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Objectives: Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. Kaplan–Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables. Results: Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3–4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p

Malignant biliary strictures are caused by pancreatobiliary cancer and other metastatic malignancies. Most of them are unresectable at diagnosis with a dismal prognosis. Various new ablation methods have been introduced. Of them, ERCP-guided intraductal radiofrequency ablation (ID-RFA) appears to be the most promising minimally invasive endoscopic treatment by delivering a high-frequency alternating current to the target tissue, leading to coagulative necrosis. Thus far, many studies have provided evidence that ERCP-guided ID-RFA is a safe, feasible, and effective treatment modality for stent patency and overall survival. Compared to other ablation treatments, ERCP-guided ID-RFA has several advantages, including ease of delivery, controlled application of thermal energy, low cost, and fewer systemic side effects with an acceptable safety profile. Therefore, ERCP-guided ID-RFA can be considered an adjunctive treatment for the palliation of unresectable malignant biliary strictures. On the other hand, the decision of local ablation treatment should be individualized by multidisciplinary team support due to the lack of comparative studies.

To perform a systematic review and meta-analysis to determine the diagnostic performance of percutaneous transluminal forceps biopsy (PTFB) for differentiating malignant from benign biliary stricture. A comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted to identify original articles published between January 2001 and January 2021 reporting the diagnostic accuracy of PTFB. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy. Fourteen studies involving 1762 patients met the inclusion criteria and were included in the meta-analysis. The meta-analysis summary estimates of PTFB for diagnosis of malignant biliary strictures were as follows: sensitivity 81% (95% confidence interval [CI], 78–81%); specificity 100% (95% CI, 98–100%); diagnostic odds ratio 85.34 (95% CI, 38.37–189.81). The area under the curve of PTFB was 0.948 in the diagnosis of malignant biliary strictures. The diagnostic sensitivity was higher in intrinsic (85%) than in extrinsic (73%) biliary strictures. The pooled rate of all complications was 10.3% (95% CI, 7.0–14.2%), including a major complication rate of 3.1%. These data demonstrate that PTFB is sensitive and highly specific for diagnosing malignancy in biliary strictures. PTFB should be incorporated into future guidelines for tissue sampling in biliary cancer, especially in cases with failed endoscopic management. • PTFB had a good overall diagnostic performance for differentiating malignant from benign biliary strictures, with a meta-analysis summary estimate of 81% for sensitivity and 100% for specificity. • PTFB had higher sensitivity for cholangiocarcinoma (85%) than for other cancers (73%). • PTFB had a 100% technical success rate and a 10.3% rate for complications, including a 3.1% rate for major complications.

Backgrounds/aims Surgical resection is the only curative treatment for biliary tract cancers; however, most patients undergo palliative chemotherapy because they are contraindicated for surgery. Conversion surgery, a treatment strategy for downsizing chemotherapy and subsequent surgical resection, is feasible for initially unresectable biliary tract cancers following the introduction of effective chemotherapeutic agents. Methods Patients initially diagnosed with unresectable biliary tract cancers, and treated with conversion surgery after palliative chemotherapy between 2013 and 2019, were reviewed retrospectively. Results Twelve patients underwent conversion surgery after palliative chemotherapy for initially unresectable biliary tract cancers. The final pathological diagnosis included six perihilar cholangiocarcinomas, four distal common bile duct cancers, and two gallbladder cancers. Different chemotherapy regimens were used, but all the patients were treated with gemcitabine at some point during their treatment. The median overall survival was 28 months, which was longer than that of patients treated with isolated palliative chemotherapy in previous studies. Conclusions Conversion surgery represents a therapeutic alternative for specific cases of unresectable biliary tract cancers. Palliative chemotherapy for initially unresectable biliary tract cancers is recommended for downsizing the tumor and expanding the indications for surgery. Further studies and clinical trials are required to develop new and effective chemotherapeutic regimens.

The diagnosis of biliary strictures in clinical practice can be challenging. Discriminating between benign and malignant biliary strictures is important to prevent the morbidity and mortality associated with incorrect diagnoses. Missing a malignant biliary stricture may delay surgery, resulting in poor prognostic outcomes. Conversely, it has been demonstrated that approximately 20% of patients who undergo surgery for suspected biliary malignancies have a benign etiology on histopathology. Traditional tissue sampling using endoscopic retrograde cholangiography does not always produce a definitive diagnosis, with a considerable proportion of cases remaining as indeterminate biliary strictures. Recent advances in endoscopic techniques have the potential to improve the diagnostic and prognostic accuracy of biliary strictures.

Purpose Platelet-related indices, including mean platelet volume (MPV) and plateletocrit (PCT), have been reported as new prognostic factors of overall survival (OS) in many cancers, but not yet in biliary tract cancer (BTC). We intended to assess these indices in predicting OS in BTC patients with the aim to build a new prognostic model for patients with BTC after surgical resection. Materials and Methods Survival analysis and time receiver operating characteristic analysis were applied to screen the platelet indices. Univariate and multivariate Cox analyses were used to identify independent prognostic factors and develop a new prognostic model. Harrell’s C-statistics, calibration curves, and decisive curve analysis were used to assess the model. Results MPV and platelet distribution width (PDW)/PCT showed the best prognostic accuracy among the platelet indices. In multivariable analysis, factors predictive of poor OS were presence of nodal involvement, Non-radical surgery, poor tumor differentiation, carbohydrate antigen 19-9 > 100 U/mL, MPV > 8.1 fl, and PDW/PCT > 190. The new model was found to be superior to the TNM staging system and our new staging system showed higher discriminative power.Conclusion MPV and PDW/PCT have high prognostic value in BTC patients, and the novel staging system based on these two indices showed good discrimination and accuracy compared with the American Joint Committee on Cancer 7th TNM staging system.

Hilar cholangiocarcinoma (HC) is a rare and highly aggressive biliary tract neoplasm. As such, the data driving the management of this disease generally are not based on prospective clinical trial data but rather consist of retrospective experiences and limited level 1 data. Surgical resection offers the best chance of a long-term survival, but local and distant recurrences are common. This report presents landmark articles that form the basis of preoperative, operative, and adjuvant strategies for HC.

Background: Malignant biliary obstruction (MBO) is usually caused by biliary tract cancer or pancreatic cancer. This study was performed to summarize the current situation regarding palliative endoscopic retrograde biliary drainage (ERBD) for MBO in Korea and to determine its clinical significance by analyzing representative nationwide data. Methods: Patients that underwent palliative ERBD for MBO between 2012 and 2015 were identified using the Health Insurance Review and Assessment database, which covers the entire Korean population. We assessed clinical characteristics and complications and compared the clinical impacts of initial metal and plastic stenting in these patients. Results: A total of 9,728 subjects (mean age, 65 ± 11.4 years; male, 61.4%) were identified and analyzed. The most common diagnosis was malignant neoplasm of liver and intrahepatic bile ducts (32.1%) and this was followed by extrahepatic or Ampulla of Vater cancer and pancreatic cancer. Initial plastic stent(s) placement was performed in 52.9% of the study subjects, and metal stent(s) placement was performed in 23.3%. The number of sessions of endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary drainage (PTBD) was significantly higher in patients that underwent initial plastic stenting than in patients that underwent metal stenting (2.2 ± 1.7 vs 1.8 ± 1.4, P < 0.0001), but rates of post-ERCP pancreatitis, hospital days, and time to second ERCP or PTBD were not significantly different. Conclusion: This nationwide assessment study suggests that initial metal stenting is associated with fewer sessions of total ERCP or PTBD following the initial procedure, despite the preference for initial plastic stenting in Korea.

Biliary tract cancer (BTC) is typically lethal due to the difficulty of early stage diagnosis. Thus, novel biomarkers of BTC precursors are necessary. Biliary intraepithelial neoplasia (BilIN) is a major precursor of BTC and is classified as low or high grade based on cell atypia. In normal gastric mucosa, gastric gland mucin‐specific O‐glycans are unique in having α1,4‐linked N‐acetylglucosamine (αGlcNAc) attached to MUC6. Previously, we reported that αGlcNAc functions as a tumor suppressor of differentiated‐type gastric adenocarcinoma and that decreased αGlcNAc glycosylation on MUC6 in gastric, pancreatic, and uterine cervical neoplasms occurs in cancer as well as in their precursor lesions. However, αGlcNAc and MUC6 expression patterns in biliary tract neoplasms have remained unclear. Here, we analyzed MUC5AC, MUC6, and αGlcNAc expression status in 51 BTC cases and compared the expression of each with progression from low‐grade BilIN to invasive adenocarcinoma (IAC). The frequency of αGlcNAc‐positive and MUC6‐positive lesions decreased with tumor progression. When we compared each marker’s expression level with tumor progression, we found that the MUC6 expression score in IAC was significantly lower than in low‐grade or high‐grade BilIN (P, Alpha‐1,4‐linked N‐acetylglucosamine glycosylation on MUC6 is already decreased in biliary intraepithelial neoplasia.

Summary Background Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. Methods This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov , NCT02034110 . These results are based on an interim analysis; the study is active but not recruiting. Findings Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Interpretation Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. Funding GlaxoSmithKline and Novartis.

BACKGROUND The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location. METHODS IPNBs were classified into two types: Type 1 IPNB, being histologically similar to intraductal papillary mucinous neoplasm of the pancreas, and Type 2 IPNB, having a more complex histological architecture with irregular papillary branching or foci of solid-tubular components. Medical data were evaluated. RESULTS Among 694 IPNB patients, 520 and 174 had Type 1 and Type 2, respectively. The levels of AST, ALT, ALP, T. Bil, and CEA were significantly higher in patients with Type 2 than in those with Type 1. Type 1 IPNB was more frequently located in the intrahepatic bile duct than Type 2, whereas Type 2 was more frequently located in the distal bile duct than Type 1 IPNB (P

Background Biliary decompression can reduce symptoms and improve quality of life in patients with malignant biliary obstruction. Endoscopically placed stents have become the standard of care for biliary drainage with the aim of improving hepatic function, relieving jaundice, and reducing adverse effects of obstruction. The purpose of this study was to evaluate the performance characteristics of a newly-designed, uncovered metal biliary stent for the palliation of malignant biliary obstruction. Methods This post-market, prospective study included patients with biliary obstruction due to a malignant neoplasm treated with a single-type, commercially available uncovered self-expanding metal stent (SEMS). Stents were placed as clinically indicated for palliation of jaundice and to potentially facilitate neo-adjuvant chemotherapy. The main outcome measure was freedom from recurrent biliary obstruction (within the stent) requiring re-intervention within 1, 3, and 6 months of stent insertion. Secondary outcome measures included device-related adverse events and technical success of stent deployment. Results SEMS were placed in 113 patients (73 men; mean age, 69); a single stent was inserted in 106 patients, and 2 stents were placed in 7 patients. Forty-eight patients survived and/or completed the 6 month study protocol. Freedom from symptomatic recurrent biliary obstruction requiring re-intervention was achieved in 108 of 113 patients (95.6, 95%CI = 90.0–98.6%) at study exit for each patient. Per interval analysis yielded the absence of recurrent biliary obstruction in 99.0% of patients at 1 month (n = 99; 95%CI = 97.0–100%), 96.6% of patients at 3 months (n = 77; 95%CI = 92.7–100%), and 93.3% of patients at 6 months (n = 48; 95%CI = 86.8–99.9%). In total, only 5 patients (4.4%) were considered failures of the primary endpoint. Most of these failures (4/5) were due to stent occlusion from tumor ingrowth or overgrowth. Overall technical success rate of stent deployment was 99.2%. There were 2 cases of stent-related adverse events (1.8%). There were no cases of post-procedure stent migration, stent-related perforation, or stent-related deaths. Conclusions This newly designed and marketed biliary SEMS system appears to be effective at relieving biliary obstruction and preventing re-intervention within 6 months of insertion in the overwhelming majority of patients. The device has an excellent safety profile, and associated high technical success rate during deployment. Trial registration The study was registered on clinicaltrials.gov on 14 October 2013 and the study registration number is NCT01962168. University of Massachusetts Medical School did not participate in the study.

BACKGROUND Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report median progression-free survival (PFS) less than 3 mo on second-line therapy. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum, though there is a paucity of data regarding its efficacy in this population. AIM To assess the efficacy of FOLFIRI in patients with biliary tract cancers. METHODS We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were collected on patient demographics, BTC subtype, response per RECIST v1.1, progression and survival. RESULTS Ninety-eight patients were included of which 74 (75%) had metastatic and 24 (25%) had locally advanced disease at the time of treatment with FOLFIRI. The median age was 60 (range, 22-86) years. The number of patients with extrahepatic cholangiocarcinoma, gall bladder cancer and intrahepatic cholangiocarcinoma were 10, 17 and 71, respectively. FOLFIRI was used as 1st, 2nd, 3rd or 4th – Nth lines in 8, 50, 36 and 4 patients, respectively. Median duration on FOLFIRI in the entire cohort was 2.2 (range, 0.5-8.4) mo. The median PFS and overall survival were 2.4 (95% confidence interval (CI): 1.7-3.1) and 6.6 (95%CI: 4.7-8.4) mo, respectively. Median PFS for patients treated with FOLFIRI in 1st, 2nd, 3rd or 4th – Nth lines were 3.1, 2.5, 2.3 and 1.5 mo, respectively. Eighteen patients received concurrent bevacizumab (n = 13) or EGFR-targeted therapy (n = 5) with FOLFIRI, with a median PFS of 2.7 mo (95%CI: 1.7-5.1). CONCLUSION In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI, efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.

Purpose This study was conducted to compare the outcome of three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for the postoperative treatment of biliary tract cancer. Materials and methods From February 2008 to June 2016, 57 patients of biliary tract cancer treated with curative surgery followed by postoperative 3D-CRT (n = 27) or IMRT (n = 30) were retrospectively enrolled. Results Median follow-up time was 23.6 months (range, 5.2 to 97.6 months) for all patients and 38.4 months (range, 27.0 to 89.2 months) for survivors. Two-year recurrence-free survival is higher in IMRT arm than 3D-CRT arm with a marginal significance (25.9% vs. 47.4%; p = 0.088). Locoregional recurrence-free survival (64.3% vs. 81.7%; p = 0.122) and distant metastasis-free survival (40.3% vs. 55.8%; p = 0.234) at two years did not show any statistical difference between two radiation modalities. In the multivariate analysis, extrahepatic cholangiocarcinoma, poorly-differentiated histologic grade, and higher stage were significant poor prognostic factors for survival. Severe treatment-related toxicity was not significantly different between two arms. Conclusion IMRT showed comparable results with 3D-CRT in terms of recurrence, and survival, and radiotherapy toxicity for the postoperative treatment of biliary tract cancer.

The combination of gemcitabine plus cisplatin (GP) is regarded as a first-line treatment for patients with unresectable or recurrent biliary tract cancer (BTC). Several proteins including human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (DCK), cytidine deaminase (CDA), and ribonucleotide reductase subunit 1 (RRM1) are known to be involved in gemcitabine uptake and metabolism. This study was aimed to identify the predictive and prognostic values of these biomarkers in patients who treated with GP for advanced BTC. Tumor samples were obtained from 34 patients with unresectable or recurrent BTC who were treated with GP between August 2015 and February 2018. Intratumoral expression of hENT1, DCK, CDA and RRM1 was determined by immunohistochemistry and analyzed for association with chemotherapy response, progression-free survival (PFS) and overall survival (OS). Median OS was significantly longer in the RRM1-negative group than in the RRM1-positive (9.9 months vs. 5.9 months, p = 0.037). Multivariate adjustment analyses also demonstrated RRM1 expression as an independent prognostic factor for OS in patients treated with GP chemotherapy. Increased intratumoral expression of RRM1 on immunohistochemical staining may be a biomarker predicting poor survival in patients with GP chemotherapy for advanced BTC. Large-scale well-predefined prospective research is needed to validate the utility of biomarkers in clinical practice.

Background Biliary tract cancers (BTCs) are rare and highly heterogenous malignant neoplasms. Because obtaining BTC tissues is challenging, the purpose of this study was to explore the potential roles of bile as a liquid biopsy medium in patients with BTC. Patients and methods Sixty-nine consecutive patients with suspected BTC were prospectively enrolled in this study. Capture-based targeted sequencing was performed on tumor tissues, whole blood cells, plasma, and bile samples using a large panel consisting of 520 cancer-related genes. Results Of the 28 patients enrolled in this cohort, tumor tissues were available in eight patients, and plasma and bile were available in 28 patients. Somatic mutations were detected in 100% (8/8), 71.4% (20/28), and 53.6% (15/28) of samples comprising tumor tissue DNA, bile cell-free DNA (cfDNA), and plasma cfDNA, respectively. Bile cfDNA showed a significantly higher maximum allele frequency than plasma cfDNA (P = 0.0032). There were 56.2% of somatic single-nucleotide variant (SNVs)/insertions and deletions (indels) shared between bile and plasma cfDNA. When considering the genetic profiles of tumor tissues as the gold standard, the by-variant sensitivity and positive predictive value for SNVs/indels in bile cfDNA positive for somatic mutations were both 95.5%. The overall concordance for SNVs/indels in bile was significantly higher than that in plasma (99.1% versus 78.3%, P < 0.0001). Moreover, the sensitivity of CA 19-9 combined with bile cfDNA achieved 96.4% in BTC diagnosis. Conclusion We demonstrated that bile cfDNA was superior to plasma cfDNA in the detection of tumor-related genomic alterations. Bile cfDNA as a minimally invasive liquid biopsy medium might be a supplemental approach to confirm BTC diagnosis., Highlights • This is the first study to compare somatic mutation profiling in tumor tissues, bile and plasma samples in BTC patients. • Our findings demonstrated that bile cfDNA outperformed plasma cfDNA in detecting somatic mutations. • Bile cfDNA might be a feasible liquid biopsy medium for BTC diagnosis.

Background Abnormal activation of the coagulation system has been reported in patients with malignancies, but its prognostic significance in biliary tract cancer (BTC) remains unclear. This study aims to analyze and compare the prognostic value of coagulation indices in patients with BTC. Methods The medical records of 450 patients with BTC who underwent surgical resection at our hospital between 2003 and 2017 were retrospectively analyzed. Time-dependent receiver operating characteristic curves were plotted to compare the predictive accuracy of coagulation indices. A predictive nomogram for overall survival (OS) was established based on the Cox regression analysis and validated in both the training and validation cohorts. A novel stratification model was created according to the total points of the nomogram. Results Fibrinogen and international normalized ratio (INR) had the best predictive accuracy among the coagulation indices considered and were also the independent prognostic factors for OS. The nomogram and the novel stratification model had satisfactory performance and outperformed TNM staging. Conclusions The study demonstrated that coagulation indices are valuable in predicting OS in BTC, with fibrinogen and INR having the best predictive ability. The nomogram and the novel stratification model could be applied to predict survival for patients with BTC.

Purpose: To compare different percutaneous approaches to manage occluded primary uncovered self-expandable metal stents (SEMS) in patients with unresectable malignant hilar biliary obstruct...

Introduction Chemotherapy is the mainstay of systemic treatment of biliary tract cancer (BTC). However, the treatment response to chemotherapy varies between patients. Currently, no prognostic biomarkers for chemotherapy efficacy have been considered for use in clinical practice. A systematic review was conducted to evaluate the prognostic value of immunohistochemical biomarkers for chemotherapy in patients with resected as well as with advanced BTC. Method Medline and EMBASE databases were searched up to March 2017 for studies that evaluated biomarker expression by immunohistochemistry in resected or advanced BTC patients treated with chemotherapy. The primary endpoints were overall survival (OS) and disease or progression free survival (DFS or PFS). Result Twenty-six studies, including a total of 1348 patients and 26 different biomarkers, met the inclusion criteria and were included in this review. The most frequently studied prognostic biomarkers in BTC were the human Equilibrative Nucleoside Transporter 1 (hENT1), Ribonucleotide Reductase M1 (RRM1), and excision repair cross-complementation 1 (ERCC1). In the meta-analysis of patients treated with gemcitabine-based chemotherapy, high hENT1 expression was associated with longer OS (HR 0.43, 95% CI: 0.28 to 0.64) and DFS/PFS (HR 0.45, 95% CI: 0.33 to 0.61). Conclusion hENT1 is a promising prognostic biomarker for gemcitabine-based chemotherapy in resected as well as in advanced BTC and should be further validated for the selection of patients for chemotherapy.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. Significance: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Purpose Gemcitabine plus cisplatin (GemCis) is the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). In ABC-02 study, the BTC patients received up to 6-8 cycles of 3-weekly GemCis; however, those without progression often receive more than 6-8 cycles. The clinical benefit of maintenance treatment in patients without progression is uncertain. Materials and methods Advanced BTC patients treated with GemCis between April 2010 and February 2015 at Asan Medical Center, Seoul, Korea, were retrospectively analysed. The patients without progression after 6-8 cycles were stratified according to further treatment i.e., with or without further cycles of GemCis (maintenance vs. observation groups). The primary endpoint was overall survival (OS) and progression-free survival (PFS). Results Among the 740 BTC patients in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group, 120 in the maintenance group). The median OS from the GemCis initiation was 20.5 months (95% confidence interval [CI], 15.4 to 25.6) and 22.4 months (95% CI, 17.0 to 27.8) in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months (95% CI, 7.0 to 13.8) and 13.2 months (95% CI, 11.3 to 15.2), respectively (p=0.320). Conclusions GemCis maintenance is not associated with an improved survival outcome.

Background/Aims Metallic stents designed to relieve malignant biliary obstruction are susceptible to occlusive tumor ingrowth or overgrowth. In a previous report, we described metallic stents covered with paclitaxel-incorporated membrane (MSCPM-I, II) to prevent occlusion from tumor ingrowth via antitumor effect. This new generation paclitaxel-eluting biliary stent is further endowed with sodium caprate (MSCPM-III) for enhanced drug delivery. The purpose of this study is to examine the safety of its drug delivery system in the porcine biliary tract. Methods MSCPM-III (10% [wt/vol] paclitaxel) and covered metal stents (CMSs) were endoscopically inserted in porcine bile ducts in vivo. Histologic biliary changes, levels of paclitaxel released, and various serum analytes (albumin, alkaline phosphate, aspartate transaminase, alanine transaminase, total protein, total bilirubin, and direct bilirubin) were assessed. Results Based on the intensity of reactive inflammation and fibrosis, changes in porcine biliary epithelium secondary to implanted MSCPM-III were deemed acceptable (i.e., safe). Histologic features in the MSCPM-III and CMS groups did not differ significantly. In a related serum analysis, paclitaxel release from MSCPM-III stents was below the limit of detection for 28 days. Biochemical analyses were also similar for the two groups, and no evidence of hepatic or renal toxicity was found in animals receiving MSCPM-III stents. Conclusions In a prototypic porcine trial, this newly devised metal biliary stent incorporating both paclitaxel and sodium caprate appears to be safe in the porcine bile duct.

Highlight Sawada and colleagues report a case of mucinous cholangiocarcinoma not originating from intraductal papillary neoplasm of the bile duct. While recognizing the imaging features of the bile ducts is difficult due to their narrow area, the detailed characteristic features may enable preoperative diagnosis of this rare type of cholangiocarcinoma.

Objective To evaluate the efficacy and safety of stent placement combined with intraluminal radiofrequency ablation (intra-RFA) and hepatic arterial infusion chemotherapy (HAIC) for patients with advanced biliary tract cancers (Ad-BTCs) and biliary obstruction (BO). Methods We retrospectively reviewed data for patients with Ad-BTCs and BO who underwent stent placement with or without intra-RFA and HAIC in three centres between November 2013 and November 2018. The stent patency time (SPT), overall survival (OS), and adverse events (AEs) were analysed. Results Of the 135 enrolled patients, 64 underwent stent placement combined with intra-RFA and HAIC, while 71 underwent only stent placement. The median SPT was significantly longer in the combination group (8.2 months, 95% confidence interval [CI]: 7.1–9.3) than in the control group (4.3 months, 95% CI: 3.6–5.0; p < 0.001). A similar result was observed for OS (combination: 13.2 months, 95% CI: 11.1–16.5; control: 8.5 months, 95% CI: 7.6–9.6; p < 0.001). The incidence of AEs related to biliary tract operation was not significantly different between the two groups (p > 0.05). The most common AE and serious AE related to HAIC were alanine aminotransferase elevation (24/64; 37.5%) and thrombocytopenia (8/64; 12.5%), respectively. All AEs were tolerable, and there was no death from AEs. Conclusions Stent placement combined with intra-RFA and HAIC may be a safe, potential treatment strategy for patients with Ad-BTCs and BO. Key Points • Advanced biliary cancers (Ad-BTCs) with biliary obstruction (BO) can rapidly result in liver failure and cachexia with an extremely poor prognosis. • Stent placement combined with intraluminal radiofrequency ablation and hepatic arterial infusion chemotherapy may be safe and effective for patients with Ad-BTCs and BO. • The long-term efficacy and safety of the combined treatment is promising.

BACKGROUND Endoscopic drainage remains the treatment of choice for unresectable or inoperable malignant distal biliary obstruction (MDBO). AIM To compare the safety and efficacy of plastic stent (PS) vs self-expanding metal stent (SEMS) placement for treatment of MDBO. METHODS This meta-analysis was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A comprehensive search was performed in MEDLINE, Cochrane, Embase, Latin American and Caribbean Health Sciences Literature, and grey literature to identify randomized clinical trials (RCTs) comparing clinical success, adverse events, stent dysfunction rate, reintervention rate, duration of stent patency, and mean survival. Risk difference (RD) and mean difference (MD) were calculated and heterogeneity was assessed with I2 statistic. Subgroup analyses were performed by SEMS type. RESULTS Twelve RCTs were included in this study, totaling 1005 patients. There was no difference in clinical success (RD = -0.03, 95% confidence interval [CI]: -0.01, 0.07; I2 = 0%), rate of adverse events (RD = -0.03, 95%CI: -0.10, 0.03; I2 = 57%), and mean patient survival (MD = -0.63, 95%CI: -18.07, 19.33; I2 = 54%) between SEMS vs PS placement. However, SEMS placement was associated with a lower rate of reintervention (RD = -0.34, 95%CI: -0.46, -0.22; I2 = 57%) and longer duration of stent patency (MD = 125.77 d, 95%CI: 77.5, 174.01). Subgroup analyses revealed both covered and uncovered SEMS improved stent patency compared to PS (RD = 152.25, 95%CI: 37.42, 267.07; I2 = 98% and RD = 101.5, 95%CI: 38.91, 164.09; I2 = 98%; respectively). Stent dysfunction was higher in the covered SEMS group (RD = -0.21, 95%CI: -0.32, -0.1; I² = 205%), with no difference in the uncovered SEMS group (RD = -0.08, 95%CI: -0.56, 0.39; I² = 87%). CONCLUSION While both stent types possessed a similar clinical success rate, complication rate, and patient-associated mean survival for treatment of MDBO, SEMS were associated with a longer duration of stent patency compared to PS.

Patient: Female, 71-year-old Final Diagnosis: Hepatic epithelioid angiomyolipoma Symptoms: Abdominal pain Medication:— Clinical Procedure: — Specialty: Pathology • Surgery Objective: Rare disease Background: The World Health Organization classification of premalignant gallbladder lesions includes adenomas, intraductal papillary neoplasms, biliary intraepithelial neoplasia, and intracystic papillary neoplasms. Noninvasive neo-plastic lesions >1 cm that originate from the pancreatobiliary system are defined as intraductal papillary neoplasia when they occur in the biliary ducts. The clinical and pathological features of preinvasive lesions arising in the gallbladder are not yet well defined. However, the most widely accepted classification is that of intracholecystic papillary neoplasm (ICPN). Case Report: We present the case of a 71-year-old woman referred to a General Surgery outpatient clinic for suspicious findings on imaging of the gallbladder, namely irregular infundibular parietal thickening. The patient underwent a laparoscopic cholecystectomy and histological examination revealed a thickened gallbladder with mucosa partially surrounded by ICPN with an intestinal pattern and some foci of low-grade dysplasia but no foci of high-grade dysplasia or invasive neoplasia. At follow-up at 30 months, the patient remains clinically well, with no changes visible on computed tomography scan. Conclusions: ICPN of the gallbladder appears to be part of a spectrum of alterations encompassing bile duct or pancreatic lesions. Although it is uncommon, more than half of the lesions are known to have foci of invasive neoplasia at the time of diagnosis. Despite that, the prognosis for these neoplasms is more favorable than for gallbladder neoplasia that originates from another type of lesion. Pathological study of ICPN is essential to define the main characteristics that impact prognosis and survival in these patients.

BACKGROUND Biliary drainage, either by the stent-in-stent (SIS) or side-by-side (SBS) technique, is often required when treating a malignant hilar biliary obstruction (MHBO). Both methods differ from each other and have distinct advantages. AIM To compare both techniques regarding their efficacy and safety in achieving drainage of MHBO. METHODS A comprehensive search of multiple electronic databases (MEDLINE, Embase, LILACS, BIREME, Cochrane) was conducted and grey literature from their inception until December 2020 with no restrictions regarding the year of publication or language, since there was at least an abstract in English. The included studies compared SIS and SBS techniques through endoscopic retrograde cholangiopancreatography. Outcomes analyzed included technical and clinical success, early and late adverse events (AEs), stent patency, reintervention, and procedure-related mortality. RESULTS Four cohort studies and one randomized controlled trial evaluating a total of 250 patients (127 in the SIS group and 123 in the SBS group) were included in this study. There were no statistically significant differences between the two groups concerning the evaluated outcomes, except for stent patency, which was higher in the SIS compared with the SBS technique [mean difference (d) = 33.31; 95% confidence interval: 9.73 to 56.90, I2 = 45%, P = 0.006]. CONCLUSION The SIS method showed superior stent patency when compared to SBS for achieving bilateral drainage in MHBO. Both techniques are equivalent in terms of technical success, clinical success, rates of both early and late AEs, reintervention, and procedure-related mortality.

Background: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. Methods: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. Results: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p

Biliary tract intraductal papillary mucinous neoplasms (BT-IPMN) are a rare entity that develop within the bile duct lumen and are recognized as a precursor of invasive carcinoma in up to 40-80 % of cases.

Importance Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. Objective To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. Design, Setting, and Participants The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. Interventions Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. Main Outcomes and Measures The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. Results Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events. Conclusions and Relevance This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response. Trial Registration ClinicalTrials.gov Identifier:NCT02923934

European radiology 31(5), 3035-3041 (2021). doi:10.1007/s00330-020-07368-6, Published by Springer, Berlin