Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients

To clarify the clinicopathological significance of promoter hypermethylation of tumor suppressor and tumor-related genes in biliary tract carcinomas, we examined the promoter methylation status of multiple genes in primary biliary tract carcinomas. These consisted of carcinomas of the bile duct, gallbladder, and duodenal ampulla. Surgical specimens were obtained from a total of 37 patients with biliary tract carcinoma. The cohort consisted of 23 patients with bile duct carcinoma, 9 patients with gallbladder carcinoma, and 5 patients with ampullary carcinoma. The methylation status of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 was examined by methylation-specific polymerase chain reaction (MSP). The correlation between methylation status and clinicopathological characteristics was then assessed. The methylation frequencies of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 genes were 16.2%, 21.4%, 27.0%, 8.1%, 24.3%, 27.0%, and 56.8%, respectively, in primary biliary tract carcinomas. The number of methylated genes per sample was 2.17 +/- 0.28 (average +/- SD) in bile duct carcinomas, 1.80 +/- 0.97 in ampullary carcinomas, and 0.89 +/- 0.35 in gallbladder carcinomas, with a statistically significant difference between bile duct carcinomas and gallbladder carcinomas (P = 0.02). As for clinicopathological significance, patients with a methylated RUNX3 promoter were significantly older than those with unmethylated RUNX3 (P = 0.01), and DAP-kinase methylation was more frequent in poorly differentiated tumors than in well to moderately differentiated ones (P = 0.04). The overall survival rate was significantly lower in patients with methylated DAP-kinase (P = 0.009) or RUNX3 (P = 0.034) compared to those with unmethylated genes. Furthermore, DAP-kinase methylation-positive status was independently associated with poor survival in multivariate analyses (hazard ratio = 8.71, P = 0.024). A significant proportion of primary biliary tract carcinomas exhibited promoter hypermethylation of tumor suppressor and tumor-related genes, although bile duct carcinomas are more prone to being affected by promoter methylation than are gallbladder carcinomas. Hypermethylation of DAP-kinase appears to be a significant prognostic factor in primary biliary tract carcinomas.     

An abnormal pancreatico-choledocho-ductal junction in cases of biliary tract carcinoma

A histopathologic study on how the common bile duct and main pancreatic duct open into the duodenum was performed on 72 autopsied cases of biliary tract carcinoma. Type IIIb which was considered to be an abnormal pancreatico-choledocho-ductal junction was identified in 8 of 34 cases in common bile duct carcinoma and in 4 of 24 cases in gallbladder carcinoma, while none of the control cases belonging to Type IIIb. In cases of Type IIIb, reflux of pancreatic juice may occur into the bile duct and produce the repeated inflammation on the biliary tract. Therefore, the abnormal pancreatico-choledocho-ductal junction was suggested to be one of the pathogenic factors which cause biliary tract carcinoma.     

胆管癌组织及胆汁中端粒酶活性的检测及意义

目的：检测胆管癌组织和胆汁中的端粒酶活性，以研究与端粒酶与胆管癌的关系及对胆管癌的诊断意义。方法：用PCR—ELISA方法检测20例胆管癌的癌组织和胆汁中端粒酶活性，同时用相同的方法检测20例正常胆管组织和胆汁中的端粒酶活性以作对照。结果：20例胆管癌组织中，端粒酶活性阳性为80％（16／20），胆汁中端粒酶活性阳性率75％（15／20）。正常胆管组织端粒酶活性阳性表达率为0（0／20），胆汁中端粒酶活性阳性率为0（0／20）。结论：端粒酶可能参与了胆管癌的发生发展过程，检测胆汁中端粒酶活性可有助于胆管癌的诊断。     

K-ras point mutations in the supernatants of pancreatic juice and bile are reliable for diagnosis of pancreas and biliary tract carcinomas complementary to cytologic examination.

In order to clarify whether DNA analysis for K-ras mutation can be used to diagnose cancers in supernatants of pancreatic juice and bile, samples from 29 cases of pancreatic, biliary tract, gastric, and neuroendocrine carcinomas, 1 malignant lymphoma case, 2 cases of pancreatic adenoma, 9 cases of chronic pancreatitis and 21 other non-cancer cases were examined. Polymerase chain reaction (PCR) products for K-ras gene codons 2 to 97 of exons 1 and 2 were generated with 33/33 (100%) pancreatic juice and 41/41 (100%) bile samples. By the single strand conformation polymorphism (SSCP) method, point mutations were detected in the pancreatic juice or bile supernatants of 13/13 (100%) pancreas cancer cases, 5/14 (35.7%) biliary tract cancer cases, 1/2 (50.0%) pancreatic adenoma cases and 3/9 (33.3%) chronic pancreatitis cases. Direct sequencing confirmed identical point mutations in the supernatants, malignant cells of cytologic smears of pancreatic juice or bile and cancer tissues. The DNA analysis demonstrated the presence of K-ras point mutations in 3 cases of pancreatic carcinomas with false-negative cytologic diagnoses. This novel method allows simultaneous testing for genetic abnormalities in supernatants of pancreatic juice and bile, after removing cells for cytologic diagnosis and screening for pancreatic and biliary tract tumors.     

k-ras Point Mutations in the Supernatants of Pancreatic Juice and Bile Are Reliable for Diagnosis of Pancreas and Biliary Tract Carcinomas Complementary to Cytologic Examination

In order to clarify whether DNA analysis for K-ras mutation can be used to diagnose cancers in supernatants of pancreatic juice and bile, samples from 29 cases of pancreatic, biliary tract, gastric, and neuroendocrine carcinomas, 1 malignant lymphoma case, 2 cases of pancreatic adenoma, 9 cases of chronic pancreatitis and 21 other non-cancer cases were examined. Polymerase chain reaction (PCR) products for K-ras gene codons 2 to 97 of exons 1 and 2 were generated with 33/33 (100%) pancreatic juice and 41/41 (100%) bile samples. By the single strand conformation polymorphism (SSCP) method, point mutations were detected in the pancreatic juice or bile supernatants of 13/13 (100%) pancreas cancer cases, 5/14 (35.7%) biliary tract cancer cases, 1/2 (50.0%) pancreatic adenoma cases and 3/9 (33.3%) chronic pancreatitis cases. Direct sequencing confirmed identical point mutations in the supernatants, malignant cells of cytologic smears of pancreatic juice or bile and cancer tissues. The DNA analysis demonstrated the presence of K-ras point mutations in 3 cases of pancreatic carcinomas with false-negative cytologic diagnoses. This novel method allows simultaneous testing for genetic abnormalities in supernatants of pancreatic juice and bile, after removing cells for cytologic diagnosis and screening for pancreatic and biliary tract tumors.     

Development and clinical pathology of carcinoma of the gallbladder and extrahepatic bile duct

We reported the causes of cancer development and clinical pathology of the gallbladder and extrahepatic bile duct carcinoma. Gallstone, secondary bile acid, and congenital malunion between the bile duct and the pancreatic duct are considered as causes of intestinal metaplasia of the mucosa of the biliary tract. The intestinal metaplasia has closely relationship with development of dysplasia and carcinoma. We treated 101 patients with gallbladder carcinoma and 85 patients with bile duct carcinoma. Sex ratios of the patients with gallbladder carcinoma and bile duct carcinoma were 1:1.8 and 1.7:1. Fifty-one of 101 patients with gallbladder carcinoma had gallstones, and 17 of them had congenital malunion between the bile duct and the pancreatic duct. In four of 23 patients with gallbladder carcinoma and 10 of 64 patients with bile duct carcinoma, superficial cancer spread was seen and it was very important for surgical operation clinically.     

胆管癌及癌旁组织中端粒酶逆转录酶蛋白和基因的表达及意义

目的 检测胆管癌和癌旁胆管组织中端粒酶逆转录酶(hTERT)蛋白和基因的表达,探讨其在胆管癌发生中的作用。方法 应用免疫组化S-P法检测71例胆管癌和39例癌旁胆管组织中hTERT。蛋白的表达,同时应用组织原位杂交技术检测这些组织标本中hTERT mRNA的表达,并与临床病理资料进行相关性分析。结果 71例胆管癌组织中,hTERT。蛋白阳性表达率为78．9％(56／71),hTERT mRNA阳性表达率为67．6％(48／71);而39例癌旁胆管组织中的hTERT蛋白阳性表达率仅为35．9％(14／39),hTERT mRNA阳性表达率仅为23．1％(9／39),且阳性信号全部见于伴有不典型增生的胆管上皮细胞内。病理资料的相关性分析显示,胆管癌组织中,HTERT蛋白和基因的表达分布与临床病理特征无相关性。结论 hTERT基因转录和蛋白表达可能参与胆管癌的发生发展过程,检测hTERT表达可能有助于阐明胆管癌的发生机制。     

Diagnostic p53 immunostaining of endobiliary brush cytology: preoperative cytology compared with the surgical specimen.

BACKGROUND: Endobiliary brush cytology is important in the distinction of malignant and benign causes of extrahepatic bile duct obstruction. The additional diagnostic value of p53 immunostaining on these cytology specimens was assessed. METHODS: All patients with extrahepatic bile duct obstruction who underwent endoscopic retrograde cholangiopancreatography (ERCP) with endobiliary brush cytology and subsequent surgery at the Academic Medical Center in Amsterdam during a 3-year period were studied. p53 Immunocytology was compared with the corresponding conventional light microscopic cytology and p53 immunostaining of the subsequent surgical specimen. RESULTS: Fifty-three patients with the following diagnoses were included: pancreatic carcinoma (23), bile duct carcinoma (15), ampullary carcinoma (5), lymph node metastases (2), carcinoma of unknown origin (4), chronic pancreatitis (3), and primary sclerosing cholangitis (1). Fifty-one percent of the carcinomas showed positive p53 immunostaining; all four surgical specimens without carcinoma were negative. The sensitivities of conventional light microscopic cytology, p53 immunocytology, and both tests combined were 29%, 24%, and 43%, respectively. These sensitivities were higher in cases of bile duct carcinoma (46%, 40%, and 66%) compared with cases of pancreatic carcinoma (13%, 9%, and 22%). Specificities of both tests were 100%. CONCLUSIONS: p53 Immunostaining on endobiliary brush cytology may be helpful in the diagnosis of malignant extrahepatic bile duct stenosis, especially in patients with bile duct carcinoma. Cancer (Cancer Cytopathol) Copyright 1999 American Cancer Society.     

血清胆汁CA19-9、CEA、CA242联合检测诊断胆道良恶性肿瘤的可行性分析

目的:探讨血清、胆汁CA19-9、CEA、CA242联合诊断胆道良恶性肿瘤的临床价值。方法:对象为2013年10月-2015年2月来我院诊治的疑似恶性胆道肿瘤的患者202例,均行手术探查。所有患者均通过穿刺的方式取胆汁进行CA19-9、CEA、CA242检测,比较不同疾病类型患者血清、胆汁中的CA19-9、CEA、CA242检测水平,分析血清胆汁联合检测在胆道良恶性肿瘤中的诊断价值。结果:202例手术探查患者中,98例经病理证实为恶性胆道肿瘤患者、22例为良性胆道肿瘤患者,82例为其他胆道疾病。恶性胆道肿瘤与良性胆道肿瘤患者胆汁中CA242、CA19-9和CEA的表达水平要显著性的高于在血清中的表达水平（P＜0.05）;恶性肿瘤组患者的胆汁中CA242、CA19-9和CEA检测水平均显著性高于良性肿瘤患者（P＜0.05);胆汁CA242、CA19-9和CEA联合诊断胆道恶性肿瘤的敏感率为33.66%,准确率为88.98%,特异性为91.16%,阳性率为35.24%。结论:利用胆汁中肿瘤标记物对胆道肿瘤的检测水平要高于血清中的水平,采用CA19-9、CEA、CA242的联合检测是诊断胆道肿瘤比较理想的组合。上述肿瘤标志物的组合能够提高胆道肿瘤良恶性的预判准确度,对于早期胆道良恶性肿瘤的发现、治疗具有十分重要的意义。     

Induction of Extrahepatic Biliary Carcinoma by N-Nitrosobis(2-oxopropyl)amine in Hamsters Given Cholecystoduodenostomy with Dissection of the Common Duct

The methods we used to produce a carcinoma in the extrahepatic bile duct and gallbladder in hamsters are described along with the characteristics of the induced tumors. Female Syrian golden hamsters were first subjected to Cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CDDB) and were, 4 weeks later, treated with weekly subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) at a dose of 10 mg/kg body weight for 9 weeks. The animals were killed at the 12th, 16th and 20th week after the initiation of BOP treatment. Extrahepatic bile duct carcinoma developed in 16%, 24% and 41% and gallbladder carcinoma occurred in 58%, 81% and 82% of the hamsters, respectively, at the corresponding times of killing. The incidences were significantly higher than those in sham-operated controls ( P <0.01). The induced extrahepatic bile duct carcinomas were predominantly of the polypoid type and gallbladder carcinomas were of the papillary type in growth form, being morphologically similar to early stage biliary carcinoma in humans. Immunohistochemical staining using bromodeoxynridine and anti-bromo-deoxyuridine monoclonal antibody demonstrated that the CDDB procedure greatly accelerated the cell kinetic activity of the biliary epithelium, and this was considered to be a major factor promoting the development of biliary carcinomas in this hamster model. In conclusion, this new model provides a high incidence of tumor development at the extrahepatic biliary tract and is expected to be useful for clarifying the characteristics of this highly malignant tumor.     

支架置入术治疗恶性低位胆道梗阻的临床价值

目的 探讨金属胆道支架置入术治疗恶性低位胆道梗阻的有效性、安全性.方法 32例恶性胆道低位梗阻患者(中位年龄61岁),术前经CT和磁共振胰胆管造影(magnetic resonance cholangiopancreatography,MRCP)证实为恶性胆道低位梗阻.其中,胆管癌12例,胰头癌11例,壶腹癌5例,转移癌2例,胆囊癌2例.32例患者行经皮经肝胆道穿刺,于胆总管中下端置入32枚自膨式金属胆道支架.结果 32例患者手术成功率100.0％,支架位置良好,胆汁引流通畅.术中无胆道出血、胆汁渗漏及胆道破裂等严重并发症.32例患者于术后7天复查肝功能,其血清总胆红素(total bilirubin,TB)由术前的(378.11±134.53) μmol/L下降至(166.10 ±74.37) μmol/L(P＜0.05);血清直接胆红素(direct bilirubin,DB)由术前的(219.14±86.37) μmol/L下降至(98.26 ±53.68) μmol/L(P＜0.05).29例于术后30天复查肝功能,其血清TB由术前的(356.78±118.21) μmol/L下降至(56.10±44.37)μmol/L;血清DB由术前的(219.14 ±86.37) μmol/L下降至(38.26±43.68) μmol/L,均P＜0.05.30例获得随访,随访1-42月(平均25.4月),9例再发支架内梗阻(30.0％),其中4例再行支架治疗,3例行导管引流治疗,2例未治疗死亡.十二指肠梗阻1例,行十二指肠支架治疗后缓解.生存期1-33月,平均生存期(11.56±2.14)月,中位生存期10.0月.结论 金属胆道支架置入术是治疗恶性低位胆道梗阻的安全、有效的方法.     

Radiation therapy of carcinoma of gallbladder and biliary tract.

Fourteen patients with carcinoma of the gallbladder of biliary tract were treated with radiation therapy. Some patients received definite palliative benefit and there were several long term survivors. Patients with bile duct carcinomas responded more often (50%) than did those with gallbladder carcinomas (20%). Only one patient was treated following total gross removal of the tumor, and he is a 6-year survivor. A plea is made for utilizing planned radiotherapy and chemotherapy for tumors arising in the biliary tract.     

Positive telomerase activity in the majority of bile duct carcinoma

Background. Studies of human tumors and human tumor cell lines indicate that telomerase activity may play a critical role in the tumor cell growth by sustaining cellular immortality. Telomerase activity has been detected in different percentages in various carcinomas, but the incidence of positive telomerase activity in bile duct carcinomas and surrounding normal bile duct tissues in its relation with malignancy grades of tumors, depth of invasion, lymphatic and vascular invasion, and lymph node metastases has not been studied. Methods. Telomerase activity was assayed in surgically resected specimens of seven human bile duct carcinomas and seven adjacent nonneoplastic tissues using the PCR-based Oncor TRAP (a telomeric repeat amplification protocol)-eze telomerase detection kit. The correlation between the results of telomerase activity and clinicopathological data was examined. Results. The telomerase activity was detected in six of seven (86%) bile duct carcinoma cases with only one negative case in our series, whereas no telomerase activity was detected in nonneoplastic adjacent bile duct tissues. Although the number of cases in our study was small, telomerase activity was regarded as independent of tumor grade, depth of invasion, lymphatic and intravascular invasion, or lymph node metastasis. Conclusions. These results indicate that increased telomerase activity is a common phenomenon in the majority of bile duct carcinomas, and that it is negative in nonneoplastic bile duct tissues. Received: June 29, 1998 / Accepted: June 16, 1999     

Association between Helicobacter bilis in Bile and Biliary Tract Malignancies: H. bilis in Bile from Japanese and Thai Patients with Benign and Malignant Diseases in the Biliary Tract

Japan and Thailand have high incidences of bile duct carcinoma and gallstones. The presence of Helicobacter bilis ( H. bilis ) detected by polymerase chain reaction (PCR) and 16S rRNA analysis in bile samples from Chileans with chronic cholecystitis was reported. The association between H. bilis in bile and biliary tract malignancies has not been investigated, and therefore the aim of this study is to determine whether malignant diseases of the biliary tract are associated with the presence of H. bilis in bile samples obtained from two high-risk populations. Bile samples from 45 Japanese and 40 Thai patients were subjected to PCR analysis using H. bilis -specific primers, and six of the H. bilis amplicons were sequenced. Thirteen out of 15 (87%) Japanese and 11 out of 14 (79%) Thai patients with bile duct or gallbladder cancer tested positive for the presence of H. bilis in their bile. Eight out of 16 (50%) Japanese and 10 out of 26 (38%) Thai patients with gallstone and/or cholecystitis tested positive for H. bilis. Only 4 out of 14 (29%) subjects without biliary disease tested positive for H. bilis among the Japanese. Bile duct and gallbladder cancer showed significantly higher positive rates for H. bilis than did the non-biliary diseases among the Japanese ( P <0.01) and the odds ratios for bile duct or gallbladder cancer with H. bilis in comparison with gallstone and/or cholecystitis were 6.50 (95%CI 1.09–38.63) in the Japanese and 5.86 (1.31–26.33) in the Thai patients. In conclusion, H. bilis infection in bile was associated with biliary tract and gallbladder cancers in two high risk populations, Japanese and Thai.     

Association between Helicobacter bilis in bile and biliary tract malignancies: H. bilis in bile from Japanese and Thai patients with benign and malignant diseases in the biliary tract.

Japan and Thailand have high incidences of bile duct carcinoma and gallstones. The presence of Helicobacter bilis (H. bilis) detected by polymerase chain reaction (PCR) and 16S rRNA analysis in bile samples from Chileans with chronic cholecystitis was reported. The association between H. bilis in bile and biliary tract malignancies has not been investigated, and therefore the aim of this study is to determine whether malignant diseases of the biliary tract are associated with the presence of H. bilis in bile samples obtained from two high-risk populations. Bile samples from 45 Japanese and 40 Thai patients were subjected to PCR analysis using H. bilis-specific primers, and six of the H. bilis amplicons were sequenced. Thirteen out of 15 (87%) Japanese and 11 out of 14 (79%) Thai patients with bile duct or gallbladder cancer tested positive for the presence of H. bilis in their bile. Eight out of 16 (50%) Japanese and 10 out of 26 (38%) Thai patients with gallstone and / or cholecystitis tested positive for H. bilis. Only 4 out of 14 (29%) subjects without biliary disease tested positive for H. bilis among the Japanese. Bile duct and gallbladder cancer showed significantly higher positive rates for H. bilis than did the non-biliary diseases among the Japanese (P < 0.01) and the odds ratios for bile duct or gallbladder cancer with H. bilis in comparison with gallstone and / or cholecystitis were 6.50 (95%CI 1.09 - 38.63) in the Japanese and 5.86 (1.31 - 26.33) in the Thai patients. In conclusion, H. bilis infection in bile was associated with biliary tract and gallbladder cancers in two high risk populations, Japanese and Thai.     

DPC4蛋白在胆道恶性肿瘤中的缺失表达

Objective To clarify the relationship between loss of expression of DPC4 proteins and pathogenesis of biliary tract carcinoma. Methods 71 primary biliary tract carcinomas (BTCa), including 38 common bile duct (CBD) carcinomas, 18 gallbladder carcinomas, and 15 hilar bile ducts (HBD) carcinomas were examined by immunohistochemical staining. In addition, the CBD carcinomas were divided into two groups, a tumor group with metastasis (M+ group, 27 cases) and a tumor group without metastasis (M− group, 11 cases). Results The frequency of loss expression of DPC4 protein was 32.8% in BTCa, 47.3% in CBD carcinoma, 11% in gallbladder carcinoma and 13% in HBD carcinoma. A comparison of the frequency of loss expression of DPC4 showed significantly statistical difference in the CBD carcinoma versus gallbladder carcinoma and HBD carcinoma (P<0.01). The frequency of loss expression of DPC4 was 48.1% in the M⁺ group and 45.4% in the M⁻ group. There was no significantly statistical difference between them (P>0.05). Conclusion There is a close relationship between the pathogenesis of BTCa and inactivation of DPC4 with different frequencies of DPC4 gene alteration in various locations of the biliary tract, but inactivation of DPC4 is not related with tumor metastasis in BTCa.     

Clinical value of K-ras codon 12 analysis and endobiliary brush cytology for the diagnosis of malignant extrahepatic bile duct stenosis.

Extrahepatic biliary stenosis can be caused by benign and malignant disorders. In most cases, a tissue diagnosis is needed for optimal management of patients, but the sensitivity of biliary cytology for the diagnosis of a malignancy is relatively low. The additional diagnostic value of K-ras mutational analysis of endobiliary brush cytology was assessed. Endobiliary brush cytology specimens obtained during endoscopic retrograde cholangiopancreaticography were prospectively collected from 312 consecutive patients with extrahepatic biliary stenosis. The results of conventional light microscopic cytology and K-ras codon 12 mutational analysis were compared and evaluated in view of the final diagnosis made by histological examination of the stenotic lesion and/or patient follow-up. The sensitivities of cytology and mutational analysis to detect malignancy were 36 and 42%, respectively. When both tests were combined, the sensitivity increased to 62%. The specificity of cytology was 98%, and the specificity of the mutational analysis and of both tests combined was 89%. Positive predictive values for cytology, mutational analysis, and both tests combined were 98, 92, and 94%, whereas the corresponding negative predictive values were 34, 34, and 44%, respectively. The sensitivity of K-ras mutational analysis was 63% for pancreatic carcinomas compared to 27% for bile duct, gallbladder, and ampullary carcinomas. K-ras mutational analysis can be considered supplementary to conventional light microscopy of endobiliary brush cytology to diagnose patients with malignant extrahepatic biliary stenosis, particularly in the case of pancreatic cancer. The presence of a K-ras codon 12 mutation in endobiliary brush cytology per se supports a clinical suspicion of malignancy, even when the conventional cytology is negative or equivocal.     

Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China.

PURPOSE: Biliary tract cancer is an uncommon malignancy with a poor survival rate. We evaluated p16 gene alteration as a prognostic marker for this disease. EXPERIMENTAL DESIGN: We studied p16 gene alterations by sequencing, methylation, and loss of heterozygosity of chromosome 9p in 118 biliary tract carcinomas, including 68 gallbladder cancers, 33 extrahepatic bile duct cancers, and 17 ampullary cancers. Survival was evaluated in 57 patients with gallbladder carcinomas, 27 with bile duct carcinomas, and 16 with ampullary carcinomas with and without somatic p16 alterations detected by two different methods. RESULTS: p16 gene alterations including silent mutations were present in 61.8% gallbladder cancers, 54.5% bile duct cancers, and 70.6% ampullary cancers. p16 gene nonsilent mutations, p16 methylation, and loss of chromosome 9p21-22 that targets p14, p15, and p16 genes were present in 13 of 53 (24.5%), 8 of 54 (14.8%), and 32 of 44 (72.7%) gallbladder tumors; 5 of 25 (20.0%), 5 of 31 (16.1%), and 12 of 21 (57.1%) bile duct tumors; and 3 of 13 (23.1%), 6 of 15 (40.0%), and 8 of 16 (50.0%) ampullary tumors, respectively. The mean survival of patients with gallbladder cancers without p16 alterations was 21.5 +/- 14.8 months compared with 12.1 +/- 11.4 months for patients with p16 alterations (P = 0.02). CONCLUSIONS: Alteration of p16 gene alone or in combination with alterations of other tumor suppressor genes on chromosome 9p is a prognostic indicator in gallbladder carcinoma, with more favorable survival rates associated with carcinomas lacking p16 gene alterations.     

Fibrinolytic activity in human tumor tissues

The fibrinolytic activity of 156 malignant and 36 benign solid tumors from autopsy and biopsy specimens was studied by the fibrin slide technique. The inhibitory activity against fibrinolysis was graded according to the lysis time of vascular tissues within the tumor. The results show that all malignant solid tumors, with the exception of prostate carcinoma, demonstrated varying degrees of inhibition of fibrinolysis. Persistently high inhibitory activity was found in squamous cell carcinoma of the esophagus, the respiratory tract, cervix uteri, and skin; carcinoma of uterus; colorectal carcinoma; small cell anaplastic carcinoma of lung; neuroblastoma, carcinoma of bile duct, while malignant tumors of the kidney show a lesser degree of inhibition. In contrast, with the exception of the hydatidiform mole, benign solid tumors show little or no inhibition. A similar absence of fibrinolytic activity is seen in metastatic disease. Further studies of the role of the fibrinolytic system in tumors seems warranted.