 0.78, 95% CI: 0.72-0.85, p < 0.01), chemotherapy (HR = 0.54, 95% CI: 0.51-0.58, p < 0.01), or surgery (HR = 0.29, 95% CI: 0.26-0.31, p < 0.01). For CSM, males exhibited higher risks (HR = 1.17, 95% CI: 1.10-1.25, p < 0.01), as did individuals in metropolitan counties with populations over 250,000 (HR = 1.18, 95% CI: 1.03-1.35, p < 0.05). Reduced CSM was observed in patients aged 40-59 years (HR = 0.52, 95% CI: 0.34-0.79, p < 0.01), those aged 60-79 years (HR = 0.57, 95% CI: 0.38-0.86, p < 0.01), and those undergoing radiation therapy (HR = 0.76, 95% CI: 0.70-0.83, p < 0.01), chemotherapy (HR = 0.55, 95% CI: 0.51-0.59, p < 0.01), or surgery (HR = 0.27, 95% CI: 0.25-0.30, p < 0.01). When examining the interaction between age and tumor stage, higher OM was observed in patients aged 40-59 with tumors involving lymph nodes (HR = 1.26, 95% CI: 1.14-2.67, p < 0.05). Similarly, CSM was elevated in patients aged 40-59 with lymph node involvement alone (HR = 2.60, 95% CI: 1.26-5.36, p < 0.05) or with direct spread (HR = 2.81, 95% CI: 1.04-7.61, p < 0.05). Among those aged 60-79, higher CSM was noted in cases with lymph node involvement only (HR = 2.24, 95% CI: 1.11-4.50, p < 0.05) or lymph node involvement accompanied by direct extension (HR = 2.93, 95% CI: 1.10-7.82, p < 0.05).

This retrospective analysis, utilizing data from the SEER database, provides new insights into mortality patterns in intrahepatic cholangiocarcinoma (ICC). This study identifies a significant interplay between two key prognostic factors, emphasizing their collective role in influencing mortality outcomes. Despite the predominance of advanced-stage diagnoses, our analysis underscores the substantial survival benefits associated with treatment interventions, with surgical procedures demonstrating the most pronounced impact. These findings highlight the importance of recognizing patients who may benefit from timely and intensive therapeutic strategies. Furthermore, the results underscore the need for future prospective randomized studies to deepen our understanding of these interactions in ICC, particularly as advancements in precision oncology continue to refine patient care.

Background/Objectives: Current guidelines recommend Cisplatin/Gemcitabine/Durvalumab as first-line treatment for inoperable or recurrent cholangiocarcinoma (CCA). Molecular tumor boards (MTB) have the expertise to support organ-specific tumor boards with evidence-based treatment recommendations for subsequent lines of treatment, based on genomic tumor data and scientific evidence. This study evaluates the adoption of an MTB at a comprehensive cancer center in Germany and whether actionable genetic alterations are associated with specific imaging phenotypes. Methods: Patients with CCA referred to MTB were enrolled from May 2019 to September 2021. For comparison, a cohort of patients from a second center was included. Data on treatment recommendations, regimens, and survival were collected from prospective registries. Baseline and follow-up contrast-enhanced CT were analyzed according to RECIST 1.1. The chi-square test and t-test were used to compare categorical and continuous variables. Results: 583 patients were referred to the MTB, and 92 patients (47 female/51%) with a mean age of 60.3 ± 11.2 were referred for CCA treatment. 65/92 patients harbored 1-3 targetable mutations. Liver metastases were more frequently observed in patients with targetable mutations (84% vs. 62%). Metastasis to the liver and lung was associated with increased sums of diameters (93 mm and 111 mm vs. 40/73 mm in patients with no liver/lung metastasis). The number of metastases in individual organs was unrelated to treatment targets. Follow-up was available for 25 patients with a median time until imaging progression of 23 weeks. Progression occurred as target progression in 63%, nontarget progression in 13%, and appearance of new lesions in 63%. Conclusions: Most patients with CCA harbored targetable mutations, some were related to disease patterns on imaging. The pattern of treatment response and progression was as diverse as the metastatic spread.

The current standard treatment for intrahepatic cholangiocarcinoma (ICC) involves complete liver resection with negative surgical margins and lymphadenectomy, followed by adjuvant chemotherapy. Debate is ongoing regarding the necessity of systematic anatomic resection (AR). This study aimed to summarize existing literature to determine whether AR leads to better oncologic outcomes than non-AR for patients with resectable ICC.

A systematic literature review (PubMed, Embase, and Google Scholar) was performed until December 2023. Only studies comparing the oncologic outcomes of AR and non-AR for ICC using propensity score matching or inverse probability of treatment weighting were considered. A meta-analysis of aggregated data for perioperative variables and a reconstructed patient-level meta-analysis for survival data were performed.

Five articles were gathered (n = 930 patients after matching: 465 AR/465 non-AR patients). The overall survival (OS) rates were higher in the AR group than in the non-AR group at 1, 3, and 5 years (71.5%, 46.1% and 34.3% vs. 63.6%, 32.9%, and 24.8%, respectively; hazard ratio [HR] 0.74; 95% CI 0.63-0.87; P < 0.001). The same results were observed for the disease-free survival (DFS) rates (58.3%, 33.4%, and 24.5% for AR vs. 45.6%, 23.1%, and 17.4% for non-AR; HR 0.74; 95% CI 0.63-0.86; P < 0.001). The results were confirmed in the two-stage meta-analysis for OS (HR 0.73; P < 0.001) and DFS (HR 0.73; P < 0.001). No differences were observed between the two approaches in terms of operative time, intraoperative blood loss, overall and major morbidity, and hospital length of stay.

By pooling the available evidence, the current study demonstrated that AR for ICC patients is associated with better OS and DFS without any negative impact on postoperative outcomes.

Cholangiocarcinoma (CCA) is a major contributor to hepatobiliary mortality in the Lao People's Democratic Republic (Lao PDR). Infection with the carcinogenic trematode Opisthorchis viverrini (OV), acquired through consumption of insufficiently-cooked river fish, is a known risk factor for the development of CCA. Together with OV, other risk factors contribute to the pathogenesis of CCA. We conducted this study to identify the burden of CCA and identify risk factors in high-risk communities in Lao PDR.

A cross-sectional study was performed in Champasack and Savannakhet provinces, southern Lao PDR, where OV infection is highly endemic. We assessed hepatobiliary morbidity with abdominal ultrasound (US). In addition, multiple risk factors known or suspected to be associated with CCA were assessed such as OV infection (examined by Kato-Katz technique for stool examination), lifestyle risks (e.g. smoking and alcohol consumption by face-to-face questionnaire), co-morbidity (e.g. diabetes mellitus) and hepatitis B infection status, both serologically tested.

In 3,400 participants, the overall prevalence of suspected CCA was 7.2% (95% confidence interval [95% CI] 5.4-9.6). The suspected CCA prevalence increased with age, and was higher in men at all ages. Almost all participants (88.3%) were infected with OV. In the multivariate regression analysis, suspected CCA was positively associated with OV infection (adjusted odds ratio [aOR] 3.4, 95% CI 1.7-6.5), and a history of cholecystectomy (aOR 2.7, 95% CI 1.5-4.9).

Our CCA screening in high OV prevalence rural areas of Lao PDR uncovers a high public health burden, primarily driven by elevated OV infection rates. Urgent interventions are needed to curb OV infection in these communities. Age and gender disparities in suspected CCA prevalence highlight the need for targeted efforts. Beyond OV, notable factors like a history of cholecystectomy offer valuable insights for preventive strategies. This research enhances our understanding of hepatobiliary morbidity and informs public health initiatives in Lao PDR.

The objective of this study was to develop nomograms for predicting outcomes following immunotherapy in patients diagnosed with intrahepatic cholangiocarcinoma (ICC).

A retrospective analysis was conducted on data from 75 ICC patients who received immunotherapy at Jinling Hospital and Drum Hospital. The discriminative power, accuracy, and clinical applicability of the nomograms were assessed using the concordance index (C-index), calibration curve, and decision curve analysis (DCA). The predictive performance of the nomograms for overall survival (OS) and progression-free survival (PFS) was evaluated using the area under the receiver operating characteristic (ROC) curve. Kaplan-Meier curves were also generated for validation purposes.

Multivariable analysis identified independent prognostic factors for OS, including CA19-9 levels, portal vein tumor thrombus (PVTT) grade, bifidobacteria administration, and surgery. The C-index of the nomogram for OS prediction was 0.722 (95% confidence interval [CI]: 0.661-0.783). Independent prognostic factors for PFS included CA19-9 levels, albumin, and bilirubin, with a C-index of 0.678 (95% CI: 0.612-0.743) for the nomogram predicting PFS. Calibration curves demonstrated strong concordance between predicted and observed outcomes, while DCA and Kaplan-Meier curves further supported the clinical utility of the nomogram.

The nomogram developed in this study demonstrated favorable performance in predicting the prognosis of ICC patients undergoing immunotherapy. Additionally, our findings, for the first time, identified probiotics as a potential prognostic marker for immunotherapy. This prognostic model has the potential to enhance patient selection for immunotherapy and improve clinical decision-making.

Biliary tract carcinoma (BTC) is relatively rare and comprises a spectrum of invasive tumors arising from the biliary tree. The prognosis is extremely poor. The incidence of BTC is relatively high in Asian countries, and a high number of cases are diagnosed annually in China owing to the large population. Therefore, it is necessary to clarify the epidemiology and high-risk factors for BTC in China. The signs associated with BTC are complex, often require collaborative treatment from surgeons, endoscopists, oncologists, and radiation therapists. Thus, it is necessary to develop a comprehensive Chinese guideline for BTC.

This clinical practice guideline (CPG) was developed following the process recommended by the World Health Organization. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of evidence and make recommendations. The full CPG report was reviewed by external guideline methodologists and clinicians with no direct involvement in the development of this CPG. Two guideline reporting checklists have been adhered to: Appraisal of Guidelines for Research and Evaluation (AGREE) and Reporting Items for practice Guidelines in Healthcare (RIGHT).

The guideline development group, which comprised 85 multidisciplinary clinical experts across China. After a controversies conference, 17 clinical questions concerning the prevention, diagnosis, and treatment of BTC were proposed. Additionally, detailed descriptions of the surgical principles, perioperative management, chemotherapy, immunotherapy, targeted therapy, radiotherapy, and endoscopic management were proposed.

The guideline development group created a comprehensive Chinese guideline for the diagnosis and treatment of BTC, covering various aspects of epidemiology, diagnosis, and treatment. The 17 clinical questions have important reference value for the management of BTC.

SEH1 like nucleoporin (SEH1L) is an important component of nuclear pore complex (NPC), which is crucial in the regulation of cell division. However, the interrelation between SEH1L expression and tumor progression is less studied. In this research, we performed a systematic bioinformatic analysis about SEH1L using TCGA, Timer 2.0, Cbioportal, UCLAN and CellMiner™ databases in pan-cancer. Besides, we further validated the bioinformatic results through in vitro and in vivo experiments in HCC, including transcriptome sequencing, real-time quantitative PCR (RT-qPCR), western blotting (WB), immunohistochemistry (IHC), cell proliferation assays, clone formation, EdU, transwell, flow cytometry and subcutaneous tumor model. Our results suggested that SEH1L was significantly up-regulated and related to poor prognosis in most cancers, and may serve as a potential biomarker. SEH1L could promote HCC progression in vitro and in vivo. Besides, the next generation sequencing suggested that 684 genes was significantly up-regulated and 678 genes was down-regulated after the knock down of SEH1L. SEH1L siliencing could activate ATF3/HMOX1/GPX4 axis, decrease mitochondrial membrane potential and GSH, but increase ROS and MDA, and these effects could be reversed by the knock down of ATF3. This study indicated that SEH1L siliencing could induce ferroptosis and suppresses hepatocellular carcinoma (HCC) progression via ATF3/HMOX1/GPX4 axis.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted.

Northern Thailand experiences high levels of air pollution in the dry season due to agricultural waste burning and forest fires. Some air pollutants can enter the bloodstream, and the liver has the role of detoxifying these along with other harmful substances. In this study, we assessed the effects of long-term exposure to air pollutants on liver cancer mortality in this area.

A cohort of 10,859 primary liver cancer patients diagnosed between 2003 and 2018 and followed up to the end of 2020 were included in the study. Extended time-varying covariates of the annually averaged pollutant concentrations updated each year were utilized. The associations between air pollutants and mortality risk were examined by using a Cox proportional hazard model.

Metastatic cancer stage had the highest adjusted hazard ratio (aHR) of 3.57 (95% confidence interval (CI):3.23-3.95). Being male (aHR = 1.10; 95% CI: 1.04-1.15), over 60 years old (aHR = 1.16; 95% CI: 1.11-1.21), having a history of smoking (aHR = 1.16; 95%CI: 1.11-1.22), and being exposed to a time-updated local concentration of PM2.5 of 40 μg/m3 (aHR = 1.10; 95% CI: 1.05-1.15) increased the mortality risk.

We found that air pollution is one of several detrimental factors on the mortality risk of liver cancer.

Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.

Recent advancements in biliary tract cancer (BTC) treatment have expanded beyond surgery to include adjuvant therapy, yet the prognosis remains poor. Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC.

To determine transmembrane serine protease 4 (TMPRSS4) utility as a prognostic biomarker of radical resection for BTC.

Medical records of patients who underwent radical resection for BTC, excluding intrahepatic cholangiocarcinoma, were retrospectively reviewed. The associations between TMPRSS4 expression and clinicopathological factors, overall survival, and recurrence-free survival were analyzed.

Among the 85 patients undergoing radical resection for BTC, 46 (54%) were TMPRSS4-positive. The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9 (CA19-9) values and greater lymphatic invasion than the TMPRSS4-negative group (P = 0.019 and 0.039, respectively). Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group (median survival time: 25.3 months vs not reached, P < 0.001; median survival time: 28.7 months vs not reached, P = 0.043, respectively). Multivariate overall survival analysis indicated TMPRSS4 positivity, pT3/T4, and resection status R1 were independently associated with poor prognosis (P = 0.032, 0.035 and 0.030, respectively). TMPRSS4 positivity correlated with preoperative CA19-9 values ≥ 37 U/mL and pathological tumor size ≥ 30 mm (P = 0.016 and 0.038, respectively).

TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.

Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20-30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden.

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.

Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis. The standard systemic treatment for BTCs has evolved to include immune checkpoint inhibitors associated with gemcitabine-cisplatin as first-line therapies. However, survival rates remain low, highlighting the critical need for personalized treatment strategies based on molecular profiling. Currently, significant advancements have been made in the molecular characterization of BTCs, where genetic alterations, such as IDH1 mutations and FGFR2 fusions, provide targets for therapy. Molecular profiling is crucial early in the management process to identify potential candidates for clinical trials and guide treatment strategy. The integration of these molecular insights into clinical practice has allowed for the development of targeted therapies, although many of them are still in the phase 2 trial stage without definitive survival benefits demonstrated in phase 3 trials. This integration of comprehensive molecular profile insights with traditional treatment approaches offers a new horizon in the personalized medicine landscape for BTCs, with the aim of significantly improving patient outcomes through precision oncology.

Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are controversial. This study aimed to elucidate the roles of GLP-1R and its agonists on intrahepatic CCA (iCCA) progression. Expressions of GLP-1R in iCCA tissues investigated by immunohistochemistry showed that GLP-1R expressions were significantly associated with poor histological grading (P = 0.027). iCCA cell lines, KKU-055 and KKU-213A, were treated with exendin-4 and liraglutide, GLP-1R agonists, and their effects on proliferation and migration were assessed. Exendin-4 and liraglutide did not affect CCA cell proliferation in vitro, but liraglutide significantly suppressed the migration of CCA cells, partly by inhibiting epithelial-mesenchymal transition. In contrast, liraglutide significantly reduced CCA tumor volumes and weights in xenografted mice (P = 0.046). GLP-1R appeared downregulated when CCA cells were treated with liraglutide in vitro and in vivo. In addition, liraglutide treatment significantly suppressed Akt and STAT3 signaling in CCA cells, by reducing their phosphorylation levels. These results suggested that liraglutide potentially slows down CCA progression, and further clinical investigation would benefit the treatment of CCA with diabetes mellitus.

Patients with intrahepatic cholangiocarcinoma can now be managed with targeted therapies directed against specific molecular alterations. Consequently, tissue samples submitted to the pathology department must produce molecular information in addition to a diagnosis or, for resection specimens, staging information. The pathologist's role when evaluating these specimens has therefore changed to accommodate such personalised approaches.

We developed recommendations and guidance for pathologists by conducting a systematic review of existing guidance to generate candidate statements followed by an international Delphi process. Fifty-nine pathologists from 28 countries in six continents rated statements mapped to all elements of the specimen pathway from receipt in the pathology department to authorisation of the final written report. A separate survey of 'end-users' of the report including surgeons, oncologists, and gastroenterologists was undertaken to evaluate what information should be included in the written report to enable appropriate patient management.

Forty-eight statements reached consensus for inclusion in the guidance including 10 statements about the content of the written report that also reached consensus by end-user participants. A reporting proforma to allow easy inclusion of the recommended data points was developed.

These guiding principles and recommendations provide a framework to allow pathologists reporting on patients with intrahepatic cholangiocarcinoma to maximise the informational yield of specimens required for personalised patient management.

Biopsy or resection lesional tissue from intrahepatic cholangiocarcinoma must yield information about the molecular abnormalities within the tumour that define suitability for personalised therapies in addition to a diagnosis and staging information. Here, we have developed international consensus guidance for pathologists that report such cases using a Delphi process that sought the views of both pathologists and 'end-users of pathology reports. The guide highlights the need to report cases in a way that preserves tissue for molecular testing and emphasises that reporting requires interpretation of histological characteristics within the broader clinical and radiological context. The guide will allow pathologists to report cases of intrahepatic cholangiocarcinoma in a uniform manner that maximises the value of the tissue received to facilitate optimal multidisciplinary patient management.

To assess the feasibility of a radiomics model based on unenhanced magnetic resonance imaging (MRI) to differentiate small hepatocellular carcinoma (S-HCC) (≤2 cm) and pre-hepatocellular carcinoma (Pre-HCC).

One hundred and fourteen histopathologically confirmed 114 hepatic nodules were analysed retrospectively. All patients had undergone MRI before surgery using a 3 T MRI system. Each nodule was segmented on unenhanced MRI sequences (T1-weighted imaging [T1] and T2WI with fat-suppression [FS-T2]). Radiomics features were extracted and the optimal features were selected using the least absolute shrinkage and selection operator (LASSO). The support vector machine (SVM) was used to establish the radiomics model. One abdominal radiologist performed the conventional qualitative analysis for classification of S-HCC and Pre-HCC. The diagnostic performances of the radiomics and radiologist models were evaluated using receiver operating characteristic (ROC) analysis.

Radiomics features (n=1,223) were extracted from each sequence and the optimal features were selected from T1, FS-T2, and T1+FS-T2 to construct the radiomics models. The radiomics model based on T1+FS-T2 showed the best performance among the three models, with areas under the ROC curves (AUCs) of 0.95 (95 % confidence interval [CI], 0.875-0.986) and 0.942 (95 % CI, 0.775-0.985), accuracies of 86 % and 88.5 %, sensitivities of 94.12 % and 100 %, and specificities of 85.48 % and 85.19 %, respectively. The radiomics model on FS-T2 showed better performance on a single sequence than that of the T1-based model. The diagnostic performance for the radiomic model was significantly higher than that for the radiologist (AUC = 0.518, p<0.05).

This study suggested that a radiomics model based on unenhanced MRI may serve as a feasible and non-invasive tool to classify S-HCC and Pre-HCC.

The most common primary liver tumors are hepatocellular carcinoma and cholangiocarcinoma. They constitute the sixth most common neoplasia and the third cause of cancer-related deaths worldwide. Although both tumors may share etiologic factors, diagnosis, prognostic factors, and treatments, they differ substantially in determining distinctive clinical management. In recent years, significant advances have been made in the management of these neoplasms, particularly in advanced stages. In this review, we focus on the most relevant diagnostic, prognostic, and treatment aspects of both, hepatocellular carcinoma and cholangiocarcinoma, underlying their applicability in Latin America.

We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.

Prediction of lymph node metastasis (LNM) for intrahepatic cholangiocarcinoma (ICC) is critical for the treatment regimen and prognosis. We aim to develop and validate machine learning (ML)-based predictive models for LNM in patients with ICC.

A total of 345 patients with clinicopathological characteristics confirmed ICC from Jan 2007 to Jan 2019 were enrolled. The predictors of LNM were identified by the least absolute shrinkage and selection operator (LASSO) and logistic analysis. The selected variables were used for developing prediction models for LNM by six ML algorithms, including Logistic regression (LR), Gradient boosting machine (GBM), Extreme gradient boosting (XGB), Random Forest (RF), Decision tree (DT), Multilayer perceptron (MLP). We applied 10-fold cross validation as internal validation and calculated the average of the areas under the receiver operating characteristic (ROC) curve to measure the performance of all models. A feature selection approach was applied to identify importance of predictors in each model. The heat map was used to investigate the correlation of features. Finally, we established a web calculator using the best-performing model.

In multivariate logistic regression analysis, factors including alcoholic liver disease (ALD), smoking, boundary, diameter, and white blood cell (WBC) were identified as independent predictors for LNM in patients with ICC. In internal validation, the average values of AUC of six models ranged from 0.820 to 0.908. The XGB model was identified as the best model, the average AUC was 0.908. Finally, we established a web calculator by XGB model, which was useful for clinicians to calculate the likelihood of LNM.

The proposed ML-based predicted models had a good performance to predict LNM of patients with ICC. XGB performed best. A web calculator based on the ML algorithm showed promise in assisting clinicians to predict LNM and developed individualized medical plans.