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.

The cellular prion protein (PrPC), traditionally associated with neurodegenerative disorders, plays an important role in cancer progression and metastasis by inhibiting apoptosis.

To investigate the influence of PrPC expression in cholangiocarcinoma (CCA) on patient outcomes following surgical resection.

Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study. Based on the immunohistochemical staining results of the surgical specimens, patients were categorized into two groups: The low PrPC group (negative or 1+) and the high PrPC group (2+ or 3+). Survival analyses, including overall survival and recurrence-free survival, were conducted using the Kaplan-Meier method and compared using the log-rank test.

In total, seventy-six patients diagnosed with CCA (39 with intrahepatic and 37 with hilar CCA) underwent curative hepatectomy from January 2011 to November 2021. Among these patients, 38 (50%) demonstrated high PrPC expression, whereas the remaining 38 (50%) showed low expression of PrPC. During a median follow-up period of 31.2 months (range: 1 to 137 months), the high PrPC group had a significantly shorter median overall survival than the low PrPC group (40.4 months vs 137.9 months, respectively; P = 0.041). Moreover, the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group (13.3 months vs 23.8 months, respectively; P = 0.026).

PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection. Thus, PrPC may be used as a prognostic factor in treatment planning.

Cdc2-like kinase 1 (CLK1) has dual-specificity kinase ability to phosphorylate tyrosine and serine/threonine protein residues. CLK1 regulates many physiologic processes and has been shown to contribute to multiple types of cancer. In this study, we investigated the functional role of CLK1 during intrahepatic cholangiocarcinoma (ICC) development. The expression of CLK1 was elevated in ICC tumors, and patients with high expression of CLK1 demonstrated poor prognosis. In hydrodynamically transfected mouse models, CLK1 alone was insufficient to induce ICC, whereas CLK1 cooperated with AKT (AKT/CLK1) to trigger ICC initiation. In addition, overexpression of CLK1 in ICC cells facilitated proliferation in vitro and tumor growth in vivo, whereas loss of CLK1 elicited the opposite effects. Moreover, RNA sequencing analysis indicated that high levels of CLK1 corresponded with activation of the Hippo-Yes-associated protein (YAP) signaling pathway. Consistently, AKT/CLK1 murine tumors displayed upregulation of YAP as well as its downstream targets. Furthermore, loss or pharmacologic inhibition of YAP in ICC cells inhibited CLK1-induced growth, and deletion of Yap completely retarded the induction of AKT/CLK1 tumors. Mechanistically, 4D label-free mass spectrometry and coimmunoprecipitation assays revealed WWC2 as a potential mediator of the CLK1-YAP cascade. Collectively, the current findings identify a critical role for CLK1 in promoting ICC development and indicate that inhibiting YAP might be an effective approach for perturbing CLK1-mediated tumorigenesis. Significance: CLK1 drives intrahepatic cholangiocarcinoma initiation and progression by increasing YAP activity, suggesting that targeting YAP could be a potential strategy for treating and preventing CLK1-driven intrahepatic cholangiocarcinoma.

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

Cholangiocarcinoma (CCA) is major health issue in Thailand, with high incidences in different parts of country. This study examines the association between spatial variables and CCA in Thailand.

Thailand's four population-based cancer registries provided data for this retrospective cohort analysis between January 1, 2012, and December 31, 2021. 6,379 diagnosed CCA cases were found in 554 sub-districts. Moran's I and Local Indicators of Spatial Association (LISA) measured geographic dispersion and estimated sex age-standardized rates (ASRs). Multivariable log-linear regression assessed geography and CCA, calculating adjusted incidence rate ratios (IRRs) and 95% confidence interval (CI).

Of 6,379 CCA cases, 63.9% were male, and the mean age at diagnosis was 66.2 years (standard deviation = 11.07 years). CCA ASRs for both sexes in Thailand was 8.9 per 100,000 person-years. The northeastern region had the greatest ASR at 13.4 per 100 000 person-years. Moran's I and LISA studies grouped regions by spatial variables. The association between spatial variables and CCA demonstrated that the northern region exhibited elevation (adjusted IRRs = 0.82, 95%CI: 0.78 to 0.87) and distance from water sources variable (adjusted IRRs = 0.91, 95%CI: 0.82 to 0.99). The central region elevation variable (adjusted IRRs = 0.85, 95%CI: 0.76 to 0.94). This was the distance from water sources (adjusted IRRs = 0.96, 95%CI: 0.93 to 0.99) and population density variable (adjusted IRRs = 0.94, 95%CI: 0.93 to 0.96) in the northeastern region. Population density (adjusted IRRs = 1.09, 95%CI: 1.02 to 1.15) and average temperature variable (adjusted IRRs = 1.05, 95%CI: 1.02 to 1.09) were significant in the southern region.

Spatial variables associated with CCA indicate that ASR differs across Thailand. So environmental and climate factors can inform targeted public health strategies to address CCA in high-risk areas throughout Thailand.

Cholangiocarcinoma (CCA) is a tumor that arises from the epithelium of the intrahepatic bile ducts. It is rarely diagnosed in individuals under 40 years of age and has a very aggressive nature: 95% of patients die within 5 years. We present the first detailed report of a case of perihilar CCA (pCCA) presenting during pregnancy masquerading as intrahepatic cholestasis of pregnancy (ICP). First, the patient exhibited typical pruritus, particularly in her limbs; second, a raised biomarker of total bile acid (TBA) was noted; third, the onset occurred in the second trimester, aligning with the epidemiological profile; and finally, importantly, there was no mass detected in her liver. First-line drugs were given to treat ICP, but they failed, and ultimately, the condition was identified as pCCA. Following an inadequate excision, traditional Chinese medicine was administered. After 26 months, she succumbed to cachexia. As gestational symptoms are sometimes associated with pregnancy-related disorders, pCCA in pregnant women is frequently misdiagnosed. Symptoms such as jaundice, pruritus, and dilated bile ducts in pregnant women may indicate pCCA. In addition, the appropriate treatment for pCCA in pregnant women may be surgery or chemotherapy; if surgery is not an option, chemotherapy may also help extend the gestational week. Our work is important and can educate on the diagnosis and treatment of pregnancy-related diseases, such as ICP and pCCA.

Artificial intelligence (AI) and image processing are revolutionising the diagnosis and management of liver cancer. Recent advancements showcase AI's ability to analyse medical imaging data, like computed tomography scans and magnetic resonance imaging, accurately detecting and classifying liver cancer lesions for early intervention. Predictive models aid prognosis estimation and recurrence pattern identification, facilitating personalised treatment planning. Image processing techniques enhance data analysis by precise segmentation of liver structures, fusion of information from multiple modalities, and feature extraction for informed decision-making. Despite progress, challenges persist, including the need for standardised datasets and regulatory considerations.

The effectiveness of ultrasonography (USG) in liver cancer screening is partly constrained by the operator's expertise. We aimed to develop and evaluate an AI-assisted system for detecting and classifying focal liver lesions (FLLs) from USG images. This retrospective study incorporated 26,288 USG images from 5444 patients to train YOLOv5 model for FLLs detection and classification of seven different types of FLLs, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), focal fatty infiltration, focal fatty sparing (FFS), cyst, hemangioma, and regenerative nodules. AI model performance was assessed for detection and diagnosis of the FLLs on a per-image and per-lesion basis. The AI achieved an overall FLLs detection rate of 84.8% (95%CI:83.3-86.4), with consistent performance for FLLs ≤ 1 cm and > 1 cm. It also exhibited sensitivity and specificity for distinguishing malignant FLLs from other benign FLLs at 97.0% (95%CI:95. 9-98.2) and 97.0% (95%CI:95.9-98.1), respectively. Among specific FLL types, CCA detection rate was at 92.2% (95%CI:88.0-96.4), followed by FFS at 89.7% (95%CI:87.1-92.3), and HCC at 82.3% (95%CI:77.1-87.5). The specificities and NPVs for regenerative nodules were 100% and 99.9% (95%CI:99.8-100.0), respectively. Our AI model can potentially assist physicians in FLLs detection and diagnosis during USG examinations. Further external validation is needed for clinical application.

Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with increasing incidence and poor survival rates. This study aims to evaluate the incidence and survival trends of iCCA patients over 20 years using a national cancer database, and assess the temporal association between survival and landmark clinical trials.

Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rates (AAIRs) were calculated from 2000 to 2020. Overall survival was analyzed based on diagnosis time and disease stage. Subgroup analysis was performed for patients diagnosed between 2015 and 2020. Landmark clinical trials were reviewed to determine temporal changes in survival.

In this analysis of 28,918 iCCA patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 [annual percent change (APC) 6.94, 95% confidence interval (CI): 6.32 to 7.56], with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted median overall survival (mOS) improved from 5.28 months in 2000 to 9.3 months in 2013, then stabilized between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 months in 2000-2010 to 9.06 months in 2010-2020. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3, 12.1, and 5.4 months for local, regional, and distant stages, respectively.

The study indicates a steady rise in iCCA incidence since 2000 across all subgroups. Survival rates improved since 2000 but stabilized after 2013, following the ABC-02 trial publication in 2010. The impact of more recent clinical trials on survival rates requires further analysis in the coming years.

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

Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and has a poor prognosis. Surgical resection is the standard of care for patients with resectable disease, representing 30-40% of cases. Increasingly, neoadjuvant systemic therapy is being utilized in patients due to high-risk anatomic or biologic considerations. However, data on the clinical effect of this approach are limited. We performed a cohort study to evaluate the effect of neoadjuvant therapy in patients with oncologically high-risk iCCA.

iCCA patients (n = 181) between the years 2014-2020 were reviewed for clinical, histopathologic, treatment, and outcome-related data. Tumor regression grade was scored per CAP criteria for gastrointestinal carcinomas.

47 iCCA patients received neoadjuvant therapy and 72 did not. Neoadjuvant treatment led to objective response and tumor regression by CAP score. After adjustment for age, clinical stage, and tumor size, the outcomes of patients who had neoadjuvant therapy followed by surgery were not significantly different from those patients who had surgery first.

In conclusion, neoadjuvant therapy in iCCA facilitated surgical care. The progression-free and overall survival for surgical patients with and without neoadjuvant therapy were not significantly different suggesting this approach needs further exploration as an effective treatment paradigm.

Opisthorchis viverrini infection is a significant health problem in several countries, especially Southeast Asia. The infection causes acute gastro-hepatic symptoms and also long-term infection leading to carcinogenesis of an aggressive bile duct cancer (cholangiocarcinoma; CCA). Hence, the early diagnosis of O. viverrini infection could be the way out of this situation. Still, stool examination by microscopic-based methods, the current diagnostic procedure is restricted by low parasite egg numbers in the specimen and unprofessional laboratorians. The immunological procedure provides a better chance for diagnosis of the infection. Hence, this study aims to produce single-chain variable fragment (scFv) antibodies for use as a diagnostic tool for O. viverrini infection.

This study uses phage display technologies to develop the scFv antibodies against O. viverrini cathepsin F (OvCatF). The OvCatF-deduced amino acid sequence was analyzed and predicted for B-cell epitopes used for short peptide synthesis. The synthetic peptides were used to screen the phage library simultaneously with OvCatF recombinant protein (rOvCatF). The potentiated phages were collected, rescued, and reassembled in XL1-blue Escherichia coli (E. coli) as a propagative host. The positive clones of phagemids were isolated, and the single-chain variable (scFv) fragments were sequenced, computationally predicted, and molecular docked. The complete scFv fragments were digested from the phagemid, subcloned into the pOPE101 expression vector, and expressed in XL1-blue E. coli. Indirect ELISA and Western analysis were used to verify the detection efficiency.

The scFv phages specific to OvCatF were successfully isolated, subcloned, and produced as a recombinant protein. The recombinant scFv antibodies were purified and refolded to make functional scFv. The evaluation of specific recognition of the particular epitopes and detection limit results by both computational and laboratory performances demonstrated that all three recombinant scFv antibodies against OvCatF could bind specifically to rOvCatF, and the lowest detection concentration in this study was only one hundred nanograms.

Our produced scFv antibodies will be the potential candidates for developing a practical diagnostic procedure for O. viverrini infection in humans in the future.

Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.

We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany.

We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs.

By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

The study aims to investigate the predictability of the radiological response in intrahepatic cholangiocarcinoma (iCC) patients undergoing Yttrium-90 transarterial radioembolization (TARE) with a combined model built on dynamic magnetic resonance imaging (MRI)-based radiomics and clinical features.

Thirty-six naive iCC patients who underwent TARE were included in this study. The tumor segmentation was performed on the axial T2-weighted (T2W) without fat suppression, axial T2W with fat suppression, and axial T1-weighted (T1W) contrast-enhanced (CE) sequence in equilibrium phase (Eq). At the sixth month MRI follow-up, all patients were divided into responders and non-responders according to the modified Response Evaluation Criteria in Solid Tumors. Subsequently, a radiomics score (rad-score) and a combined model of the rad-score and clinical features for each sequence were generated and compared between the groups.

Thirteen (36.1%) patients were considered responders, and the remaining 23 (63.9%) were non-responders. Responders exhibited significantly lower rad-scores than non-responders (P < 0.050 for all sequences). The radiomics models showed good discriminatory ability with an area under the curve (AUC) of 0.696 [95% confidence interval (CI), 0.522–0.870] for the axial T1W-CE-Eq, AUC of 0.839 (95% CI, 0.709–0.970) for the axial T2W with fat suppression, and AUC of 0.836 (95% CI, 0.678–0.995) for the axial T2W without fat suppression.

Radiomics models created by pre-treatment MRIs can predict the radiological response to Yttrium- 90 TARE in iCC patients with high accuracy. Combining radiomics with clinical features could increase the power of the test. Large-scale studies of multi-parametric MRIs with internal and external validations are needed to determine the clinical value of radiomics in iCC patients.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.hpb.2024.04.011. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

While cholangiocarcinoma (CCA) incidence and mortality rates are increasing globally, whether there are regional/temporal variations in these rates for different biliary tract cancer (BTC) subtypes, or whether they differ by sex, socioeconomic status, or route to diagnosis (RtD) remains unknown. In this work, we aimed to perform an in-depth analysis of data on the incidence, mortality, survival and RtD of CCA and other BTCs.

Data on all BTCs diagnosed in England between 2001 and 2018 were extracted from NHS Digital's National Cancer Registration Dataset. Age-standardised incidence rates (ASRs), mortality rates (ASMRs) and net survival rates were calculated, and Kaplan-Meier overall survival estimates and RtD trends were analysed. Analyses were stratified by sex, socioeconomic deprivation, tumour subtype and region.

The ASR for CCA rose from 2.9 in 2001-2003 to 4.6 in 2016-2018 and from 1.0 to 1.8 for gallbladder cancers (GBCs). ASMR trends mirror those of incidence, with most deaths due to iCCA. Over 20% of patients with CCA were under 65 years old. The ASRs and ASMRs were consistently higher in the most socioeconomically deprived group for CCA and GBC. The most common RtD was the emergency route (CCA 49.6%, GBC 46.2% and ampulla of Vater cancer 43.0%). The least deprived patients with CCA and ampulla of Vater cancer had better overall survival (p <0.001). Net survival rates rose for all BTCs, with 3-year net survival for CCA increasing from 9.2% in 2001 to 12.6% in 2016-2018. There was notable geographical variation in ASRs, ASMRs and net survival for all BTCs.

BTC incidence and mortality rates are increasing, with differences observed between tumour types, socioeconomic deprivation groups, RtDs and geographical regions. This highlights the need for targeted interventions, earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals.

Cholangiocarcinoma (CCA) incidence and mortality rates are rising globally, particularly for intrahepatic CCA. However, it has not previously been reported if, within a single country, there are temporal and regional differences in incidence, mortality and survival rates for different biliary tract subtypes, and whether these differ by sex, socioeconomic status, or route of diagnosis. In this study we show that mortality rates for patients with CCA continue to rise and are almost 40% higher in the most socioeconomically deprived compared to the least; additionally, we observed regional variation within England in incidence, mortality and survival. This study is relevant to researchers and policy makers as it highlights regional variation and inequality, as well as emphasising the need for earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals.

This study compared the clinical efficacy and safety of laparoscopic versus open resection for hilar cholangiocarcinoma (HCCA) and analyzed potential prognostic factors.

The study included patients who underwent HCCA resection at our center from March 2012 to February 2022. Perioperative complications and postoperative prognosis were compared between the laparoscopic surgery (LS) and open surgery (OS) groups.

After screening 313 HCCA patients, 68 patients were eligible for the study in the LS group (n = 40) and OS group (n = 28). Kaplan-Meier survival curve analysis revealed that overall survival > 2 years and 3-year disease-free survival (DFS) were more common in the LS than OS group, but the rate of 2-year DFS was lower in the LS group than OS group. Cox multivariate regression analysis revealed age (< 65 years), radical resection, and postoperative adjuvant therapy were associated with reduced risk of death (hazard ratio [HR] = 0.380, 95% confidence interval [CI] = 0.150-0.940, P = 0.036; HR = 0.080, 95% CI = 0.010-0.710, P = 0.024 and HR = 0.380, 95% CI = 0.150-0.960, P = 0.040), whereas preoperative biliary drainage was an independent factor associated with increased risk of death (HR = 2.810, 95% CI = 1.130-6.950, P = 0.026). Perineuronal invasion was identified as an independent risk factor affecting DFS (HR = 5.180, 95% CI = 1.170-22.960, P = 0.030).

Compared with OS, laparoscopic HCCA resection does not significantly differ in terms of clinical efficacy. Age (<65 years), radical resection, and postoperative adjuvant therapy reduce the risk of death, and preoperative biliary drainage increases the risk of death.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Cases when found are often advanced with vascular invasion, and radical resection is often difficult. Despite curative resection, the postoperative recurrence rate of patients with histological lymph node metastasis is high, and their prognosis is poor. Therefore, there is an urgent need to establish multidisciplinary treatment that combines chemotherapy and surgical resection. The efficacy of neoadjuvant chemotherapy (NAC) for locally advanced ICC is unclear. In this report, a case of locally advanced ICC in which pathological complete response (pCR) was achieved after NAC is described.

A 79-year-old woman was admitted to a local hospital with appetite loss. Computed tomography showed a 100 × 90 mm low-contrast tumor in the left hepatic lobe and segment 1 with invasion to the inferior vena cava (IVC), and several lymph nodes along the left gastric artery and lesser curvature were enlarged. Therefore, she was treated with a combined chemotherapy regimen of gemcitabine and cisplatin. After four courses, the tumor size decreased to 30 × 60 mm without invasion to the IVC. Left hepatectomy extending to segment 1 with bile duct resection combined with middle hepatic vein resection (H1234-B-MHV), dissection of regional lymph nodes and pyloroplasty were performed. After radical resection, pCR was achieved. She is alive with no evidence of disease, 2 years after surgery.

In this case, a patient with locally advanced ICC achieved pCR to NAC. NAC may be effective for ICC. Patients who achieve pCR may have a better prognosis.

Hilar cholangiocarcinoma is considered a biologically aggressive disease for which surgical resection remains the only curative treatment. Preoperative evaluation for resectability is challenging given tumor proximity to the porta hepatis, but minimal benefit and increased morbidity precludes recommendation for margin positive resection. This article reviews the determination of unresectability in hilar cholangiocarcinoma through discussion of the preoperative assessment, the intraoperative assessment, and key steps of surgical resection, as well as treatment options for unresectable tumors. Overall, evaluating patients preoperatively for resectability requires a multidisciplinary, holistic, and individualized approach to accurately determine resectability and optimize clinical outcomes for patients with hilar cholangiocarcinoma.

A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA.

We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center.

In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p < 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0-13.6%) in the gem-cis group versus 34.3% (95% CI 28.1-41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19-0.39).

This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.

In the 8th edition of the American Joint Committee on Cancer, the nodal staging of intrahepatic cholangiocarcinoma (ICC) is classified as N0 and N1 in accordance with lymph node (LN) metastases. Recently, several studies have reported that the number of metastatic LNs is associated with prognosis in patients with ICC. However, the majority of these studies were published in Eastern countries, and there are few available data for Western countries. This study aimed to investigate the association between metastatic LN number and prognosis in ICC patients using the Surveillance, Epidemiology, and End Results (SEER) database.

Data from 658 ICC patients in the SEER database who underwent hepatectomy with LN dissection from 2000 to 2018 were retrospectively reviewed. Hazard ratios (HRs) according to increasing numbers of metastatic LN were calculated. The patients were then divided into three groups according to their metastatic LN numbers (N0: no metastatic LNs; N+ <4: 1-3 metastatic LNs; N+ ≥4: ≥4 metastatic LNs), and cause-specific survival (CSS) was compared.

Metastatic LN number was a prognostic factor of oncologic survival [CSS: HR =1.300; 95% confidence interval (CI): 1.225-1.379; P<0.001]. In survival analysis, an increasing number of metastatic LNs was significantly correlated with poorer oncologic outcomes [CSS: N0 vs. N+ <4 vs. N+ ≥4: 40.856 (95% CI: 38.806-42.919) vs. 22.000 (95% CI: 18.283-25.717) vs. 15.000 (95% CI: 11.520-18.480) months, P<0.001]. In post hoc analysis, a significant difference was found between adjacent groups (N0 vs. N+ <4, P<0.001; N+ <4 vs. N+ ≥4, P=0.004).

Patients with ICC in the SEER database were reaffirmed to have worse prognosis with an increasing number of metastatic LNs.

We performed a retrospective analysis within a national cancer registry on outcomes following resection or ablation for intrahepatic cholangiocarcinoma (iCCA).

The National Cancer Database was queried for patients with clinical stage I-III iCCA diagnosed during 2010-2018, who underwent resection or ablation. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods.

Of 2140 patients, 1877 (87.7%) underwent resection and 263 (12.3%) underwent ablation, with median tumor sizes of 5.5 and 3 cm, respectively. Overall, resection was associated with greater median OS (41.2 months (95% confidence interval [95% CI]: 37.6-46.2) vs. 28 months (95% CI: 15.9-28.6) on univariable analysis (p < 0.0001). There was no significant difference on multivariable analysis (p = 0.42); however, there was a significant interaction between tumor size and management. On subgroup analysis of patients with tumors <3 cm, there was no difference in OS between resection versus ablation. However, ablation was associated with increased mortality for tumors ≥3 cm.

Although resection is associated with improved OS for tumors ≥3 cm, we observed no difference in survival between management strategies for tumors < 3 cm. Ablation may be an alternative therapeutic strategy for small iCCA, particularly in patients at risk for high surgical morbidity.

Cholangiocarcinoma (CCA) refers to a collection of malignant tumors that develop from the biliary epithelium. Extensive clinical evidence and epidemiological observations indicate a concerning increase in both the incidence and mortality rates of CCA. Surgical resection is currently the sole available cure for CCA. However, it is unfortunate that only a fraction of patients has access to surgery at the time of diagnosis. Moreover, there is a high incidence of cancer recurrence after resection, and systemic treatments have limited efficacy. Therefore, the identification of novel biomarkers for CCA-targeted molecular therapy remains a crucial task in oncology research.

Our study demonstrated that low expression of RSPO3 was associated with poorer survival rates in patients with CCA. We found that the RSPO3 promoter DNA was hypermethylated in CCA, which was correlated with the low expression of RSPO3. The expression of RSPO3 was influenced by the balance between the DNA methyltransferase DNMT3a and the DNA demethylase TET1 in CCA. In vitro and in vivo experiments showed that targeting RSPO3 promoter DNA methylation using dCas9DNMT3a promoted tumorigenicity of CCA, while targeted RSPO3 promoter DNA demethylation using dCas9TET1CD inhibited CCA tumorigenicity. Additionally, in our primary CCA model, knockdown of Rspo3 promoted CCA progression, whereas overexpression of Rspo3 inhibited CCA progression.

Our findings suggest that increased methylation and decreased expression of RSPO3 may indicate a poor prognosis in CCA. Restoring RSPO3 expression by targeting promoter DNA demethylation could offer insights for precise treatment of CCA.

Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive malignant tumor arising within the liver, with a 5-year survival rate of only 20-40% after surgery. The role of interleukin-8 (IL-8) in ICC progression remains elusive. A transcriptomic approach based on IL-8 stimulation first revealed significant upregulation of the prometastatic gene CD97 and key epithelial-mesenchymal transition (EMT) factors E-cadherin and vimentin. Immunohistochemistry of 125 ICC tissues confirmed the positive correlation between IL-8 and CD97. Multivariable Cox regression indicated that they are both independent predictors of ICC prognosis. Mechanistically, IL-8 treatment induced CD97 expression at 50 and 100 ng/ml in QBC-939 and QBE cells, respectively. Moreover, the induction of cell migration and invasion upon IL-8 treatment was attenuated by CD97 RNA interference, and the expression of EMT-associated genes was dramatically inhibited. To determine whether CXCR1 or CXCR2 are downstream effectors of IL-8, siCXCR2 was applied and shown to significantly attenuate the oncogenic effects of IL-8 by inhibiting the phosphorylation of PI3K/AKT. Finally, the induction of CD97 expression by the PI3K pathway was verified by treatment with the inhibitor LY294002. In vivo, the significant tumor growth and lung metastasis effects induced by intraperitoneal injection of IL-8 were greatly inhibited by silencing CD97 in nude mice. Collectively, the study presents a novel mechanism of the IL-8-CXCR2-PI3K/AKT axis in regulating CD97 expression, which leads to ICC metastasis mainly through EMT. The study may provide alternatives for targeting the tumor microenvironment in metastatic ICC.

Hepatectomy is the cornerstone of curative-intent treatment for intrahepatic cholangiocarcinoma (ICC). However, in patients unable to be resected, data comparing efficacy of alternatives including thermal ablation and radiation therapy (RT) remain limited. Herein, we compared survival between resection and other liver-directed therapies for small ICC within a national cancer registry.

Patients with clinical stage I-III ICC < 3 cm diagnosed 2010-2018 who underwent resection, ablation, or RT were identified in the National Cancer Database. Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods.

Of 545 patients, 297 (54.5%) underwent resection, 114 (20.9%) ablation, and 134 (24.6%) RT. Median OS was similar between resection and ablation [50.5 months, 95% confidence interval (CI) 37.5-73.9; 39.5 months, 95% CI 28.7-58.4, p = 0.14], both exceeding that of RT (20.9 months, 95% CI 14.1-28.3). RT patients had high rates of stage III disease (10.4% RT vs. 1.8% ablation vs. 11.8% resection, p < 0.001), but the lowest rates of chemotherapy utilization (9.0% RT vs. 15.8% ablation vs. 38.7% resection, p < 0.001). In multivariable analysis, resection and ablation were associated with reduced mortality compared with RT [hazard ratio (HR) 0.44, 95% CI 0.33-0.58 and HR 0.53, 95% CI 0.38-0.75, p < 0.001, respectively].

Resection and ablation were associated with improved survival in patients with ICC < 3 cm compared with RT. Acknowledging confounders, anatomic constraints of ablation, limitations of available data, and need for prospective study, these results favor ablation in small ICC where resection is not feasible.

The study was to develop a Gd-EOB-DTPA-enhanced MRI radiomics model for differentiating atypical intrahepatic mass-forming cholangiocarcinoma (aIMCC) from poorly differentiated hepatocellular carcinoma (pHCC).

A total of 134 patients (51 aIMCC and 83 pHCC) who underwent Gadoxetic acid-enhanced MRI between March 2016 and March 2022 were enrolled in this study and then randomly assigned to the training and validation cohorts by 7:3 (93 patients and 41 patients, respectively). The radiomics features were extracted from the hepatobiliary phase of Gadoxetic acid-enhanced MRI. In the training cohort, the SelectKBest and the least absolute shrinkage and selection operator (LASSO) were used to select the radiomics features. The clinical, radiomics, and clinical-radiomics model were established using four machine learning algorithms. The performance of the model was evaluated by the receiver operating characteristic (ROC) curve. Comparison of the radiomics and clinical-radiomics model was done by the Delong test. The clinical usefulness of the model was evaluated using decision curve analysis (DCA).

In 1132 extracted radiomic features, 15 were selected to develop radiomics signature. For identifying aIMCC and pHCC, the radiomics model constructed by random forest algorithm showed the high performance (AUC = 0.90) in the training cohort. The performance of the clinical-radiomics model (AUC = 0.89) was not significantly different (P = 0.88) from that of the radiomics model constructed by random forest algorithm (AUC = 0.86) in the validation cohort. DCA demonstrated that the clinical-radiomics model constructed by random forest algorithm had a high net clinical benefit.

The clinical-radiomics model is an effective tool to distinguish aIMCC from pHCC and may provide additional value for the development of treatment plans.

Intrahepatic cholangiocarcinoma (iCCA) presents the similar trend and prevalence of lymph node metastasis to other biliary tract cancer. There is still a necessity and possibility for the current classification of lymph node in the 8th TNM of iCCA, which is the same as the criteria of hepatoma carcinoma (HCC), to further improve the prognostic capacity. We aim to explore the optimal positive lymph nodes cutoff value that could predict the survival outcomes of patients with iCCA and further establish a prognostic nomogram.

Clinical characteristics were retrospectively collected in 292 patients with iCCA from Sun Yat-sen University Cancer Center (SYSUCC) for preliminary analysis. A retrospective analysis of 107 patients with iCCA in the First Hospital of Dalian Medical University (FHDMU) was performed for verification. R software was used to determine the optimal cutoff value of positive lymph nodes (PLN) and further establish the nomogram with the Cox regression model in the primary cohort.

In those patients who were graded into the N1 stage in 8th TNM staging system, the patients with PLN between 1 and 3 showed significantly better overall survival than those patients with more than 4 PLN (P < 0.0001). Moreover, there was a significant correlation between the new PLN classification and adverse clinical characteristic including Micro Invasion (P = 0.001), Lymph Vessel Invasion (P = 0.040), Satellite Sites (P < 0.001), and Tumor Size (P = 0.005). The PLN and ELN were both independent prognostic factors for survival outcomes in the multivariate analysis, and further showed large contribution to the nomogram. The nomogram achieved a satisfied C-index of 0.813 for overall survival (OS), 0.869 for progression-free survival (PFS) in the primary cohort, and 0.787 for OS, 0.762 for PFS in the validation cohort.

The modified classification of PLN in iCCA could accurately stratify the N1 stage patients in 8th TNM staging system into two groups with significantly different overall survival. The development of this nomogram can offer new evidence to precisely post-operative management of iCCA patients.

Intrahepatic cholangiocarcinoma (iCCA) is a disease characterized by rarity, heterogeneity, and high mortality, where surgical resection is often not possible. Nowadays, due to the recent introduction of new therapeutic options such as trans-arterial radioembolization (TARE), it is increasingly important to define the role of morphofunctional imaging methods for the prognostic stratification of patients affected by iCCA. The aim of the study was to verify the prognostic value of morphofunctional imaging methods at the baseline in patients with inoperable iCCA.

In total, 45 patients with iCCA were sent to our center between January 2016 and March 2021 for being evaluated to be treated with TARE. All of them underwent both [18F]-FDG-PET/CT and contrast-enhanced CT (ceCT) in a single procedure and were included in our study. The inclusion criteria were as follows: a diagnosis of inoperable iCCA; both [18F]-FDG-PET/CT and ceCT scans; and washout from therapy for at least 2 months before baseline [18F]-FDG-PET/CT and ceCT scans. Both clinical and laboratory data and baseline imaging data (ceCT and [18F]-FDG-PET/CT) were collected. In particular, regarding clinical and laboratory data, we collected overall survival (OS), gender, age, prior therapies, liver function indices, and tumor markers. Regarding ceCT, we collected TNM staging, lesion diameter, volume, vascularization, and presence of intravascular necrosis. Regarding [18F]-FDG-PET/CT, we collected TNM staging, Standard-Uptake-Value max (SUVmax), Metabolic-Tumor-Volume (MTV), and Total-Lesion-Glycolysis (TLG=MTV^*lesions SUVmean). Philips-Vue-PACS software was used, setting hepatic SUVmean as TLG threshold.

A statistically significant correlation was found between some examined parameters at morphofunctional investigations at the baseline and OS. [18F]-FDG-PET/CT parameters statistically correlated with OS were the stage of disease greater than M0 (p = 0.037), major lesion SUVmax (p = 0.010), MTV (p ≤ 0.001), and TLG (p < 0.001). Other parameters at ceCT correlated with OS were the stage of disease greater than T2 (p = 0.038), maximum lesion diameter (p = 0.07), volume of the major lesion (p = 0.016), and total volume of lesions (p = 0. 009). Biochemical parameters correlated with OS were gamma glutamyl transferase (GGT, p = 0.014), alkaline phosphatase (ALP, p = 0.019), carcinoembryonic antigen (CEA, p = 0.004), and carbohydrate antigen 19-9 (CA 19-9, p < 0.001). From the parameters estimated by the multivariate model, we derived a four-variable score for OS combining nodal involvement and SUVmax at [18F]-FDG-PET/CT, GGT, and CA 19-9 levels.

Considering our data, performing integrated pre-therapy imaging is critical for the prognostic stratification of patients with iCCA.

Cholangiocarcinoma (CCA) is a common malignant tumor of the biliary tract that carries a high burden of morbidity and a poor prognosis. Due to the lack of precise diagnostic methods, many patients are often diagnosed at advanced stages of the disease. The current treatment options available are of varying efficacy, underscoring the urgency for the discovery of more effective biomarkers for early diagnosis and improved treatment. Recently, single-cell sequencing (SCS) technology has gained popularity in cancer research. This technology has the ability to analyze tumor tissues at the single-cell level, thus providing insights into the genomics and epigenetics of tumor cells. It also serves as a practical approach to study the mechanisms of cancer progression and to explore therapeutic strategies. In this review, we aim to assess the heterogeneity of CCA using single-cell sequencing technology, with the ultimate goal of identifying possible biomarkers and potential treatment targets.

There have been significant advances in the treatment of hepatobiliary cancers, especially for advanced-stage disease. However, data is limited for optimal therapy selection in the first line and sequencing of available options.

This review covers the systemic treatment of hepatobiliary cancers with an emphasis on the advanced stage. The previously published and ongoing trials will be discussed to create an algorithm for the current practice and to give future perspectives on how the field could go forward.

While there is no standard-of-care option in the adjuvant treatment of hepatocellular cancer, capecitabine is the standard of care for biliary tract cancer. The efficacy of adjuvant gemcitabine and cisplatin and the added benefit of radiotherapy to chemotherapy are yet to be defined. For the advanced stage, immunotherapy-based combinations became the standard of care for both hepatocellular and biliary tract cancers. The molecularly targeted therapy has profoundly changed the second-line and later treatment for biliary tract cancers, while the optimal second-line treatment for advanced hepatocellular cancer is yet to be defined due to rapid advances in the first-line setting.

This study aims to construct a risk classification system and a nomogram in intrahepatic cholangiocarcinomafor patients (ICC).

Three thousand seven hundred thirty-seven patients diagnosed with ICC between 2010 and 2015 were selected from the Surveillance, Epidemiology and End Results. The consistency index, time-dependent receiver operating characteristic curve, and the calibration plots were adopted to evaluate the effective performance of nomogram. Decision curve analysis (DCA), net reclassification index (NRI), and comprehensive discrimination improvement (IDI) were used to compare the advantages and disadvantages of two models. Kaplan-Meier curve showed the difference in prognosis among different groups.

Ten variables were selected to establish the nomogram for ICCA. The C-index (training cohort: 0.765, P < 0.05; validation cohort: 0.776, P < 0.05) and the time-dependent AUCs (the training cohort: the values of 1, 3, 5 years were 0.836, 0.873, and 0.888; the validation cohort: the values of 1, 3, 5 years were 0.833, 0.838, and 0.881) showed satisfactory discrimination. The calibration curves also revealed that the nomogram was consistent with the actual observations. The NRI (training cohort: 1-, 3-, 5-year CSS: 0.879, 0.94, 0.771; validation cohort: 1-, 3-, 5-year CSS: 0.905, 0.945, 0.717) and IDI (training cohort: 1-, 3-, 5-year CSS: 0.24, 0.23, 0.22; validation cohort: 1-, 3-, 5-year CSS: 0.24, 0.46, 0.27) (P < 0.05) (compared with AJCC staging). DCA showed that the new model was more practical and had better recognition than AJCC staging.

A new risk stratification system for ICC patients has been developed, which can be a practical tool for patient management.

Radiomics was proposed by Lambin et al. in 2012 and since then there has been an explosion of related research. There has been significant interest in developing high-throughput methods that can automatically extract a large number of quantitative image features from medical images for better diagnostic or predictive performance. There have also been numerous radiomics investigations on intrahepatic cholangiocarcinoma in recent years, but no pertinent review materials are readily available. This work discusses the modeling analysis of radiomics for the prediction of lymph node metastasis, microvascular invasion, and early recurrence of intrahepatic cholangiocarcinoma, as well as the use of deep learning. This paper briefly reviews the current status of radiomics research to provide a reference for future studies.

Immune checkpoint inhibitor (ICI), coupled with systemic chemotherapy, may enhance the clinical benefit of cancer by potentiating antitumor immunity, but its efficacy and safety are not clear in advanced intrahepatic cholangiocarcinoma (ICC). This study aims to assess the efficacy and safety of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) for the treatment of advanced ICC in the real world.

Advanced ICC patients receiving at least one session of camrelizumab plus GEMOX combination treatment from March 2020 to February 2022 at two high-volume centers were considered eligible. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The primary endpoint was objective response rate (ORR), disease control rate (DCR), time to response (TTR), and duration of response (DOR). The secondary end points included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs).

30 eligible ICC patients were enrolled and analyzed in this observational retrospective study. The median follow-up time was 24.0 (21.5-26.5) months. The ORR and DCR were 40% and 73.3%, respectively. The median TTR was 2.4 months and the median DOR was 5.0 months. The median PFS and OS were 7.5 months and 17.0 months, respectively. The most common TRAEs were fever (83.3%), fatigue (73.3%), and nausea (70%). Of all TRAEs, thrombocytopenia, and neutropenia were the most frequent severe AE (both 10%).

The combination of camrelizumab and GEMOX is a potentially efficacious and safe treatment modality for advanced ICC patients. Potential biomarkers are needed to identify patients who might benefit from this treatment option.