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[A case of biliary tract obstruction due to metastatic hepatic cancer, in which topical injection of CDDP and ADM into PTCD with concomitant use of UFT resulting in partial reopening of biliary tract].

One year after total gastrectomy due to gastric cancer, the 50-year-old male patient underwent lateral segmentectomy, since metastatic foci occurred in the outer region of the liver. Three months thereafter, metastatic foci occurred in the right anterior lobe of the liver, causing obstructive jaundice. PTCD was performed, and after repeated anticancer doses of 10 mg of Cis-diamminedichloroplatinum (CDDP) plus 10 mg of adriamycin (ADM) in the tubing, partial opening of the obstructive bile duct was achieved.

Antineoplastic Combined Chemotherapy Protocols↗

Biliary tract neoplasms: update 2003.

PURPOSE OF REVIEW: Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Most cancers of the biliary tract will have grown beyond the limits of curative resection by the time they become clinically evident. This reality has fostered therapeutic nihilism, and most physicians and surgeons, in their pessimism, have to run ambitious trials evaluating new diagnostic tools and therapeutic techniques in this disease. RECENT FINDINGS: Advances in imaging over the period of the last 5 years now allow for earlier diagnosis and better surgical planning. Recent improvements in operative technique have substantially improved the outlook of patients with this cancer. Palliative management of obstructive disease recently has been improved with the advent of photodynamic therapy. Among the different drugs tested in this disease, gemcitabine seems to have the best efficacy:toxicity ratio. However, efficacy results remain disappointing, and combination schedules need to be developed to improve the results. Among them, the gemcitabine-oxaliplatin combination seems to be one of the most promising schedules. Biological studies, especially those evaluating mutation-independent activation of the Hedgehog pathway, have provided interesting information on the carcinogenesis of this rare tumor. Furthermore, these results bring us the opportunity of development of future targeted therapies in biliary tract cancer. SUMMARY: Biliary tract neoplasm remains one of the most aggressive malignancies. However, as for other gastrointestinal malignancies, biological studies and diagnostic and therapeutic improvements have provided interesting results that could lead to a major improvement in the prognosis of this disease.

Adenocarcinoma↗

Relationship between types of common channel and development of biliary tract cancer in pancreaticobiliary maljunction.

BACKGROUND/AIMS: The incidence of biliary tract cancer development is high among patients with pancreaticobiliary maljunction. However, there have been no reports published evaluating the incidence of development of biliary tract cancers in pancreaticobiliary maljunction based on the morphology of the common channel at the junction of the bile and pancreatic ducts. We evaluated between types of common channel and development of biliary tract cancers in pancreaticobiliary maljunction. METHODOLOGY: During the last 21 years, we have experienced 78 patients with pancreaticobiliary maljunction. Of those patients, 44 adult patients, whose morphologic types of common channel were identified by cholangiography, were enrolled in this study. The dilatation patterns of the common channel were classified into 3 types: A type (moderately dilated type), B type (markedly dilated type), and C type (non-dilated type). Evaluated items included the length and dilation patterns of the common channel, incidence of development of biliary tract cancers and proliferative activity in the biliary tract epithelium. RESULTS: Seventeen patients had a common channel shorter than 20 mm, while 27 had a common channel of 20 mm or longer. Eleven patients with a common channel of 20 mm or longer had development of bile tract cancers. The dilation patterns of the common channel were classified as A (11 patients), B (16 patients) and C type (17 patients). Amylase levels in the biliary tract were higher in patients with A and B type than in patients with the C type. Development of gallbladder cancer was observed in 6 patients with A, 2 patients with B and one patient with C, while development of bile duct cancer was observed in 2 patients with C and one patient with B. The PCNAL.I. of the biliary epithelium was higher in patients with A, B and C type in descending order. CONCLUSIONS: The incidence of development of biliary tract cancer was higher in patients with common channel of 20 mm or longer. The proliferative activity in the biliary epithelium was accelerated in patients with A type, together with a high incidence of development of gallbladder cancer.

Bile Ducts, Extrahepatic↗

Biliary Tract Dysmotility.

Biliary pain resulting from motility disorders is common and may be overlooked due to the difficulty of diagnosing the presence of these disorders. A sound, logical approach to the evaluation and treatment of these specific groups of disorders is essential. In patients who have a gallbladder, we initially exclude the presence of gallstones by use of transcutaneous ultrasonography. If a patient's symptoms are atypical, we initiate therapy (eg, antispasmodics) for irritable bowel syndrome. Subsequently, we perform a quantitative cholescintigraphy with a low-dose infusion of cholecystokinin in patients with typical symptoms and in those with persistent atypical symptoms. Those patients who have abnormally low gallbladder ejection fractions are subsequently referred for laparoscopic cholecystectomy. In postcholecystectomy patients, a standard approach should include obtaining serum liver associated laboratory chemistries, amylase and lipase levels, and a transcutaneous ultrasound to measure bile duct size. Endoscopic retrograde cholangiopancreatography (ERCP) is done to measure bile duct size, assess biliary duct emptying, and exclude other etiologies for pain. In patients with more than two abnormal findings on these tests (type I sphincter of Oddi dyskinesia), we recommend performing an empiric endoscopic biliary sphincterotomy. In patients with no objective abnormalities (type III sphincter of Oddi dyskinesia), it is appropriate to begin medical therapy with antispasmodics and calcium-channel antagonists. In individuals who have one or two abnormalities (type II sphincter of Oddi dyskinesia) we prefer endoscopic biliary sphincterotomy; however, these individuals are offered the opportunity to have endoscopic biliary manometry performed in order to establish a clear diagnosis. If patients refuse this procedure, after careful explanation of risks, alternatives, and possible benefits of the procedure, empiric endoscopic biliary sphincterotomy is performed.

Journal Article↗

The histologic pattern of "biliary tract pathology" is accurate for the diagnosis of biliary complications.

A histologic pattern comprising centrilobular cholestasis and portal changes including edema, predominantly neutrophil polymorph infiltration, cholangiolar proliferation, and cholangiolitis is well known to correspond to biliary obstruction. This pattern, referred as biliary tract pathology (BTP) in this text, remains unclear in terms of its clinical significance. We aimed to assess the incidence, timing, and diagnostic accuracy of BTP after liver transplantation. All 248 liver biopsies and clinical records, from 94 patients, including 30 living donor, 17 split, 15 domino, and 32 cadaveric full-size primary liver transplantation, were reviewed. BTP was diagnosed in 21% of biopsies from 31% of patients at a median of 28 days after transplantation (range, 5-763 days). When radiologic imaging of the biliary tree was taken as the gold standard, biopsy was found to have a sensitivity of 87% (95% confidence interval, 73%-100%) and a specificity of 87% (95% confidence interval, 80%-95%) for the diagnosis of biliary complications. An underlying clinical condition was found in 86% of cases, which included biliary complications (69%), arterial thrombosis (3%), sepsis (10%), and recurrent disease (3%). In 14% of cases, BTP remained unexplained. In conclusion, BTP after liver transplantation has clinical significance in most cases, with a particular emphasis for true biliary complications. This pattern must incite radiographic verification of the biliary tract.

Bile Ducts, Intrahepatic↗

[Present situation of and prospects for standardization of surgery for biliary tract cancer].

Surgery remains the primary treatment for biliary tract malignancies. A standard therapy is required in the era of evidence-based medicine. However, guidelines for biliary tract cancer surgery have not yet been adopted. We review the current literature on the treatment of biliary tract malignancies and surveyed the prospects for standardization of biliary tract cancer surgery. For patients with gallbladder cancer, surgical procedures should be selected based on the depth of invasion. In aggressive surgery for stage IV gallbladder cancer, attention should be paid to the high incidence of operative mortality. Hepatopancreatoduodenectomy and extended lymph node dissection have been investigated in clinical trials. For hilar cholangiocarcinoma patients, surgical procedures should be selected based on tumor location. For Bismuth types III and IV, hepatectomy combined with caudate lobectomy appears to be the standard surgery. Liver transplantation for hilar cholangiocarcinoma patients is currently being examined in clinical trials. Pancreatoduodenectomy is considered the standard procedure for middle and lower bile duct and ampullary cancer. It is necessary to continue developing adjuvant therapies for patients with negative prognostic factors. The appropriateness of adjuvant therapies such as chemotherapy and radiation therapy should be confirmed in further clinical trials. It is necessary to reach a definite consensus on standard therapy for biliary tract malignancies in the near future, and therefore multicenter, randomized trials to address the issues involved should be initiated in Japan.

Biliary Tract Neoplasms↗

Establishment and characterisation of six human biliary tract cancer cell lines.

Human cell lines established from biliary tract cancers are rare, and only five have been reported previously. We report the characterisation of six new six biliary tract cancer cell lines (designated SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079 and SNU-1196) established from primary tumour samples of Korean patients. The cell lines were isolated from two extrahepatic bile duct cancers (one adenocarcinoma of common bile duct, one hilar bile duct cancer), two adenocarcinomas of ampulla of Vater, one intrahepatic bile duct cancer (cholangiocarcinoma), and one adenocarcinoma of the gall bladder. The cell phenotypes, including the histopathology of the primary tumours and in vitro growth characteristics, were determined. We also performed molecular characterisation, including DNA fingerprinting analysis and abnormalities of K-ras, p15, p16, p53, hMLH1, hMSH2, DPC4, beta-catenin, E-cadherin, hOGG1, STK11, and TGF-betaRII genes by PCR-SSCP and sequencing analysis. In addition, we compared the genetic alterations in tumour cell lines and their corresponding tumour tissues. All lines grew as adherent cells. Population doubling times varied from 48-72 h. The culture success rate was 20% (six out of 30 attempts). All cell lines showed (i) relatively high viability; (ii) absence of mycoplasma or bacteria contamination; and (iii) genetic heterogeneity by DNA fingerprinting analysis. Among the lines, three lines had p53 mutations; and homozygous deletions in both p16 and p15 genes were found three and three lines, respectively; one line had a heterozygous missense mutation in hMLH1; E-cadherin gene was hypermethylated in two lines. Since the establishment of biliary tract cancer cell lines has been rarely reported in the literature, these newly established and well characterised biliary tract cancer cell lines would be very useful for studying the biology of biliary tract cancers, particularly those related to hypermethylation of E-cadherin gene in biliary tract cancer.

AMP-Activated Protein Kinase Kinases↗

Early phase II study of uracil-tegafur plus doxorubicin in patients with unresectable advanced biliary tract cancer.

BACKGROUND: Standard chemotherapy for advanced biliary tract cancer has not been established. The purpose of this study was to evaluate the efficacy and toxicity of a combination chemotherapy of uracil-tegafur (UFT) and doxorubicin in patients with unresectable advanced biliary tract cancer. METHODS: Patients with histologically or cytologically confirmed, measurable biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of Vater cancer, which was not amenable to surgery, were eligible for the study. Patients received oral UFT 300 mg/m(2) per day divided into two doses on Days 1-14 and intravenous doxorubicin 30 mg/m(2) on Day 1. This cycle was repeated every 21 days. Additional courses of this regimen were given until a maximum of 15 courses, disease progression or the appearance of unacceptable toxicity. RESULTS: Twenty-four patients from five institutions were enrolled between March 2004 and November 2004. Of the 24 patients, three had partial responses for an objective response rate of 12.5% (95% confidence interval, 2.7-32.4%), 13 patients had stable disease, 7 had progressive disease and the final patient was not evaluated. Grade 3 toxicity was observed in 5 of the 24 patients (20.8%), and these toxicities included anorexia, fatigue, anemia and neutropenia. None had grade 4 toxicity. The median progression-free and overall survival time was 2.5 and 7.6 months, respectively. CONCLUSIONS: Combination chemotherapy of UFT and doxorubicin was well tolerated and showed preliminary moderate activity against advanced biliary tract cancer. Further investigation in a late phase II study involving a large number of patients is recommended.

Aged↗

Biliary tract cancer: our experience with gemcitabine treatment.

Biliary tract cancers are uncommon tumors, with a poor prognosis because most patients present an invasive cancer at diagnosis that makes them inoperable. Chemotherapy is a palliative treatment, but single drugs or combination schedules have demonstrated a response rate of 14-18%, with a duration of response of 8.5 months. We report a single center experience with gemcitabine in the treatment of patients with advanced biliary tract cancers. We report on four cases of chemonaive patients with advanced biliary tract cancers treated with gemcitabine 1 g/m q days 1, 8 and 15. After three cycles of treatment we observed one partial response and three stable disease (according to WHO criteria), with an increase in performance status and a complete relief of pain in all patients. The median time to progression observed was 10.7 months. Although this experience is limited to a small number of patients, it shows that gemcitabine appears to be worthy of clinical research in this neoplastic pathology and makes the drug a particularly interesting agent for investigation in patients with biliary tract malignancies.

Adenocarcinoma↗

Chemotherapy for biliary tract cancer in Japan.

The incidence of biliary tract cancer has increased markedly in Japan over the past several decades and ranks as the sixth leading cause of cancer death. Currently, there is no standard chemotherapy for biliary tract cancer. Early phase investigation of cisplatin and cisplatin/epirubicin/5-fluorouracil yielded disappointing results in this setting. Gemcitabine is currently approved for use in the treatment of non-small cell lung cancer and pancreatic cancer in Japan. Based on the single-agent activity of gemcitabine in biliary tract cancer in other locales combined with the drug's established safety profile, gemcitabine is currently being evaluated as single-agent therapy in the treatment of advanced biliary tract cancer patients in Japan.

Antimetabolites, Antineoplastic↗

[Therapeutic effects of cefotiam in biliary tract infections].

As useful antibiotics for biliary tract infections, smooth transmigration to lesion and potent antibacterial activities will be demanded. Usually the antibiotics having potent antibacterial activities against E. coli and Klebsiella, which are considered to be main causative organisms of biliary tract infections, will be used for treatment. The concentrations of cefotiam (CTM) in bile and gallbladder wall tissue were investigated, and CTM showed very high concentrations in these tissues for several hours. And very good correlation between concentration of CTM in bile and laboratory findings, especially ICG R15 value, was obtained. CTM showed also very potent antibacterial activities against E. coli and Klebsiella. These results suggest that CTM will be useful agent for the treatment of biliary tract infections.

Adult↗

Experimental foreign-body infection in the biliary tract in rats.

BACKGROUND: Biomaterials used for biliary drainage may potentially result in biomaterial-associated infections. METHODS: Foreign-body infection in the biliary tract was investigated in rats. Rubber drain pieces were implanted in the biliary tract in rats for 1-4 weeks, followed by challenges with 10(2) to 10(4) colony-forming units (cfu) Escherichia coli injected into the common bile duct. The rate of infection was calculated, the bacterial growth in the biliary tract was observed over 72 h after challenges, and the opsonic activity in bile and in sera was assessed. RESULTS: In the group with drain material, inocula as small as 10(2) cfu produced persisting infection in the common bile duct in 90% of animals, whereas the same number of E. coli infected only 30% of rats in the control and sham implantation groups (p < 0.01, chi-square test). Complement-mediated opsonic activity in bile of animals with implanted drain pieces gradually decreased with time, whereas opsonic activity in sera from the same animals remained unchanged. CONCLUSIONS: Implants in the biliary tract impair local host defense, resulting in an increased susceptibility to microbial infection.

Animals↗

Management of biliary tract complications following liver transplantation.

BACKGROUND: A review of biliary tract complications was performed in 32 patients who underwent liver transplantation by the Western Australian Liver Transplantation Service during a 2-year period. METHODS: A review was made of patient data collected prospectively, and confirmed by retrospective casenote review. RESULTS: A total of 30 patients (31 grafts) survived more than 2 days after transplantation, and of these 28 had an end-to-end biliary anastomosis. Analysis of these 28 patients found that eight of 17 patients with T-tubes had complications: three leaks at T-tube removal; two strictures and leaks; and three strictures. Six of 11 patients without a T-tube had complications: one leak; three strictures and leaks; and two strictures. Predisposing factors were present in eight of the 14 patients with biliary tract complications: hepatic artery stenosis in three; and one each with hepatic artery thrombosis; biliary calculi; donor-recipient bile duct mismatch; severe cellular rejection: and prolonged postoperative hypotension. Acute rejection, steroid-resistant rejection and cytomegalovirus infection were all significantly more common in those patients with biliary tract complications compared with those without. There was no difference in cold ischaemic time or donor age. Twelve of the 14 patients with biliary complications required endoscopic stenting with or without balloon dilation, and eight patients required radiological percutaneous drainage of bile collections. Only one patient required biliary reconstruction and two patients required re-transplantation. One patient died of uncontrolled infection. Of three patients who underwent choledochojejunostomy, biliary leak developed in two patients, both of whom required operative biliary and hepatic repair. One of the three patients died from disseminated Aspergillus infection. The median total hospital stay of patients with biliary complications was 61 days (range: 30-180 days) compared with 33.5 days (range: 22-70 days) for patients without. Of patients with end-to-end biliary anastomosis, 50% had biliary tract complications and more than half of these had predisposing factors. The majority of biliary complications were managed without the need for surgery. CONCLUSION: A total of 50% of patients with end-to-end biliary anastomosis had biliary tract complications. Biliary strictures presented later than leaks, and the majority of these complications were managed without the need for surgery.

Adolescent↗

Time-resolved immunofluorometric assay of trypsin-1 complexed with alpha(1)-antitrypsin in serum: increased immunoreactivity in patients with biliary tract cancer.

BACKGROUND: Increased serum concentrations of trypsin immunoreactivity occur in patients with biliary tract cancer. To characterize this trypsin, we developed a sensitive time-resolved immunofluorometric assay for trypsin-1 complexed with alpha(1)-antitrypsin (AAT) and studied the concentrations of this complex in sera from healthy individuals (n = 130) and patients with benign biliary disease (n = 32), biliary tract cancer (n = 17), pancreatic cancer (n = 27), and hepatocellular cancer (n = 12). METHODS: We used a trypsin-1-specific monoclonal antibody on the solid phase and a europium-labeled polyclonal antibody to AAT as tracer. The detection limit was 0.42 microgram/L. The validity of the trypsin-1-AAT test for detection of biliary tract cancer was compared with trypsin-2-AAT and CA19-9. RESULTS: Increased concentrations of trypsin-1-AAT (>33 microgram/L) were found in 76% of patients with biliary tract cancer, and the concentrations were significantly higher than in those with benign biliary disease (P <0. 0001). The median concentration of trypsin-1-AAT in serum from patients with biliary tract cancer was 3.7-fold higher than in healthy controls, 2.6-fold higher than in patients with benign biliary tract disease, 1.7-fold higher than in patients with pancreatic cancer, and 2.0-fold higher than in patients with hepatocellular cancer. CONCLUSIONS: Of the markers studied, trypsin-1-AAT had the largest area (0.83) under the receiver operating curve in differentiating biliary tract cancer from benign biliary tract disease. Our results suggest that trypsin-1-AAT is a new potential marker for biliary tract cancer.

Biliary Tract Diseases↗

Biliary tract cancers: current concepts and controversies.

Biliary tract cancer, which consists of gall bladder cancer and cholangio-carcinoma, presents many challenges to practising physicians. It is a relatively rare cancer that often causes a diagnostic dilemma, as its presentation may be similar to that of non-malignant conditions. In many cases, histological or cytological confirmation of a cancer diagnosis is not possible preoperatively. The management of this disease is also complex due to a morbid patient population and limited data on the optimal therapeutic approach. Surgery remains the mainstay of treatment, although the extent of resection required is still debated. The role of adjuvant therapy is also controversial, but a combined modality approach appears to be beneficial in patients with a high risk of recurrence, such as those with node positive tumors or positive resection margins. When surgery is not possible, the prognosis of patients with biliary tract cancer is very poor. In unresectable patients, the combination of chemotherapy and radiotherapy can result in a prolonged survival for some patients. In the palliative setting, biliary stenting and other supportive measures can alleviate symptoms and improve survival. Gemcitabine-based combination chemotherapy may also provide successful palliation and has achieved response rates of approximately 30% and a median survival of > 15 months in one study. Ultimately, treatment decisions should be individualised and participation in clinical trials is encouraged. Further progress in the management of biliary tract cancer is anticipated using biological therapies and continued research is essential to discover the optimal treatment for this challenging disease.

Antineoplastic Agents↗

A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas.

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.

Aged↗

Usefulness of bile cytology in the diagnostic management of patients with biliary tract obstruction.

Eighteen patients with evidence of biliary tract obstruction had a total of 29 satisfactory bile samples submitted for diagnostic cytology during a two-year period. These 29 specimens were reviewed in order to determine if bile cytology is useful in the diagnostic management of patients with obstructive biliary tract disease. Twenty-one of the bile specimens were from patients with malignant biliary stricture, and eight were from patients with benign biliary obstruction. Bile cytology was positive for carcinoma in eight samples from patients with malignant stricture and was inconclusive for malignancy in two. There were no false positives. The diagnostic specificity of bile cytology was 100%, the diagnostic sensitivity was 48%, and the diagnostic accuracy was 62%. When carefully collected and promptly processed, bile proved an excellent specimen for cytologic evaluation and was a valuable adjunct to other diagnostic procedures for the detection of carcinoma causing biliary tract obstruction.

Adenoma, Bile Duct↗

Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer.

BACKGROUND: Patients with advanced biliary tract carcinoma face a dismal prognosis as no effective palliative therapy has been defined. The aim of the present phase II investigation was to evaluate the therapeutic efficacy and tolerance of a two-weekly high-dose gemcitabine regimen in this patient population. PATIENTS AND METHODS: Thirty-two consecutive patients with locally unresectable or metastatic biliary tract cancer were enrolled in this multicenter phase II trial. Treatment consisted of gemcitabine 2200 mg/m2 given as a 30-min intravenous infusion every two weeks for a duration of six months unless there was prior evidence of progressive disease. RESULTS: After a median number of 12 treatment courses, 7 of 32 (22%) patients had a partial response that lasted for a median duration of 6.0 months (range 3.5-10.0). Fourteen additional patients (44%) had stable disease, whereas eleven patients (34%) progressed despite therapy. The median time to progression was 5.6 months (range 1.8-13.0); median survival time was 11.5 months (range 3.0-24.0), and the probability of surviving beyond 12 months was 44%. The tolerance of treatment was remarkable with only two patients each experiencing grade 3 leukocytopenia, granulocytopenia and/or thrombocytopenia, and one patient had grade 3 anaemia. Similarly, nonhaematologic side effects were infrequent, and generally mild to moderate. CONCLUSIONS: Two-weekly high-dose gemcitabine seems to represent a potentially effective, safe and well-tolerated regimen for the palliative treatment of patients with advanced biliary tract cancer.

Adult↗