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.

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.

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.

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

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.

Primary liver cancer is the third leading cause of cancer deaths worldwide and has one of the worst 5-year survival rates. This study examines US primary liver cancer incidence and incidence-based mortality trends over four decades.

The SEER-9 registry was used to study primary liver cancer cases from 1978 to 2018. The incidence and mortality rates were calculated based on gender, age, race, and stage of diagnosis. Joinpoint regression software was used to calculate the annual percent change.

The overall incidence rate of primary liver cancer from 1978 to 2018 increased by 2.71%/year (p<0.001). Rates in patients <50 years old began to fall in 2002 at a rate of -3.62%/year (p<0.001). Similarly, the incidence-based mortality rates for primary liver cancer increased by 2.15%/year (p<0.001). Whereas Whites incidence-based mortality rates began to plateau in 2012 (0.18%/year; p = 0.84), Blacks rates have declined since 2010 (-2.93%/year; p = 0.03), and Asian rates have declined since 1999 (-1.30%/year; p<0.001).

While the overall primary liver cancer incidence and incidence-based mortality have been increasing over the last four decades, there was an observed decline in incidence and incidence-based mortality in recent years, especially among at-risk subgroups.

Recent advancements in proteomics have shown promise in identifying biomarkers for various cancers. Our study is the first to compare the serum proteomes of intrahepatic cholangiocarcinoma (iCCA) with cirrhosis (CIR), primary sclerosing cholangitis (PSC), and hepatocellular carcinoma (HCC), aiming to identify a proteomic signature that can effectively distinguish among these conditions. Utilizing high-throughput mass spectrometry on serum samples, we identified 845 proteins, of which 646 were suitable for further analysis. Unique clustering patterns were observed among the five groups, with significant proteomic differences. Our key findings include: S100 calcium-binding protein A9 (S100A9) and haptoglobin (HP) were more abundant in iCCA, while intercellular adhesion molecule 2 (ICAM2) was higher in HCC. Serum amyloid A1 (SAA1) and A4 (SAA4) emerged as potential biomarkers, with SAA1 significantly different in the iCCA vs healthy controls (HC) comparison, and SAA4 in the HCC vs HC comparison. Elevated levels of vascular cell adhesion molecule 1 (VCAM-1) in HCC suggested its potential as a differentiation and diagnostic marker. Angiopoietin-1 receptor (TEK) also showed discriminatory and diagnostic potential in HCC. ELISA validation corroborated mass spectrometry findings. Our study underscores the potential of proteomic profiling in distinguishing iCCA from other liver conditions and highlights the need for further validation to establish robust diagnostic biomarkers.

Intrahepatic cholangiocarcinoma (ICC) is the second commonly-seen liver malignancy and one of the most fatal cancers in Taiwan. Survival after diagnosis of ICC remains poor. This study aimed to investigate the survival and prognostic factors in patients with ICC. All patients with newly diagnosed ICC during 2004 to 2018 were identified from a national cancer database and followed until December 2020. Estimates of overall survival (OS) were conducted using the Kaplan-Meier method and Cox proportional hazards model. Hazard ratios with 95% confidence intervals were calculated. Initially, 7940 patients with ICC disease (stage IV: 55.6%, 4418/7940) were eligible for this study. Only 32.3% (2563/7940) patients with ICC underwent liver resection. After Propensity score matching, 969 pairs (N = 1938) of patients were matched and selected (mean age 62.8 ± 11.0 years, 53.1% were male, 29.7% had cirrhosis). The median follow-up time was 80.0 months (range 25-201 months). The 3-, 5-year OS rates were 44.0%, 36.4% in the surgical group and 26.0%, 23.7% in the non-surgical group, respectively. Surgery, young patients (≤ 54 years), small tumor size, no vascular invasion and chemotherapy were associated with better OS in patients with stages I-III disease. Surgery benefit was maximum in stage I disease followed by stage II. In patients with stage IV disease, factors such as surgery, young patients (≤ 64 years), single tumor, and no vascular invasion were associated with better OS. Chemotherapy was insignificantly associated with better OS. Long-term survival in patients with ICC is very poor. Compared to non-surgical patients, surgery conveys approximately 18% and 12% better OS rates at 3-year and 5-year, respectively. Early detection and surgical intervention may improve OS substantially in patients with ICC.

Primary liver cancer (PLC) has placed an increasing economic and resource burden on the health care system of the United States. We attempted to quantify its epidemiology and associated costs using a national inpatient database.

Hospital discharge and insurance claims data from the National Inpatient Sample were used to conduct this analysis. Patients diagnosed with PLC (hepatocellular carcinoma or cholangiocarcinoma) were included in the study population, which was then stratified using patient demographics, comorbidities, degree of cancer spread, liver disease complications, and other descriptors. Trends were analyzed via regression curves for each of these strata from the years 2016 to 2019, with special attention to patterns in hospitalization incidence, inpatient mortality rate, total costs, and average per-capita costs. The resulting curves were evaluated using goodness-of-fit statistics and P -values.

Aggregate hospitalization incidence, inpatient mortality rates, and total costs were found to significantly increase throughout the study period ( P =0.002, 0.002, and 0.02, respectively). Relative to their demographic counterparts, males, White Americans, and those older than 65 years of age contributed the largest proportions of total costs. These population segments also experienced significant increases in total expenditure ( P =0.04, 0.03, and 0.02, respectively). Admissions deemed to have multiple comorbidities were associated with progressively higher total costs throughout the study period ( P =0.01). Of the categorized underlying liver diseases, only admissions diagnosed with alcoholic liver disease or nonalcoholic fatty liver disease saw significantly increasing total costs ( P =0.006 and 0.01), although hepatitis C was found to be the largest contributor to total expenses.

From 2016 to 2019, total costs, admission incidence, and inpatient mortality rates associated with PLC hospitalization increased. Strata-specific findings may be reflective of demographic shifts in the PLC patient populations, as well as changes in underlying chronic liver disease etiologies.

Biliary tract cancers, including cholangiocarcinoma, gallbladder, and ampulla of Vater cancers, rank second among hepatobiliary cancers, known for their poor prognoses. The United States has witnessed a notable increase in intrahepatic cholangiocarcinoma incidence. This study examines the incidence and survival outcomes of biliary tract cancers in Olmsted County, Minnesota from 1976 to 2018. Using data from the Rochester Epidemiology Project (REP), residents aged 20 and above were analyzed across four eras. Incidence rates were calculated and adjusted for age and sex, and temporal trends were assessed using Poisson regression. Intrahepatic cholangiocarcinoma exhibited a significant escalation in incidence rates over time, while gallbladder cancers showed a decline among women. Median survival times for biliary tract cancers notably improved. These findings confirm the rising incidence of intrahepatic cholangiocarcinoma and suggest improving survival rates. Nevertheless, the overall prognosis for biliary tract cancers remains very poor, emphasizing the continual need for enhanced management strategies and further research.

Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10-20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA.

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.

Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients.

Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality.

Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69-2.68) or 90-day mortality (OR 1.22; 95% CI 0.62-2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41-1.41) or 90-day mortality (OR 0.60; 95% CI 0.33-1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36-4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31-4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36-4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30-3.87).

In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA.

Hepatobiliary cancers (HBCs) include hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, which originate from the liver, bile ducts, and gallbladder, respectively. They are responsible for a substantial burden of cancer-related deaths worldwide. Despite knowledge of risk factors and advancements in therapeutics and surgical interventions, the prognosis for most patients with HBC remains bleak. There is evidence from familial aggregation and case-control studies to suggest a familial risk component in HBC susceptibility. Recent progress in genomics research has led to the identification of germline variants including single nucleotide polymorphisms (SNPs) and pathogenic or likely pathogenic (P/LP) variants in cancer-associated genes associated with HBC risk. These findings emerged from genome-wide association studies and next-generation sequencing techniques such as whole-exome sequencing. Patients with other cancer types, including breast, colon, ovarian, prostate, and pancreatic cancer, are recommended by guidelines to undergo germline genetic testing, but similar recommendations are lagging in HBC. This prompts the question of whether multi-gene panel testing should be integrated into clinical guidelines for HBC management. Here, we review the hereditary genetics of HBC, explore studies investigating SNPs and P/LP variants in HBC patients, discuss the clinical implications and potential for personalized treatments and impact on patient's family members, and conclude that additional studies are needed to examine how genetic testing can be applied clinically.

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease's underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), and AT-rich interactive domain-containing protein 1A (ARID1A). The rate of mutations varies significantly for each population. Targeting TP53 and KRAS is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated IDH1 and target therapy for ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC's molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy.

Cancer cell stemness contributes significantly to intrahepatic cholangiocarcinoma (ICC) progression. However, the roles of deubiquitinating enzymes (DUBs) in ICC modulation are poorly understood. Ubiquitin specific peptidase 10 (USP10) was highly expressed in ICC spheres. The interaction between USP10 and snail family transcriptional repressor 1 (SNAI1) reduced the polyubiquitination of the SNAI1 protein and stabilized the SNAI1 protein. USP10 knockdown in RBE cells inhibited cell proliferation, promoted cell apoptosis and decreased the diameter of the formed spheres and the expression levels of CD44, EpCAM, OCT4 and SOX2. SNAI1 overexpression alleviated the effect of USP10 knockdown in RBE cells. In addition, the knockdown of USP10 attenuated the ability of RBE cells to form tumors subcutaneously in nude mice. Our results revealed that USP10 attenuates ICC cell malignancy by deubiquitinating SNAI1, indicating that USP10 could be developed as a therapeutic target for ICC treatment.

Cholangiocarcinoma (CCA) is the most common biliary tract malignancy and the second most frequent primary hepatic malignancy after hepatocellular carcinoma. During the past three decades, the incidence of intrahepatic cholangiocarcinoma (iCCA) has risen in Western Europe, while the incidence of extrahepatic cholangiocarcinoma (eCCA) has remained stable or fallen. The mortality rates of iCCA, which are greater than those of eCCA, showed also an increasing trend, while those of eCCA remained stable. Well-known risk factors like hepatobiliary flukes, hepatolithiasis and choledochal cysts are important in the development of iCCA particularly in Asian countries. In Western countries, the primary sclerosing cholangitis is the most common risk factor for CCA. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and cirrhosis are considered to be risk factors for iCCA. Emergent risk factors such as obesity, diabetes and MAFLD are increasingly associated mostly with iCCA.

Cartilage oligomeric matrix protein (COMP) interacts with various extracellular matrix proteins in tissues. Elevated COMP levels recently linked to worse overall survival in multiple cancer types. COMP's significance in intrahepatic cholangiocarcinoma (iCCA) remains uncertain. Here we report a retrospective study to explore COMP's impact on iCCA outcomes. We collected 182 patients' iCCA tumor tissues. COMP overexpression was associated with adverse factors like R1 resection (p = 0.008), advanced T stage (p < 0.001), large duct type (p = 0.004), and poorly differentiated histology (p = 0.002). COMP overexpression correlates with poorer DFS (HR, 3.651; p = 0.001), OS (HR, 1.827; p = 0.023), LRFS (HR, 4.077; p < 0.001), and MFS (HR, 3.718; p < 0.001). High COMP expression ties to worse overall survival (p = 0.0001), DSS (p < 0.0001), LRFS (p < 0.0001), and MFS (p < 0.0001). In conclusion, COMP overexpression links to poor prognosis and pathological features in iCCA, indicating its potential as a biomarker.

Bile duct obstruction is a common issue for patients with advanced cholangiocarcinoma (CCA). Percutaneous transhepatic cholangial drainage (PTCD) is often required to relieve the obstruction. However, PTCD may alter the intestinal microbiota, which can affect the efficacy of immunotherapy. Antibiotics (ATB) can also have significant immunomodulatory effects by perturbing the gut microbiota. Therefore, this study aimed to investigate whether PTCD or ATB therapy is associated with overall survival (OS) or progression-free survival (PFS) in patients with advanced CCA receiving first-line chemotherapy plus immune checkpoint blockade (ICB) in clinical practice. We also explored whether the gut microbiota changes after receiving PTCD.

We conducted a single-center retrospective analysis of PTCD and ATB therapy in patients with advanced CCA. PTCD was performed before ICB initiation, and ATB was administered within 1 month before and 6 weeks after ICB initiation. Our primary outcomes were PFS and OS. Moreover, we used 16s rRNA sequencing to analyze fecal and bile samples obtained from patients who underwent PTCD.

In total, 107 patients with CCA were included. Among patients who did not undergo PTCD, ICB plus chemotherapy significantly improved OS vs. chemotherapy alone (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.45, p < 0.0001). PFS was also significantly improved in patients who received ICB plus chemotherapy compared with chemotherapy alone (HR 0.36, 95% CI 0.16-0.80, p = 0.0024). However, ICB plus chemotherapy did not improve survival compared with chemotherapy alone among patients who received PTCD. Overall changes in the fecal microbiota of patients after PTCD involved significant reductions in which Escherichia - Shigella.

The use of ATB or PTCD in patients with CCA receiving ICB was associated with worse OS compared with chemotherapy alone, and PTCD affects the gut microbiota. Escherichia - Shigella was significantly reduced in feces of patients after PTCD.

Cholangiocarcinoma, also referred to as CCA, is a highly complex epithelial malignancy that can impact various organs and regions of the body, including the perihilar, intrahepatic, and distal organs. This cancer is characterized by the malignant growth of the epithelial lining in the bile ducts, which spans the entire biliary tree and is accountable for disease progression. The current state of affairs concerning CCA is concerning, with poor prognoses, high recurrence rates, and dismal long-term survival rates significantly burden healthcare facilities worldwide. Studies have identified numerous signaling pathways and molecules involved in the development and progression of CCA, including microRNAs, an important class of non-coding RNAs that have the ability to modulate these cellular signaling pathways significantly. In addition, microRNAs may serve as an innovative target for developing novel therapeutic approaches for CCA. In this review, we explore the underlying mechanisms and signaling pathways implicated in the initiation and progression of CCA, focusing on the future direction of utilizing microRNAs as a promising treatment option for this challenging malignancy.

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.

Intrahepatic cholangiocarcinoma (iCCA) has shown a substantial increase in mortality globally. On the contrary, perihilar cholangiocarcinoma and distal cholangiocarcinoma have been decreasing. We aim to evaluate the causes of death after iCCA diagnosis.

We studied 8,962 patients with iCCA diagnosed between 2000 and 2018 in the United States. The standardized mortality ratio for each cause of death was calculated. We used R software version 3.5 to perform Kaplan-Meier survival tests and covariate-adjusted Cox models.

Of the 8,962 patients diagnosed with iCCA, 7,335 (81.8%) died during the follow-up period with a mean age of death of 67.88 years. The highest number of deaths (4,786; 65.2%) occurred within the first year following iCCA diagnosis. 4,832 (66%) were from iCCA, 2,063 (28%) were from other cancers, and 440 (6%) were from non-cancer causes mainly cardiovascular disease. The overall mean survival after 1 year of diagnosis was 40.8% (39.8-41.9); however, the overall mean survival was 9.8% (9-10.5) after 5 years of diagnosis. The multivariable analysis showed that age, sex, stage, and management of iCCA have a statistically significant impact on survival.

Following iCCA diagnosis, about 34% died from non-iCCA causes. The most common non-iCCA cancer cause was liver cancer, and cardiovascular disease represents a substantial percentage of non-cancer deaths. Our findings provide insights into how iCCA survivors should be followed up regarding future risks.

The management and follow-up should be tailored to the needs of each patient with iCCA.

At present, there is no definitive conclusion about the relative prognostic factors on intrahepatic cholangiocarcinoma perihilar large duct type (iCCAphl) and iCCA peripheral small duct type (iCCApps).

To compare the prognoses of two different types of iCCA, and identify the independent risk factors affecting the long-term survival of patients undergoing radical resection for iCCA.

This study included 89 patients with iCCA who underwent radical resection at the Department of Hepatobiliary Surgery of the East Yard of the Shandong Provincial Hospital between January 2013 and March 2022. According to the tumor origin, these patients were divided into the iCCAphl group (n = 37) and iCCApps group (n = 52). The prognoses of the two groups were compared using Kaplan-Meier analysis, whereas the independent risk factors of their prognoses were identified using Cox univariate and multivariate regression analyses.

In the iCCApps group, the independent risk factors for overall survival included diabetes history (p = 0.006), lymph node metastasis (p = 0.040), and preoperative carbohydrate antigen 19-9 (p = 0.035). In the iCCAphl group, the independent risk factors for overall survival included multiple tumors (p = 0.010), tumor differentiation grade (p = 0.008), and preoperative jaundice (p = 0.009).

Among the iCCA patients who underwent radical resection, the long-term prognosis of iCCApps maybe better than that of iCCAphl. The prognoses of these two types of iCCA were affected by different independent risk factors.

The long-term comprehensive prognosis of chronic hepatitis C after direct-acting antiviral (DAA) therapy is unclear. This study aimed to investigate the prognosis and incidence of immunological and oncological complications after DAA therapy.

The study included a total of 1461 patients who received DAA therapy in our university hospital and affiliated hospitals between September 3, 2014 and September 30, 2018.

The incidence rates of total malignancies in overall or female patients after DAA therapy were significantly greater than expected in the corresponding general population. The same was true for lung malignancies. Predictive risk factors associated with the occurrence and recurrence of hepatic malignancies after DAA therapy in patients with sustained virological response were cirrhosis and insulin use, protein induced by vitamin K absence or antagonist-II level, and albumin-bilirubin score, respectively. Eight (0.5%) patients were diagnosed with autoimmune diseases after starting DAA therapy. Importantly, the attending physician considered a possible causal relationship between DAA therapy and these autoimmune diseases in five cases (four rheumatoid arthritis and one membranoproliferative glomerulonephritis). The 5-year overall survival rate was 91.6%. The most frequent primary cause of death was malignancy in 41 (60.2%) patients, including 25 with hepatic malignancies. Lung and colorectal cancers were the next most common.

Given that the incidence of total and lung cancers might increase and DAA-related autoimmune diseases might emerge after DAA therapy, we should be alert for the development of these diseases as well as hepatic malignancies.

Intrahepatic cholangiocarcinoma (ICC) is a poorly understood and aggressive malignancy with increasing incidence and mortality. Hepatitis B virus (HBV) infection is recognized as one of the important risk factors of ICC. There are few reports focusing on whether isolated antibody to hepatitis B core antigen (isolated anti-HBc, IAHBc) have prognostic role in ICC, while positive hepatitis B surface antigen (HBsAg) has been reported to be associated with the prognosis of ICC. The aim of this study was to investigate the prognostic value of IAHBc in ICC patients after curative resection, in order to identify those who have the high risk of ICC recurrence in the early stage.

We divided 209 ICC patients who underwent curative resection into 4 groups: group I (n = 40), HBsAg (-)/antibody to hepatitis B surface antigen (anti-HBs) (-)/anti-HBc (+); group II (n = 70), HBsAg (+)/anti-HBc (-); group III (n = 55), HBsAg (-)/anti-HBs (+)/anti-HBc (+); and group IV (n = 44), HBsAg (-)/anti-HBc (-). We compared the recurrence-free survival (RFS) and overall survival (OS) among these four groups.

The median follow-up time was 16.93 months (range 1-34.6 months). The 1- and 2-year RFS and OS rates were 60% and 42%, and 78% and 63% respectively in all patients. Compared to the whole non-IAHBc patients (group II + group III + group IV), IAHBc patients (group I) showed significantly lower RFS at 1 year (39.8% vs. 64.4%, P = 0.001) and 2 years (20.7% vs. 46.7%, P = 0.001). When compared to other three individual groups, IAHBc patients (group I) also had the lowest RFS. We did not find significant difference in OS among the four groups. Further multivariate analysis revealed that IAHBc was an independent risk factor of RFS.

IAHBc is an independent poor prognostic factor for tumor recurrence in ICC patients after curative resection.

To offer new prognostic evaluations by exploring potentially distinctive genetic features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).

There were 12 samples for gene expression profiling processes in this study. These included three HCC lesion samples and their matched adjacent nontumor liver tissues obtained from patients with HCC, as well as three ICC samples and their controls collected similarly. In addition to the expression matrix generated on our own, profiles of other cohorts from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus (GEO) were also employed in later bioinformatical analyses. Differential analyses, functional analyses, protein interaction network analyses, and gene set variation analyses were used to identify key genes. To establish the prognostic models, univariate/multivariate Cox analyses and subsequent stepwise regression were applied, with the Akaike information criterion evaluating the goodness of fitness.

The top three pathways enriched in HCC were all metabolism-related; they were fatty acid degradation, retinol metabolism, and arachidonic acid metabolism. In ICC, on the other hand, additional pathways related to fat digestion and absorption and cholesterol metabolism were identified. Consistent characteristics of such a metabolic landscape were observed across different cohorts. A prognostic risk score model for calculating HCC risk was constructed, consisting of ADH4, ADH6, CYP2C9, CYP4F2, and RDH16. This signature predicts the 3-year survival with an AUC area of 0.708 (95%CI = 0.644 to 0.772). For calculating the risk of ICC, a prognostic risk score model was built upon the expression levels of CYP26A1, NAT2, and UGT2B10. This signature predicts the 3-year survival with an AUC area of 0.806 (95% CI = 0.664 to 0.947).

HCC and ICC share commonly abrupted pathways associated with the metabolism of fatty acids, retinol, arachidonic acids, and drugs, indicating similarities in their pathogenesis as primary liver cancers. On the flip side, these two types of cancer possess distinctive promising biomarkers for predicting overall survival or potential targeted therapies.

Intrahepatic cholangiocarcinoma is the second most common primary cancer of the liver. It is highly malignant and its prognosis is very poor. Although there have been various reports on the effects of calcium channel blockers on cancer, the effects of calcium channel blockers on intrahepatic cholangiocarcinoma have not been reported so far.

Seventy-nine patients diagnosed with intrahepatic cholangiocarcinoma by hepatectomy between January 2002 and May 2019 were retrospectively evaluated. We compared prognosis and time to recurrence between patients treated with calcium channel blockers (CCBs) (n = 29) and those not treated with CCBs (n = 50). Propensity score matching reduced confounding biases and yielded 25 matched patient pairs. Survival between groups was compared using Kaplan-Meier analyses, logrank tests, and Cox proportional hazard regression models.

Overall survival and recurrence-free survival of the CCBs group were significantly longer than those of the non-CCBs group OS in the original cohort and matched cohort (98 months vs 45 months, p = 0.010; 96 months vs 22 months, p = 0.020, respectively). Multivariate analyses showed that CCBs treatment was independently associated with overall survival (HR, 0.37; 95% CI 0.16-0.85; p = 0.019) and recurrence-free survival (HR, 0.39; 95% CI 0.17-0.90; p = 0.020) in the original cohort and matched cohort, respectively.

CCBs treatment might improve prognosis of patients with intrahepatic cholangiocarcinoma.

Insulin and incretin-based drugs are important antidiabetic agents with complex effects on cell growth and metabolism. Emerging evidence shows that insulin and incretin-based drugs are associated with altered risk of biliary tract cancer (BTC). Observational study reveals that insulin is associated with an increased risk of extrahepatic cholangiocarcinoma (ECC), but not intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC). This type-specific effect can be partly explained by the cell of origin and heterogeneous genome landscape of the three subtypes of BTC. Similar to insulin, incretin-based drugs also exhibit very interesting contradictions and inconsistencies in response to different cancer phenotypes, including BTC. Both epidemiological and experimental evidence suggests that incretin-based drugs can be a promoter of some cancers and an inhibitor of others. It is now more apparent that this type of drugs has a broader range of physiological effects on the body, including regulation of endoplasmic reticulum stress, autophagy, metabolic reprogramming, and gene expression. In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) have a more complex effect on cancer due to the multi-functional nature of DPP-4. DPP-4 exerts both catalytic and non-enzymatic functions to regulate metabolic homeostasis, immune reaction, cell migration, and proliferation. In this review, we collate the epidemiological and experimental evidence regarding the effect of these two classes of drugs on BTC to provide valuable information.

Precision medicine has become a dominant theme in the treatment of biliary tract cancers (BTCs). Although prognosis remains poor, technologies for improved molecular characterization along with the US Food and Drug Administration approval of several targeted therapies have changed the therapeutic landscape of advanced BTC. The hallmark of BTC oncogenesis is chronic inflammation of the liver and biliary tract regardless of the anatomical subtype. Subtypes of BTC correspond to distinct molecular characteristics, making BTC a molecularly heterogenous collection of tumors. Collectively, up to 40% of BTCs harbor a potentially targetable molecular abnormality, and the National Comprehensive Cancer Network guidelines recommend molecular profiling for all patients with advanced BTC. Use of circulating tumor DNA, immunohistochemistry, and next-generation sequencing continues to expand the utility for biomarker-driven management and molecular monitoring of BTC. Improving outcomes using biomarker-agnostic treatment for nontargetable tumors also remains a priority, and combinational treatment strategies such as immune checkpoint inhibition plus chemotherapy hold promise for this subgroup of patients.

Circular RNAs have a unique covalent closed-loop structure, which is mainly formed by the reverse splicing of exons from a precursor mRNA. With the development of key technologies such as high-throughput sequencing and the advancement of bioinformatics in recent years, our understanding of circular RNAs has become increasingly more detailed, and their abnormal expression in a variety of cancers has attracted increasing attention. Studies have shown that circSNARCA5 not only plays a crucial role in the occurrence and development of cancer but may also serve as a reliable indicator for tumor screening or a good marker for evaluating cancer prognosis. Nevertheless, there are no reviews focusing on the relationship between circSMARCA5 and cancer. Therefore, we will first explain the main biological characteristics of circSMARCA5, such as biogenesis and biological effects. Then, the focus will be on its role and significance in cancer. Finally, we will summarize the known information on circSMARCA5 in cancer and discuss future research prospects.

The evolutionary history of hepatobiliary cancers is embedded in their genomes. By analysing their catalogue of somatic mutations and the DNA sequence context in which they occur, it is possible to infer the mechanisms underpinning tumorigenesis. These mutational signatures reflect the exogenous and endogenous origins of genetic damage as well as the capacity of hepatobiliary cells to repair and replicate DNA. Genomic analysis of thousands of patients with hepatobiliary cancers has highlighted the diversity of mutagenic processes active in these malignancies, highlighting a prominent source of the inter-cancer-type, inter-patient, intertumour and intratumoural heterogeneity that is observed clinically. However, a substantial proportion of mutational signatures detected in hepatocellular carcinoma and biliary tract cancer remain of unknown cause, emphasizing the important contribution of processes yet to be identified. Exploiting mutational signatures to retrospectively understand hepatobiliary carcinogenesis could advance preventative management of these aggressive tumours as well as potentially predict treatment response and guide the development of therapies targeting tumour evolution.

Cholangiocarcinoma (CCA), especially intrahepatic CCA, is known to share several risk factors with hepatocellular carcinoma (HCC) and liver cirrhosis has been proposed as a common pathogenic factor. We aimed to identify the risk factors of CCA and to examine differences in risk factors between CCA and HCC. We followed 510,217 Korean adults who underwent health checkups during 2002−2003 until 2013 via linkage to national hospital discharge records. Hazard ratios (HRs) were calculated after adjustment for confounders. During the mean follow-up of 10.5 years, 1388 and 2920 individuals were diagnosed with CCA and HCC, respectively. Choledocholithiasis (HR = 13.7; 95% confidence interval (CI) = 7.58−24.88) was the strongest risk factor for CCA, followed by cholelithiasis (HR = 2.94) and hepatitis B virus (HBV) infection (HR = 2.71). Two of the strongest risk factors for HCC—liver cirrhosis (HR = 1.29; 95% CI = 0.48−3.45) and hepatitis C virus infection (HR = 1.89; 95% CI = 0.49−7.63)—were not significantly associated with the risk of CCA. HBV infection and diabetes increased the risk of both HCC and CCA, but the HRs were lower for CCA than for HCC (Pheterogeneity < 0.001 for HBV; Pheterogeneity = 0.001 for diabetes). The magnitudes of the effects of age, sex, obesity, alcohol consumption, and smoking on the development of both cancers were different (Pheterogeneity < 0.05 for each variable). In conclusion, choledocholithiasis, cholelithiasis, HBV, older age, male sex, diabetes, smoking, alcohol drinking, and obesity were found to be potential risk factors of CCA. Liver cirrhosis did not increase the risk of CCA. The magnitudes of the potential effects of common risk factors were generally different between CCA and HCC.

The poor prognosis of cholangiocarcinoma in humans is related to several factors, such as (i) the heterogeneity of the disease, (ii) the late onset of symptoms and (iii) the limited comprehension of the carcinogenic pathways determining neoplastic changes, which all limit the pursuit of appropriate treatment. Several risk factors have been recognized, including different infective, immune-mediated, and dysmorphogenic disorders of the biliary tree. In this review, we report the details of possible mechanisms that lead a specific premalignant pathological condition to become cholangiocarcinoma. For instance, during liver fluke infection, factors secreted from the worms may play a major role in pathogenesis. In primary sclerosing cholangitis, deregulation of histamine and bile-acid signaling may determine important changes in cellular pathways. The study of these molecular events may also shed some light on the pathogenesis of sporadic (unrelated to risk factors) forms of cholangiocarcinoma, which represent the majority (nearly 75%) of cases.

The objective of our study was to investigate and compare the epidemiologic characteristics, prognostic factors, and survival between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) patients.

Age-adjusted incidence rates were evaluated from 1975 to 2016 using the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) was investigated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factors for OS.

In the last 10 years, the incidence rate of ICC increased rapidly by 109% (annual percentage change (APC) = 8.24, 95% CI = 6.64 to 9.86; P < .001), compared with a much more modest 12% increase in the incidence of HCC (APC = 1.59, 95% CI = .56 to 2.62; P < .001). This trend persisted throughout the study across different age groups, sexes, and races. Males older than 70 years and of other races (non-African American and non-Caucasian) showed the highest incidence rates of HCC and ICC. Multivariate Cox regression analysis demonstrated that other race, married status, later year of diagnosis, more examined lymph nodes, and surgery were significant protective factors of OS in HCC patients. In contrast, the race and year of diagnosis were not independent prognostic factors, but radiation and chemotherapy were protective factors of OS in ICC patients. The median OS was 18 months and 12 months in HCC and ICC patients, respectively.

In the last 10 years, the incidence of HCC had a slow growth in the United States, whereas ICC showed a remarkable increase. The 5-year OS of the former has improved in recent years while that of the latter showed no significant improvement. Therefore, surgery could contribute to superior survival outcomes as compared to other treatments.

Cholangiocarcinoma (CCA) is the most common neoplasm of the biliary tract. The biological behavior and prognosis of CCA vary depending on the tumor's location in the biliary tree, dictating a different diagnostic, and treatment approach. Establishing a diagnosis of CCA remains a challenge and up to 20% of biliary strictures can yield indeterminate results, despite extensive evaluation. Endoscopic ultrasound (EUS) has become an effective diagnostic tool, as it provides high-quality images of the bile duct and allows for the sampling of strictures in the same plane of view. In this chapter, we explore the utility of EUS as a diagnostic and staging tool for biliary cancers.

Cholangiocarcinoma (CCA) is a malignant disease of the epithelial cells of the intrahepatic and extrahepatic bile ducts. This review focuses on various aspects of cholangiocarcinoma such as its associated causes, treatment criteria, and more.

Although it remains a rare malignancy and is the second most common primary malignancy of the liver, the incidence is increasing, especially the incidence of intrahepatic CCA. Several studies suggested that surgery is not only solution; recently, reported targeted drugs may have the potential to become an alternative option.

This review provides an overview of the current scenario of targeted therapies for CCA, which were tabulated with their current status and it also included its associated causes and its treatment criteria.

Because of its rarity and complexity, surgery remains the preferred treatment in resectable patients. Howerver, the studies suggested that the recently reported drugs may have the potential to be an alternative option for the treatment of CCA and related complications. In addition, this review will certainly benefit the community and researcher for further investigation.