Cholangiocarcinoma Research Articles

58P Efficacy and safety of liposomal irinotecan (nal-IRI) plus fluorouracil (5-FU) and leucovorin (LV) versus 5-FU/LV alone for advanced biliary tract cancer (BTC) after progression on gemcitabine-based therapy: A pooled analysis of the NIFTY and NALIRICC trials

58P Efficacy and safety of liposomal irinotecan (nal-IRI) plus fluorouracil (5-FU) and leucovorin (LV) versus 5-FU/LV alone for advanced biliary tract cancer (BTC) after progression on gemcitabine-based therapy: A pooled analysis of the NIFTY and NALIRICC trials

Multimodal Convolutional Neural Network-Based Algorithm for Real-Time Detection and Differentiation of Malignant and Inflammatory Biliary Strictures in Cholangioscopy: a Proof of Concept Study with Video

Deep learning algorithms gained attention for detection (CADe) of biliary tract cancer (BTC) in digital single-operator cholangioscopy (dSOC). We developed a multimodal convolutional neural network (CNN) for detection (CADe) characterization and discriminating (CADx) between malignant, inflammatory and normal biliary tissue in raw dSOC videos. In addition, clinical metadata was included in the CNN algorithm to overcome limitations of image-only models. Based on dSOC videos and images of 111 patients (total of 15,158 still frames), we developed and validated a real-time CNN-based algorithm for CADe and CADx. We established an image-only model and metadata injection approach. In addition, we validated frame-wise and case-based predictions on complete dSOC video sequences. Model embeddings were visualized and class-activation maps highlighted relevant image regions. The concatenation-based CADx approach achieved a per-frame AUC of 0.871, sensitivity of 0.809 (95% CI: [0.784-0.832]), specificity of 0.773 [0.761-0.785], PPV of 0.450 [0.423-0.467], and NPV of 0.946 [0.940-0.954] with respect to malignancy on 5,715 test frames from complete videos of 20 patients. For case-based diagnosis using average prediction scores, six out of eight malignant cases and all twelve benign cases were identified correctly. Our algorithm distinguishes malignant and inflammatory bile duct lesions in dSOC videos, indicating the potential of CNN-based diagnostic support systems for both, CADe and CADx. The integration of non-image data can improve CNN based support systems, targeting current challenges in the assessment of biliary strictures.

Beyond body mass index: Body composition profiling for perioperative risk stratification in intrahepatic cholangiocarcinoma patients.

Intrahepatic cholangiocarcinoma (iCC) is an aggressive tumor, usually detected at an advanced stage. Our aim was to investigate the potential of body composition analysis (BCA) derived from presurgical staging computed tomography (CT) in predicting perisurgical complications. In this retrospective cohort study, we enrolled 86 patients who underwent CT imaging prior to liver surgery. Cox and logistic regression were performed to assess risk factors for prolonged hospital and intensive care unit (ICU) stays, as well as the occurrence of various complications. BCA parameters served as covariates besides conventional risk factors. Postoperative complications after resection of iCC significantly prolonged the overall length of hospitalization (p < .001). Presence of sarcopenia was associated with longer ICU stays. Complications were common, with 62.5% classified as Clavien-Dindo grade IIIa or lower and 37.5% as more severe. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were identified as risk factors for complications, including bile leakage (in 24 cases, p = .025), pleural effusions (in 26 cases, p = .025), and intra-abdominal abscess formation (in 24 cases, p = .043). SAT was associated with severe complications requiring interventional therapy, whereas VAT was correlated with abscess formation. Despite normal prevalence of obesity (22%), body mass index (BMI) did not have an impact on the development of perioperative complications. BCA is a useful tool for preoperative risk stratification in patients with iCC and is superior to BMI assessment. Increased SAT and VAT were associated with the risk of perisurgical complications, prolonging hospitalization. Therefore, BCA derived from routine staging CT should be considered in the preoperative assessment of patients with iCC.

Tumor Apparent Diffusion Coefficient is Associated with Early Recurrence of Intrahepatic Cholangiocarcinoma

Rationale and ObjectivesIdentifying intrahepatic cholangiocarcinoma (iCCA) patients who are at high risk for early recurrence (ER) can guide personalized treatment strategy and improve survival. This study aimed to investigate the value of preoperative MRI, especially diffusion-weighted imaging, in predicting ER, including in patients receiving neoadjuvant therapy. Materials and methodsThis study included 175 pathologically-confirmed iCCA patients who underwent curative resection (114 men, 61 women; mean age 59.0±9.56 years). MRI features, particularly apparent diffusion coefficient (ADC), were analyzed and compared between ER and non-ER cases. Survival analyses of ER were evaluated using Cox regression and Kaplan-Meier analysis. ResultsER occurred in 54.3% (95/175) of patients. Multivariate logistic regression analysis identified tumor ADC as the only independent predictor of ER (odds ratio=0.034, P<0.001), with AUCs of 0.758 (95%CI 0.664, 0.836) in the testing cohort and 0.779 (95%CI 0.622, 0.893) in the validation cohort. The optimal ADC threshold was 1.273×10-3mm2/s. Tumor ADC was comparable to the AJCC 8th staging system in predicting ER (AUC 0.758 vs 0.650 in testing cohort and 0.779 vs 0.661 in validation cohort). Multivariate Cox analysis identified high tumor burden score (HR=1.109, P=0.009), non-smooth margin (HR=2.265, P=0.008) and tumor ADC (HR=0.111, P<0.001) as independent risk factors for ER. Lower ADC values were linked to shorter RFS in both testing and validation cohorts (P<0.001 and 0.0219), as well as in patients receiving neoadjuvant therapy (P=0.003). ConclusionPreoperative MRI, particularly ADC, can help predict ER in iCCA, regardless of the application of neoadjuvant therapy, comparable to the AJCC 8th staging system.

Age and Sex Affects the Frequency and Mutation Type of FGFR2 Alterations in Cholangiocarcinoma

PURPOSE FGFR2 alterations are infrequent but currently represent the most common targetable mutation in cholangiocarcinoma. We performed a large-scale genomic analysis to assess associations between FGFR2 and other driver gene alterations in cholangiocarcinoma with patient demographics. METHODS Clinical and molecular data for patients with intrahepatic cholangiocarcinoma were abstracted from the Foundation Medicine (FMI) and Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) genomic databases. The Chi-squared test was used to assess the association between sex and alterations in driver genes. FGFR2 fusion partners were analyzed using descriptive statistics. RESULTS Across both FMI (N = 7,859) and GENIE (N = 1,395) cohorts, FGFR2 rearrangements were more frequent in female than male patients with cholangiocarcinoma (odds ratio, 1.69 and 2.45). By contrast, FGFR2 missense mutations, TP53 mutations, and KRAS mutations were not associated with sex. Stratifying patients by age groups showed that FGFR2 rearrangements were specifically enriched in younger ages (&lt;45 years). Although the most common FGFR2 fusion partners were shared across both sexes, a subset of fusion partners was recurrent and uniquely associated with female or male patients. CONCLUSION FGFR2 rearrangements but not other driver alterations in cholangiocarcinoma are concentrated in young female patients, where the prevalence reached nearly 20% across two large patient cohorts. These results suggest that the molecular basis of FGFR2 rearrangements may be distinct between sexes. These results indicate the importance of genetic testing in cholangiocarcinoma, particularly for younger patients, and suggest that patient recruitment strategies in trials for FGFR2-targeting therapies should seek to reduce barriers to enhance the enrollment of young female patients.

46P The comparison outcome of GEMOX and PD-1 inhibitors combined with or without lenvatinib for advanced intrahepatic cholangiocarcinoma (ICC): A prospective, single-center, open-label, double-arm phase II trial

46P The comparison outcome of GEMOX and PD-1 inhibitors combined with or without lenvatinib for advanced intrahepatic cholangiocarcinoma (ICC): A prospective, single-center, open-label, double-arm phase II trial

Primary neuroendocrine tumor of the perihilar bile duct: A case report

Neuroendocrine tumors (NETs) arising from extrahepatic bile ducts are very rare. We present a patient with perihilar NET who was operated on with a preoperative diagnosis of Klatskin tumor. A 58-year-old female patient was admitted with abdominal pain and jaundice. Laboratory data showed elevated serum bilirubin levels and liver function tests. Computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) findings were consistent with perihilar bile duct tumor. The patient was operated on with a diagnosis of Klatskin tumor. She underwent right hepatectomy, resection of the extrahepatic bile duct, portal lymphadenectomy and Roux-en-Y hepaticojejunostomy. The final pathologic examination of the resected specimen demonstrated a well differentiated neuroendocrine tumor (Grade 1). NETs originating from perihilar bile ducts are extremely rare, and preoperative definite diagnosis is very difficult. It should be kept in mind that NET may be one of the rare causes of perihilar bile duct obstruction.

52P Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial

52P Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial

Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models.

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.

53P Envafolimab and chidamide in combination with GEMOX as first-line treatment for advanced and metastatic biliary tract cancer (B-Enefits/SCOG-B001): A single-arm, exploratory, phase II trial: Interim report

53P Envafolimab and chidamide in combination with GEMOX as first-line treatment for advanced and metastatic biliary tract cancer (B-Enefits/SCOG-B001): A single-arm, exploratory, phase II trial: Interim report

45P Durvalumab (D) plus gemcitabine-based (gem-based) chemotherapy as first-line therapy for Chinese patients (pts) with advanced biliary tract cancers (aBTC): A phase IIIb, single arm, open-label, multi-center study (TopDouble)

45P Durvalumab (D) plus gemcitabine-based (gem-based) chemotherapy as first-line therapy for Chinese patients (pts) with advanced biliary tract cancers (aBTC): A phase IIIb, single arm, open-label, multi-center study (TopDouble)

44P Chemo-immunotherapy combination of mFOLFOX6, bevacizumab and atezolizumab after first-line therapy for advanced biliary tract cancer: The COMBATBIL imCORE trial

44P Chemo-immunotherapy combination of mFOLFOX6, bevacizumab and atezolizumab after first-line therapy for advanced biliary tract cancer: The COMBATBIL imCORE trial

Clinical impact of pancreatic invasion in T1-stage distal bile duct cancer and prognostic factors associated with long-term survival: A multicenter study.

The eighth edition of the AJCC staging system introduced a shift in the staging of distal bile duct cancer (DBC), emphasizing the depth of invasion over adjacent organ invasion. This study aimed to evaluate the clinical impact of pancreatic invasion in pT1-stage DBC and identify prognostic factors for long-term survival. This multicenter retrospective analysis encompassed DBC patients who underwent pancreaticoduodenectomy between 2009 and 2019 in six Korean tertiary centers, specifically those with final pathology confirming AJCC eighth edition T1 stage and intrapancreatic bile duct tumor origin. Primary endpoints were five-year recurrence-free survival (RFS) and overall survival (OS). Secondary objectives included the identification of prognostic determinants. This study involved 287 patients, comprising 190 without and 97 with pancreatic invasion. Pancreatic invasion did not significantly influence five-year OS and RFS rates (OS: without pancreatic invasion 69.9% vs. with pancreatic invasion 54.1%, p = .25; RFS: 56.3% vs. 55.4%, p = .97). Multivariate analysis highlighted male gender, age, lymphovascular invasion, and N stage as significant OS determinants. Notably, male gender, ampulla of Vater invasion, lymphovascular invasion, and N1 stage were also associated with RFS. In pT1 DBC, pancreatic invasion demonstrates no substantial impact on long-term prognosis, in accordance with the depth-based paradigm of the eighth edition AJCC staging system. The prognostic factors influencing OS were identified as male gender, age, lymphovascular invasion, and nodal metastasis.

Analytic validation of an FGFR -focused cell-free DNA liquid biopsy assay (FGFR-Dx).

Commercial liquid biopsy assays are routinely used by oncologists to monitor disease response and resistance to therapy. Additionally, in cases where tumor tissue is not available, clinicians may rely on cell-free DNA (cfDNA) testing as a surrogate for comprehensive tumor testing. While some gene rearrangements are well detected, current commercial liquid biopsy assays exhibit low sensitivity for fibroblast growth factor receptor ( FGFR ) rearrangements. FGFRs are altered in ∼2.5% of all cancers, including FGFR2 rearrangements in 10% of intrahepatic cholangiocarcinoma and FGFR3 point mutations and rearrangements in 10-15% of urothelial carcinoma. Therefore, we developed and analytically validated FGFR-Dx, an FGFR -focused cfDNA assay with improved sensitivity for FGFR rearrangements. FGFR-Dx comprehensively targets the introns in FGFR1-3 previously shown to be involved in gene fusions as well as all coding exons. Custom FGFR synthetic reference standards representing both single nucleotide variants (SNVs) and gene rearrangements were utilized at a range of variant frequencies and revealed a detection limit of 0.5% with sensitivities of 97.2% and 92.9% for SNVs and rearrangements, respectively. Furthermore, FGFR-Dx detected rearrangements and identified the intronic breakpoints from cfDNA collected from 13 of 15 patients with known FGFR fusions.

971P Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative optionfor advanced unresectable intrahepatic cholangiocarcinoma: A retrospective real-world study

971P Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative optionfor advanced unresectable intrahepatic cholangiocarcinoma: A retrospective real-world study

HSPB8-BAG3 chaperone complex modulates cell invasion in intrahepatic cholangiocarcinoma by regulating CASA-mediated Filamin A degradation

ABSTRACT The incidence of intrahepatic cholangiocarcinoma (ICC) is steadily rising, and it is associated with a high mortality rate. Clinical samples were collected to detect the expression of HSPB8 and BAG3 in ICC tissues. ICC cells were cultured and transfected with plasmids that overexpressed or silenced specific genes to investigate the impact of gene expression alterations on cell function. qPCR and Western blot techniques were utilized to measure gene and protein expression levels. A wound healing assay was conducted to assess cell migration ability. The Transwell assay was used to assess cell invasion ability. Co-IP was used to verify the binding relationship between HSPB8 and BAG3. The effects of HSPB8 and BAG3 on lung metastasis of tumors in vivo were verified by constructing a metastatic tumor model. Through the above experiments, we discovered that the expressions of HSPB8 and BAG3 were up-regulated in ICC tissues and cells, and their expressions were positively correlated. The metastatic ability of ICC cells could be promoted or inhibited by upregulating or downregulating the expression of BAG3. Furthermore, the HSPB8-BAG3 chaperone complex resulted in the abnormal degradation of Filamin A by activating autophagy. Increased expression of Filamin A inhibits the migration and invasion of ICC cells. Overexpression of HSPB8 and BAG3 in vivo promoted the lung metastasis ability of ICC cells. The HSPB8-BAG3 chaperone complex promotes ICC cell migration and invasion by regulating CASA-mediated degradation of Filamin A, offering insights for enhancing ICC therapeutic strategies.

Development and validation of a diagnostic and prognostic model for bone metastasis of intrahepatic cholangiocarcinoma: a population-based analysis.

Bone metastasis (BM) is a common site of metastasis in patients with intrahepatic cholangiocarcinoma (ICC), significantly impacting the quality of life and prognosis of affected individuals. This investigation aimed to assess the risk of BM development in ICC patients and to prognosticate for patients with ICC-associated BM (ICCBM) through the construction of two nomograms. We conducted a retrospective analysis of data from 2,651 ICC patients, including 148 cases of BM, documented in the Surveillance, Epidemiology, and End Results (SEER) database spanning 2010 to 2017. Independent predictors for the occurrence of BM in ICC patients were identified via univariate and multivariate logistic regression analyses; simultaneously, independent prognostic indicators for ICCBM patients were ascertained through univariate and multivariate Cox regression analyses. The utility of the nomograms was evaluated through calibration curves, receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and Kaplan-Meier (KM) analysis. Independent risk factors for BM in ICC included sex, tumor size, lung metastasis, brain metastasis, and intrahepatic metastasis. For ICCBM patients, independent prognostic factors comprised age, chemotherapy, and radiotherapy. The prognostic nomogram exhibited C-indexes of 0.737 [95% confidential interval (CI): 0.682-0.792] for the training cohort and 0.696 (95% CI: 0.623-0.769) for the validation cohort. Calibration curves demonstrated strong concordance between predicted outcomes and observed events. The areas under the curve (AUC) for 3-, 6-, and 12-month cancer-specific survival (CSS) were 0.853, 0.781, and 0.739, respectively, in the training cohort, and 0.794, 0.822, and 0.780 in the validation cohort. DCA illustrated significant net benefits across a broad spectrum of threshold probabilities. KM analysis revealed 1-, 2-, and 3-year CSS rates of 23.91%, 7.55%, and 2.35%, respectively, with a median CSS of 6 months, underscoring the nomograms' capacity to distinctly stratify patients according to survival risk. The development of these nomograms offers substantial clinical utility in forecasting BM risk among ICC patients and prognosticating for those with ICCBM, thereby facilitating the formulation of more efficacious treatment modalities.

Safety and efficacy of hepaticoduodenostomy for biliary reconstruction after extrahepatic mid-bile duct cancer surgery.

Bile duct resection and reconstruction for bile duct cancer (BDC) is a complex surgical and oncologic procedure that requires extensive resection and reconstruction of the biliary tract. Hepaticojejunostomy is commonly performed for biliary reconstruction after extrahepatic mid-bile duct resection, while hepaticoduodenostomy (HD) is performed only rarely due to the risk of ascending cholangitis. However, the efficacy of HD has not been well-established in extrahepatic mid-BDC surgery. In this study, we aimed to analyze the outcomes of HD in patients who underwent bile duct resection for extrahepatic mid-BDC. We retrospectively analyzed 38 extrahepatic mid-BDC patients who underwent bile duct resection in our center between January 2018 and June 2023. We compared postoperative outcomes, cancer recurrence, and patient survival between hepaticojejunostomy (n=20) and HD (n=18) groups. Operation time for the HD group was significantly shorter than that of the hepaticojejunostomy group (188 vs. 206 min, P=0.044) with no significant differences in postoperative outcomes. Regression analysis showed that a HD was not associated with a significantly high risk of cancer recurrence or decrease in patient survival. HD appears to have comparable operative benefits, postoperative complications, and oncologic outcomes to hepaticojejunostomy in extrahepatic mid-BDC patients.

Epidemiology, survival and new treatment modalities for intrahepatic cholangiocarcinoma.

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.

Unveiling the unexplored secret: Aggressive behavior and poor survival in intrahepatic mucinous adenocarcinoma compared to conventional adenocarcinoma.

Intrahepatic bile duct mucinous adenocarcinoma (IHBDMAC) is a rare pathological subtype of intrahepatic cholangiocarcinoma (IHCC), and its tumor biological features and survival outcomes have rarely been explored, especially when compared to the most common subtype, intrahepatic bile duct adenocarcinoma (IHBDAC). Therefore, the aim of this study was to explore the clinical features and survival outcomes of IHBDAC and IHBDMAC using the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2021. A total of 1,126 patients were included, with 1,083 diagnosed with IHBDAC and 43 diagnosed with IHBDMAC. Patients with IHBDMAC presented with a more advanced T stage (55.8% vs. 36.9%, P = 0.012) and higher rate of lymph node metastasis (37.2% vs. 24.9%, P = 0.070). Cox regression identified advanced T stage, lymph node metastasis, and distant metastasis as poor survival predictors, while chemotherapy and surgery were protective factors. Survival analyses revealed significantly worse overall survival (OS) and cancer-specific survival (CSS) for IHBDMAC compared to IHBDAC (P < 0.05). Even after matching, patients with IHBDMAC still had a worse prognosis than those with IHBDAC. These findings highlight the aggressive nature of IHBDMAC and the need for tailored therapeutic strategies. Future research should focus on prospective studies and molecular insights to develop targeted treatments for IHBDMAC.