Extrahepatic Cholangiocarcinoma Research Articles

Prognostic model for oversurvival and tumor-specific survival prediction in patients with advanced extrahepatic cholangiocarcinoma: a population-based analysis

BackgroundThe prognosis of patients with extrahepatic cholangiocarcinoma (ECCA) must be determined with precision. However, the usual TNM staging system has the drawback of ignoring age, adjuvant therapy, and gender and lacks the ability to more correctly predict patient prognosis. Therefore, we determine the risk factors of survival for patients with advanced ECCA patients and developed brand-new nomograms to forecast patients with advanced ECCA’s overall survival (OS) and cancer-specific survival (CSS).MethodFrom the Epidemiology and End Results (SEER) database, patients with advanced ECCA were chosen and randomly assigned in a ratio of 6:4 to the training and validation subgroups. The cumulative incidence function (CIF) difference between groups was confirmed by applying Gray’s and Fine test and competing risk analyses. Next, the cancer-specific survival (CSS) and overall survival (OS) nomograms for advanced ECCA were developed and validated.ResultsIn accordance with the selection criteria, 403 patients with advanced ECCA were acquired from the SEER database and then split at random into two groups: a training group (n = 241) and a validation group (n = 162). The 1-, 2-, and 3-year cancer-specific mortality rates were 58.7, 74.2, and 78.0%, respectively, while the matching mortality rates for the competition were 10.0, 13.8, and 15.0%. Nomograms were generated for estimating OS and CSS, and they were assessed using the ROC curve and the C-index. The calibration curves showed that there was a fair amount of agreement between the expected and actual probabilities of OS and CSS. Additionally, greater areas under the ROC curve were seen in the newly developed nomograms for OS and CSS when compared to the 7th AJCC staging system. The advanced ECCA patients were divided into groupings with an elevated risk and those with a low risk and the Kaplan-Meier method was used for the survival analysis, which showed that survival time was shorter in the high-risk group than in the low-risk group.ConclusionThe proposed nomograms have good predictive ability. The nomograms may can help doctors determine the prognosis of patients with advanced ECCA as well as provide more precise treatment plans for them.

FOLFIRI-bevacizumab as a second-line treatment for advanced biliary tract cancer after gemcitabine-based chemotherapy.

Advanced biliary tract cancer (BTC) has a poor prognosis. Gemcitabine with platinum chemotherapy was the standard first-line chemotherapeutic regimen until the recent addition of anti-PD-1/PD-L1 antibodies. After disease progression, the only second-line chemotherapy that has demonstrated a survival benefit versus supportive care is FOLFOX (folinic acid, fluorouracil, and oxaliplatin), with a modest benefit. This study aimed to assess the efficacy and safety of second-line FOLFIRI (folinic acid, fluorouracil, and irinotecan) combined with bevacizumab for advanced BTC. This single-center retrospective study enrolled patients with metastatic BTC (intrahepatic cholangiocarcinoma [ICC], extrahepatic cholangiocarcinoma [ECC], or gallbladder carcinoma) that progressed after first-line gemcitabine-based chemotherapy. FOLFIRI-bevacizumab was administered intravenously every 2 weeks [folinic acid 200 mg/m², fluorouracil 400 mg/m² (bolus), fluorouracil 2400 mg/m² (46-h continuous intravenous infusion), irinotecan 180 mg/m², and bevacizumab 5 mg/kg] until unacceptable toxicity, patient refusal, or disease progression. Overall, 28 patients received the FOLFIRI-bevacizumab regimen after gemcitabine-based chemotherapy. The median overall survival (OS) was 9.0 months (95% CI 6.4-16.5). The OS rate was 39.3% (95% CI 24.8-62.3) and 10.7% (95% CI 3.7-32.1) at 12- and 24-months respectively. The median progression-free survival (PFS) was 5.2 months (95% CI 3.1-10.2) with FOLFIRI-bevacizumab. The PFS rates at 12 months and 24 months were 17.9% (95% CI 8.19-39.5] and 10.7% (95% CI 3.7-31.2), respectively. The overall response rate (ORR) to FOLFIRI-bevacizumab was 23.1%, with a disease control rate (DCR) of 69.3%. Grade 3-4 adverse events (sAE) were reported in 20 patients (71.4%) treated with FOLFIRI-bevacizumab. FOLFIRI-bevacizumab as a second-line treatment for advanced BTC after gemcitabine-based chemotherapy showed efficacy and safety with a promising tumor response rate in this retrospective single-center study.

Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated. The ALPPS procedure in our center was modified in 2016 by minimizing the first stage of the surgical procedure through biliary externalization after the first stage, antibiotic administration during the interstage phase, and performing biliary reconstructions during the second stage. The rate of postoperative major morbidity and 90-day mortality, as well as the one- and three-year disease-free and overall survival rates were calculated and compared between patients operated before and after 2016. The ALPPS risk score before the second stage of the procedure was lower in patients who were operated on after 2016 (before 2016: median 6.4; after 2016: median 4.4; p = 0.010). Major morbidity decreased from 42.9% before 2016 to 31.3% after 2016, and the 90-day mortality rate decreased from 35.7% before 2016 to 12.5% after 2016. The three-year survival rate increased from 40.8% before 2016 to 73.4% after 2016. Our modified ALPPS procedure improved perioperative and postoperative outcomes in patients with extrahepatic and intrahepatic cholangiocarcinoma. Minimizing the first step of the ALPPS procedure was key to these improvements.

MRI-based automatic identification and segmentation of extrahepatic cholangiocarcinoma using deep learning network

BackgroundAccurate identification of extrahepatic cholangiocarcinoma (ECC) from an image is challenging because of the small size and complex background structure. Therefore, considering the limitation of manual delineation, it’s necessary to develop automated identification and segmentation methods for ECC. The aim of this study was to develop a deep learning approach for automatic identification and segmentation of ECC using MRI.MethodsWe recruited 137 ECC patients from our hospital as the main dataset (C1) and an additional 40 patients from other hospitals as the external validation set (C2). All patients underwent axial T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI). Manual delineations were performed and served as the ground truth. Next, we used 3D VB-Net to establish single-mode automatic identification and segmentation models based on T1WI (model 1), T2WI (model 2), and DWI (model 3) in the training cohort (80% of C1), and compared them with the combined model (model 4). Subsequently, the generalization capability of the best models was evaluated using the testing set (20% of C1) and the external validation set (C2). Finally, the performance of the developed models was further evaluated.ResultsModel 3 showed the best identification performance in the training, testing, and external validation cohorts with success rates of 0.980, 0.786, and 0.725, respectively. Furthermore, model 3 yielded an average Dice similarity coefficient (DSC) of 0.922, 0.495, and 0.466 to segment ECC automatically in the training, testing, and external validation cohorts, respectively.ConclusionThe DWI-based model performed better in automatically identifying and segmenting ECC compared to T1WI and T2WI, which may guide clinical decisions and help determine prognosis.

First report on establishment and characterization of the extrahepatic cholangiocarcinoma sarcoma cell line CBC2T-2

Inflammatory bowel disease (IBD) has as a main characteristic the exacerbation of the immune system against enterocytes, compromising the individual’s intestinal microbiota. This inflammatory cascade causes several nutritional deficiencies, which further compromise immunological functioning and, as a result, worsen the prognosis. This vicious cycle can be interrupted as the patient’s dietary pattern meets their needs according to their clinical condition, acting directly on the inflammatory process of IBD through the interaction of food, intestinal microbiota, and epigenome. Specific nutritional intervention for IBD has a crucial role in preventing and managing disease activity. This review addresses epigenetic modifications through dietary compounds as a mechanism for modulating the intestinal microbiota of patients with IBD.

New epidemiologic trends in cholangiocarcinoma.

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

Improved Diagnosis of Adjacent Organ Invasion of Extrahepatic Cholangiocarcinoma by Adding Arterial and Delayed Phases.

To clarify the role of dynamic computed tomography (CT) in diagnosing extrahepatic cholangiocarcinoma (eCCA) involving adjacent organs. We retrospectively analyzed patients diagnosed with eCCA in Iwate Medical University Hospital (Morioka, Japan) during January 2011-December 2021 who underwent dynamic contrast-enhanced CT before biliary intervention, surgery, or chemotherapy. For surgical cases, two radiologists independently reviewed CT images in the portal, dual (adding arterial phase), and triple (adding delayed phase) phases. The mean attenuations of the abdominal aorta, portal vein (PV), hepatic parenchyma, pancreatic parenchyma, and eCCA were measured. The biliary segment-wise longitudinal tumour extent, arterial and PV invasion, organ invasion (liver, pancreas, and duodenum), and regional lymph node metastasis were assessed on a five-point scale. Imageperformances were compared using the sensitivity, specificity, and area under the curve (AUC). We included 120 patients (mean age, 71.7 ± 8.9; 84 males). The PV and liver differed most from the bile duct tumour in the portal phase. The abdominal aorta and pancreas differed most from eCCA in the arterial phase. For 80 patients evaluated on the five-point scale, adding phases increased the AUC for pancreatic, duodenal, and arterial invasion for each observer (observer 1, 0.79-0.93, p<0.01, 0.71-0.86, p = 0.04, 0.74-0.99, p = 0.02; observer 2, 0.88-0.96, p = 0.01, 0.73-0.94, p<0.01, 0.80-0.99 p = 0.04; respectively). The AUC for biliary segment-wise longitudinal tumor extent, hepatic, and PV invasion remained unchanged with additional phases. Portal-phase information is sufficient to evaluate the segmental extent of bile duct and liver/PV invasion. Arterial- and delayed-phase information can help evaluate pancreatic, duodenal, and arterial invasion.

Interplay between the Human Microbiome and Biliary Tract Cancer: Implications for Pathogenesis and Therapy.

Biliary tract cancer, encompassing intrahepatic and extrahepatic cholangiocarcinoma as well as gallbladder carcinoma, stands as a prevalent malignancy characterized by escalating incidence rates and unfavorable prognoses. The onset of cholangiocarcinoma involves a multitude of risk factors and could potentially be influenced by microbial exposure. The human microbiome, encompassing the entirety of human microbial genetic information, assumes a pivotal role in regulating key aspects such as host digestion, absorption, immune responses, and metabolism. The widespread application of next-generation sequencing technology has notably propelled investigations into the intricate relationship between the microbiome and diseases. An accumulating body of evidence strongly suggests a profound interconnection between biliary tract cancer and the human microbiome. This article critically appraises the existing evidence pertaining to the microbiome milieu within patients afflicted by biliary tract cancer. Furthermore, it delves into potential mechanisms through which dysregulation of the human microbiome could contribute to the advancement of biliary tract cancer. Additionally, the article expounds on its role in the context of chemotherapy and immunotherapy for biliary tract cancer.

Prognostic and predictive value of human equilibrative nucleoside transporter 1 (hENT1) in extrahepatic cholangiocarcinoma: a translational study.

Introduction: Effective (neo) adjuvant chemotherapy for cholangiocarcinoma is lacking due to chemoresistance and the absence of predictive biomarkers. Human equilibrative nucleoside transporter 1 (hENT1) has been described as a potential prognostic and predictive biomarker. In this study, the potential of rabbit-derived (SP120) and murine-derived (10D7G2) antibodies to detect hENT1 expression was compared in tissue samples of patients with extrahepatic cholangiocarcinoma (ECC), and the predictive value of hENT1 was investigated in three ECC cell lines. Methods: Tissues of 71 chemonaïve patients with histological confirmation of ECC were selected and stained with SP120 or 10D7G2 to assess the inter-observer variability for both antibodies and the correlation with overall survival. Concomitantly, gemcitabine sensitivity after hENT1 knockdown was assessed in the ECC cell lines EGI-1, TFK-1, and SK-ChA-1 using sulforhodamine B assays. Results: Scoring immunohistochemistry for hENT1 expression with the use of SP120 antibody resulted in the highest interobserver agreement but did not show a prognostic role of hENT1. However, 10D7G2 showed a prognostic role for hENT1, and a potential predictive role for gemcitabine sensitivity in hENT1 in SK-ChA-1 and TFK-1 cells was found. Discussion: These findings prompt further studies for both preclinical validation of the role of hENT1 and histochemical standardization in cholangiocarcinoma patients treated with gemcitabine-based chemotherapy.

Molecular Analysis of Biliary Tract Cancers with the Custom 3' RACE-Based NGS Panel.

The technique 3' rapid amplification of cDNA ends (3' RACE) allows for detection of translocations with unknown gene partners located at the 3' end of the chimeric transcript. We composed a 3' RACE-based RNA sequencing panel for the analysis of FGFR1-4 gene rearrangements, detection of activating mutations located within FGFR1-4, IDH1/2, ERBB2 (HER2), KRAS, NRAS, BRAF, and PIK3CA genes, and measurement of the expression of ERBB2, PD-L1, and FGFR1-4 transcripts. This NGS panel was utilized for the molecular profiling of 168 biliary tract carcinomas (BTCs), including 83 intrahepatic cholangiocarcinomas (iCCAs), 44 extrahepatic cholangiocarcinomas (eCCAs), and 41 gallbladder adenocarcinomas (GBAs). The NGS failure rate was 3/168 (1.8%). iCCAs, but not other categories of BTCs, were characterized by frequent FGFR2 alterations (17/82, 20.7%) and IDH1/2 mutations (23/82, 28%). Other potentially druggable events included ERBB2 amplifications or mutations (7/165, 4.2% of all successfully analyzed BTCs) and BRAF p.V600E mutations (3/165, 1.8%). In addition to NGS, we analyzed microsatellite instability (MSI) using the standard five markers and revealed this event in 3/158 (1.9%) BTCs. There were no instances of ALK, ROS1, RET, and NTRK1-3 gene rearrangements or MET exon 14 skipping mutations. Parallel analysis of 47 iCCA samples with the Illumina TruSight Tumor 170 kit confirmed good performance of our NGS panel. In conclusion, targeted RNA sequencing coupled with the 3' RACE technology is an efficient tool for the molecular diagnostics of BTCs.

Immune checkpoint inhibitor-related molecular markers predict prognosis in extrahepatic cholangiocarcinoma.

Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications. Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI). Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36. TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.

S2 Prospective Evaluation of Procedural Factors Related to False Negative Fluorescence In-Situ Hybridization (FISH) in Patients With Extrahepatic Cholangiocarcinoma

S2 Prospective Evaluation of Procedural Factors Related to False Negative Fluorescence In-Situ Hybridization (FISH) in Patients With Extrahepatic Cholangiocarcinoma

94MO Advanced extrahepatic cholangiocarcinoma: Post-hoc analysis of the ABC-01, -02 and -03 clinical trials

94MO Advanced extrahepatic cholangiocarcinoma: Post-hoc analysis of the ABC-01, -02 and -03 clinical trials

Clinical Significance of Sphingosine 1-phosphate Receptor 2 and Takeda G Protein-coupled Receptor 5 in Extrahepatic Cholangiocarcinoma Patients.

In biliary epithelial cells, two bile acid receptors, sphingosine 1-phosphate receptor 2 (S1PR2) and Takeda G protein-coupled receptor 5 (TGR5) have been reported to trigger cell proliferation, as well as neoplastic cell invasiveness. In this study, we aimed to investigate the clinical significance of S1PR2/ TGR5 expression in extrahepatic cholangiocarcinoma (CCA) patients. Patients who underwent surgical resection of extrahepatic CCA at Korea University Guro Hospital between 2002 and 2018 were included. Data on immunohistochemical staining and H-score of S1PR2 and TGR5 were evaluated using digital image analysis. A total of 115 cases of invasive CCA were analyzed. The H-score of S1PR2 showed a decrease in invasive CCA (p=0.052) but that of TGR5 showed a significant increase (p=0.02). Overall survival and disease-free survival were significantly lower in the low S1PR2 expression group (p<0.05) than in the control group; however, TGR5 expression was not significant (p=0.096). In multivariate analysis, low S1PR2 was only significant for poor prognosis. Low S1PR2 level was the only independent poor prognostic factor in patients with resected extrahepatic CCA.

Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers.

BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a "genomic cohort" [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional "clinical cohort" of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT). In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.

A Rare Axillary Lymph Node Metastasis on 18F-FDG PET/CT for Staging in a Patient with Common Bile Duct Cancer.

Distant metastasis of cholangiocarcinoma is most commonly diagnosed in the liver; however, it can also be found in the lungs, distant lymph nodes, bones, and brain. Distant lymph node metastasis outside the abdominal region without concurrent abdominal metastasis is exceedingly rare in extrahepatic cholangiocarcinoma. Herein, we present interesting 18F-FDG PET/CT images of a 49-year-old male patient with common bile duct cancer. In this case, the patient, who was scheduled for surgery, unexpectedly showed axillary lymph node metastasis on a preoperative 18F-FDG PET scan, which was subsequently confirmed via histological examination. Although such cases are exceptionally rare, this accurate diagnosis prompted a modification of the treatment plan, leading to a positive therapeutic response.

Comparison between regular additional endobiliary radiofrequency ablation and photodynamic therapy in patients with advanced extrahepatic cholangiocarcinoma under systemic chemotherapy.

Extrahepatic cholangiocarcinoma (eCCA) remains a malignancy with a dismal prognosis. The first-line standard of care includes systemic chemotherapy (SC) and biliary drainage through stenting. Endobiliary ablative techniques, such as photodynamic therapy (ePDT) and radio-frequency ablation (eRFA), have demonstrated feasibility and favorable survival data. This study aimed to compare the oncologic outcome in patients treated with SC and concomitant eRFA or ePDT. All patients with eCCA were evaluated for study inclusion. Sixty-three patients receiving a combination of SC and at least one endobiliary treatment were retrospectively compared. Patients were stratified into three groups: SC + ePDT (n = 22), SC + eRFA (n = 28), and SC + ePDT + eRFA (n = 13). The median overall survival (OS) of the whole cohort was 14.2 months with no statistically significant difference between the three therapy groups but a trend to better survival for the group receiving ePDT as well as eRFA, during SC (ePDT + SC, 12.7 months; eRFA + SC, 13.8 months; ePDT + eRFA + SC, 20.2 months; p = 0.112). The multivariate Cox regression and subgroup analysis highlighted the beneficial effect of eRFA on OS. Overall, combined therapy was well tolerated. Only cholangitis occurred more often in the SC + eRFA group. Additional endobiliary ablative therapies in combination with SC were feasible. Both modalities, eRFA and ePDT, showed a similar benefit in terms of survival. Interestingly, patients receiving both regimes showed the best OS indicating a possible synergism between both ablative therapeutic techniques.

How Molecular Discoveries Have Changed Liver Tumor Pathology: A Brief Review.

Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors.

Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.

Extrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs). We examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102). Among the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (P<0.001). The association of survival with IES, either on the extrahepatic bile duct or on the CyD, differed depending on the tumor location and type of eCCA. The extension properties of IES were also dependent on different types of tumors among BTCs; usually, the IES incidence became higher than 50% in the tissues that the tumor developed, whereas IES extension to other tissues decreased the incidence. Thus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial)

BackgroundBiliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients.MethodsThe NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China.DiscussionThe NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research.Trial registrationChinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.