Carcinoma Of Extrahepatic Biliary Tract Research Articles

Tislelizumab in combination with GEMOX and lenvatinib for conversion therapy of unresectable extrahepatic biliary tract carcinoma (eBTC): A prospective, single-arm, phase 2 study.

e16163 Background: Resection is the only possibility for cure but only less than 1/3 patients with BTC are diagnosed at resectable stages. PD-1 monoclonal antibody plus GEMOX and Lenvatinib regimens have shown promising efficacy for intrahepatic cholangiocarcinoma. However, owing to the extrahepatic and intrahepatic BTC are highly heterogeneous, the efficacy of combination regimen on eBTC is not clear. In this study, we explored the efficacy and safety of Tislelizumab plus GEMOX and Lenvatinib for conversion therapy of unresectable eBTC. Methods: In this prospective, single-arm phase 2 study, major eligible criteria were unresectable locally advanced or metastatic extrahepatic BTC, no previous systemic treatment, ECOG PS 0 or 1. Patients received tislelizumab (200 mg, iv, d1, every 3 weeks) in combination with GEMOX (gemcitabine: 1000 mg/m2, iv, d1,d8, every 3 weeks; oxaliplatin: 85 mg/m2, iv, d1, every 3 weeks) and Lenvatinib (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day, po) until disease progression, intolerable toxicity or surgery. Surgery was performed after treatment response was assessed to meet the criteria of resection. Primary endpoint was the rate of radical resection. Second endpoints included ORR, DCR per RECIST 1.1, and safety, major pathologic response (MPR), PFS, OS. Results: Between Mar 1st 2022 and Feb 1st 2024, 35 patients were enrolled with a median age of 57.5 years (range 52-65); 20 males (57.1%), 15 females (42.9%); ECOG PS 0 (n = 13, 37.1%) or 1 (n = 17, 62.9%); 7 distal cholangiocarcinoma (20.0%), 16 hilar cholangiocarcinoma (45.7%), 12 gallbladder carcinoma (34.3%). 30 patients were evaluated for tumor response. The best overall responses were 2 complete response (6.7%), 16 partial response (53.3%), 9 stable disease (30.0%) and 3 progressive disease (10.0%). The ORR was 60.0% and DCR was 90.0%. 7 patients (20.0%) received radical resection and the complete pathological response (pCR) rate was 42.9% (n = 3). Any-grade adverse events (AEs) occurred in 91.4% (n = 32) patients. Grade 3-4 AEs occurred in 20.0% (n = 7) patients. The most frequent grade 3-4 AEs (incidence > 5%) were thrombocytopenia (8.6%), elevated AST/ALT (8.6%), neutropenia (5.7%) and leukopenia (5.7%). No grade 5 AEs. Conclusions: Tislelizumab plus GEMOX and Lenvatinib showed promising efficacy with manageable safety profile for conversion therapy of unresectable extrahepatic BTC. More patients were recruiting to further prove these results. Clinical trial information: ChiCTR2200056808.

Establishment and drug screening of patient-derived extrahepatic biliary tract carcinoma organoids

BackgroundPatient-derived organoids (PDO) have been proposed as a novel in vitro method of drug screening for different types of cancer. However, to date, extrahepatic biliary tract carcinoma (eBTC) PDOs have not yet been fully established.MethodsWe collected six samples of gallbladder carcinoma (GBC) and one sample of extrahepatic cholangiocarcinoma (eCCA) from seven patients to attempt to establish eBTC PDOs for drug screening. We successfully established five GBC and one eCCA PDOs. Histological staining was used to compare structural features between the original tissues and cancer PDOs. Whole exome sequencing (WES) was performed to analyze the genetic profiles of original tissues and cancer PDOs. Drug screening, including gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, infigratinib, and ivosidenib, was measured and verified by clinical effects in certain cases.ResultsDifferent PDOs exhibited diverse growth rates during in vitro culture. Hematoxylin and eosin staining demonstrated that the structures of most cancer PDOs retained the original structures of adenocarcinoma. Immunohistological and periodic acid-schiff staining revealed that marker expression in cancer PDOs was similar to that of the original specimens. Genetic profiles from the four original specimens, as well as paired cancer PDOs, were analyzed using whole exome sequencing. Three of the four PDOs exhibited a high degree of similarity when compared to the original specimens, except for GBC2 PDO, which only had a concordance of 74% in the proportion of single nucleotide polymorphisms in the coding sequence. In general, gemcitabine was found to be the most efficient drug for eBTC treatment, as it showed moderate or significant inhibitory impact on cancer growth. Results from drug screening were confirmed to a certain extent by three clinical cases.ConclusionsOur study successfully established a series of eBTC PDOs, which contributed to the field of eBTC PDOs. Additional enhancements should be explored to improve the growth rate of PDOs and to preserve their immune microenvironment.

Evaluation of Bile Ductal Brushing Cytology in Diagnosis of Extrahepatic Biliary Tract and Pancreatic Ductal Carcinoma

Evaluation of Bile Ductal Brushing Cytology in Diagnosis of Extrahepatic Biliary Tract and Pancreatic Ductal Carcinoma

Occupational exposure to pesticides and bile tract carcinoma in men: results from a European multicenter case–control study

To estimate the associations between occupational exposure to pesticides and extrahepatic biliary tract carcinoma in men, a population-based case-control study was carried out. Cases (n = 104), aged 35-70, diagnosed in 1995-1997, were sampled by active reporting systems from hospitals. Controls (n = 1,401) were a random sample of the general male population. Information on occupation and confounding factors was obtained by questionnaires. Exposures were quantified with respect to time, application methods, and use of personal protective equipment. Intensity was evaluated by using a published algorithm which weighted the exposure assigned according to the use of personal protective equipment and mode of application. Logistic regression analyses were conducted adjusted for gallstones, age, and country. Being ever exposed to pesticides resulted in an odds ratio (OR) of 1.0 [95%-confidence interval (CI) 0.6-1.6]. A modestly elevated risk was found for backpack mounted sprayers OR = 1.4 [95% CI 0.7-2.6] and vine farmers OR = 2.5 [95% CI 0.9-7.2]. Using time periods and exposure frequency as intensity measure, no elevated risks were found. The only exception was year of maximum exposure which yielded an OR of 1.6 [95% CI 0.7-3.5]. However, no clear trend was observed in this analysis. This study does not rule out that pesticide exposure represents an occupational risk factor for extrahepatic biliary tract carcinoma, but no indication of a strong association was observed. Some modes of exposure were weakly, albeit not significantly associated with carcinoma risk. The observed estimates of effects may be influenced by a lack of precise exposure assessment. Different chemical compositions of pesticides were utilized during a long time span of pesticide exposure, and it should be considered that the exposure is assessed with substantial uncertainty that could non-differential and bias results toward the null.

Survivin and Smac Expression in Extrahepatic Biliary Tract Carcinoma

Objective To investigate the expression of Survivin and Smac and evaluate whether Survivin and Smac protein play a role in the progression from normal epithelium to dysplasia to carcinoma of extrahepatic biliary tract. Methods The expressions of Survivin and Smac were examined immunohistochemically in 27 specimens surgically removed extrahepatic biliary tract carcinoma, ten cases of dysplasia lesions and 5 cases of normal epithelial tissues.Results Survivin protein expression was found in 20 of 27 (74.1%) invasive carcinoma, 5 of 10 (50%) dysplasia lesions and 1 of 5 (20%) normal epithelium. The difference of Survivin expression between invasive carcinoma and normal epithelium was significant (P=0.037). For Smac protein expression, positive rate of expression was 23/27(85.2%) in invasive carcinoma, 5/10 (50%) in dysplasia lesions and 2/5(40%) in normal epithelium. The difference of Smac expression between dysplasia lesions and invasive carcinoma was significant (P=0.041). There was no significance between Survivin expression and histopathological features or clinical stages in invasive carcinoma, neither was Smac. Conclusion The increased tendency of Survivin and Smac expression in dysplasia-carcinoma sequence of extrahepatic biliary tract indicates Survivin and Smac may be involved in neoplastic development.

Purpose, use, and preparation of clinical practice guidelines for the management of biliary tract and ampullary carcinomas

Apart from periampullary carcinoma, the prognosis of biliary tract carcinomas, including hilar cholangiocarcinoma, extrahepatic biliary tract carcinoma, and gallbladder carcinoma, remains poor. Sophisticated diagnostic skills and treatment methods and their application are naturally required to achieve better treatment results for biliary tract carcinomas. However, it is not too much to say that, due to the paucity of high-level evidence for the management of these carcinomas, medical care by healthcare providers in clinics and at medical institutes throughout the world is currently delivered without common consensus and common standards. The clinical practice guidelines for the management of biliary carcinoma outlined here were produced with the aim that they could be used by physicians involved in the care of biliary tract carcinomas, as indicators that could help them provide their patients with the most appropriate care possible at this time. Also, the guidelines were prepared to provide measures that could assure patients with biliary tract carcinomas of safe medical care. The present guidelines are characterized by their clarification of clinical questions assumed to be often shared by healthcare professionals. For clarity, we divided the contents of the guidelines into eight areas. In each area, clinical questions are presented, together with recommendations of clinical actions in response to the question. As mentioned already, there is a paucity of high-level evidence in this area; therefore, the recommendations are classified into grades, of which there are five: A, strongly recommend performing the clinical action; B, recommend performing the clinical action; C1, the clinical action may be useful, although there is a lack of high-level scientific evidence; C2, clinical action not definitively recommended ecause of insufficient scientific evidence; D, recommend not performing the clinical action. The grading of the recommendations is based on the determination of the level of evidence in references on which the recommendation is based.

Risk factors for extrahepatic biliary tract carcinoma in men: medical conditions and lifestyle

To identify risk factors of carcinoma of the extrahepatic biliary tract in men. Newly diagnosed and histologically confirmed patients, 35-70 years old, were interviewed between 1995 and 1997 in Denmark, Sweden, France, Germany and Italy. Population controls were frequency-matched by age and region. Adjusted odds ratios and 95%-confidence intervals were estimated by logistic regression. The analysis included 153 patients and 1421 controls. The participation proportion was 71% for patients and 61% for controls. Gallstone disease was corroborated as a risk factor for extrahepatic biliary tract carcinoma in men (odds ratio 2.49; 95% confidence interval 1.32-4.70), particularly for gall bladder tumors (odds ratio 4.68; 95% confidence interval 1.85-11.84). For a body mass index [height (m) divided by squared weight (kg2)] >30 at age 35 years, an excess risk was observed (odds ratio 2.58; 95% confidence interval 1.07-6.23, reference: body mass index 18.5-25) that was even stronger if the body mass index was >30 for the lowest weight in adulthood (odds ratio 4.68; 95% confidence interval 1.13-19.40). Infection of the gall bladder, chronic inflammatory bowel disease, hepatitis or smoking showed no clear association, whereas some increase in risk was suggested for consumption of 40-80 g alcohol per day and more. Our study corroborates gallstones as a risk indicator in extrahepatic biliary tract carcinoma. Permanent overweight and obesity in adult life was identified as a strong risk factor for extrahepatic biliary tract carcinoma, whereas we did not find any strong lifestyle-associated risk factors. Inconsistent results across studies concerning the association of extrahepatic biliary tract carcinoma with overweight and obesity may be explained by the different approaches to assess this variable.

Frequent activation of mitogen-activated protein kinase relative to Akt in extrahepatic biliary tract cancer

Lack of effective adjuvant therapy against advanced extrahepatic biliary tract carcinoma (BTC) requires that new therapeutic methods, such as molecular targeted therapy, be developed. The mitogen-activated protein kinase (MAPK) and Akt signaling pathways, which activate cell proliferation and suppress apoptosis, respectively, may function as important targets for such therapies. The aim of this study was to examine the expression patterns of phosphorylated MAPK (p-MAPK) and phosphorylated Akt (p-Akt) proteins in BTC cell lines and clinical specimens. Expression of p-MAPK and p-Akt proteins in four human BTC cell lines and in frozen sections of 20 advanced extrahepatic BTC specimens was analyzed by Western blotting. Thirty formalin-fixed BTC specimens were immunohistochemically stained for p-MAPK and p-Akt using labeled streptavidin-biotin conjugates. Expression of p-MAPK was observed in three of four (75%) BTC cell lines, whereas no expression of p-Akt was observed. Twenty-three of 30 formalin-fixed specimens stained positive for p-MAPK (77%), whereas only 47% stained positively for p-Akt. Expression of p-MAPK relative to that of p-Akt was also seen more frequently in the frozen specimens. The results of this study suggest that MAPK is activated more frequently than Akt in extrahepatic biliary tract carcinoma.

P16 expression as prognostic indicater in extrahepatic biliary tract carcinoma

P16 expression as prognostic indicater in extrahepatic biliary tract carcinoma

Expression of Bcl-2 and Bax in extrahepatic biliary tract carcinoma and dysplasia.

To compare the difference of expression of Bcl-2 and Bax in extrahepatic biliary tract carcinoma and dysplasia, and to analyze the role of Bcl-2 and Bax proteins in the progression from dysplasia to carcinoma and to evaluate the correlation of Bcl-2/Bax protein expression with the biological behaviors. Expressions of Bcl-2 and Bax were examined immunohistochemically in 27 cases of extrahepatic biliary tract carcinomas (bile duct carcinoma: n=21, carcinoma of ampulla of Vater: n=6), and 10 cases of atypical dysplasia. Five cases of normal biliary epithelial tissues were used as controls. A semiquantitative scoring system was used to assess the Bcl-2 and Bax reactivity. The expression of Bcl-2 was observed in 10 out of 27 (37.0%) invasive carcinomas, 1 out of 10 dysplasias, none out of 5 normal epithelial tissues. Bax expression rate was 74.1% (20/27) in invasive carcinoma, 30% (3/10) in dysplasia, and 40% (2/5) in normal biliary epithelium. Bcl-2 and Bax activities were more intense in carcinoma than in dysplasia, with no significant difference in Bcl-2 expression (P=0.110), and significant difference in Bax expression (P=0.038). Level of Bax expression was higher in invasive carcinoma than in dysplasia and normal tissue (P=0.012). Bcl-2 expression was correlated to Bax expression (P=0.0059). However, Bcl-2/Bax expression had no correlation with histological subtype, grade of differentiation, or level of invasion. Increased Bcl-2/Bax expression from dysplasia to invasive tumors supports the view that this is the usual route for the development of extrahepatic biliary tract carcinoma. Bcl-2/Bax may be involved, at least in part, in the apoptotic activity in extrahepatic biliary carcinoma.

Clinical significance of hepatocyte growth factor and c-Met expression in extrahepatic biliary tract cancers.

Hepatocyte growth factor (HGF)/c-Met expression is known to be correlated with poor prognosis in several cancers. We investigated HGF/c-Met immunoreactivity and its correlation with clinical features in 51 patients with curatively resected extrahepatic biliary tract carcinoma. c-Met showed significant correlations with tumor location, T category, stage, perineural invasion and local recurrence. Overall survival in patients with HGF and c-Met immunopositivity was significantly worse than in those who were negative. Our findings suggest that HGF/c-Met play some roles in tumor development and that HGF/c-Met immunoreactivity could be a predictor of the mode of recurrence and poor prognosis.

A STUDY OF THE RESECTION AND RECONSTRUCTION OF ARTERIES IN PATIENTS WITH PANCREATIC CANCER OR EXTRAHEPATIC BILIARY TRACT CARCINOMA

The results of microsurgery carried out during associated arterial resection with reconstruction in cases of progressive pancreatic and biliary tract cancer accompanyning by infiltration into the hepatic or superior mesenteric artery were investigated. The significance and problem in performing this procedure are briefly discussed. Of 10 patients subjected to this study, 6 patients had pancreatic carcinoma and 4, biliary tract cancer. Portal vein resection was performed in 6 cases. In 7 cases, in which postoperative blood circulation of the reconstructed artery was checked by arteriography, excellent patency was confirmed. Six patients had postoperative complications and 4 of the 6 died postoperatively resulting from complications accompanied with reconstruction of the hepatic artery. The longest postoperative survival period was 11 months in patients with pancresatic carcinoma and 14 months in cholangiocarcinoma. Microsurgery-applying associated arterial resection with reconstruction improved the rate of postoperative patency of arteries, however, it could not contribute to improve the surgical outcome in patients with pancreatic or extrahepatic biliary tract carcinoma.

Primary and adjuvant radiation therapy in gallbladder and extrahepatic biliary tract carcinoma.

The natural history and pathways by which carcinomas of the gallbladder and extrahepatic bile ducts spread after attempted curative surgery offer a rationale for postoperative radiation therapy. We review: 1) the increasing use of primary-curative radiation therapy for these cancers, along with 2) the early results of innovative intraoperative irradiation and the transluminal insertion of radioactive sources into transhepatic catheters, 3) the efficacy of irradiation for metastases to the portahepatis, and 4) the overall effects of irradiation on the gallbladder and extrahepatic biliary system.

Patterns of failure after curative surgery for extra-hepatic biliary tract carcinoma: Implications for adjuvant therapy

Curative resection was accomplished in 28 of 82 patients with biopsy-proven carcinoma of the extra-bepstic bile ducts, gallbladder, and ampulla of Vater seen initially at the Massachusetts General Hospital from 1962 through 1978. None of the 28 had adjuvant radiation therapy nor chemotherapy. Later evidence of cancer (failure) was found in 16 of 25 patients who were post-op survivors. Local-regional recurrence ± distant metastases (documented at re-exploration, autopsy, or clinically) occurred in 13 16 , and only 3 developed distant disease only. Local-regional failure rates varied with anatomic location: 4 10 ampulla of Vater, 7 11 gallbladder, 1 3 common bile duct, land 1 1 hepatic duct (“Klatskin”) The time to local-regional recurrence ranged from 2 to 100 months post-operatively with a median of 17 months. Only 5 patients of the 28 are presently alive NED. The prognostic significance of tumor grade, lymph node involvement, perineural-lymphatic-venous invasion, and extension through the waq relative to patterns of failure are presented, and the implications for adjuvant therapy are discussed.

Patterns of failure after curative surgery for extra-hepatic biliary tract carcinoma

Patterns of failure after curative surgery for extra-hepatic biliary tract carcinoma

An appraisal of the pathogenesis of primary carcinoma of the extrahepatic biliary tract.

An appraisal of the pathogenesis of primary carcinoma of the extrahepatic biliary tract.