Biomedical subjects

Asif Rashid

Publications and source records attributed to Asif Rashid.

64 records · Page 4Linked to original sources

PubMed2002

Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin.

PURPOSE: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. PATIENTS AND METHODS: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. RESULTS: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P =.027) and endothelial cell apoptosis (P =.027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. CONCLUSION: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.

Adenocarcinoma↗

PubMed2002

DNA methylation and environmental exposures in human hepatocellular carcinoma.

BACKGROUND: Hypermethylation of a CpG-rich promoter (CpG island) blocks expression of the corresponding gene. The CpG island methylator phenotype (CIMP), defined as a variable pattern of hypermethylation of CpG islands in tumor suppressor genes, may be associated with carcinogenesis. To determine whether CIMP is associated with the development of hepatocellular carcinoma (HCC) and with exposure to environmental agents, we examined the methylation status of CpG islands in HCCs from countries with various HCC risks. METHODS: We examined the methylation status of 12 CpG islands (eight for known genes) in 85 HCC tumors from various geographic locations by use of bisulfite-polymerase chain reaction methylation assays and analyzed results with univariate and multivariable methods. All statistical tests were two-sided. RESULTS: Eight CpG islands were hypermethylated. The frequency of hypermethylation in the 85 tumors was 62% for the estrogen receptor (ER), 42% for p16, 18% for cyclooxygenase-2, 21% for the T-type calcium channel gene, 38% for MINT31, 28% for MINT1, 15% for MINT27, and 11% for MINT2 (the latter four CpG islands are not yet associated with genes). Methylation levels of the eight frequently methylated CpG islands were positively correlated (from R =.2 [P =.05] to R =.6 [P<.001]), supporting the presence of CIMP. p16 methylation had statistically significant geographic variation (34.4% in tumors from China and Egypt versus 12.2% in tumors from the United States and Europe, difference = 22.2%; 95% confidence interval [CI] = 11.2% to 33.2%; P<.001). Similar geographic variations were observed for ER methylation and CIMP. This observation was partly related to higher methylation in tumors from patients with cirrhosis (33.6% for patients with cirrhosis versus 11.7% for those without it; difference = 21.9%; 95% CI = 10.9% to 32.8%; P<.001) or hepatitis (34.2% for patients with hepatitis versus 6.2% for those without it; difference = 28%; 95% CI = 18.3% to 37.6%; P<.001). CONCLUSION: Geographic variations in the methylation status of various CpG islands indicate that environmental factors may influence the frequent and concordant degree of hypermethylation in multiple genes in HCC tumors.

Aflatoxins↗

PubMed2002

Simplified staging for hepatocellular carcinoma.

PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) fails to stratify patients adequately with respect to prognosis. PATIENTS AND METHODS: The ability of the currently proposed tumor (T) categories to effectively stratify the survival of 557 patients who underwent complete resection for HCC at four centers was examined. Independent predictors of survival were combined into a new staging system. RESULTS: Using the current AJCC T classification, patients with T1 and T2 tumors had similar 5-year survivals (P =.6). In addition, the survival of patients with multiple bilobar tumors (T4) matched that of T3 patients (P =.5). Independent predictors of death were major vascular invasion (P <.001), microvascular invasion (P =.001), severe fibrosis/cirrhosis of the host liver (P =.001), multiple tumors (P =.007), and tumor size greater than 5 cm (P =.01). Based on our results, a simplified stratification is proposed: (a) patients with a single tumor and no microvascular invasion, (b) patients with a single tumor and microvascular invasion or multiple tumors, none more than 5 cm, and (c) patients with either multiple tumors, any more than 5 cm, or tumor with major vascular invasion (P <.001). Severe fibrosis/cirrhosis had a negative impact on survival within all categories. The survival of patients with lymph node involvement matched that of patients with major vascular invasion (P =.3). CONCLUSION: The current AJCC staging system for HCC is unnecessarily complex. We propose a simplified model of stratification that is based on vascular invasion, tumor number, and tumor size and incorporates the effect of fibrosis on survival.

Adolescent↗

PubMed2002

Effects of sex and racial/ethnic group on the pattern of gastric cancer localization.

BACKGROUND: In Western countries, the overall incidence of gastric cancer is declining, while the incidence of proximal gastric cancer is rising. We evaluated the effect of sex, racial/ethnic group, and age on the localization of gastric cancer. METHODS: The records of all gastric cancer patients who registered at The University of Texas M. D. Anderson Cancer Center from January 1, 1985, to May 31, 1998, were reviewed. Tissue diagnosis and established tumor location were required. RESULTS: The case records of 1242 eligible patients, consisting of 821 non-Hispanic white, 230 Hispanic, 125 African American, 63 Asian, and 3 Native American patients, were analyzed. Among the 459 women, racial/ethnic group did not have a significant impact on gastric cancer localization (P = 0.57). However, among the 783 men, proximal cancers were significantly more frequent in the non-Hispanic white patients (57% vs 38% Hispanic, 41% African American, 17% Asian; P < 0.0001). Symptoms at diagnosis significantly varied for proximal vs non-proximal cancers. CONCLUSION: Proximal gastric cancer localization was more frequent among non-Hispanic white men, while non-Hispanic white women had a localization pattern similar to those of other racial/ethnic groups. Proximal gastric cancer represents a distinct subtype of gastric cancer that may have different biology, risk factors, and clinical behavior.

Adenocarcinoma↗

PubMed2002

CpG island methylation in aberrant crypt foci of the colorectum.

Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesion in colorectal carcinogenesis, and CpG island methylation has been described as an important molecular pathway. We therefore studied methylation in ACF from patients with familial adenomatous polyposis (FAP) or sporadic colorectal cancer. We assessed methylation status of the p16 tumor suppressor gene, MINT1 (methylated in tumor 1), MINT2, MINT31, O(6)-methylguanine-DNA methyltransferase gene, and hMLH1 mismatch repair gene. We compared methylation to ACF histopathology, K-ras proto-oncogene mutation, loss of heterozygosity at chromosome 1p, and microsatellite instability. Methylation was present in 34% (21 of 61) of ACF, including both FAP and sporadic types, but was more frequent in sporadic ACF [53% (18 of 34) versus 11% (3 of 27), P = 0.002], especially dysplastic sporadic ACF [75% (3 of 4) versus 8% (2 of 24), P = 0.004]. MINT31 was more frequently methylated in heteroplastic ACF than dysplastic ACF [35% (11 of 31) versus 7% (2 of 30), P = 0.01]. Strong associations of ACF methylation with K-ras mutation (P = 0.007) and with loss of chromosome 1p (P = 0.04) were observed, but methylation was the only molecular abnormality identified in 16% (10 of 61) of ACF. Our findings suggest that methylation in ACF is an early event in the pathogenesis of a subset of colorectal carcinomas, and that ACF from FAP patients and patients with sporadic colorectal cancer have distinct epigenetic changes that reflect differences in molecular pathogenesis.

Adolescent↗

PubMed2002

Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma.

Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.

Adenocarcinoma↗

PubMed2002

Concordant CpG island methylation in hyperplastic polyposis.

The CpG island methylator phenotype (CIMP) is a newly described mechanism for carcinogenesis in colorectal carcinomas and adenomas characterized by methylation of multiple CpG islands. The causes of CIMP are unknown. We studied CIMP in hyperplastic polyps (HPs), with emphasis on patients with multiple HPs (5 to 10 HPs), large HPs (one HP >1 cm) or hyperplastic polyposis (>20 HPs). Methylation of p16, MINT1, MINT2, MINT31, and hMLH1 was analyzed by methylation-specific polymerase chain reaction in 102 HPs, 8 serrated adenomas, 19 tubular adenomas, and 9 adenocarcinomas from 17 patients, with multiple/large HPs or hyperplastic polyposis and in 16 sporadic HPs from 14 additional patients. Sporadic HPs were CIMP-negative (not methylated at any locus), but 43% of HPs from multiple/large HPs, or hyperplastic polyposis were CIMP-high (two or more methylated loci, P = 0.00001). Methylation among the four loci was correlated within HPs (odds ratio, 3.41; P = 0.002), and the methylation status of HPs within the same patient was also correlated (odds ratio, 5.92; P = 0.0001). CIMP-high HPs were present primarily in patients with a predominance of HPs in the right colon and/or serrated adenomas (P = 0.0009) and were associated with the absence of K-ras proto-oncogene mutations (odds ratio, 5.08; P = 0.03). Our findings of concordant CpG island methylation of HPs in multiple/large HPs or hyperplastic polyposis supports the concept that some patients have a hypermethylator phenotype characterized by methylation of multiple HPs and other colorectal lesions. The hypermethylator phenotype is related to patient-specific factors, such as carcinogenic exposure or genetic predisposition.

Adenocarcinoma↗

PubMed2002

Cellular and molecular biology of biliary tract cancers.

Cancer of the biliary tract has been associated with point mutations of K-ras and beta-catenin proto-oncogenes; alterations of p53, p16, APC, and DPC4 tumor suppressor genes by a combination of chromosomal deletion, mutation, or methylation; and infrequently microsatellite instability. The frequencies of these alterations vary by location and race of the patient, tumor subsite, histology, and associated disease. Advances in the understanding of the genetics of this disease will help in diagnosing biliary tract cancer, screening at-risk patients, and developing therapies.

Bile Duct Neoplasms↗

PubMed2002

Mucinous and nonmucinous appendiceal adenocarcinomas: different clinicopathological features but similar genetic alterations.

The genetic alterations of appendiceal carcinomas have not been reported in detail. We studied the clinicopathological factors and genetic alterations including microsatellite instability, p53 overexpression, and mutations of the K-ras proto-oncogene of 30 appendiceal adenocarcinomas, consisting of 23 mucinous and 7 nonmucinous carcinomas. Sixteen (70%) mucinous carcinomas presented with pseudomyxoma peritonei, but 6 of 7 (86%) nonmucinous carcinomas presented with appendicitis (P =.002). All carcinomas were microsatellite stable, and p53 overexpression was present in only 1 of 30 (3%) carcinomas. K-ras mutation was present in 11 of 20 (55%) carcinomas, including 8 of 16 (50%) mucinous and 3 of 4 (75%) nonmucinous carcinomas. The mean survival of patients with mucinous carcinomas was 26 +/- 19 months compared with 13 +/- 9 months for patients with nonmucinous carcinomas (P =.0002). Our findings suggest that mucinous and nonmucinous carcinomas of appendix have similar genetic alterations, but different clinical presentation and prognosis.

Adenocarcinoma↗

PubMed2002

K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China.

PURPOSE: The genetic alterations in biliary tract cancer and clinicopathological associations have not been studied in large population-based studies. EXPERIMENTAL DESIGN: We evaluated genetic alterations such as K-ras mutation, p53 overexpression, microsatellite instability (MSI), and alterations of the polyadenine tract present in the transforming growth factor beta receptor type II (TGFbetaRII) gene in 126 biliary tract cancers: 75 gallbladder cancers, 33 bile duct cancers, and 18 ampullary cancers. These genetic alterations were compared with patient demographics and clinicopathological characteristics of the tumors. RESULTS: Mutation of the K-ras gene was present in 18 of 126 (14.3%) biliary tract cancers. K-ras mutation was present in 11 of 18 (61.1%) ampullary cancers, 5 of 33 (15.2%) bile duct cancers, and 2 of 75 (2.7%) gallbladder cancers (P = 0.000001). The mean survival of patients who had bile duct carcinomas with K-ras mutation was 3.0 +/- 2.2 months compared with 15.5 +/- 12.5 months for those without mutation (P = 0.03) but was not different for other tumor sites. p53 overexpression was present in 34 of 123 (27.6%) cancers. MSI-high (allelic shifts in 40% or more loci or alteration of the TGFbetaRII gene) was present in 4 of 126 (3.2%) biliary tract cancers without hereditary nonpolyposis colorectal cancer. MSI-high was more common in mucinous adenocarcinomas (P = 0.006) and in patients with early age of onset of cancer (P = 0.04). CONCLUSIONS: The genetic alterations in biliary tract cancers are dependent on the tumor subsite, histology, and age of onset and are associated with prognosis.

Adenocarcinoma↗