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PubMed2026

Ex Vivo Tumor-Derived Organoid Pharmacotyping Identifies Personalized Therapeutic Options for Patients with Biliary Tract Cancer.

UNLABELLED: Biliary tract cancers (BTC) pose clinical challenges due to poor chemotherapy response and aggressive disease course. We evaluated patient-derived tumor organoid-based drug sensitivity testing as a tool to guide therapy. In this multicenter study, 26 tumor organoids were successfully derived from 43 patients with BTC and tested with an average of 50 cancer-directed therapies using the Clinical Laboratory Improvement Amendments-certified PARIS assay. Despite most organoids being from late-stage disease, 24/26 (92.3%) exhibited strong sensitivity to one or more targeted agents. Active drugs included inhibitors of EGFR/HER2, MEK, ERK, BCR-ABL and SRC family, mTOR, PI3K, MDM2, BCL2, and BET. Drug sensitivities aligned with known genetic biomarkers but were also observed in cultures lacking them, indicating ex vivo testing can expand actionability beyond genomics. In five cases, results guided therapy; one patient with an FGFR-BICC1 fusion refractory to FGFR inhibitors responded to dasatinib, achieving symptomatic improvement, stable disease, and >8-month survival. SIGNIFICANCE: Ex vivo drug testing of tumor-derived organoids is clinically feasible and can be used to identify personalized treatment options for patients with BTC, to evaluate the functional relevance of genomic biomarkers, and to guide treatment in real time.

Humans↗
PubMedDate not supplied

[Relation of pathoanatomic substrate and incidence of bacterial infection in the acute biliary tract disease].

Acute biliary diseases have become the most common indication for major abdominal surgery. We investigated 60 patients who underwent surgery for the acute biliary diseases, within 48 hours from the onset of the illness (group I), and over longer preoperative interval (48 h up to 5 days) (group II). Surgical specimen (gallbladder) was histologically examined. Samples for microbiological exams were obtained from gallbladder, common bile duct, Lund's node, gallbladder bed and peritoneal cavity. Positive bile cultures were found in 43% of group I, and in 70% of group II (p<0.05). Microbiological analysis revealed 13 different species, mostly Gram negative aerobic rods (69%). The incidence of bacteriobilia was in correlation with HP of lesions (79% in the acute and 18% in chronic lesions; p<0.01), what testified the importance of time interval and role of bacterial factor in the acute biliary pathology. Septic complications strictly occurred in patients with positive biliary findings. Early surgical treatment eliminates focus, and stops further development of intraabdominal and systemic septic complications. Correlation between bacteriobilia and septic sequelae calls for prophylactic use of antibiotics.

Acute Disease↗
PubMed2002

The role of microorganisms in biliary tract disease.

The biliary tract is normally sterile, but bile-tolerant bacteria are frequently isolated from patients with cholecystitis. Since the identification of about 25 Helicobacter species, some of which may grow in bile, studies have addressed the role of these organisms in primary biliary cirrhosis, primary sclerosing cholangitis, and cholelithiasis. Most of these bacteria show the presence of Helicobacter DNA or antigens in the bile tract and in liver samples. Altogether, data from studies on biliary and hepatic diseases, as well as pancreatic disorders, suggest that bile-tolerant Helicobacter species may induce a chronic infection with possible malignant transformation.

Animals↗
PubMed2000

Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas.

Adenocarcinomas of the pancreas and biliary tract are highly malignant neoplasms, which are found in the advanced stage. Chemotherapy commonly plays a palliative role in the treatment of pancreatic and biliary tract cancers. 5-Fluorouracil (5-FU) is the most widely studied single agent; the response rate of 5-FU is only 20%. Recently, some reports presented interesting results, in which 5-FU, modulated with levofolinic acid (leucovorin), was active in patients with colorectal cancer. In relation, we performed a phase II study of 5-FU, modulated with leucovorin, in patients affected by advanced pancreatic or biliary tract cancer. Fifty-one patients with nonresectable carcinomas of the pancreas or biliary tract admitted to Korea University Hospital between May 1995 and December 1998 were included in this study. Chemotherapy consisted of leucovorin 25 mg/m2/day by 2-hour intravenous infusion, followed by 5-FU 375 mg/m2/day by bolus intravenous infusion, from day I to day 5. The treatment was repeated every 3 to 4 weeks. A total of 51 eligible patients with advanced adenocarcinoma of the pancreas or biliary tract were enrolled. Of 23 enrolled patients with pancreatic adenocarcinoma, one patient showed complete remission with a survival duration of 13 months (response duration was 9 months). Three patients had partial responses (PRs) with survival times of 6, 12, and 15 months, respectively. The overall response rate was 17.4% (95% confidence interval [CI], 7.2%-36.2%). The median time of overall survival was 6 months (range: 1-15 months). Of 28 enrolled patients with biliary tract cancer, complete responses were observed in 2 patients (7.1%) with survival time of 14 and 16 months, respectively. Seven patients had PRs with a median survival of 8 months. The overall response rate was 32.1% (95% CI, 20.3%-57.5%). The median time of overall survival was 6 months (range: 1-16 months). The most prominent toxicity was mucositis. Hematologic toxicity was less severe. 5-Fluorouracil in modulation with intravenous leucovorin is well tolerated by patients with stage IV pancreatic adenocarcinoma or biliary tract cancer. Although the response rate for patients with pancreatic adenocarcinoma is not better than that achieved using 5-FU monochemotherapy, the 32.1% overall response rate achieved in patients with biliary tract cancer suggests that 5-FU modulation with leucovorin is active in biliary tract cancer.

Adenocarcinoma↗
PubMed2005

[Injuries to the biliary tract during cholecystectomy].

Injuries to the biliary tract during both the laparoscopic or the open cholecystectomic procedures, remain among the most serious iatrogenic injuries with high morbidity and mortality rates. The higher the number of the laparoscopic cholecystectomies, the higher the number of the injuries to the biliary tract. Early peroperative recognition of these injuries is a prerequisite for successful biliary tract reconstructions. Mucosal hepaticojejunoanastomosis according to Roux is the golden standard of the reconstrucion treatment. Stenoses in anastomoses followed by development of cholangitides are considered serious postoperative complications. In these cases, endoscopic and transparietal dilation with plastic stents implantation is the method of choice. Technically exacting reoperations then follow. The authors present a trial group of 11 patients, who were treated in the Surgical Clinic of the Faculty Hospital in Plzen for biliary tract injuries during cholecyctomic procedures (8 were laparoscopic and 3 open), from 01-01-2000 to 01-09-2004. Severe inflammatory changes in the region of the Calot triangle, were the commonest cause of the biliary tract injuries during primary operations. In most cases (N = 8) the injury was diagnosed and managed immediately during the primary procedure. Hepaticojejunoanastomosis according to Roux was the principal procedure used to repair the biliary tract (N = 8). Postoperative morbidity reached 36.4%, 2 elderly patients exited (18.2%) due to septic multiorgan failure on the 15th day and the 7th month after the surgical procedure. Multidisciplinary approach of a team of experienced surgeons, endoscopists and radiologists in the hepatobiliary region is a fundamental prerequisite for long-term successful outcomes of technically exacting reconstructive procedures of the hepatobiliry tract.

Adult↗
PubMed2005

Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers.

Carcinomas of the biliary tract have a poor prognosis. It is important to understand the molecular genetic characteristics of these tumours in order to employ newer effective treatments and to improve patient prognosis. There is increasing evidence that overexpression of tyrosine kinase growth factor receptors such as ErbB-2, epidermal growth factor receptor (EGFR), and Met may play important roles in the development of biliary tract carcinomas. The aim of this study was to assess the potential for novel chemotherapies targeting these receptors. Overexpression of the tyrosine kinase receptor proteins was examined by immunohistochemistry in 221 biliary tract carcinomas, of which 28 were from the intrahepatic bile duct, 78 from the extrahepatic bile duct, 89 from the gall bladder, and 26 from the ampulla of Vater. Positively stained tumours were further examined for gene amplification by fluorescence in situ hybridization. Overexpression of ErbB-2 was found in 15.7%, 11.5%, and 5.1% of carcinomas of the gall bladder, ampulla of Vater, and extrahepatic bile duct, respectively, and gene amplification was present in 79% of these. Overexpression of EGFR was found in 8.1% of tumours with no predominant location and was also associated with gene amplification with high frequency (77%). Met overexpression, most frequent in intrahepatic bile duct carcinomas (21.4%), was not associated with gene amplification. It is proposed that the new adjuvant chemotherapies could be directed to carcinomas of the biliary tract in which ErbB-2 and EGFR are overexpressed.

Adenocarcinoma↗
PubMed2002

Review of gemcitabine in biliary tract carcinoma.

Cancers of the biliary tract are rare, and remain a major challenge to surgical, medical, and radiation oncologists. Unfortunately, the large majority of these tumors are not resectable at the time of initial diagnosis, and patients with advanced disease face a dismal prognosis. The efficacy of conventional palliative systemic chemotherapy (eg, with 5-fluorouracil, mitomycin-C, and cisplatin) seems negligible, and there is presently no agreement on the best chemotherapeutic regimen. Gemcitabine is among several different new anticancer drugs under investigation in the treatment of advanced biliary tract cancer. Apart from its favorable toxicity profile, this novel nucleoside analog has shown activity in many solid tumors, including pancreatic adenocarcinoma. In view of the histogenetic affinity between the pancreas and the biliary tract, and several case reports describing the efficacy of gemcitabine in advanced gallbladder or cholangiocellular carcinoma, a number of phase II investigations have been undertaken. In the majority of these trials a conventional gemcitabine dose regimen of 1,000 to 1,200 mg/m(2) given over 30 minutes on 3 consecutive weeks followed by a week of rest has been used. In a total of seven studies involving 167 assessable patients, objective response rates up to 60% (36% in the largest trial composed of 39 evaluable patients), abrogation of progressive disease (complete response + partial response + stable disease) in 50% to 93%, and overall survival times ranging from 6.3 to 16 months, have been reported. The consensus is that the tolerance of treatment was remarkable with only exceptional patients (< or = 5%) experiencing grade 4 hematologic toxicities. Nonhematologic side effects were infrequent and almost exclusively mild to moderate. In three of the trials, a formal clinical benefit analysis was included, suggesting that a considerable proportion of symptomatic patients will experience relief of tumor-related symptoms and/or weight gain. Possible options currently being investigated to further improve the therapeutic results of gemcitabine monotherapy include modifications of the dose regimen as well as combinations with other potentially synergistic anticancer drugs. In the latter approach, preliminary data have been reported for gemcitabine plus cisplatin, oxaliplatin, docetaxel, mitomycin-C, and continuous-infusion 5-fluorouracil/leucovorin. Objective response rates as high as 53% (for gemcitabine/cisplatin), and median survival times > or = 11 months with only a slight increase in frequency and severity of side effects have been reported. In conclusion, while the best available chemotherapeutic treatment for advanced biliary tract cancer remains to be determined, accumulating data from recent phase II trials suggest that single-agent gemcitabine represents an active and very well-tolerated treatment option. It may also be safely combined with other drugs, though further improvements in response activity and survival warrant confirmation in future randomized studies.

Antimetabolites, Antineoplastic↗
PubMed1981

Radionuclide imaging of the biliary tract.

Cholescintigraphy with technetium-labeled biliary agents has great value in evaluation of the patient with suspected acute cholecystitis. Visualization of the gall bladder virtually excludes acute cholecystitis and obstruction of the cystic duct. Nonvisualization of the gall bladder, however, is not specific for acute cholecystitis and may also occur in some patients with chronic cholecystitis or pancreatitis. Interpretation of gall bladder nonvisualization, therefore, must be correlated with the clinical presentation. Biliary tract imaging is also useful in evaluation of some focal abnormalities within the liver, neonatal jaundice, detection of bile leaks or bile reflux, and biliary-enteric shunts. The role of technetium-labeled biliary agents in the evaluation of patients with jaundice is less clear. Excretion of tracer into the gut excludes complete biliary tract obstruction, but the test may be nonconclusive at higher serum bilirubin levels. If persistent common bile duct activity is observed with delayed excretion into the gut, the diagnosis of partial obstruction may be made, but this procedure will be inconclusive if the common bile duct is not visualized and/or significant hepatocellular disease is present. Ultrasonography and abdominal CT are the preferred tools for the diagnosis of biliary tract obstruction at present, but newer biliary tract agents which achieve better hepatic extraction and greater bile concentration at high serum bilirubin levels may improve the diagnostic efficacy of cholescintigraphy.

Biliary Tract↗
PubMed2007

[Molecular mechanisms in the development and progression of pancreas and biliary tract cancers].

Pancreatic and biliary tract cancers are the most lethal malignancies in the gastrointestinal tract. Investigators have actively investigated to elucidate molecular mechanisms involved in the carcinogenesis, growth, invasion and metastasis of these cancers. This review describes those molecular mechanisms and their correlation with clinicopathological features of pancreatic and biliary tract cancers. Furthermore, recent experimental developments in the gene therapy technologies toward these cancers are also summarized.

Biliary Tract Neoplasms↗
PubMed1983

Ultrasonographic evaluation of ascaris in the biliary tract.

Ascaris in the biliary tract may cause cholecystitis and obstruction of the common bile ducts. Two cases are presented where worms that were identified in the common bile duct caused obstructive jaundice. The image of the ascaris is typical in its morphology and movement. Ultrasonography is useful in the identification of this parasite in the biliary tract where other conventional radiological methods are frequently unsatisfactory.

Adult↗
PubMed1997

Postsurgical biliary tract complications.

Cholecystectomy and other biliary tract operations are being performed with an increasing frequency due to the prevalence of gallstones and pancreaticobiliary disorders among the aging population of the United States. Even in the current era of modern medicine, however, a wide spectrum of postsurgical biliary complications are encountered. Most are the result of preventable iatrogenic trauma or technical mishaps that occur with a much higher incidence during laparoscopic cholecystectomy than the conventional open procedure. These include bile leakage from an overlooked transection of normal or aberrant bile ducts, obstructive jaundice due to inadvertent ligation of the common duct or its postsurgical stricture, instrumentation injuries induced during biliary tract exploration, and the various types of biliary fistulas. These lesions are detectable by intraoperative or T-tube cholangiography, if the examination is performed and interpreted correctly. In most instances, however, the postoperative evaluation of the abdomen by computed tomography or ultrasonography will provide the initial clues to an otherwise unsuspected lesion. Radiologic imaging and interventional techniques play a crucial role in the diagnosis and management of postsurgical biliary tract complications, as illustrated in this review article.

Biliary Tract Diseases↗
PubMed1981

Biliary tract surgery concomitant with other intra-abdominal operations.

Biliary tract operations were performed in conjunction with another intra-abdominal operation in 253 patients. Of this group, 137 patients had unplanned or "incidental" biliary procedures, with a morbidity rate of 15% and a mortality rate of 7%. Three of the 20 nonfatal complications were related to the biliary tract surgery. A planned biliary tract operation concomitant with another intra-abdominal procedure was performed in 65 patients, with a morbidity rate of 20% and mortality rate of 2%. None of these postoperative complications or deaths were attributed to the biliary tract operation. A planned biliary tract procedure plus another incidental and unplanned operation were performed in 51 patients, with a morbidity rate of 11.8% and no deaths. The complications were not specific to the biliary tract operation. The data suggest that it is feasible to perform concomitant cholecystectomy for cholecystostomy for calculous biliary tract disease in patients operated on for nonbiliary diseases. It is also reasonable to perform definitive surgery for most gastrointestinal diseases discovered incidental to a planned cholecystectomy. These recommendations are valid only if the condition of the patient permits the additional operative stress and the exposure is adequate to perform a safe procedure on the gallbladder. Concomitant operations that require choledochotomy are not recommended, except under unusual circumstances.

Abdomen↗
PubMed1993

Cefepime for infections of the biliary tract.

Antibiotic treatment of biliary tract infections is widely accepted. An open, prospective, randomized, multicenter trial comparing cefepime (2 grams every 12 hours) with gentamicin (1.5 milligrams per kilograms every eight hours) plus mezlocillin (3 grams every four hours) for a minimum of five days was undertaken. Of the 149 patients enrolled, 120 were evaluable; 80 were randomized to receive cefepime and 40 were randomized to receive gentamicin plus mezlocillin (two to one randomization schedule). The diagnosis was acute cholecystitis in 101 patients and acute cholangitis in the remainder. There were no differences between the two treatment groups with regard to gender, age, disease, signs and symptoms, admitting temperature or laboratory values. All patients (100 percent) treated with gentamicin and mezlocillin were cured of the infection, as were 78 (97.5 percent) of the patients treated with cefepime (difference not significant). The incidence and spectrum of adverse events and complications were similar between the two groups (8.8 percent for cefepime versus 10 percent for gentamicin and mezlocillin). Our data show that the efficacy and safety of cefepime administered every 12 hours is equivalent to that of gentamicin and mezlocillin combination for treating patients with acute infections of the biliary tract. In addition, twice-daily administration of cefepime may be more cost-effective than the aminoglycoside-based combination.

Adult↗
PubMed1995

Brush cytology of the extrahepatic biliary tract: comparison of cytologic features of adenocarcinoma and benign biliary strictures.

Malignant strictures of the extrahepatic biliary tract are difficult to discern from benign strictures solely by clinical and/or radiographic findings. Endoscopic retrograde wire-guided brushings of strictures have proven to be useful in evaluating such lesions. Because the reported sensitivity of diagnosing adenocarcinoma of the extrahepatic biliary tract by this technique has varied considerably (44 to 100%), we undertook a retrospective study to determine if the diagnostic accuracy could be increased by identifying key cytologic features by reviewing a series of 90 biliary tract brushings from 80 patients. The cytologic diagnosis was confirmed either by additional pathologic material and/or clinical follow-up. Utilizing a multiple logistic regression analysis, three key cytologic features were identified that were useful in separating benign from malignant strictures; these features included: nuclear molding, chromatin clumping, and increased nuclear-cytoplasmic ratio. The presence of two of these three features resulted in a sensitivity of 83%; the corresponding specificity was 98%. The use of these key features should aid the cytologist in better recognizing malignant cells in biliary tract brushings.

Adenocarcinoma↗
PubMedDate not supplied

Iatrogenic injury in videolaparoscopic cholecystectomy: difficult surgical correction biliary tract.

Two cases of biliary tract serious lesions during videolaparoscopic cholecystectomy are reported. In the first case of lithiasic cholecystitis there had been a complete damage of the common biliary duct; in the second case there had been a double main biliary duct binding with removal of a biliary tract segment. In both cases a biliary confluence-jejunal anastomosis with Roux-en-Y loop was made up. In the first one the operation was difficult because of the main bile duct's fragility and modest expansion. In the second one the presence of a secondary biliary duct in gallbladder fossa not recognized, but drained outside with a common drainage placed during the operation prevented appearance of jaundice with dilatation of biliary ducts. It was heavily conditioned performing confluence-jejunal anastomosis with Roux-en-Y loop. The post-operative course was characterized by appearance of an external biliary fistula which has spontaneously disappeared. One year later, neither of the two patients had any stenosis or cholangitis problems.

Adult↗
PubMed2002

Microsatellite instability in intraductal papillary neoplasms of the biliary tract.

Intraductal papillary neoplasms of the biliary tree are unusual lesions characterized by solitary or diffuse growth along the intra- and/or extrahepatic biliary tract. Biliary papillary neoplasms bear some clinicopathologic similarity to intraductal papillary mucinous neoplasms of the pancreas. Like intraductal papillary mucinous neoplasms of the pancreas, biliary papillary neoplasms can be purely intraductal lesions or can give rise to invasive adenocarcinomas. We recently studied the genetic alterations present in a series of biliary papillary neoplasms and noted the presence of allelic shifts in some biliary tumors during allelic loss assays on chromosomes 5q and 18q. This suggested that microsatellite instability might play a role in the molecular pathogenesis of biliary papillary neoplasms. Genomic DNA was extracted from 17 intraductal papillary neoplasms, 6 associated invasive cholangiocarcinomas, and corresponding normal tissues, and microsatellite instability testing was performed using the 5 microsatellite loci recommended by the 1997 National Cancer Institute-sponsored consensus conference (D2S123, D5S346, D17S250, Bat-25, and Bat-26). High-level microsatellite instability was considered to be present when at least two of five microsatellite loci showed allelic shifts, and low-level microsatellite instability, when only one locus was shifted, as per the National Cancer Institute criteria. We also determined the methylation status of the DNA mismatch repair gene hMLH1 by bisulfite treatment of genomic DNA, followed by methylation-specific PCR. High-level microsatellite instability was present in 2 of 17 (11.8%) biliary papillary neoplasms, including 1 case of purely intraductal tumor and 1 case with both intraductal and invasive cholangiocarcinoma components. In both cases there was extensive microsatellite instability, with allelic shifts in five of five and four of five microsatellite markers, respectively. Low-level microsatellite instability was present in 6 of 17 (35.3%) biliary papillary neoplasms, including 2 cases of purely intraductal tumor and 4 cases with both intraductal and invasive cholangiocarcinoma components. Interestingly, the pattern of allelic shifts was frequently not identical between the intraductal and invasive cholangiocarcinoma components; although the same microsatellite markers were shifted, alleles of differing lengths were generated in the intraductal and invasive components of the neoplasms with high-level microsatellite instability and of two neoplasms with low-level microsatellite instability. None of the biliary papillary neoplasms (0 of 10 cases with adequate DNA for evaluation) showed methylation of hMLH1. These results indicate that microsatellite instability is a relatively frequent event in papillary neoplasms of the biliary tree but is not associated with hMLH1 promoter hypermethylation. The finding that alleles of differing lengths were frequently generated between the intraductal and invasive components of those tumors with microsatellite instability suggests that there is significant genetic heterogeneity within these neoplasms.

Adaptor Proteins, Signal Transducing↗