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Allelic loss on chromosome bands 13q11-q13 in esophageal squamous cell carcinoma.
Li G, Hu N, Goldstein AM, Tang ZZ, Roth MJ, Wang QH, Dawsey SM, Han XY, Ding T, Huang J, Giffen C, Taylor PR, Emmert-Buck MR.
Shanxi Cancer Hospital, Taiyuan, Shanxi, P.R. China.
Allelic loss on chromosome 13 occurs frequently in esophageal squamous cell carcinoma. However, studies of the two known tumor suppressor genes located on 13q, RB1 and BRCA2, have shown few mutations, suggesting that other genes are likely to be involved in the development of this tumor type. To identify a minimal deletion interval, we first analyzed 42 microsatellite markers spanning chromosome bands 13q11-q13 in 56 esophageal squamous cell carcinoma patients, including 34 with a family history of upper gastrointestinal cancer and 22 without a family history of cancer. Lifestyle risk factors and clinical/pathologic characteristics were also collected. Two commonly deleted regions were identified: one was located on band 13q12.11, between markers D13S787 and D13S221; the other was located on bands 13q12.3-q13.1 from markers D13S267 to D13S219. We observed higher allelic loss frequencies for eight of the microsatellite markers in those patients with a family history of upper gastrointestinal cancer compared to patients without such a history. This study suggests that one or more unidentified tumor suppressor genes are located on chromosome arm 13q that play a role in the development of esophageal squamous cell carcinoma. Copyright 2001 Wiley-Liss, Inc.
PMID: 11433530 [PubMed - indexed for MEDLINE]
Genetic progression and heterogeneity associated with the development of esophageal squamous cell carcinoma.
Roth MJ, Hu N, Emmert-Buck MR, Wang QH, Dawsey SM, Li G, Guo WJ, Zhang YZ, Taylor PR.
Cancer Prevention Studies Branch, National Cancer Institute, 6006 Executive Plaza, Bethesda, MD 20892, USA. [email protected]
Esophageal squamous cell carcinoma is a common fatal cancer, and Shanxi province, a region in north-central China, has some of the highest esophageal cancer rates in the world. Chromosomal regions with frequent allelic loss may point to major susceptibility genes that will assist us in understanding the molecular events involved in esophageal carcinogenesis and may serve as the basis for the development of markers for genetic susceptibility and screening for early detection of this cancer. This study was designed to identify events in the molecular progression of precursor and invasive lesions of squamous esophageal cancer. Twelve marker loci identified during our previous studies as having some of the highest rates of loss of heterozygosity (LOH) in invasive esophageal cancer were evaluated in laser-microdissected DNA obtained from low- and high-grade dysplastic lesions and invasive tumor foci from 10 fully embedded esophageal resection specimens. Each resection specimen contained a spectrum of disease, from epithelium that appeared histologically normal to invasive cancer, including a single dominant tumor surrounded by a region of precursor lesions (low- and high-grade dysplasia) and occasional "remote," nonadjacent precancerous foci. Using the 12 polymorphic markers, LOH was found in all of the three stages of disease. The frequency of LOH for all of the markers together increased with increasing disease severity. Among the informative low-grade dysplasia samples, LOH was detected with markers D3S1766 (3p), D4S2632 (4p), D9S910 (9q), and D13S1493 (13q), suggesting that LOH at these loci may be associated with early stages of tumor initiation and/or progression. LOH was detected among the informative high-grade (but not low-grade) dysplasia samples for the other eight markers tested, suggesting that LOH at these loci may occur later in the neoplastic process. In addition to the association between disease progression and these genetic changes, considerable genetic heterogeneity was found in each fully embedded resection specimen both between and within geographically separate neoplastic lesions.
PMID: 11358832 [PubMed - indexed for MEDLINE]
Frequent inactivation of the TP53 gene in esophageal squamous cell carcinoma from a high-risk population in China.
Hu N, Huang J, Emmert-Buck MR, Tang ZZ, Roth MJ, Wang C, Dawsey SM, Li G, Li WJ, Wang QH, Han XY, Ding T, Giffen C, Goldstein AM, Taylor PR.
Divisions of clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide, and north central China has some of the highest rates in the world. Previous studies from tumors in this area of China have shown high frequencies of allelic loss on chromosome 17p13-11, which includes the region where the TP53 gene is found. We examined 56 ESCC patients using single-strand conformation polymorphism and DNA sequencing to assess the frequency and spectrum of TP53 mutation and the association between allelic loss at microsatellite marker TP53 and TP53 mutations. Ninety-six % of cases were found to have at least one genetic alteration, including TP53 mutation (77%), allelic loss within the TP53 gene (73%), and/or loss of heterozygosity at the TP53 microsatellite marker (80%); 75% had two or more such alterations, including 59% with both a point mutation and an intragenic allelic loss ("two hits"). The majority of mutations observed were in exon 5, where the most common type of nucleotide substitution was a G:C-->A:T or C:G-->T:A transition, including half that occurred at CpG sites. Allelic loss was most commonly found in exon 4 but was very common in exon 5 as well. Taken together, the multiple genetic alterations of TP53 in this population at high risk for ESCC indicate that there is a very high degree of genetic instability in these tumors, that TP53 is a primary target for inactivation, and that this tumor suppressor gene plays a critical role in the carcinogenesis process for ESCC.
PMID: 11309337 [PubMed - indexed for MEDLINE]
Association between GSTM1*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, China.
Roth MJ, Dawsey SM, Wang G, Tangrea JA, Zhou B, Ratnasinghe D, Woodson KG, Olivero OA, Poirier MC, Frye BL, Taylor PR, Weston A.
The Cancer Prevention Studies Branch, Division of Clinical Sciences, National Cancer Institute NIH, Bethesda, MD 20892, USA. [email protected]
Individuals with specific phase I and phase II enzyme polymorphisms may be at increased risk for squamous cell carcinoma of the esophagus. However, to our knowledge there has been only one previous report that evaluates a potential role for these polymorphisms in increasing risk for preneoplastic squamous lesions of the esophagus. To explore this further, we examined polymorphisms in CYP1A1, CYP2E1, GSTM1 and GSTT1, both independently and in combination, for potential associations with the risk of biopsy-proven squamous dysplasia of the esophagus in asymptomatic adults from Linxian, a high risk region in China. Cases consisted of 56 individuals from an esophageal cancer screening study with an endoscopic biopsy diagnosis of mild or moderate squamous dysplasia. Each case was matched on age (+/- 1 year) and gender to a control. Controls were defined as screening study participants with an endoscopic biopsy diagnosis of normal mucosa or esophagitis. DNA was extracted from frozen cell samples obtained by cytologic balloon examination and genotyped using standard methods. Individuals who were GSTM1 null (homozygous for GSTM1*0) were found to have a tendency for an increased risk of esophageal squamous dysplasia (odds ratio=2.6, 95% CI, 0.9-7.4). No excess risks were observed for inheritance of other putative at risk genotypes CYP1A1*2B, CYP2E1*6 or GSTT1*0. The risk associated with the inheritance of combined genotypes was not significantly different than the risk estimates from the univariate analysis. These results are consistent with the notion that exposure to environmental carcinogens that are detoxified by GSTM1, such as polycyclic aromatic hydrocarbons, may contribute to the etiology of esophageal cancer in Linxian.
PMID: 10840162 [PubMed - indexed for MEDLINE]
Comment in:
Differences in diagnostic criteria for esophageal squamous cell carcinoma between Japanese and Western pathologists.
Schlemper RJ, Dawsey SM, Itabashi M, Iwashita A, Kato Y, Koike M, Lewin KJ, Riddell RH, Shimoda T, Sipponen P, Stolte M, Watanabe H.
Department of Internal Medicine, Fukuoka University School of Medicine, Fukuoka, Japan.
BACKGROUND: Large discrepancies have been found between Western and Japanese pathologists in the diagnosis of adenoma/dysplasia versus carcinoma for gastric and colorectal glandular lesions. It is important to determine whether similar differences exist in the diagnosis of esophageal squamous lesions. METHODS: Eleven expert gastrointestinal pathologists from Japan, North America, and Europe individually reviewed a set of microscopic slides containing 21 sections of biopsies and corresponding endoscopic mucosal resection specimens from Japanese patients with superficial esophageal squamous neoplastic lesions. The pathologists indicated the pathologic findings on which they based each diagnosis. RESULTS: Invasion was the most important diagnostic criterion of carcinoma for the Western pathologists whereas nuclear and structural features were more important for the Japanese pathologists. For two sections showing low grade dysplasia according to most Western pathologists, the Japanese pathologists diagnosed suspected carcinoma in one case and definite carcinoma in the other. For nine sections with high grade dysplasia according to the Western pathologists, the Japanese pathologists diagnosed suspected carcinoma in two cases and definite carcinoma in seven cases. For six sections with suspected carcinoma according to most Western pathologists, the Japanese pathologists diagnosed suspected carcinoma in one case and definite carcinoma in five cases. Four sections showed definite carcinoma according to both the Western and Japanese pathologists. Thus, there was agreement among the Western and Japanese pathologists for only 5 of the 21 sections (kappa value, 0.04). However, when high grade dysplasia, noninvasive carcinoma, and suspected carcinoma were grouped together, the agreement was excellent (19 of the 21 sections; kappa value, 0.75). CONCLUSIONS: In Japan, esophageal squamous cell carcinoma is diagnosed mainly based on nuclear criteria, even in cases judged to be noninvasive low grade dysplasia in the West. This difference in diagnostic practice may contribute to the relatively high incidence rate and good prognosis of superficial esophageal carcinoma in Japan. To improve the comparability of research data, the authors recommend that high grade dysplasia, noninvasive carcinoma, and suspected carcinoma be grouped together into one category of "noninvasive high grade neoplasia." [See editorial on pages 969-70, this issue.] Copyright 2000 American Cancer Society.
PMID: 10699887 [PubMed - indexed for MEDLINE]
Comment in:
Histopathologic changes seen in esophagectomy specimens from the high-risk region of Linxian, China: potential clues to an etiologic exposure?
Roth MJ, Guo-Qing W, Lewin KJ, Ning L, Dawsey SM, Wesley MN, Giffen C, Yong-Qiang X, Maher MM, Taylor PR.
Cancer Prevention Studies Branch, National Cancer Institute, Bethesda, MD 20892-7058, USA.
Esophageal cancer is one of the most fatal cancers worldwide and is characterized by great variation in rates among different populations. Linxian, a county in Henan Province, located in north-central China, has one of the highest rates of esophageal squamous cell carcinoma in the world. Most squamous cell carcinomas in low-risk populations are attributable to alcohol and tobacco consumption, but the causative agents in high-risk populations are less clear. The prevention and treatment of esophageal cancer in high-risk regions, such as Linxian, are limited by our inability to identify these agent(s). During a preliminary histological review, the authors noticed characteristic findings in the arteries, nerves, and lymph nodes of esophagectomy specimens from Linxian and wondered whether these findings might offer clues to the cause of squamous cell carcinoma (eg, polycyclic aromatic hydrocarbon exposure) in the Linxian population. The purpose of this study was to report these previously undescribed histopathologic changes and to compare their presence and severity with those found in esophageal squamous cell carcinomas and adenocarcinomas from a lower-risk population in the United States. Forty esophagectomies were reviewed, including 13 squamous cell carcinomas from Linxian and 21 squamous cell carcinomas and six adenocarcinomas from the United States. The presence and severity of arteriosclerosis and myxoid degeneration of nerves and the presence of anthracosis in periesophageal lymph nodes were recorded. The prevalence and severity of these findings in the three groups of esophagectomies were compared. The esophageal squamous cell carcinomas from Linxian, China, had a higher prevalence of arteriosclerotic vessels, nerves with myxoid degeneration, and anthracotic lymph nodes than the squamous cell carcinomas from the United States (Wilcoxon test, P < .04 for all comparisons). There were also significant differences in the prevalence of arteriosclerotic vessels and anthracotic lymph nodes between the esophageal squamous cell carcinomas from Linxian and the adenocarcinomas from the United States. Arteriosclerosis and the myxoid degeneration were significantly more severe in the esophageal squamous cell carcinomas from Linxian than in the esophageal squamous cell carcinomas or adenocarcinomas from the United States (Mantel trend test, P < .006 for all comparisons). Arteriosclerotic vessels, nerves with myxoid degeneration, and anthracotic lymph nodes can be seen in association with esophageal squamous cell carcinomas from the high-risk region of Linxian, China. These changes appear to be more prevalent and severe than those seen in association with esophageal squamous cell carcinomas or adenocarcinomas from a low-risk population in the United States. These characteristic changes may be causatively significant and may represent histological evidence of high-level environmental exposure to polycyclic aromatic hydrocarbons.
PMID: 9824110 [PubMed - indexed for MEDLINE]
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Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China.
Dawsey SM, Fleischer DE, Wang GQ, Zhou B, Kidwell JA, Lu N, Lewin KJ, Roth MJ, Tio TL, Taylor PR.
Cancer Prevention Studies Branch, National Cancer Institute, Bethesda, Maryland 20892-7058, USA.
BACKGROUND: In previous studies in the high risk population of Linxian, China, the majority of foci of high grade (moderate and severe) squamous dysplasia (HGD) and invasive squamous carcinoma (CA) of the esophagus were associated with endoscopically visible lesions that could be targeted for biopsy, but some foci of HGD were missed by routine endoscopic examination. This study examined whether spraying the mucosa with Lugol's iodine solution, which stains normal epithelium brown but leaves dysplasia and carcinoma unstained, could improve endoscopic detection and delineation of these lesions. METHODS: Two hundred twenty-five Linxian adults with balloon cytologic evidence of dysplasia or carcinoma underwent endoscopy. All visible lesions were described and photographed before and after staining with 1.2% Lugol's iodine solution. Biopsies were taken from all lesions visible before staining, from all unstained lesions (USLs) after applying the stain, and from representative control areas of stained mucosa. RESULTS: Two hundred fifty-three USLs and 255 control sites were biopsied. No complications occurred. Ninety-four biopsy sites contained HGD and 20 contained CA. Before staining, the sensitivity of visible lesions for identifying HGD or CA was 62%, and the specificity was 79%. After staining, the sensitivity of USLs for identifying HGD or CA was 96%, and the specificity was 63%. Eighty-eight percent of the HGD and CA lesions were larger or more clearly defined after staining. The diagnostic lesions in 17 of 31 patients with moderate dysplasia (55%), 8 of 35 patients with severe dysplasia (23%), and none of the 19 patients with invasive carcinoma (0%) were identified only after staining. CONCLUSIONS: Mucosal iodine staining improved endoscopic detection and delineation of HGD and CA in these patients. This simple technique is highly sensitive for identifying these precursor and invasive squamous lesions, and it should be used whenever optimal visualization of squamous mucosal abnormalities is required.
Publication Types:
- Review
- Review of Reported Cases
PMID: 9669803 [PubMed - indexed for MEDLINE]
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Quantitative fluorescence image analysis of DNA content and nuclear morphology on esophageal balloon cytology smears and subsequent development of esophageal and gastric cardia cancer in Linxian, China.
Hu N, Taylor PR, Rao JY, Hemstreet GP, Liu SF, Zou XN, Mark SD, Dawsey SM.
National Cancer Institute, Bethesda, Maryland 20892, USA.
The highest incidences of esophageal and gastric cardia cancer in the world occur in northern China. Chinese scientists have developed esophageal balloon cytology screening to detect these cancers, but traditional cytology is sometimes inadequate to find some early, curable lesions. Several studies suggest that quantitative fluorescence image analysis (QFIA) of DNA ploidy and nuclear morphology may be able to improve upon traditional cytology results. In October 1987, esophageal balloon cytology was performed on 1331 adults in Linxian, China, and all samples were evaluated both by traditional cytology and QFIA. From 1987 to May 1991, 62 new squamous esophageal cancers and 44 new adenocarcinomas of the cardia were identified in this cohort. Proportional hazards models were used to evaluate the relationship of cytological diagnoses and six QFIA variables to subsequent cancer risk. These models showed significant trends for increasing esophageal cancer risk, with increasing values in five of the QFIA variables and with increasing severity of the traditional cytological diagnoses. A comparison of models with only cytology variables versus models with both cytology and QFIA variables indicated that the QFIA provided an important additional predictive value. Persons with both cytological dysplasia and high cellular DNA were 8 times more likely to develop esophageal cancer than were individuals with neither of these conditions. For cardia cancer, associations between QFIA variables or cytological diagnoses and later cancer were more limited. This study suggests that the QFIA variables evaluated here are independent predictors of squamous esophageal cancer and that combining QFIA with traditional cytology can improve prediction of esophageal cancer risk.
PMID: 9456244 [PubMed - indexed for MEDLINE]
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Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China.
Roth MJ, Liu SF, Dawsey SM, Zhou B, Copeland C, Wang GQ, Solomon D, Baker SG, Giffen CA, Taylor PR.
Cancer Prevention Studies Branch, National Cancer Institute, Bethesda, Maryland, USA.
BACKGROUND: The principal reason for the poor prognosis of esophageal carcinoma is that most tumors are asymptomatic and go undetected until they are unresectable. Previous studies have shown that cytologic screening of asymptomatic high risk individuals can detect curable esophageal carcinomas and precursor lesions, but the sensitivity of such screening is not well documented. The current study evaluated the sensitivity and specificity of currently available balloon and sponge cytologic samplers for detecting biopsy-proven squamous dysplasia and carcinoma in asymptomatic individuals from a high risk population in Linxian, China. METHODS: Asymptomatic adults were examined with both balloon and sponge samplers, in random order, followed by endoscopy with mucosal iodine staining and biopsy of all unstained lesions. The cytology slides were interpreted using the criteria of the Bethesda System. The balloon and sponge cytologic diagnoses (test) were compared with the biopsy diagnosis (truth) in each patient to estimate the sensitivity and specificity of each sampler. RESULTS: Of the 439 patients with adequate biopsies, 123 (28%) had histologic squamous dysplasia and 16 (4%) had an invasive squamous carcinoma. The sensitivities/specificities of the balloon and sponge were 44%/99% and 18%/100%, respectively, for detecting biopsy-proven squamous cell carcinoma, and 47%/81% and 24%/92%, respectively, for identifying squamous dysplasia or carcinoma. CONCLUSIONS: In this study, the balloon sampler was more sensitive than the sponge sampler for detecting esophageal squamous disease, but both techniques were less than optimal. Improved samplers and/or cytologic criteria should increase the sensitivities observed in this baseline study.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 9392326 [PubMed - indexed for MEDLINE]
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Studies of esophageal balloon cytology in Linxian, China.
Dawsey SM, Shen Q, Nieberg RK, Liu SF, English SA, Cao J, Zhou B, Wang GQ, Lewin KJ, Liu FS, Roth MJ, Taylor PR.
National Cancer Institute, Bethesda, Maryland 20892, USA.
Esophageal cancer is the second leading cause of cancer death in China. Esophageal cancer has a very poor prognosis, principally because most tumors are asymptomatic until they are unresectable. Esophageal balloon cytology is an early detection method developed by Chinese scientists to identify resectable early cancers and precursor lesions. Previous studies have reported high sensitivities for detecting esophageal cancer in symptomatic patients. The current report describes several studies evaluating this diagnostic technique in asymptomatic individuals. A comparison of Chinese and U. S. cytological diagnoses of the same esophageal samples showed that the Chinese categories of precancerous neoplasia were more inclusive than the corresponding U. S. categories. Comparisons of both Chinese and U. S. cytological diagnoses with concurrent histological findings showed low (14-36%) sensitivities for the cytological detection of biopsy-proven cancers. Prospective follow-up studies of several screened cohorts showed a consistent progression of risk for developing esophageal cancer with increasing severity of initial cytological diagnosis. These preliminary studies suggest that esophageal balloon cytology is a useful technique that can benefit from additional research to improve its optimal performance.
PMID: 9037563 [PubMed - indexed for MEDLINE]
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Items 1-10 of 10 |
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One page. |
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