RORc-expressing immune cells play important roles in inflammation, autoimmune disease and cancer. They are required for lymphoid organogenesis and have been implicated in tertiary lymphoid structure (TLS) formation. TLSs are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, some TLSs are pro-tumorigenic as they harbor tumor progenitor cells and support their growth. The processes involved in TLS development and acquisition of pro- or anti-tumorigenic roles are largely unknown. This study aims to explore the role of RORc-expressing cells in TLS development in the context of inflammation-associated liver cancer.

IKKβ(EE)Hep mice, exhibiting chronic liver inflammation, TLS formation and liver cancer, were crossed with RORc knockout mice to explore RORc's effect on TLS and tumor formation. TLS phenotypes were analyzed using transcriptional, proteomic, and immunohistochemical techniques. CD4, CD8, and B-cell depletions were used to assess their contribution to liver TLS and tumor formation.

RORc-expressing cells are detected within TLSs of both human patients and mice developing intrahepatic cholangiocarcinoma. In mice, these cells negatively regulate TLS formation, as excess TLSs form in their absence. CD4 cells are essential for liver TLS formation, while B cells are required for TLS formation specifically in the absence of RORc-expressing cells. Importantly, in chronically inflamed livers lacking RORc-expressing cells, TLSs become anti-tumorigenic, reducing tumor load. Anti-tumorigenic TLSs revealed enrichment of exhausted CD8 cells with effector functions, germinal center B cells and plasma cells. B cells are key in limiting tumor development, possibly via tumor-directed antibodies.

RORc-expressing cells negatively regulate B-cell responses and facilitate the pro-tumorigenic functions of hepatic TLSs.

RORc-expressing immune cells play critical roles in immune regulation, yet their specific influence on tertiary lymphoid structures (TLSs) in liver pathology and cancer has not been elucidated. Our study reveals that RORc-expressing cells act as negative regulators of TLS formation and shape the immune microenvironment in a manner that promotes tumor development. In the absence of RORc-expressing cells, TLSs not only increase in number but also acquire anti-tumorigenic properties. These findings suggest that RORc-expressing cells serve as key modulators of liver immune dynamics, with potential implications for the use of RORc as a biomarker to differentiate between pro- and anti-tumorigenic immune environments and as a target for manipulating TLS abundance and phenotype in liver cancer.

Inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are often elevated in liver cancer, making it difficult to monitor for bacterial infection. Hence, it is tempting to use more bacterial-specific sepsis markers such as procalcitonin (PCT) during immunosuppressive chemotherapy. This case study highlights the challenges of interpreting clinical chemistry sepsis biomarkers in patients with advanced cholangiocarcinoma (CCA).

A 55-year-old man presented with a liver mass on routine ultrasonography. MRI and CT showed multiple liver and bone metastases. The immunohistochemistry findings were consistent with an adenocarcinoma of the pancreaticobiliary system. After the diagnosis of primary hepatic CCA (NTM stage IV; FGFR2-SHROOM3 translocation) and 14 months of chemotherapy, the patient developed progressive liver lesions and new lung metastases.

During the last chemotherapy, PCT was highly elevated (>100 ng/mL), usually observed in severe sepsis or septic shock, whereas CRP was moderately elevated (<50 mg/L). The patient had mild leukopenia but no fever, systemic infection or septic shock. Blood and urine cultures were negative.

After referral to best supportive care, the patient died of liver failure. Retrospective blood analysis revealed high levels of soluble CD14 subtype, a bacterial sepsis marker known as presepsin. Calcitonin and IL-6 levels were above normal, consistent with advanced CCA, but not with a PCT/calcitonin-secreting tumor or systemic inflammation.

Oncologists are aware that CRP and IL-6 values can be elevated in liver cancer. Here, we further demonstrate that highly elevated, septic shock-like PCT values can occur even in the absence of bacterial sepsis. In addition, presepsin may be elevated, although mechanistically unrelated to PCT. Therefore, sepsis markers should be interpreted with caution and in the clinical context, not only in patients with neuroendocrine or hepatocellular carcinoma, which are known to secrete PCT and calcitonin, but also in patients with advanced CCA.

Standard of care first-line systemic treatment for advanced biliary tract cancer includes chemo-immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo-immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo-immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty-eight patients were included in this study. Two hundred twenty-seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first-line chemo-immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil-to-lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

Cholangiocarcinoma, a cancer of the biliary duct, is frequently diagnosed in advanced stages with poor prognosis. Understanding the molecular mechanisms driving its progression is crucial for developing effective treatment approaches. This research delves into the role of LINC00313 in regulating the aggressiveness of cholangiocarcinoma cells.

Clinical samples were collected to examine the expression pattern of LINC00313, miR-320b, and MITF using RT-qPCR and western blot analysis. Functional experiments, including cell proliferation, migration, and invasion assays, as well as apoptosis detection, were performed to assess the malignant properties of cholangiocarcinoma cells. The tumorigenic potential of cholangiocarcinoma cells was further investigated in a xenograft mouse model.

Elevated levels of LINC00313 were detected in both cholangiocarcinoma tumors and cell lines. Knocking down LINC00313 reduced the aggressiveness of cholangiocarcinoma cells and hindered their ability to form tumors in vivo. It was discovered that miR-320b is a target of LINC00313, exhibiting an expression pattern and functional role that contrasts with LINC00313. Moreover, the LINC00313/miR-320b axis was found to regulate the expression of MITF, thereby influencing the aggressiveness of cholangiocarcinoma cells.

LINC00313/miR-320b/MITF axis is implicated in the malignant progression of cholangiocarcinoma, indicating the potential of targeting LINC00313 as a strategy for cholangiocarcinoma clinical management.

Studies on lung metastases from extrahepatic cholangiocarcinoma (ECC) are rare. This study aims to fill this gap by analyzing the influencing factors, prognosis, and chemotherapeutic efficacy of ECC lung metastases, and to provide insights for optimizing medical care for patients with ECC lung metastases.

We retrieved data from the Surveillance, Epidemiology and End Results (SEER) database for patients with metastatic ECC (stage M1) from 2018 to 2021. The study analyzed these characteristics using descriptive statistics. To calculate Hazard Ratios (HR), multivariate COX regression analyses were performed. Overall survival (OS) was estimated using the Kaplan-Meier method, and the survival of patients between groups was compared using the log-rank test.

A total of 762 people participated in the study, 50.4% of whom were men. At the time of diagnosis, 17.8% of patients had pulmonary metastases. 52.5% received chemotherapy. Multivariate COX analysis identified lung metastases as a significant risk factor for death from metastatic ECC (HR 1.64, CI 1.32-2.03, p < 0.001). Treatment with chemotherapy (HR 0.20, CI 0.17-0.25, p < 0.001) and female sex (HR 0.80, CI 0.67-0.94, p = 0.008) were associated with a better prognosis. Therefore, we further compared the prognosis and chemotherapy outcomes of male and female patients with ECC lung metastases. The median survival of male patients with and without lung metastases was 2 and 5 months, respectively (p = 0.016), whereas there was no significant difference in female patients (p = 0.19). Regardless of gender, patients with lung metastases had significantly worse OS even after receiving chemotherapy (p = 0.0065 in the male group and p = 0.0075 in the female group). Regardless of gender, patients with lung metastases who did not receive chemotherapy had significantly shorter overall survival than those who received chemotherapy. Not receiving chemotherapy vs. receiving chemotherapy (male: 1 month vs. 5 months, p < 0.0001; female: 2 months vs. 9 months, p < 0.0001).

Pulmonary metastasis is an important prognostic factor in ECC and is associated with poorer survival, especially in male patients. Therefore, preventive measures and effective control of lung metastases (e.g., chemotherapy), especially in male patients, may improve survival in patients with ECC.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the primary hepatic malignancies with established pathways to transplantation and model for end-stage liver disease (MELD) exception points. Other tumors managed with liver transplantation (LT) include hepatic epithelioid hemangioendothelioma and fibrolamellar HCC. LT for metastatic neuroendocrine tumor has been established with patient selection criteria and a path to MELD exception points. Additionally, recent data on LT for patients with unresectable hepatic colorectal metastases demonstrate increasingly encouraging initial results.

Gallbladder and biliary tract cancers (GBC and BTC) are highly malignant, with poor prognoses and substantial regional variability in the disease burden. Although advances in medical science have improved outcomes in high-income regions, low- and middle-income regions continue to face rising incidence and mortality rates owing to delayed detection and treatment. Understanding the global trends and risk factors of GBC and BTC is essential for targeted interventions to reduce disease burden.

A retrospective analysis of GBC and BTC was conducted using the 2021 Global Burden of Disease study. Data from 204 countries and territories between 1990 and 2021 were analyzed for incidence, mortality, and disability-adjusted life years stratified by age, sex, and sociodemographic index (SDI). Trends were quantified using age-standardized rates and estimated annual percentage changes.

In 2021, 216,768 new cases and 171,961 deaths were reported globally, with age-standardized incidence and mortality rates of 2.6 and 2.0 per 100,000, respectively. The high-income Asia-Pacific and Latin American regions exhibited the highest disease burdens. While global age-standardized rates declined estimated annual percentage changes for incidence: -0.44; mortality: -0.97), low-SDI regions experienced increases. High BMI emerged as the leading risk factor, contributing to 12% of the disability-adjusted life years. Projections indicate a stable incidence but rising mortality by 2036.

Although the global age-standardized rates of GBC and BTC are decreasing, disparities persist, with low-SDI regions experiencing increasing burdens. Targeted interventions addressing modifiable risk factors such as obesity, along with improved healthcare infrastructure and early detection, are critical for mitigating this global health challenge.

Intrahepatic cholangiocarcinoma (ICC) is a malignancy with rising incidence and mortality in the United States. This study aimed to investigate temporal trends in the place of death among patients with ICC and assess demographic disparities.

We used the CDC WONDER database (2003-2020) for a retrospective study of patients who died from intrahepatic cholangiocarcinoma identified through death certificates. Place of death was categorized as hospice, home, inpatient, nursing home, or other. Age-adjusted mortality rates were calculated per 100 000. Temporal trends were assessed using the Mann-Kendall trend test, and associations between demographic characteristics and place of death were examined using the χ 2 test.

Of 101 631 ICC-related deaths (AAMR: 1.61; 95% CI 1.60-1.62), the AAMR rose from 1.19 (95% CI 1.15-1.23) in 2003 to 2.04 (95% CI 2.00-2.08) in 2020. Over the study period, home was the most frequent place of death (44.6%), followed by inpatient facilities (28.4%), hospice (11.1%), and nursing homes (9.5%). Deaths at home and in hospice increased significantly (p < 0.01), while inpatient and nursing home deaths declined (p < 0.01). Disparities were observed across race, sex, age groups, and urbanization. Younger patients more often died in inpatient facilities, and minority racial groups were less likely to die at home or utilize hospice.

ICC-related deaths in the USA nearly doubled over the study period, with a marked shift from inpatient and nursing home deaths to hospice and home. Demographic disparities in end-of-life care underscore the need for targeted interventions to improve equitable access to palliative services.

Cholangiocarcinoma (CCA) is an aggressive malignancy with poor clinical outcomes. The current "gold standard" diagnostic approach, endoscopic retrograde cholangiopancreatography (ERCP)-obtained biopsy, has a relatively low sensitivity (i.e., ∼50%). Here, we developed a bile-based diagnostic system using transient stimulated Raman scattering (T-SRS). Except for the tolerance to autofluorescence inherited from traditional SRS spectroscopy, T-SRS features quantum-limit spectral line shapes and is further improved with self-calibration ability in this research. These advantages make the acquired Raman spectra insensitive to the drifting of the excitation parameters, facilitating long-term reliability. Based on the T-SRS spectra in the C-H stretching region from 76 bile samples accumulated over more than 1 year, we demonstrated high accuracy (i.e., 85 ± 3%) and sensitivity (i.e., 87 ± 9%) for classification between CCA and benign diseases. The T-SRS acquisition only requires ∼9-μL bile samples and features a drastically improved time cost. This study suggests that the self-calibrated T-SRS analysis of the bile sample offers a promising approach for rapid CCA diagnosis.

The prevalence of intrahepatic cholangiocarcinoma (ICC) is increasing globally. Despite advancements in comprehending this intricate malignancy and formulating novel therapeutic approaches over the past few decades, the prognosis for ICC remains poor. Owing to the high degree of malignancy and insidious onset of ICC, numerous cases are detected at intermediate or advanced stages of the disease, hence eliminating the chance for surgical intervention. Moreover, because of the highly invasive characteristics of ICC, recurrence and metastasis postresection are prevalent, leading to a 5-year survival rate of only 20%-35% following surgery. In the past decade, different methods of treatment have been investigated, including transarterial chemoembolization, transarterial radioembolization, radiotherapy, systemic therapy, and combination therapies. For certain patients with advanced ICC, conversion treatment may be utilized to facilitate surgical resection and manage disease progression. This review summarizes the definition of downstaging conversion treatment and presents the clinical experience and evidence concerning conversion treatment for advanced ICC.

Exosomes are submicron-sized extracellular vesicles involved in immune regulation, tumor metastasis, and cellular communication. Their lipid composition, distinct from parental cells, plays a crucial role in diseases like cancer. However, lipidomic analysis of exosomes, particularly in complex samples like blood, requires advanced techniques. This study optimizes miniaturized flow field-flow fractionation (mFlFFF) coupled with electrospray ionization mass spectrometry (ESI-MS) for direct lipidomic analysis of exosomes in serum. The mFlFFF technique resolves exosomes for size-based lipid analysis without prior extraction. Lipidomic profiling of serum exosomes from patients with extrahepatic cholangiocarcinoma (eCCA) identified over 1000 lipid species, with 64 showing significant changes compared to healthy controls. Target lipids were analyzed by mFlFFF-ESI-MS, revealing 35 species that distinguish eCCA patients from controls, suggesting their potential as biomarkers. Elevated levels of lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol (PI) were observed in the eCCA group, indicating lipid alterations linked to cancer progression and inflammation. Notably, PI 38:4, involved in the release of arachidonic acid, highlights its role in inflammatory processes associated with cancer. This study demonstrates the potential of mFlFFF-ESI-MS for lipidomic analysis of exosomes and offers a non-invasive approach for cancer diagnosis, with future implications for therapeutic targeting of lipid pathways in cholangiocarcinoma.

This study was aimed at examining the causes of death (CODs) in patients with advanced intrahepatic cholangiocarcinoma (ICC) undergoing chemotherapy (CT). In addition, machine learning models were incorporated to predict the treatment outcomes of patients with advanced ICC and identify the factors most closely related to prognosis.

A total of 5564 patients (CT group, 3632; non-CT group, 1932) were included in the Surveillance Epidemiology and End Results registries between 2000 and 2020. The CODs were compared between the two groups before and after the inverse probability of treatment weighting (IPTW). Furthermore, seven machine learning models were utilized as predictive tools to select variable features, aiming to assess the therapeutic effectiveness in patients with advanced ICC.

After IPTW, the CT group exhibited a lower cumulative incidence of cholangiocarcinoma-related deaths (30%, 49%, and 73% vs. 59%, 66%, and 73%; P < 0.001), secondary malignant neoplasms (8.5%, 13%, and 20% vs. 19%, 22%, and 24%; P < 0.001), and other CODs (1.8%, 2.9%, and 4.4% vs. 4.1%, 4.6%, and 5.4%; P < 0.001) at 0.5-, 1-, and 3- years than the non-CT group, whereas the cumulative incidence of cardiovascular diseases (P = 0.4) was comparable between the two groups. Of the seven machine learning models, the random forest model showed the highest predictive effectiveness. This model verified that variables such as CT, radiotherapy, tumor dimensions, sex, and distant metastasis were strongly correlated with the prognosis of advanced ICC.

CT has improved the therapeutic efficacy of advanced ICC without significantly increasing other CODs. Furthermore, the analysis of various features using machine learning models has confirmed that the random forest model demonstrates the highest predictive performance.

The interindividual variability of CYP3A4 activity complicates precision pharmacotherapy, particularly for drugs with narrow therapeutic windows. To explore the relationship between CYP3A4 polymorphisms and metabolic phenotypes, this study used abemaciclib as a probe substrate within a translational framework. The in vitro platform combined a reconstituted enzyme catalysis system for high-throughput inhibitor screening with UPLC-MS/MS metabolic profiling. In vivo pharmacokinetic studies were performed in female SD rats, with optimized sampling during the elimination phase. Human CYP3A4 baculosomes were engineered using baculovirus-mediated expression in Sf21 cells to investigate genetic influences on metabolic variability. Molecular docking and dynamics simulations were also performed to investigate structural differences in inhibitory activity. Results showed that letrozole significantly inhibited CYP3A4-mediated abemaciclib metabolism, reduced its clearance and increased its area under the blood concentration-time curve (AUC) and maximum blood concentration (Cmax) through mixed inhibition. Moreover, CYP3A4 polymorphisms substantially impacted abemaciclib pharmacokinetics. Kinetic simulations revealed that the CYP3A4.28 variant formed a stable complex with letrozole, enhancing inhibition, while the CYP3A4.30 variant lost catalytic activity. These findings underscored the critical role of CYP3A4 activity and genetic polymorphisms in drug metabolism and highlighted the necessity for personalized treatment approaches.

Biliary tract cancer (BTC) is a highly heterogeneous aggressive tumor, and advanced patients have poor prognosis. This work aimed to evaluate the efficacy and safety of camrelizumab combined with chemotherapy in treating advanced BTC, and to explore predictive biomarkers for distinguishing effective population.

183 advanced BTC patients admitted from September 2018 to September 2021 were retrospectively selected. 93 patients were treated with camrelizumab combined with chemotherapy (C+C group) and 90 patients were treated with chemotherapy alone (C group). Objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were analyzed between two groups. Peripheral blood lymphocyte subsets were assessed by flow cytometry pre- and post-treatment.

The mPFS (6.9 months) and mOS (12.1 months) in the C+C group were significantly longer than those in the C group, which were 5.2 months and 9.8 months respectively (HR 0.46, 95% CI 0.38-0.54, p=0.017; HR 0.39, 95% CI 0.32-0.47, p=0.033). The percentage of Total T, CD4+T, natural killer (NK) cells, lymphocyte, and CD4+/CD8+ cell ratios were significantly increased in effective patients after C+C treatment, but didn't increase in progressive disease (PD) patients. Higher percentage of Total T, CD4+T, and higher CD4+/CD8+ cell ratios post-treatment were associated with longer OS.

Camrelizumab combining chemotherapy significantly prolonged the mPFS and mOS of advanced BTC patients. Immunotherapy may improve the immune status of advanced patients, and immunotherapy efficacy might be predicted based on the peripheral blood lymphocyte subsets.

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.

This large-scale, population-based cohort study examined the associations between metabolic syndrome and cholangiocarcinoma risk, including its intrahepatic and extrahepatic forms.

A total of 4,932,211 adults aged ≥40 years participated in a government-initiated health checkup program (2012-2017), which collected lifestyle data, anthropometric measurements, and biochemical tests. Follow-up continued until 2021, with data linkage to National Cancer and Death Registries to ascertain the occurrence of cholangiocarcinoma and obtain vital status information. Fine and Gray models accounted for competing risks. During 35,879,371 person-years of follow-up, 6117 cholangiocarcinoma cases were identified, with an incidence rate of 17.05 (95% CI: 15.90-18.20) per 100,000 person-years. Individuals with metabolic syndrome had significantly higher incidences of both intrahepatic and extrahepatic cholangiocarcinoma ( p <0.0001). The multivariate-adjusted HR for cholangiocarcinoma among those with metabolic syndrome was 1.20 (1.14-1.27). Stratification analyses by age, sex, liver enzyme levels, and comorbidities consistently demonstrated an increased cholangiocarcinoma risk among individuals with metabolic syndrome. A dose-response relationship was observed, with a higher number of metabolic components correlating with an elevated cholangiocarcinoma risk, even after accounting for all-cause mortality as a competing risk. The adjusted subdistribution HRs ranged from 1.16 (95% CI: 1.02-1.32) for individuals with one metabolic component to 1.67 (95% CI: 1.45-1.94) for those with five ( p for trend <0.0001).

The positive association between metabolic syndrome and cholangiocarcinoma risk suggests that managing metabolic risk factors might reduce the occurrence of both intrahepatic and extrahepatic cholangiocarcinoma.

The aim of this study is to explore the prognostic value of CRP-Albumin-Lymphocyte (CALLY) index in patients undergoing radical resection of intrahepatic cholangiocarcinoma (ICC).

Retrospectively collected clinical data of 286 patients with ICC who underwent radical surgery at Shandong Provincial Hospital from July 2010 to July 2021. Univariate and multivariate analyses were used to evaluate the correlation between the CALLY index and overall survival (OS) and recurrence-free survival (RFS), and a nomogram prediction model was established based on the results. The accuracy of the model was evaluated using concordance index (C-index), calibration curves, decision curve analysis (DCA), and the receiver operating characteristic (ROC) curve was used to compare the prognostic value of the nomogram model with the TNM staging system.

The optimal cut-off value of CALLY index was 1.81. In the training set, multifactorial Cox regression analysis showed that CALLY index <1.81 was an independent risk factor for OS and RFS (p < 0.05). Compared to neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and modified Glasgow prognostic score (mGPS), CALLY index had a higher area under the curve (AUC). The nomogram established based on the results of multifactorial analysis demonstrated strong efficacy in survival prediction, and the ROC curve showed that the nomogram had a higher prognostic value than TNM staging.

The CALLY index is independently associated with OS and RFS in patients after radical resection of ICC, and the nomogram model based on it shows significantly higher efficacy in predicting the long-term prognosis of patients after radical resection of ICC, and is more accurate than TNM staging.

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

The biliary tract is a ductal network comprising the intrahepatic (IHBDs) and extrahepatic bile duct (EHBDs). Biliary duct disorders include cholangitis, neoplasms, and injury. However, the underlying mechanisms are not fully understood. With advancements in 3D culture technology, cholangiocyte organoids (COs) derived from primary tissues or induced pluripotent stem cells (iPSCs) can accurately replicate the structural and functional properties of biliary tissues. These organoids have become powerful tools for studying the pathogenesis of biliary diseases, such as cystic fibrosis and primary sclerosing cholangitis, and for developing new therapeutic strategies for cholangiocarcinoma. Additionally, COs have the potential to repair bile duct injuries and facilitate transplantation therapies. This review also discusses the use of organoids in genetically engineered mouse models to provide mechanistic insights into tumorigenesis and cancer progression. Continued innovation and standardization of organoid technology are crucial for advancing precision medicine for biliary diseases and cancer.

Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6-167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6-167aa on IκBα ubiquitination within the NF-κB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF-κB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic-lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA-driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient-derived xenograft (PDX), organoids, and organoid-derived PDX models, higher levels of circPCSK6-167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6-167aa, offering vital biological insights and clinical directions for developing cutting-edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments.

We conducted this observational study to investigate patterns of fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements, and how they relate to other characteristics of patients with unresectable advanced cholangiocarcinoma.

Patients aged 20 years or older with intrahepatic cholangiocarcinoma (ICC) or perihilar cholangiocarcinoma (PHC) had tumor samples assessed for FGFR2 fusions or rearrangements by a break-apart fluorescence in situ hybridization probe kit analyzed at a central laboratory; multivariate analyses using a logistic regression model were conducted to investigate the relationship between FGFR2 fusions or rearrangements and patients' baseline characteristics; two cut-off values (p-values of 0.15 and 0.05) were used.

Of the 453 patients observed, 25 (5.5%) had FGFR2 fusions or rearrangements, corresponding with 7.4% (23/306) of patients with ICC and 1.4% (2/144) of patients with PHC. Of 426 evaluable patients, FGFR2 fusions or rearrangements were associated with hepatitis C antibodies (odds ratio [OR] 6.901; p < 0.05); patients who had PHC versus ICC (OR 0.273; p < 0.05) or were men (OR 0.431; p < 0.15) were less likely to have FGFR2 fusions or rearrangements. Of 252 evaluable patients with ICC, FGFR2 fusions or rearrangements were associated with hepatitis C antibodies (OR 9.500; p < 0.05); patients who were men (OR 0.419; p < 0.05) or were aged ≥65 years (OR 0.406; p < 0.15) were less likely to have FGFR2 fusions or rearrangements.

This large observational study helps to characterize factors associated with FGFR2 fusions or rearrangements. Further study is warranted to explore differences in prevalence among different geographic populations and patients with PHC.

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

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

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

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

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

To assess the efficacy and safety of PD-1 and PD-L1 immune checkpoint inhibitors (ICIs) in managing advanced intrahepatic cholangiocarcinoma (ICC).

A retrospective analysis of treatment data for patients with advanced ICC who received ICIs at the Second Affiliated Hospital of Chongqing Medical University from the inception of the inpatient medical record database until 30 April 2024. The analysis concentrated on the safety and efficacy of the treatment. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS) and safety. The Kaplan-Meier method was employed to plot survival curves, and differences between groups were assessed using log-rank tests.

96 patients diagnosed with ICC were included, comprising 60 males (62.50%) and 36 females (37.50%). 85 patients exhibited disease progression, 22 patients succumbed, and 38 patients were lost to follow-up finally. Those who initiated immunotherapy promptly following first-line antitumor treatment exhibited a notably prolonged PFS compared to those experiencing tumor progression (5.63 months (95%CI: 3.12~8.14) vs 2.50 months (95%CI: 1.83~3.17), P=0.002). However, no significant disparity in the PFS with immunotherapy in different lines therapy(P=0.406) and the OS was observed between the two groups(P=0.360). 18 patients (18.75%) experienced treatment-emergent adverse events (AEs), with 3 patients encountering AEs of grade ≥3. All patients returned to normal after symptomatic treatment.

In patients with advanced ICC, the timely initiation of ICIs as adjuvant therapy following first-line antitumor treatment can result in favorable efficacy and a good safety profile.

Cholangiocarcinoma (CCA) is known for its high aggressiveness and dismal prognosis, whose effectiveness of systemic therapy remains limited. As a multi-target drug, lenvatinib has exhibited promising effects in many solid tumors. However, the therapeutic role of lenvatinib in CCA is rarely investigated. Here, the in vitro assays including EdU, colony formation, transwell, wound healing, and apoptosis analyses demonstrated that lenvatinib significantly inhibited the proliferation, migration, and invasion, while simultaneously inducing apoptosis of CCA cells. Mechanistically, lenvatinib downregulated the expression of FGF19 and inactivated the PI3K/AKT signaling pathway. Depletion of FGF19 enhanced the anti-tumor effects of lenvatinib, which was attributed to the inhibition of p-PI3K and p-AKT expression in CCA cells. In contrast, overexpression of FGF19 activated the PI3K/AKT signaling pathway, thereby impairing the inhibitory effects of lenvatinib against CCA. In addition, the AKT inhibitor, MK-2206, reinforced the lenvatinib-induced CCA inhibition. Notably, the in vivo experiment confirmed that the subcutaneous tumorigenicity of CCA cells in nude mice was weakened by lenvatinib. Lenvatinib markedly downregulated the expression of FGF19, p-AKT, Ki-67, vimentin, and VEGF in the xenograft tumor tissues. Collectively, these findings demonstrated that lenvatinib inhibits CCA progression by targeting the FGF19/PI3K/AKT signaling pathway. The present study provides novel experimental evidence for the potential clinical application of lenvatinib in CCA, which also highlights the promising role of targeting FGF19 in combined therapeutic approaches for CCA.

Regional lymph node metastasis (LNM) assessment is crucial for predicting intrahepatic cholangiocarcinoma (iCCA) prognosis. However, imaging assessment has limitations for identifying LNM.

To investigate the association between MRI radiomics features, regional LNM status, and prognosis in iCCA.

Retrospective.

Two hundred ninety-six patients (male = 197) with surgically confirmed iCCA.

1.5 T and 3.0 T. DWI, T2WI, and contrast-enhanced T1WI.

Clinical information, radiologic, and MRI-based radiomics features associated with LNM status were collected to establish models. Performance of MRI, PET/CT, and the combined LNM models were compared in training (N = 207) and test (N = 89) datasets. Overall survival (OS) was compared based on LNM status.

The independent features were selected by 5-fold cross-validation. The performance of MRI, PET/CT, and the models was evaluated using the area under receiver operating characteristic curve (AUC). Univariable and multivariable Cox regression were used to identify independent variables for OS. Kaplan-Meier curves were compared with the log-rank test between LNM positive and negative groups. P < 0.05 was considered statistically significant.

Intrahepatic duct dilatation, enhancement pattern, and CA19-9 were independent clinicoradiologic features. The radiomics model was constructed by the independent radiomics features extracted from T2WI and delay phase T1WI. The combined LNM model showed AUC of 0.888, 0.884, and 0.811 in training, validation, and test cohorts with a positive net benefit. PET/CT exhibited similar sensitivity to the combined LNM model (0.750 vs. 0.733, P > 0.999) while the combined LNM model showed higher specificity (0.703 vs. 0.630, P = 0.039) in the test cohort. High risk of regional LNM was significantly associated with worse OS (median: 24 months) than low risk (median: 30 months, P < 0.0001).

The combined LNM model has the strongest correlation with LNM status for mass-forming iCCA patients.

3 TECHNICAL EFFICACY: Stage 2.

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%.

The recent clinical outcomes of multi-regimen chemotherapy included prolonged survival and a high rate of conversion to surgery in Asian patients with advanced biliary tract cancer. The ability of single-operator cholangioscopy (SOC) to detect and stage extrahepatic cholangiocarcinoma (CCC) in intraductal lesions is becoming more important in determining the extent of surgery. The aim of this study was to evaluate the role of SOC in surgical planning for extrahepatic CCC. We reviewed the consecutive data of patients who received nab-paclitaxel plus gemcitabine-cisplatin for the management of extrahepatic CCC and underwent preoperative evaluations between June 2020 and August 2022. SOC was performed to determine the precise extent of the disease in patients with a good response to chemotherapy who were considering surgical treatment. Among the 38 patients included, 30 (79%) were diagnosed with perihilar CCC, six (16%) with distal CCC, and two (5%) with intraductal papillary neoplasm of the bile duct. Intraductal evaluation with SOC altered disease extent defined by previous imaging findings in 14 (37%) patients. In those patients, five (36%) were changed to less extensive surgery, four (29%) to conversion surgery, four (29%) avoided surgery, and one (7%) was changed to more extensive surgery. Among the 38 included patients, 27 (71%) underwent surgery, and the accuracy of the visual impressions was 93%, as confirmed by the surgical pathology report. In conclusion, SOC examination of patients with potentially resectable extrahepatic CCC was more precise than conventional diagnostic evaluations and could help in planning surgical options.

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

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

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

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

Cholangiocarcinoma (CCA) or bile-duct cancer is most prevalent in Southeast Asian counties including Thailand. Patients present at an advanced stage when the cancer is often drug resistant, leading to chemotherapy failure. Curcumin has therapeutic potential with various anticancer properties. However, its effectiveness is limited by its low bioavailability, poor solubility, and instability. This study aimed to synthesize, characterize and evaluate the efficacy of curcumin-loaded maltodextrin-based proniosomes (CMPNs) to overcome the limitations of curcumin for treating gemcitabine-resistant CCA cells (KKU-213BGemR) in vitro and in vivo. Various proniosome formulations were developed and tested for their efficacy against KKU-213BGemR cells using cytotoxicity, clonogenic, migration, and invasion assays. The potential mechanism involving in cell cycle arrest, apoptosis, expression of C/EBP homologous protein (CHOP), a pro-apoptotic transcription factor, and other apoptotic markers were investigated. The results showed that nanoscale CMPNs exhibited a good curcumin loading capacity and an entrapment efficiency of over 97%, as well as good stability and permeability through porcine esophageal mucosa. CMPNs inhibited proliferation, colony formation, migration/invasion and induced apoptosis in KKU-213BGemR cells. Western blot analysis revealed CMPNs significantly increased CHOP, the cleavage products of poly(ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor, and caspase-3 expression in KKU-213BGemR cells. A xenograft model revealed that 62.5 mg/kg BW CMPNs significantly suppressed proliferating cell nuclear antigen and increased CHOP-mediated apoptosis, leading to significantly reduced tumor volume. In conclusion, CMPNs effectively overcome limitations of curcumin and offer an effective strategy against gemcitabine-resistant CCA via CHOP-mediated pathways. These proniosomes are promising as an alternative treatment approach for CCA.

Cholangiocarcinoma is the second most common primary liver cancer, and its global incidence has increased in recent years. Radical surgical resection and systemic chemotherapy have traditionally been the standard treatment options. However, the complexity of cholangiocarcinoma subtypes often presents a challenge for early diagnosis. Additionally, high recurrence rates following radical treatment and resistance to late-stage chemotherapy limit the benefits for patients. Immunotherapy has emerged as an effective strategy for treating various types of cancer, and has shown efficacy when combined with chemotherapy for cholangiocarcinoma. Current immunotherapies targeting cholangiocarcinoma have predominantly focused on T lymphocytes within the tumor microenvironment, and new immunotherapies have yielded unsatisfactory results in clinical trials. Therefore, it is essential to achieve a comprehensive understanding of the unique tumor microenvironment of cholangiocarcinoma and the pivotal role of T lymphocytes within it. In this review, we describe the heterogeneous immune landscape and intercellular communication in cholangiocarcinoma and summarize the specific distribution of T lymphocytes. Finally, we review potential immune checkpoints in cholangiocarcinoma.

Cholangiocarcinoma (CCA), a highly aggressive form of cancer, is known for its high mortality rate. A Disintegrin and Metalloprotease Domain-like Protein Decysin-1 (ADAMDEC1) can promote the development and metastasis in various tumors by degrading the extracellular matrix. However, its regulatory mechanism in CCA remains unclear. Public databases and clinical tissue samples were used to evaluate whether ADAMDEC1 expression was correlated with the prognosis of CCA. We investigated the expression of ADAMDEC1-related regulatory genes and proteins in CCA and assessed the biological behaviors of CCA cells in vitro through functional experiments. Meanwhile, the interacting proteins of ADAMDEC1 and its involvement in the nuclear factor-kappa B (NF-κB) signaling pathway were screened and verified through bioinformatics analysis. The tumorigenicity of CCA was also assessed in a xenograft nude mouse model. Our results showed that ADAMDEC1 was highly expressed in tumor tissues from CCA patients and was positively correlated with poor prognosis. Interference cell lines targeting ADAMDEC1 in CCA cells were successfully constructed. Knockdown of ADAMDEC1 or MMP12 both affected the biological behaviors of CCA cells, and ADAMDEC1 silencing inhibited tumorigenicity and tumor growth of CCA in vivo. Moreover, ADAMDEC1 interacted with MMP12, modulating its expression and promoting the activation of the NF-κB signaling pathway. Our study uncovered the expression patterns and functional roles of ADAMDEC1 in CCA cells and tissues, highlighting its connection to the NF-κB pathway and MMP12 in the development of CCA. Therefore, ADAMDEC1 may serve as a potential therapeutic target for CCA.

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