bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcium, Vitamin D, and Apoptosis in the Rectal Epithelium
Authors: Miller Eric A. , Keku Temitope O. , Satia Jessie A. , Martin Christopher F. , Galanko Joeseph A. , Sandler Robert S.
Published: September 2005

Objective: Decreased apoptosis in the colon is potentially an early indicator of colon cancer risk and may be influenced by calcium and vitamin D. This report describes the associations of calcium intake and 25-hydroxyvitamin D levels with apoptosis in colorectal epithelium.

Methods: Consecutive patients undergoing colonoscopies were recruited for a study designed to examine risk and etiologic factors for colorectal adenomas. Diet was assessed by food frequency questionnaire, and in one subpopulation, serum 25-hydroxyvitamin D levels were measured using an enzyme immunoassay. Apoptosis was scored from normal rectal mucosal pinch biopsies. Linear and logistic regression analyses were used to examine associations between calcium, serum vitamin D, and apoptotic scores. Data were available for 498 and 280 patients for the calcium and vitamin D analyses, respectively.

Results: Associations of calcium intake and vitamin D with apoptosis were modified by adenoma case-status. In an adjusted logistic regression model, patients with adenomas in the highest versus lowest tertile of dietary calcium intake had 3.4 times higher odds [95% confidence interval (CI), 0.9-12.9] of elevated apoptotic scores. In adenoma-free patients, high calcium intake was not related to apoptosis (OR, 1.2; 95% CI, 0.6-2.7). In contrast, the highest level of 25-hydroxyvitamin D was associated with higher apoptosis in adenoma-free patients (OR, 2.6; 95% CI, 1.1-6.2) and slightly lower levels in patients with adenomas (OR, 0.6; 95% CI, 0.2-2.2).

Conclusion: These results are consistent with a calcium and vitamin D-mediated apoptotic mechanism in colon carcinogenesis.
Nonsteroidal Anti-inflammatory Drugs and Risk of Esophageal and Gastric Cancer
Authors: Lindblad Mats , Lagergren Jesper , García Rodríguez Luis A.
Published: September 2005

Introduction: Nonsteroidal anti-inflammatory drugs (NSAID) might reduce risks of esophageal and gastric cancer, but previous studies are limited and provide somewhat conflicting results.

Methods: We tested these associations in a prospective, nested case-control study based on the General Practitioners Research Database, including over 2 million persons in the United Kingdom between 1994 and 2001. In multivariate analyses we calculated odds ratios (OR) with 95% confidence intervals (95% CI). Data were stratified by history of upper gastrointestinal (UGI) disorders and recalculated using 2 years lag time on data (i.e., excluding all information 2 years before index date).

Results: Among 4,340,207 person-years of follow-up, we identified 909 patients with esophageal cancer and 1,023 patients with gastric cancer. We randomly selected 10,000 control subjects. Overall analysis suggested that long-term users of nonaspirin NSAIDs were at reduced risks of esophageal (OR, 0.82; 95% CI, 0.57-1.18) and gastric cancer (OR, 0.65; 95% CI, 0.44-0.94), whereas long-term aspirin users might be at decreased risk of esophageal cancer (OR, 0.76; 95% CI, 0.53-1.08), but not of gastric cancer (OR, 1.09; 95% CI, 0.82-1.45). All estimates of reduced risk were weakened in the 2 years lag time analysis except the association between nonaspirin NSAIDs long-term users and gastric cancer. Potentially protective effects were suggestive of being more marked among subjects with a history of UGI disorders.

Conclusions: Nonaspirin NSAIDs long-term use was associated with a reduced risk of gastric cancer, whereas no other studied associations could be firmly established. Our results suggest that UGI disorders could distort the associations, although we could not show this with statistical significance. If such bias was to be true, the previously reported inverse associations might, at least partly, be explained by lack of appropriate adjustment for such disorders.
Influence of Type of Cigarette on Peripheral versus Central Lung Cancer
Authors: Brooks Daniel R. , Austin John H.M. , Heelan Robert T. , Ginsberg Michelle S. , Shin Victor , Olson Sara H. , Muscat Joshua E. , Stellman Steven D.
Published: September 2005

Objectives: Adenocarcinoma has replaced squamous cell carcinoma as the most common cell type of lung cancer in the United States. It has been proposed that this shift is due to the increased use of filter and lower-tar cigarettes, resulting in increased delivery of smoke to peripheral regions of the lungs, where adenocarcinoma usually occurs. We reviewed radiologic data to evaluate the hypothesis that tumors in smokers of cigarettes with lower-tar yield are more likely to occur peripherally than tumors in smokers of higher-yield cigarettes.

Methods: At two urban academic medical centers, we reviewed computed tomographic scans, chest radiographs, and medical records to assign tumor location (peripheral or central) for 330 smokers diagnosed with carcinoma of the lung between 1993 and 1999. We compared the proportion of tumors in a peripheral versus central location by lifetime filter use and average lifetime tar rating (<21 and ≥21 mg).

Results: Tumor location (69% peripheral and 31% central) was unrelated to cigarette filter use. Smokers of cigarettes with lower-tar ratings were more likely than those with higher ratings to have peripheral rather than central tumors (odds ratio, 1.76; 95% confidence interval, 0.89-3.47). When restricted to subjects with adenocarcinoma or squamous cell carcinoma, the odds ratio (95% confidence interval) was 2.31 (1.05-5.08).

Conclusions: Among cigarette smokers with lung cancer, use of cigarettes with lower-tar yield was associated with preferential occurrence of tumors in peripheral sites. Our findings support the hypothesis that changes in smoking associated with lower-tar cigarettes have led to a shift in the location of smoking-related lung cancer.
Matrix Metalloproteinase-1 Promoter Polymorphism and Lung Cancer Risk
Authors: Su Li , Zhou Wei , Park Sohee , Wain John C. , Lynch Thomas J. , Liu Geoffrey , Christiani David C.
Published: September 2005

Extracellular matrix-degrading matrix metalloproteinase-1 (MMP-1) is an interstitial collagenase that degrades the interstitial types I, II, and III collagens, and overexpression of MMP-1 is associated with cancer development and cellular invasion. The 2G allele of the MMP-1 −1607 1G/2G polymorphism is associated with enhanced transcriptional activity. We investigated the association between the MMP-1 1G/2G polymorphism and lung cancer risk in 1,752 Caucasian lung cancer patients and 1,363 healthy controls. There were no overall associations between the MMP-1 genotypes and risk of lung cancer, with the adjusted odds ratios of 1.15 [95% confidence interval (CI), 0.94-1.40] for the 1G/2G genotype and 1.14 (95% CI, 0.90-1.45) for the 2G/2G genotype, when versus the 1G/1G genotype. Stratified analyses suggested higher lung cancer risk for the 2G allele in never-smokers and males, with the adjusted odds ratios of 1.67 (95% CI, 1.02-2.76; 1G/2G) and 1.50 (95% CI, 0.86-2.62; 2G/2G) in never-smokers; and 1.30 (95% CI, 1.00-1.75; 1G/2G) and 1.23 (95% CI, 0.88-1.73; 2G/2G) in males, respectively. In conclusion, genotypes containing the 2G allele of the MMP-1 polymorphism are associated with higher risk of lung cancer in never-smokers and in males.
Diet, Lifestyle, and Genomic Instability in the North Carolina Colon Cancer Study
Authors: Satia Jessie A. , Keku Temitope , Galanko Joseph A. , Martin Christopher , Doctolero Ryan T. , Tajima Akihiro , Sandler Robert S. , Carethers John M.
Published: September 2005

Objective: Microsatellite instability (MSI) is one form of genomic instability that occurs in 10% to 20% of sporadic colon tumors and almost all hereditary nonpolyposis colon cancers. However, little is known about how environmental factors (e.g., diet) may influence MSI in sporadic colon cancer.

Methods: We used data from a population-based case-control study in North Carolina (486 colon cancer cases and 1,048 controls) to examine associations of diet (total energy, macronutrients, micronutrients, and food groups) with MSI. In-person interviews elicited information on potential colon cancer risk factors, and a previously validated food frequency questionnaire adapted to include regional foods was used to assess diet over the year before diagnosis or interview date. MSI was classified as MSI-high (MSI-H) and MSI-low or microsatellite stable (MSI-L/MSS). Multivariate logistic regression models estimated energy-adjusted and non-energy-adjusted odds ratios (OR).

Results: Ten percent of the cases (n = 49) had MSI-H tumors (29% African American). The strongest associations between diet and MSI were observed in case-control comparisons: there was a robust inverse association between MSI-H status and β-carotene [OR, 0.4; 95% confidence interval (95% CI), 0.2-0.9] and positive associations with energy-adjusted refined carbohydrates (OR, 2.2; 95% CI, 0.9-5.4) and non-energy-adjusted read meat intake (OR, 2.0; 95% CI, 0.9-4.2). Compared with controls, MSI-L/MSS tumors were statistically significantly associated with energy-adjusted vitamin C, vitamin E, calcium, dietary fiber, and dark green vegetables and positively associated with total energy intake (all Ps for trend < 0.05). In case-case comparisons, no dietary factors were significantly differently related to MSI-H compared with MSI-L/MSS tumors.

Conclusion: Refined carbohydrate and red meat consumption may promote development of MSI-H tumors, whereas β-carotene may be associated with lower risk.
The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer
Authors: Li Tong , Sun Limei , Miller Naomi , Nicklee Trudey , Woo Jennifer , Hulse-Smith Lee , Tsao Ming-Sound , Khokha Rama , Martin Lisa , Boyd Norman
Published: September 2005

Background: We have examined the relationships between the measured properties of breast tissue and mammographic density and other risk factors for breast cancer, using breast tissue obtained at forensic autopsy and not selected for the presence of abnormalities.

Methods: We used randomly selected tissue blocks taken from breast tissue slices obtained by s.c. mastectomy at the time of forensic autopsy to measure histologic features using quantitative microscopy. The proportions of the biopsy occupied by cells (estimated by nuclear area), glandular structures, and collagen were determined. These measurements were examined in relation to the percent density in the faxitron image of the tissue slice from which the biopsy was taken and other risk factors for breast cancer.

Results: The percent mammographic density was associated with the proportion of the area of the biopsy occupied by nuclei, both epithelial and nonepithelial, and by collagen and the area of glandular structures. Several other risk factors for breast cancer, notably body weight, parity, and number of births, and menopausal status, that are associated with variations in mammographic density, were also associated with differences in one or more of these tissue features.

Conclusion: All risk factors for breast cancer must ultimately exert their influence by an effect on the breast, and these findings suggest that, for some risk factors, this influence includes an effect on the number of cells and the quantity of collagen.
Smoking Topography, Brand Switching, and Nicotine Delivery: Results from an In vivo Study
Authors: Hammond David , Fong Geoffrey T. , Cummings K. Michael , Hyland Andrew
Published: September 2005

Objective: Exposure to toxins in tobacco smoke is influenced by how a cigarette is smoked. Cigarettes have been designed to allow for a range of puffing behavior and to provide different, nonlinear tar and nicotine yields in response to different puffing profiles. However, puffing behavior and its influence upon risk-exposure has yet to be assessed outside the laboratory, in smokers' natural environment.

Method: Fifty-nine adult smokers used a portable device to measure smoking topography over the course of three 1-week trials. Participants were asked to smoke their usual “regular yield” brand through the device for trial 1 and again, 6 weeks later, at trial 2. Half the subjects were then randomly assigned to switch to a “low-yield” brand for trial 3.

Results: The findings show a high degree of stability in puffing behavior within the same subject over time but considerable variability between smokers. Smokers who were switched to a “low-yield” cigarette increased their total smoke intake per cigarette by 40% (P = 0.007), with no significant change in their salivary cotinine levels. Cigarettes smoked per day and nicotine yield were only weakly associated with salivary cotinine levels; however, salivary cotinine was strongly associated with a composite measure that included cigarettes per day, brand elasticity, and puffing behavior (sr = 0.61, P < 0.001).

Conclusions: These findings provide strong evidence of behavioral compensation to low-yield cigarettes from in vivo measures of smoking behavior. The findings also show the importance of brand elasticity and smoking topography in predicting nicotine uptake and smoke exposure.
Polymorphisms ofMethionine SynthaseandMethionine Synthase Reductaseand Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis
Authors: Zhang Zhengdong , Shi Qiuling , Liu Zhensheng , Sturgis Erich M. , Spitz Margaret R. , Wei Qingyi
Published: September 2005

Although tobacco and alcohol use are the major risk factors, folate deficiency has been implicated in the risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) in the folate matabolic pathway are associated with SCCHN risk. In a hospital-based case-control study of 721 SCCHN cases and 1,234 controls of non-Hispanic Whites, frequency matched by age, sex, and smoking status, we genotyped the MTR A2756G and MTRR G66A polymorphisms. We found that the MTR variant AG and AG/GG genotypes were associated with a significantly increased SCCHN risk [adjusted odd ratio (OR), 1.31; 95% confidence interval (95% CI), 1.07-1.60 for AG and OR, 1.28; 95% CI, 1.05-1.56 for AG/GG] compared with the AA genotype. In contrast, the MTRR variant AA genotype was associated with a significantly decreased SCCHN risk (OR, 0.68; 95% CI, 0.52-0.90) compared with the 66GG genotype. When the two polymorphisms were evaluated together by the number of risk alleles, the SCCHN risk was significantly increased in a dose-dependent manner (Ptrend = 0.002). The risk of SCCHN was 1.47 (95% CI, 1.08-1.99) for one risk allele, 1.67 (95% CI, 1.23-2.27) for two risk alleles, and 1.74 (95% CI, 1.18-2.54) for three or four risk alleles compared with the wild-type (0 risk allele) genotype. In conclusion, our data provide evidence that support the association between the MTR A2756G and MTRR G66A polymorphisms and SCCHN risk and that these two polymorphisms may have a joint effect on risk of SCCHN.
A Digital Image Analysis System for Identifying Filter Vent Blocking on Ultralight Cigarettes
Authors: O'Connor Richard J. , Stitt Joseph P. , Kozlowski Lynn T.
Published: September 2005

Filter ventilation is the dominant design feature on modern cigarettes, diluting the mainstream smoke with air and reducing tar and nicotine yields in the standard assay. Smokers are generally unaware of vent holes and often cover them with lips or fingers while smoking, reducing or eliminating the air dilution effect and increasing intake of tar and nicotine particularly on ultra–low tar brands. A digital imaging and analysis system for the detection of vent blocking was developed. Two studies were designed to evaluate the effectiveness of three color measures (hue, saturation, and value) at discriminating whether at least 50% blocking had occurred. In study 1, saturation showed perfect discrimination between unblocked Carlton butts and butts with at least 50% of the vents blocked during syringe smoking. In study 2, saturation showed 95% accuracy at identifying Marlboro Ultra Light butts with at least four puffs blocked by smokers' lips. The results indicate that the pattern of color saturation is related to vent blocking. Implications for tobacco control research and policy are discussed.
Frequent Methylation ofEyes Absent 4Gene in Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Zou Hongzhi , Osborn Neal K. , Harrington Jonathan J. , Klatt Kristie K. , Molina Julian R. , Burgart Lawrence J. , Ahlquist David A.
Published: September 2005

Most esophageal adenocarcinomas arise within Barrett's esophagus but the cause of this increasingly prevalent condition remains unknown. Early detection improves survival and discriminant screening markers for Barrett's esophagus and cancer are needed. This study was designed to explore the natural history of eyes absent 4 (EYA4) gene methylation in the neoplastic progression of Barrett's esophagus and to evaluate methylated EYA4 as a candidate marker. Aberrant promoter methylation of EYA4 was studied by methylation-specific PCR using bisulfite-treated DNA from esophageal adenocarcinomas, Barrett's esophagus, and normal epithelia, and then confirmed by sequencing. Eight cancer cell lines were treated with the demethylation agent 5-aza-2′-deoxycytidine, and EYA4 mRNA expression with and without treatment was quantified by real-time reverse-transcription PCR. EYA4 hypermethylation was detected in 83% (33 of 40) of esophageal adenocarcinomas and 77% (27 of 35) of Barrett's tissues, but only in 3% (2 of 58) of normal esophageal and gastric mucosa samples (P < 0.001). The unmethylated cancer cell lines had much higher EYA4 mRNA expression than the methylated cancer cell lines. Demethylation caused by 5-aza-2′-deoxycytidine increased the mRNA expression level by a median of 3.2-fold in methylated cells, but its effect on unmethylated cells was negligible. Results indicate that aberrant promoter methylation of EYA4 is very common during tumorigenesis in Barrett's esophagus, occurs in early metaplasia, seems to be an important mechanism of down-regulating EYA4 expression, and represents an intriguing candidate marker for Barrett's metaplasia and esophageal cancer.
SerumTrans-Fatty Acids Are Associated with Risk of Prostate Cancer in β-Carotene and Retinol Efficacy Trial
Authors: King Irena B. , Kristal Alan R. , Schaffer Steve , Thornquist Mark , Goodman Gary E.
Published: September 2005

Biomarkers of trans-fatty acid consumption have been associated with increased risks of breast and colon cancer, although no studies have examined their associations with prostate cancer risk. Using data from the β-Carotene and Retinol Efficacy Trial, this nested case-control study examined the relationships between serum phospholipid trans-fatty acids and prostate cancer incidence in 272 case and 426 control men. Trans-fatty acids were measured using organic extraction followed by separations with TLC and gas chromatography. Adjusted odds ratios for risk of prostate cancer with increasing levels of trans-fatty acids were calculated using logistic regression. There were consistent trends for increasing prostate cancer risk with higher levels of C18 but not C16 trans-fatty acids, although only trends for Δ11t 18:1 trans-vaccenic and Δ9c,12t 18:2 fatty acids reached statistical significance. Odds ratios (95% confidence interval) contrasting low versus high quartiles for these fatty acids were 1.69 (1.03-2.77) and 1.79 (1.02-3.15), respectively. There were no consistent differences in associations between low-grade and high-grade cancer among the subset of 209 cases with information on tumor grade. Additional studies are needed to confirm these findings and better control for factors, such as use of prostate-specific antigen screening, which may confound this association.
Nonsteroidal Anti-inflammatory Drugs and Risk of Prostate Cancer in the Baltimore Longitudinal Study of Aging
Authors: Platz Elizabeth A. , Rohrmann Sabine , Pearson Jay D. , Corrada Maria M. , Watson Douglas J. , De Marzo Angelo M. , Landis Patricia K. , Metter E. Jeffrey , Carter H. Ballentine
Published: September 2005

Background: Laboratory and epidemiologic studies suggest that aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAID) reduce the risk of cancer, possibly via inhibition of the cyclooxygenase enzymes. We evaluated the association of aspirin and nonaspirin NSAIDs with subsequent prostate cancer in a prospective study. We also assessed whether use of these drugs influences serum prostate-specific antigen (PSA) concentration.

Methods: Participants were 1,244 male members of the Baltimore Longitudinal Study of Aging. Use of prescription and over-the-counter drugs was collected by questionnaire and interview at multiple study visits. One hundred forty-one prostate cancer cases diagnosed between 1980 and May 2004 were confirmed by medical record review. We used Cox proportional hazards regression to estimate the rate ratio (RR) of prostate cancer updating drug use over time and taking into account age and year. We used generalized estimating equations to calculate age-adjusted geometric mean PSA concentration by aspirin or nonaspirin NSAIDs use among 933 of the men without prostate cancer, for whom 3,749 PSA measurements in archived sera had been done previously.

Results: On 46.0% and 21.5% of the visits, current use of aspirin or nonaspirin NSAIDs (mostly ibuprofen) was reported, respectively. The RRs of prostate cancer comparing ever to never use were 0.76 [95% confidence interval (95% CI), 0.54-1.07] for aspirin, 0.79 (95% CI, 0.54-1.16) for nonaspirin NSAIDs, and 0.71 (95% CI, 0.49-1.02) for either medication. The association for ever use of either aspirin or nonaspirin NSAIDs was suggestively more pronounced in men <70 years (RR, 0.54; 95% CI, 0.27-1.03) than in men ≥70 years (RR, 0.78; 95% CI, 0.50-1.22; Pinteraction = 0.73). The RR for current use of either drug was attenuated relative to ever use. Mean PSA concentration did not differ between users and nonusers of either aspirin or nonaspirin NSAIDs (1.01 versus 0.98 ng/mL, P = 0.56).

Conclusion: In this prospective study, men, in particular younger men, who had ever used aspirin or nonaspirin NSAIDs had a modest nonstatistically significant lower risk of prostate cancer. The modest inverse association was unlikely due to detection bias that might have resulted if anti-inflammatory drugs had influenced serum PSA concentration.
Haplotype-Phenotype Relationships of Paraoxonase-1
Authors: Chen Jia , Chan Wendy , Wallenstein Sylvan , Berkowitz Gertrud , Wetmur James G.
Published: September 2005

Paraoxonase 1 (PON1) is an enzyme with multiple activities, including detoxification of organophosphates. It is believed to be important in preventing neurotoxic damage and has also been implicated in atherosclerosis. The PON1 gene contains five common polymorphisms, three in the promoter (−909G > C, −162A > G, −108C > T) and two in the coding region (M55L, Q192R) with varying but incomplete linkage disequilibrium. Our previous study showed that functional polymorphisms in PON1 were strongly associated with enzymatic activity in both pregnant women [26-30 weeks of gestation] and neonates. However, there was substantial overlapping of enzyme activities between genotypes. In this study, we investigated whether haplotype (genotype + phase) information would strengthen the genotype-phenotype relationship for PON1. The study consisted of a multiethnic population of 402 mothers and 229 neonates. Haplotypes were imputed by two widely used programs, PHASE and tagSNPs, which yielded very similar results. There were seven haplotypes with a frequency of 5% or higher in at least one ethnic group of the study population. Haplotype composition varied substantially with respect to ethnicity. Haplotypes in Caucasians and African-Americans showed the largest difference, and Caribbean Hispanics seemed to be a mixture of Caucasian and African ancestry. Collectively, the genetic (genotype or haplotype) contribution to PON1 enzymatic activity (measured as phenylacetate hydrolysis) was greater in neonates compared with mothers. Specifically, 16.6% of PON1 variability was explained by genotypes in mothers compared with 30.9% in neonates. Haplotype information offered a slightly increased power in predicting PON1 activity; they explained 35.5% and 19.3% of PON1 variability in neonates and mothers, respectively.
Dietary Marinen-3 Fatty Acids in Relation to Risk of Distal Colorectal Adenoma in Women
Authors: Oh Kyungwon , Willett Walter C. , Fuchs Charles S. , Giovannucci Edward
Published: September 2005

Epidemiologic studies of dietary marine n-3 fatty acids and risk of colorectal cancer have been inconsistent, and their relation to risk of colorectal adenoma has not been evaluated in detail. We examined dietary marine n-3 fatty acids and the ratio of marine n-3 to total n-6 fatty acids (n-3/n-6 ratio) in relation to risk of adenoma of the distal colon or rectum among 34,451 U.S. women who were initially free of colorectal cancer or polyps, who completed a semiquantitative food frequency questionnaire in 1980, and who underwent endoscopy from 1980 to 1998. We documented 1,719 distal colorectal adenoma cases (705 large adenomas, 897 small adenomas, 1,280 distal colon adenomas, and 505 rectal adenomas) during 18 years of follow-up. Neither dietary marine n-3 fatty acids nor n-3/n-6 ratio were associated with risk of total distal colorectal adenoma after adjustment for age and established risk factors [multivariable relative risk (RR) for extreme quintiles of dietary marine n-3 fatty acids = 1.04; 95% confidence interval (95% CI), 0.84-1.27, Ptrend = 0.66; RR for extreme quintiles of n-3/n-6 ratio = 1.02; 95% CI, 0.83-1.25; Ptrend = 0.86]. Similarly, no significant associations were observed separately for distal colon or rectal adenoma. However, higher intake of dietary marine n-3 fatty acids was nonsignificantly but suggestively inversely associated with large adenoma (RR, 0.74; 95% CI, 0.54-1.01; Ptrend = 0.16) but directly associated with small adenoma (RR, 1.36; 95% CI, 1.02-1.81; Ptrend = 0.09). Our findings do not support the hypothesis that a higher intake of marine n-3 fatty acids or a higher n-3/n-6 ratio reduces the risk of distal colorectal adenoma but are suggestive that higher intake may reduce the progression of small adenomas to large adenomas.
Salivary Soluble CD44: A Potential Molecular Marker for Head and Neck Cancer
Authors: Franzmann Elizabeth J. , Reategui Erika P. , Carraway Kermit L. , Hamilton Kara L. , Weed Donald T. , Goodwin W. Jarrard
Published: September 2005

Objective: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease which is cured only 50% of the time. If diagnosed early, survival rates could reach 80%, but there is currently no practical method for early detection. CD44 comprises a family of isoforms that, in certain tumors, are alternatively spliced and overexpressed in tissues and circulation. Here we examine salivary soluble CD44 (solCD44) expression in HNSCC patients and normal controls to determine its potential as a screening tool.

Method: We did a solCD44 ELISA on saliva from 26 HNSCC patients, 10 normal volunteers, conditioned media (CM) of 4 HNSCC cell lines, and 1 CD44-negative cell line (COS-7). Western blot was done on CM from 2 HNSCC cell lines (UMSS11B and FaDu), COS-7, 3 HNSCC, and 2 normal saliva specimens to verify ELISA antibody specificity. SolCD44 levels were significantly elevated in HNSCC patients compared with normal controls (7.85 ng/mL for HNSCC patients and 1.09 ng/mL for normal controls, P < 0.001).

Results: The test detected 79% of mucosally invasive HNSCC using preliminary cutoff points. SolCD44 levels did not vary significantly with tumor size, stage, recurrence, history of radiation treatment, or tobacco and alcohol risk factors. A 65 to 75 kDa band, corresponding to solCD44, was detected in all of the HNSCC cell line CM and saliva whereas normal samples showed a fainter band or were undetectable.

Conclusion: In this preliminary analysis, the salivary solCD44 ELISA seems to effectively detect HNSCC at all stages. Further study is indicated because early detection is clearly important in this disease.
Cimetidine and Other Histamine2-Receptor Antagonist Use in Relation to Risk of Breast Cancer
Authors: Coogan Patricia F. , Zhang Yuqing , Palmer Julie R. , Strom Brian L. , Rosenberg Lynn
Published: September 2005

Objective: Cimetidine, a histamine2-receptor antagonist (H2 blocker) commonly used to treat symptoms of peptic and duodenal ulcer, influences both hormonal and immune pathways. We investigated the influence of cimetidine use on the risk of breast cancer in our hospital-based case control surveillance study.

Methods: Data on medication use and other factors were elicited from patients admitted to hospitals from 1977 to 2002. We compared 6,994 breast cancer cases with a control group comprising cancer (n = 2,478) and noncancer (n = 6,004) diagnoses. Conditional logistic regression models were used to estimate odds ratios for H2 blocker use that began at least 1 year prior to admission. Regular use was defined as use for at least 4 days per week for at least 3 continuous months.

Results: The odds ratio for breast cancer among regular users of cimetidine was 0.9 (95% confidence interval, 0.6-1.2) using a combined cancer and noncancer control group. For use of 4 or more years' duration, the odds ratio was <1.0 but was not statistically significant. The odds ratio for the regular use of other H2 blockers was 0.9 (95% confidence interval, 0.6-1.3).

Conclusions: Our data agree with data from three prior studies which indicate that cimetidine is not associated with the risk of breast cancer. Other H2 blockers were also unrelated to the risk of breast cancer.
Association of Dietary Vitamin A, Carotenoids, and Other Antioxidants with the Risk of Ovarian Cancer
Authors: Tung Ko-Hui , Wilkens Lynne R. , Wu Anna H. , McDuffie Katharine , Hankin Jean H. , Nomura Abraham M.Y. , Kolonel Laurence N. , Goodman Marc T.
Published: September 2005

Antioxidants may protect the ovaries from oxidative damage and reduce the risk of ovarian cancer. Although a few studies have examined the relation of antioxidant intake to the risk of ovarian cancer, the results have been inconclusive. Questions still remain regarding the effects of confounding factors, such as menopause, tobacco smoking, and alcohol drinking, on the association between antioxidants and ovarian cancer development.

Objective: To examine the association of the consumption of micronutrients from foods and supplements with the risk of ovarian cancer.

Methods: A structured questionnaire was administered to 558 histologically confirmed epithelial ovarian cancer cases and 607 population controls from a multiethnic, population-based case-control study conducted between 1993 and 1999 in Hawaii and Los Angeles.

Results: Overall, vitamin A and carotene intakes were modestly associated with a reduced risk of ovarian cancer. Inverse gradients in ovarian cancer risk with increasing dietary intake of vitamin A and β-carotene were somewhat stronger among women with mucinous histologic types, smokers, and nondrinkers. A significant positive trend in risk associated with increasing β-cryptoxanthin intake was observed among postmenopausal women, among women with nonmucinous tumors, and among nonsmokers. The intake of other carotenoids and antioxidants, either from foods or supplements, was unrelated to ovarian cancer risk.

Conclusion: Our findings suggest that dietary vitamin A and β-carotene are modestly protective against ovarian cancer, particularly among smokers. Our data suggest a role for retinoic acid signaling pathways in ovarian carcinogenesis.
Physician Recommendation for Papanicolaou Testing Among U.S. Women, 2000
Authors: Coughlin Steven S. , Breslau Erica S. , Thompson Trevor , Benard Vicki B.
Published: September 2005

Objective: Many women in the U.S. undergo routine cervical cancer screening, but some women have rarely or never had a Papanicolaou (Pap) test. Studies of other cancer screening tests (for example, mammograms) have shown that physician recommendation to get a screening test is one of the strongest predictors of cancer screening.

Methods: In this study, we examined whether women in the U.S. had received a physician recommendation to get a Pap test using data from the 2000 National Health Interview Survey. Reported reasons for not receiving a Pap test were also explored.

Results: Among women aged ≥18 years who had no history of hysterectomy, 83.3% [95% confidence interval (CI), 82.4-84.1%] of the 13,636 women in this sample had had a Pap test in the last 3 years. Among 2,310 women who had not had a recent Pap test, reported reasons for not receiving a Pap test included: “No reason/never thought about it” (48.0%; 95% CI, 45.5-50.7), “Doctor didn't order it” (10.3%; 95% CI, 8.7-12.0), “Didn't need it/didn't know I needed this type of test” (8.1%; 95% CI, 6.7-9.6), “Haven't had any problems” (9.0%; 95% CI, 7.6-10.5), “Put it off” (7.4%; 95% CI, 6.2-8.7), “Too expensive/no insurance” (8.7%; 95% CI, 7.3-10.2), “Too painful, unpleasant, embarrassing” (3.5%; 95% CI, 2.5-4.6), and “Don't have doctor” (1.7%; 95% CI, 1.2-2.4). Among women who had had a doctor visit in the last year but who had not had a recent Pap test, about 86.7% (95% CI, 84.5-88.6) reported that their doctor had not recommended a Pap test in the last year. African-American women were as likely as White women to have received a doctor recommendation to get a Pap test. Hispanic women were as likely as non-Hispanic women to have received a doctor recommendation to get a Pap test. In multivariate analysis, factors positively associated with doctor recommendation to get a Pap test included being aged 30 to 64 years, having been born in the U.S., and having seen a specialist or general doctor in the past year.

Conclusion: These findings suggest that lack of a physician recommendation contributes to underuse of Pap screening by many eligible women. Given research that shows the effectiveness of physician recommendations in improving use, increased physician recommendations could contribute significantly to increased Pap screening use in the U.S.
Tanning Beds, Sunlamps, and Risk of Cutaneous Malignant Melanoma
Authors: Gallagher Richard P. , Spinelli John J. , Lee Tim K.
Published: September 2005

Background: A number of studies have been conducted evaluating the risk of cutaneous malignant melanoma after exposure to sunlamps and/or sunbeds. The proportion of subjects in the individual studies who have reported exposure has, in general, been modest, and the resulting risk estimates for melanoma have been unstable with wide 95% confidence intervals (95% CI). The inconclusive results seen in individual studies have resulted in confusion as to the carcinogenicity of these devices.

Methods: We conducted a systematic review and meta-analysis of these studies. A review of the literature from Jan 1, 1984 to April 2004 using MEDLINE identified 12 case-control studies and 1 cohort study which quantitatively evaluated the use of sunlamps and/or sunbeds and subsequent melanoma. After applying exclusion/inclusion criteria, 9 case-control and 1 cohort study provided data for the analysis. Summary odds ratios (OR) and 95% CIs for sunlamp/sunbed use and subsequent melanoma were calculated using a random-effect model.

Results: Ten studies provided data for assessment of melanoma risk among subjects who reported “ever” being exposed compared with those “never” exposed. A positive association was found between exposure and risk (summary OR, 1.25; 95% CI, 1.05-1.49). Significant heterogeneity between studies was present. Evaluation of the metrics “first exposure as a young adult” (5 studies) and “longest duration or highest frequency of exposure” (6 studies) also yielded significantly elevated risk estimates (summary OR, 1.69; 95% CI, 1.32-2.18, and 1.61; 95% CI, 1.21-2.12, respectively, with no heterogeneity in either analysis).

Conclusions: Results indicate a significantly increased risk of cutaneous melanoma subsequent to sunbed/sunlamp exposure.
Chromosomal Aberrations in Cord Blood Are Associated with Prenatal Exposure to Carcinogenic Polycyclic Aromatic Hydrocarbons
Authors: Bocskay Kirsti A. , Tang Deliang , Orjuela Manuela A. , Liu Xinhua , Warburton Dorothy P. , Perera Frederica P.
Published: September 2005

Molecular and traditional epidemiology studies have indicated a possible relationship between in utero environmental exposures and increased risk for childhood cancers, especially acute leukemias. Chromosomal aberrations have been associated with environmental exposures and cancer risk in adults. In order to more clearly define the association between prenatal exposures to carcinogenic polycyclic aromatic hydrocarbons (PAH) and chromosomal aberrations, chromosomal aberration frequencies were measured in a subset of 60 newborns from the Columbia Center for Children's Environmental Health (CCCEH) Prospective Cohort Study. The subset was composed of African American and Dominican, nonsmoking mother-newborn pairs residing in low-income neighborhoods of New York City, who were exposed to varying levels of airborne PAHs. Prenatal exposure was assessed by questionnaire, personal air monitoring during the third trimester, and PAH-DNA adducts in umbilical cord blood. Chromosomal aberrations were measured in cord blood lymphocytes by fluorescence in situ hybridization. PAH-DNA adducts were not associated with chromosomal aberrations. However, airborne PAHs were significantly associated with stable aberration frequencies in cord blood (P < 0.01). Moreover, stable aberration frequencies were significantly higher among African American newborns compared with Dominican, despite no significant differences in PAH exposure. These results show for the first time an association between prenatal exposure to airborne carcinogenic PAHs and chromosomal aberrations in cord blood, suggesting that such prenatal exposures have the potential to cause cytogenetic damage that has been related to increased cancer risk in other populations. If confirmed, this finding may open new avenues for prevention.
Urinary Metabolites of a Tobacco-Specific Lung Carcinogen in Nonsmoking Hospitality Workers
Authors: Tulunay Ozlem E. , Hecht Stephen S. , Carmella Steven G. , Zhang Yan , Lemmonds Charlotte , Murphy Sharon , Hatsukami Dorothy K.
Published: September 2005

Exposure of nonsmokers to environmental tobacco smoke results in increased risk for cancer and other diseases. In spite of this finding, some restaurants and bars continue to permit smoking. This study examined the uptake of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent lung carcinogen, in nonsmokers who work in restaurants and bars that permitted smoking. Urine samples were collected for 24 hours on working and nonworking days and were analysed for total NNAL [the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Glucs)], metabolites of NNK. In addition, urine samples were analysed for total nicotine (nicotine plus nicotine glucuronide), and total cotinine (cotinine plus cotinine-N-glucuronide). The results showed significant increases in urinary levels of total NNAL, total nicotine, and total cotinine on working days compared with nonworking days. The results of this study show that smoke exposure in bars and restaurants may have important health effects on nonsmoking employees, elicited by the increase in carcinogen levels.
Retinoic Acid Receptor-β2 Promoter Methylation in Random Periareolar Fine Needle Aspiration
Authors: Bean Gregory R. , Scott Victoria , Yee Lisa , Ratliff-Daniel Brooke , Troch Michelle M. , Seo Pearl , Bowie Michelle L. , Marcom Paul K. , Slade Jaimie , Kimler Bruce F. , Fabian Carol J. , Zalles Carola M. , Broadwater Gloria , Baker Joseph C. , Wilke Lee G. , Seewaldt Victoria L.
Published: September 2005

Methylation of the retinoic acid receptor-β2 (RARβ2) P2 promoter is hypothesized to be an important mechanism for loss of RARβ2 function during early mammary carcinogenesis. The frequency of RARβ2 P2 methylation was tested in (a) 16 early stage breast cancers and (b) 67 random periareolar fine needle aspiration (RPFNA) samples obtained from 38 asymptomatic women who were at increased risk for breast cancer. Risk was defined as either (a) 5-year Gail risk calculation ≥1.7%; (b) prior biopsy exhibiting atypical hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ; or (c) known BRCA1/2 mutation carrier. RARβ2 P2 promoter methylation was assessed at two regions, M3 (−51 to 162 bp) and M4 (104-251 bp). In early stage cancers, M4 methylation was observed in 11 of 16 (69%) cases; in RPFNA samples, methylation was present at M3 and M4 in 28 of 56 (50%) and 19 of 56 (38%) cases, respectively. RPFNAs were stratified for cytologic atypia using the Masood cytology index. The distribution of RARβ2 P2 promoter methylation was reported as a function of increased cytologic abnormality. Methylation at both M3 and M4 was observed in (a) 0 of 10 (0%) of RPFNAs with Masood scores of ≤10 (nonproliferative), (b) 3 of 20 (15%) with Masood scores of 11 to 12 (low-grade proliferative), (c) 3 of 10 (30%) with Masood scores of 13 (high-grade proliferative), and (d) 7 of 14 (50%) with Masood scores of 14 of 15 (atypia). Results from this study indicate that the RARβ2 P2 promoter is frequently methylated (69%) in primary breast cancers and shows a positive association with increasing cytologic abnormality in RPFNA.
Centralized Blood Processing for the Selenium and Vitamin E Cancer Prevention Trial: Effects of Delayed Processing on Carotenoids, Tocopherols, Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein 3, Steroid Hormones, and Lymphocyte Viability
Authors: Kristal Alan R. , King Irena B. , Albanes Demetrius , Pollak Michael N. , Stanzyk Frank Z. , Santella Regina M. , Hoque Ashraful
Published: September 2005

This experiment examined the effects of delays in separation and freezing of whole blood components on analytes of interest in studies of prostate cancer prevention, in order to evaluate the feasibility of centralized processing of blood for the multisite Selenium and Vitamin E Cancer Prevention Trial. Blood from 40 healthy men was subjected to four treatment protocols, allowing the contrast of immediate processing to delays of 32, 72, and 144 hours. At 32 hours, simulating refrigerated storage and overnight shipping, there was a 2.9% decrease (95% confidence interval, 0.7-5.1) in insulin-like growth factor-I (IGF-I) but no significant change in carotenoids, tocopherols, testosterone, 3α-androstanediol glucuronide (AAG), sex hormone–binding globulin (SHBG) or insulin-like growth factor binding protein 3 (IGFBP3). A 144-hour processing delay, simulating weekend blood collection or shipping delay, resulted in significant changes in γ-tocopherol (−1.5%), IGF-I (−5.7%), IGFBP3 (−2.9%), SHBG (−4.0%), testosterone (+4.7%), and AAG (+5.5%). The rank-order and intraclass correlations between analytes from blood processed immediately and those subjected to delayed processing were 0.96 or higher for carotenoids, tocopherols, AAG, and SHBG, and between 0.87 and 0.95 for IGF-I, IGFBP3, and testosterone. A 32-hour delay decreased lymphocyte viability from 82.5% to 75.0% (P = 0.45), but a 72-hour delay decreased viability to 36.8% (P < 0.001). Overnight shipping and centralized processing is an acceptable approach to blood collection in large multisite trials examining the cancer-related measures proposed in the Selenium and Vitamin E Cancer Prevention Trial. Longer processing delays, however, have small but statistically significant effects on many analytes and substantially decrease lymphocyte viability.
A Common Genetic Variant inFCGR3A-V158F and Risk of Kaposi Sarcoma Herpesvirus Infection and Classic Kaposi Sarcoma
Authors: Brown Elizabeth E. , Fallin M. Daniele , Goedert James J. , Chen Renee , Whitby Denise , Foster Charles B. , Lauria Carmela , Alberg Anthony J. , Messina Angelo , Montella Mauizio , Rezza Giovanni , Vitale Francesco , Chanock Stephen J. ,   the Kaposi Sarcoma Genetics Working Group
Published: September 2005

Associations of FCGR3A among men with HIV/acquired immunodeficiency syndrome suggest that host responses affect the pathogenesis of Kaposi sarcoma herpesvirus (KSHV) infection and risk of acquired immunodeficiency syndrome–associated Kaposi sarcoma. Using DNA from two HIV seronegative case-control populations in Italy, we examined whether the functional FCGR3A-V158F variant was associated with risk of KSHV infection or classic Kaposi sarcoma (CKS). In population I, we examined FCGR3A variants and risk of KSHV infection in 34 KSHV latent nuclear antigen (LANA)-seropositive and 120 LANA-seronegative adults from Sardinia (52% male; median age, 45 years; range, 31-60), whereas in population II, we examined risk of CKS from 133 CKS cases and 172 KSHV LANA-seropositive controls from Sicily, Rome, and Naples (70% males; median age, 74 years; range, 29-91). FCGR3A variants were determined by direct sequence analysis of a nested PCR of genomic DNA assay using allele-specific primers. KSHV LANA was determined by immunofluorescence assay. Overall, compared with the 158F allele, 158V was overrepresented among controls from both Mediterranean populations (frequency = 0.52 and 0.51, respectively). After controlling for age, 158V homozygous women were at increased risk of KSHV infection and CKS compared with 158F homozygous women [odds ratio (OR), 8.7; 95% confidence interval (95% CI), 0.8-98 and OR, 3.8; 95% CI, 1.0-14, respectively], whereas homozygous men were at decreased risk (OR, 0.4; 95% CI, 0.1-2.3 and OR, 0.4; 95% CI, 0.2-0.8, respectively). Significant gene-dose effects were observed among men and women at risk for CKS (Ptrend ≤ 0.05). Our findings suggest that gender differences could possibly modify the effect of FCGR3A on risk of KSHV infection and CKS. Additional studies are required to confirm these relationships and determine their etiologic significance.
α-Methylacyl-CoA Racemase Protein Expression Is Associated with the Degree of Differentiation in Breast Cancer Using Quantitative Image Analysis
Authors: Witkiewicz Agnieszka K. , Varambally Sooryanarayana , Shen Ronglai , Mehra Rohit , Sabel Michael S. , Ghosh Debashis , Chinnaiyan Arul M. , Rubin Mark A. , Kleer Celina G.
Published: September 2005

α-Methylacyl-CoA racemase (AMACR) is an enzyme involved in the metabolism of fatty acids and is an important tissue biomarker in the prostate to distinguish normal glands from prostate cancer. Here, for the first time, we evaluated the expression of AMACR protein in normal breast, ductal carcinoma in situ, and invasive carcinomas. By immunofluorescence and immunohistochemistry, AMACR was seen in cytoplasmic granules consistent with a mitochondrial and peroxisomal localization. AMACR expression was determined by immunohistochemistry on 160 invasive carcinomas with long follow-up, using a high-density tissue microarray, and evaluated by two methods: standard pathology review and quantitative image analysis. AMACR was overexpressed in 42 of 160 (26%) invasive carcinomas, and it was associated with a decrease in tumor differentiation, a feature of aggressive breast cancer. Quantitative analysis allowed for better discrimination and more accurate evaluation of low-intensity staining. In conclusion, AMACR protein is expressed in normal breast and its expression seems to increase in invasive carcinomas. We observed stronger AMACR protein expression in high-grade carcinomas when compared with low-grade ones. Quantitative image analysis is a novel way to accurately and reproducibly evaluate immunohistochemistry in breast tissue samples using high-density tissue microarrays.