Biomedical subjects

Asif Rashid

Publications and source records attributed to Asif Rashid.

At least 37 records · Page 2Linked to original sources

PubMed2005

Inactivation of ELF/TGF-beta signaling in human gastrointestinal cancer.

TGF-beta/Smads regulate a wide variety of biological responses through transcriptional regulation of target genes. ELF, a beta-spectrin, plays a key role in the transmission of TGF-beta-mediated transcriptional response through Smads. ELF was originally identified as a key protein involved in endodermal stem/progenitor cells committed to foregut lineage. Also, as a major dynamic adaptor and scaffolding protein, ELF is important for the generation of functionally distinct membranes, protein sorting and the development of polarized differentiated epithelial cells. Disruption of elf results in the loss of Smad3/Smad4 activation and, therefore, a disruption of the TGF-beta pathway. These observations led us to pursue the function of ELF in gastrointestinal (GI) epithelial cell-cell adhesion and tumor suppression. Here, we show a significant loss of ELF and reduced Smad4 expression in human gastric cancer tissue samples. Also, of the six human gastric cancer cell lines examined, three show deficient ELF expression. Furthermore, we demonstrate the rescue of E-cadherin-dependent homophilic cell-cell adhesion by ectopic expression of full-length elf. Our results suggest that ELF has an essential role in tumor suppression in GI cancers.

Antibodies, Monoclonal↗

PubMed2005

Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries.

PURPOSE: The epidemiology of colorectal carcinoma is well known to differ among countries but the molecular characteristics are usually assumed to be similar. International differences in molecular pathology have not been studied extensively but have implications for the management of patients in different countries and of immigrant patients. EXPERIMENTAL DESIGN: We evaluated the CpG island methylator phenotype pathway characterized by concordant methylation of gene promoters that often silences transcription of the genes, the microsatellite instability pathway, and K-ras and p53 gene status in 247 colorectal carcinomas from the three selected Middle Eastern countries of Egypt, Jordan, and Turkey. RESULTS: Colorectal carcinoma from Egypt had the lowest frequencies of methylation. In multinomial logistic regression analysis, Jordanian colorectal carcinoma more frequently had methylation involving the p16 tumor suppressor gene (odds ratio, 3.5; 95% confidence interval, 1.2-10.6; P = 0.023) and MINT31 locus (odds ratio, 2.3; 95% confidence interval, 1.0-5.1; P = 0.041). The K-ras proto-oncogene was more frequently mutated in colorectal carcinoma from Turkey (odds ratio, 2.9; 95% confidence interval, 1.2-6.7; P = 0.016), but p53 overexpression was more common in both Jordanian and Turkish colorectal carcinoma than in Egyptian cases (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = 0.019; and odds ratio, 3.6; 95% confidence interval, 1.8-7.1; P = 0.0003, respectively). The findings in Turkish colorectal carcinoma were most similar to those reported for Western cases. CONCLUSIONS: Colorectal carcinoma from Middle Eastern countries have differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures. These molecular differences could affect prevention strategies, therapeutic efficacy, and transferability of clinical trial results.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Chemical effects in biological systems--data dictionary (CEBS-DD): a compendium of terms for the capture and integration of biological study design description, conventional phenotypes, and 'omics data.

A critical component in the design of the Chemical Effects in Biological Systems (CEBS) Knowledgebase is a strategy to capture toxicogenomics study protocols and the toxicity endpoint data (clinical pathology and histopathology). A Study is generally an experiment carried out during a period of time for the purpose of obtaining data, and the Study Design Description captures the methods, timing, and organization of the Study. The CEBS Data Dictionary (CEBS-DD) has been designed to define and organize terms in an attempt to standardize nomenclature needed to describe a toxicogenomics Study in a structured yet intuitive format and provide a flexible means to describe a Study as conceptualized by the investigator. The CEBS-DD will organize and annotate information from a variety of sources, thereby facilitating the capture and display of toxicogenomics data in biological context in CEBS, i.e., associating molecular events detected in highly-parallel data with the toxicology/pathology phenotype as observed in the individual Study Subjects and linked to the experimental treatments. The CEBS-DD has been developed with a focus on acute toxicity studies, but with a design that will permit it to be extended to other areas of toxicology and biology with the addition of domain-specific terms. To illustrate the utility of the CEBS-DD, we present an example of integrating data from two proteomics and transcriptomics studies of the response to acute acetaminophen toxicity (A. N. Heinloth et al., 2004, Toxicol. Sci. 80, 193-202).

Acetaminophen↗

PubMed2005

Catalytic subunit of human telomerase reverse transcriptase is an independent predictor of survival in patients undergoing curative resection of hepatic colorectal metastases: a multicenter analysis.

PURPOSE: To determine the role of the catalytic subunit of human telomerase reverse transcriptase (hTERT) in predicting survival after resection of hepatic colorectal metastases (CRM). PATIENTS AND METHODS: Two hundred one patients who underwent curative resection of hepatic CRM between 1990 and 2000 were identified from a multicenter database. The CRM were analyzed for hTERT nucleolar expression by standard immunohistochemical techniques. hTERT expression and known clinicopathologic factors of survival were examined. RESULTS: With a median follow-up of 80 months, 152 patients (75.6%) had died; the 5-year overall survival was 30.7%. On univariate analysis, number of metastases greater than two (P = .0005), extrahepatic disease (P = .0054), disease-free interval less than 12 months (P = .006), carcinoembryonic antigen level greater than 200 ng/mL (P = .0071), and positive hTERT nucleolar staining (P < .0001) were associated with decreased survival. On multivariate analysis, three factors independently predicted survival: number of metastases (relative risk [RR] = 1.74; P = .0011); disease-free interval (RR = 1.70; P = .0035); and positive hTERT nucleolar staining (RR = 2.03; P < .0001). Patients with none or one of these factors had a 5-year survival rate of 48%, whereas those with two or three of these factors had a 5-year survival of 15% (P < .0001). CONCLUSION: hTERT nucleolar expression is associated with worse survival after resection of hepatic CRM. hTERT expression in conjunction with number of hepatic metastases and disease-free interval may permit more accurate prediction of survival after resection of hepatic CRM.

Adult↗

PubMed2005

Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation.

BACKGROUND: In patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent preoperative chemoradiation, it is unclear whether survival was better predicted by pretherapy clinical stage or by posttherapy pathologic stage. METHODS: The authors studied 235 consecutive patients with pretherapy clinical Stage II, III, or IVA (according to American Joint Committee on Cancer criteria) carcinoma of the esophagus or esophagogastric junction who were treated with chemoradiation followed by esophagectomy. Posttherapy cancer status was classified using pathologic stage and semiquantitative assessment of residual carcinoma. Clinicopathologic features, residual carcinoma status, and pretherapy and posttherapy stage were compared with disease-free and overall survival. RESULTS: Posttherapy pathologic stage was Stage 0 in 29% of patients, Stage I in 11% of patients, Stage II in 34% of patients, Stage III in 20% of patients, and Stage IV in 6% of patients. Cancer downstaging occurred in 56% of patients. In univariate analysis, disease-free and overall survival were predicted by posttherapy pathologic stage (both with P < 0.001), margin status (P = 0.002 and P = 0.01, respectively), extent of residual carcinoma (both with P < 0.001), and downstaging (both with P = 0.001), but not by age, gender, type of cancer, pretherapy clinical stage, or preoperative regimen. However, in multivariate analysis, disease-free and overall survival were independently predicted by posttherapy pathologic stage (both with P = 0.02). Extent of residual carcinoma was a marginally significant predictor of overall survival (P = 0.04). CONCLUSIONS: Posttherapy pathologic stage was the best available predictor of outcome for patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent chemoradiation therapy followed by esophagectomy. The findings in the current study supported the concept of downstaging by preoperative therapy.

Carcinoma↗

PubMed2005

[A survey on the diagnosis and treatment of biliary tract cancers in Shanghai].

OBJECTIVE: To survey the status of diagnosis and treatment of biliary tract cancer in Shanghai. METHODS: A clinical epidemiology investigation was carried out on 658 new cases of biliary duct cancers aged 35-74, that registered between June 1997 and May 2001 in urban Shanghai. Clinical findings were collected in 390 gallbladder cancer, 195 bile duct cancer and 73 ampullary cancer. RESULTS: Biliary tract cancers mainly occurred in elderly patients. Ratio of males to female was 1:2.61 in gallbladder cancer, while bile duct cancer and ampullary cancer were slightly more common in men. Association with gallstones was 68.5%, 43.1% and 22.4% for gallbladder cancer, bile duct cancer and ampullary cancer, respectively. Diagnostic accuracy rate of B-ultrasonography was 63.1% in gallbladder cancer. Incidental gallbladder cancer accounted for 20%, while stage IVA and IVB patients reached up to 43.6%. Misdiagnosis rate was still high in bile duct cancer and ampullary cancer, it was 19.1% and 47.1% respectively. In addition, most patients presented jaundice at diagnosis. 69 cases (18.2%) of gallbladder cancer, 50 cases (25.6%) of bile duct cancer and 54 cases (74%) of ampullary cancer underwent radical resection, the 1-, 3- and 5-year survival rates were 58.5%, 42.8% and 40.7%, 58%, 28.3% and 11.1%, 81.5%, 39.2% and 26.9%, respectively. 79 patients with bile duct cancer underwent palliative drainage, and most cases died within 1 year. Metal endo-prostheses or plastic stents were placed into the biliary tract in 38 patients. The median survival was about 7 months. CONCLUSIONS: It is difficult to make early diagnosis of biliary tract cancers. Standardization of the operation for gallbladder cancer must be respected. Surgical exploration should be undertaken when a bile duct cancer is suspected and there are no contraindications to surgery. Pancreatoduodenectomy should be recommended for ampullary cancer.

Biliary Tract Neoplasms↗

PubMed2005

Signet-ring cell or mucinous histology after preoperative chemoradiation and survival in patients with esophageal or esophagogastric junction adenocarcinoma.

PURPOSE: The survival of patients with local-regional adenocarcinoma of the esophagus or esophagogastric junction (EGJ) treated with preoperative chemoradiation is much better in patients with pathologic complete response than those with residual tumor. Some adenocarcinomas have mixed patterns, including signet-ring cell and mucinous histology, but the clinical significance of these subtypes is unknown. EXPERIMENTAL DESIGN: We studied 412 consecutive patients with esophageal or EGJ adenocarcinoma treated with chemoradiation followed by esophagectomy (193 patients) or surgery alone (219 patients). We evaluated signet-ring cell and mucinous histology in the resection and pretherapy biopsy specimens and compared clinicopathologic features with overall survival. RESULTS: The fraction of signet-ring cell and mucinous histology was similar in evaluated specimens of patients treated with preoperative chemoradiation or surgery alone (17% and 18%, respectively). The overall survival rate at 5 years of patients treated with preoperative chemoradiation was significantly better if residual signet-ring cell or mucinous histology was present in the esophagectomy specimen (63% versus 28%; P = 0.02). All 13 patients with acellular mucin pools and no residual carcinoma are still alive after an average follow-up time of 36 months. By contrast, in patients treated with surgery alone, overall survival rate was significantly worse if signet-ring cell or mucinous histology was present (14% versus 30%; P = 0.05). In multivariate analysis, overall survival was independently predicted by presence of signet-ring cell or mucinous histology (P = 0.04). CONCLUSIONS: Our study showed that patients with esophageal or EGJ adenocarcinoma who have signet-ring cell or mucinous histology benefited substantially from preoperative chemoradiation and esophagectomy.

Adenocarcinoma, Mucinous↗

PubMed2005

Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma.

PURPOSE: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. EXPERIMENTAL DESIGN: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. RESULTS: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). CONCLUSIONS: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not an independent predictor of prognosis in resected gastric cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668.

PURPOSE: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. RESULTS: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. CONCLUSIONS: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Adult↗

PubMed2005

BRAF mutations in aberrant crypt foci and hyperplastic polyposis.

Patients with hyperplastic polyposis have multiple hyperplastic polyps (HPs) and increased risk of colorectal carcinomas. Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesions in colorectal carcinogenesis. We evaluated BRAF mutations by DNA sequencing in 53 ACF from patients with sporadic colorectal carcinomas and familial adenomatous polyposis, in 18 sporadic HPs from patients with resected colorectal cancer, and in 70 HPs, 4 serrated adenomas, 3 admixed hyperplastic-adenomatous polyps, 10 tubular adenomas, and 6 carcinomas from 17 patients with multiple/large HPs and/or hyperplastic polyposis. BRAF mutation status was compared with clinicopathological features and other genetic alterations by marginal logistic regression. BRAF mutation was present in only 2% of ACF and 6% of sporadic HPs. In contrast, BRAF mutation was present in 43% of HPs (P = 0.01 versus sporadic HPs), 75% of serrated adenomas, 33% of admixed hyperplastic-adenomatous polyps, 30% of tubular adenomas, and 33% of carcinomas from patients with multiple/large HPs and/or hyperplastic polyposis. BRAF mutation status in patients with multiple/large HPs and/or hyperplastic polyposis correlated with HPs from the same patient (odds ratio, 5.8; P = 0.0002) but associated with younger age (odds ratio, 0.83; P = 0.006 compared to older age), with a large HP (odds ratio, 22.5; P = 0.01 compared with patients with multiple HPs), with location of HPs in the right colon (odds ratio, 3.0; P = 0.03), and with methylation of the p16 gene and the MINT31 locus [odds ratio, 12.2 (P = 0.0001) and 4.4 (P = 0.02), respectively]. Our study shows that BRAF mutation status is heterogeneous among patients with multiple/large HPs and/or hyperplastic polyposis, suggesting differences in pathogenesis of HPs that indicate subsets within this phenotype.

Adenocarcinoma↗

PubMed2005

Genetic analysis of sinonasal adenocarcinoma phenotypes: distinct alterations of histogenetic significance.

Sinonasal adenocarcinomas, a relatively rare entity, are composed of distinctly different morphologic subtypes with variable biological behavior. To investigate the genetic events associated with their development and clinicopathologic features, we analyzed the alterations in K-ras, APC, beta-catenin, hMLH1 and hMSH2 and p53 genes expression in a cohort of 15 primary tumors comprising the two main sinonasal adenocarcinoma subtypes (enteric and seromucinous). The patients consisted of 13 men and two women, who ranged in age from 50 to 87 years. Tumors were predominantly located in the ethmoid sinus. Eight tumors were Enteric-type, and seven were seromucinous type. Nine patients were smokers and four were nonsmokers; and no information was available on two patients. Two of the eight enteric-type, had K-ras mutation at codons 12A and 12B, and one showed microsatellite instability at BAT-25. Two patients with enteric-type tumors had a history of wood-dust exposure, and one had a K-ras mutation at 12A codon as well as p53 overexpression. No patients with the seromucinous type had any genetic abnormalities, except for overexpression of p53 in two tumors. Our results show that (1) a subset of enteric-type sinonasal adenocarcinoma shares certain genetic alterations with colonic adenocarcinomas, (2) the seromucinous-type sinonasal adenocarcinoma lacks alterations and may develop through a different pathway, (3) high p53 expression is associated with aggressive tumor features in both subtypes and (4) the enteric-type runs a more malignant course than the seromucinous counterpart.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors.

Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P=0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P=0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P=0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P=0.02). Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.

Adult↗

PubMed2005

Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis.

Well-differentiated neuroendocrine tumors including pancreatic endocrine tumors and carcinoid tumors are uncommon neoplasms that have site-specific differences in clinicopathological features, clinical course and genetic alterations. The epigenetic alterations in these tumors are not well characterized. We therefore compared methylation of the RAS-association domain family 1, isoform A (RASSF1A), p14, p16 and O6-methyl-guanine methyltransferase genes in neuroendocrine tumors from 47 patients including 16 pancreatic, 15 nonileal and 16 ileal neuroendocrine tumors. Methylation of the RASSF1A gene was present in 57% of tumors, p14 in 49%, p16 in 26% and O6-methyl-guanine methyltransferase in 13% of tumors. Ileal neuroendocrine tumors lacked methylation of O6-methyl-guanine methyltransferase gene (P = 0.04). RASSF1A methylation was associated with histopathologic type of tumors (P = 0.03) and lymph node metastasis (P = 0.004), and p16 methylation with older patient age (P = 0.002) and liver metastasis (P = 0.04). Two or more genes were methylated in 53% of tumors, one gene was methylated in 30% of tumors, and all four genes were unmethylated in 17% of tumors. Methylation of one or more gene was associated with older age of patients (P = 0.01), and methylation of two or more genes was associated with liver metastasis (P = 0.044). Our study shows that in neuroendocrine tumors epigenetic alterations vary by tumor subsite and clinicopathologic features, including age of onset, histopathologic type and metastasis status.

Aged↗

PubMed2005

Aspirin use and risk of biliary tract cancer: a population-based study in Shanghai, China.

The association of gallbladder and bile duct cancers with gallstones, cholecystitis, and cholangitis suggest that chronic inflammation contributes to the carcinogenic process. However, the effect of nonsteroidal anti-inflammatory drugs, such as aspirin, on biliary tract cancer has not been well studied. In a population-based case-control study conducted in Shanghai, China, we examined the relationship between aspirin use and the risk of biliary disease. A total of 627 patients with biliary tract cancer, including cancers of the gallbladder (n = 368), extrahepatic bile duct (n = 191), and ampulla of Vater (n = 68); 1,037 patients with biliary stones; and 958 healthy adults were included in the study. Self-reported data on aspirin use was collected from study participants by in-person interview. The prevalence of aspirin use was low, with 5.7% of the population controls being regular users. After controlling for age, sex, education, and biliary stone status, aspirin use was associated with a reduced risk of gallbladder cancer [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.17-0.88]. An inverse relationship was also observed for frequency and duration of use and with younger age when starting use. In addition, there was a nonsignificant reduction in the risk of bile duct (OR, 0.48; 95% CI, 0.19-1.19) and ampullary cancers (OR, 0.22; 95% CI, 0.03-1.65) associated with aspirin use, whereas no clear association was seen with biliary stones (OR, 0.92; 95% CI, 0.59-1.44). Further studies of biliary tract cancer in other populations are needed to confirm these results and to elucidate the mechanisms that underlie the reduced risk associated with use of aspirin and possibly other nonsteroidal anti-inflammatory drugs.

Adult↗

PubMed2005

Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive (T1) esophageal adenocarcinoma.

Superficially invasive esophageal adenocarcinomas are a heterogeneous group of tumors, including tumors invading into mucosa and submucosa. The prognostic significance of the depth of tumor invasion and lymph node status in this group of patients remain unclear. We evaluated 90 consecutive patients with resected T1 adenocarcinoma of esophagus or esophagogastric junction. The T1 tumors were classified into four groups based on the depth of invasion: T1a, invading into lamina propria; T1b, into muscularis mucosae; T1c, into superficial submucosa; and T1d, into deep submucosa. The depth of tumor invasion was compared with clinicopathologic features. The depth of tumor invasion was significantly associated with the presence of lymph node metastasis (36% in T1d, 8% in T1c, 12% in T1b, and 0% in T1a; P < 0.001) and with tumor size (76% > 1.2 cm in T1d, 75% in T1c, 35% in T1b, and 25% in T1a; P < 0.001). The 5-year recurrence-free and overall survivals were significantly better in patients with tumors confined to mucosa (100% and 91%, respectively) than invasive into submucosa (60% and 58%; P = 0.0005 and P = 0.02, respectively). Lymph node metastasis was associated with tumor recurrence (P = 0.01) but not overall survival. Lymphovascular invasion was associated with both tumor recurrence (P = 0.001) and overall survival (P < 0.001) and was an independent prognostic factor in multivariate analysis (P = 0.04). Our study indicated evaluation of depth of tumor invasion, status of lymph nodes, and lymphovascular invasion is important in resected superficially invasive esophageal adenocarcinoma and may provide supportive information for the decision about postoperative adjuvant therapy.

Adenocarcinoma↗

PubMed2005

[Tea consumption and risk of biliary tract cancers and gallstone disease: a population-based case-control study in Shanghai, China].

OBJECTIVE: To investigate the relationship between tea consumption, biliary tract cancers and gallstone disease. METHODS: A population-based case-control study was conducted in urban Shanghai from 1 June 1997 to 31 May 2001 involving interviews with 627 new cases of biliary tract cancers (including 368 cases of gallbladder cancer, 191 cases of extrahepatic bile duct cancer and 68 cases of cancer of the ampulla of Vater) aged 35 to 74 years and 959 population controls frequency-matched to cases by gender and age in five-year group. 1037 patients of gallstone disease were selected from the same hospital. All subjects were interviewed in person by trained interviewers by use of a structured questionnaire. Unconditional logistic regression analysis was used to calculate adjusted odds ratio (OR) and 95% confidence interval (CI). RESULTS: Compared with tea non-drinkers, current tea consumption was inversely associated with risk of gallbladder cancer, extrahepatic bile duct cancer and gallstone disease among females with OR of 0.57 (95% CI: 0.34-0.96), 0.53 (95% CI: 0.27-1.03) and 0.71 (95% CI: 0.51-0.99), respectively. OR declined with younger age at initiation of tea drinking and with longer duration of tea consumption (P for trend < 0.05). Among males, the corresponding OR were mostly below one, although not statistically significant. CONCLUSION: Tea consumption may decrease the risk of cancers of the gallbladder and extrahepatic bile duct among females. The protective effect appears to be independent of gallstone disease.

Adult↗

PubMed2004

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas.

Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumor-related genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P=0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of high-level CpG island methylation (CIM-H, methylation index > or =0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P=0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellite-stable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions.

Adaptor Proteins, Signal Transducing↗

PubMed2004

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.

Base Sequence↗