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Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study provided blood samples at trial enrollment for serological testing. A Luminex assay based on glutathione s-transferase-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58). We analyzed the relationship between seroprevalence in women free of precancer (N = 2,464) and HPV DNA status, age, sexual behavior and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and ∼20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR = 1.36, 95%CI: 1.04-1.79) and HPV18 (OR = 2.31, 95%CI: 1.61-3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants' HPV serostatus.
Copyright © 2013 UICC.
PURPOSE - To carry out pattern analyses of dietary and lifestyle factors in relation to risk of esophageal and gastric cancers.
METHODS - We evaluated risk factors for esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GCA), and other gastric cancers (OGA) using data from a population-based case-control study conducted in Connecticut, New Jersey, and western Washington state. Dietary/lifestyle patterns were created using principal component analysis (PCA). Impact of the resultant scores on cancer risk was estimated through logistic regression.
RESULTS - PCA identified six patterns: meat/nitrite, fruit/vegetable, smoking/alcohol, legume/meat alternate, GERD/BMI, and fish/vitamin C. Risk of each cancer under study increased with rising meat/nitrite score. Risk of EA increased with increasing GERD/BMI score, and risk of ESCC rose with increasing smoking/alcohol score and decreasing gastroesophageal reflux disease (GERD)/body mass index (BMI) score. Fruit/vegetable scores were inversely associated with EA, ESCC, and GCA.
CONCLUSIONS - PCA may provide a useful approach for summarizing extensive dietary/lifestyle data into fewer interpretable combinations that discriminate between cancer cases and controls. The analyses suggest that meat/nitrite intake is associated with elevated risk of each cancer under study, whereas fruit/vegetable intake reduces risk of EA, ESCC, and GCA. GERD/obesity were confirmed as risk factors for EA and smoking/alcohol as risk factors for ESCC.
Copyright © 2011 Elsevier Inc. All rights reserved.
Esophageal cancer is a prototypic squamous cell cancer that carries a poor prognosis, primarily due to presentation at advanced stages. We used human esophageal epithelial cells as a platform to recapitulate esophageal squamous cell cancer, thereby providing insights into the molecular pathogenesis of squamous cell cancers in general. This was achieved through the retroviral-mediated transduction into normal, primary human esophageal epithelial cells of epidermal growth factor receptor (EGFR), the catalytic subunit of human telomerase (hTERT), and p53(R175H), genes that are frequently altered in human esophageal squamous cell cancer. These cells demonstrated increased migration and invasion when compared with control cells. When these genetically altered cells were placed within the in vivo-like context of an organotypic three-dimensional (3D) culture system, the cells formed a high-grade dysplastic epithelium with malignant cells invading into the stromal extracellular matrix (ECM). The invasive phenotype was in part modulated by the activation of matrix metalloproteinase-9 (MMP-9). Using pharmacological and genetic approaches to decrease MMP-9, invasion into the underlying ECM could be suppressed partially. In addition, tumor differentiation was influenced by the type of fibroblasts within the stromal ECM. To that end, fetal esophageal fibroblasts fostered a microenvironment conducive to poorly differentiated invading tumor cells, whereas fetal skin fibroblasts supported a well-differentiated tumor as illustrated by keratin "pearl" formation, a hallmark feature of well-differentiated squamous cell cancers. When inducible AKT was introduced into fetal skin esophageal fibroblasts, a more invasive, less-differentiated esophageal cancer phenotype was achieved. Invasion into the stromal ECM was attenuated by genetic knockdown of AKT1 as well as AKT2. Taken together, alterations in key oncogenes and tumor suppressor genes in esophageal epithelial cells, the composition and activation of fibroblasts, and the components of the ECM conspire to regulate the physical and biological properties of the stroma.
PURPOSE - There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls.
PATIENTS AND METHODS - We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training-testing paradigm with application of the model profile defined in a training set to a blinded test cohort.
RESULTS - Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A.
CONCLUSIONS - We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.
p63 is a homologue of p53 that functions to maintain progenitor cell populations in stratified epithelia. Delta Np63 alpha is overexpressed in epithelial cancers and has been shown to have oncogenic properties. We have previously reported that inhibition of epidermal growth factor receptor signaling results in a decrease in Delta Np63 alpha expression. Here, we demonstrate Delta Np63 alpha is a target of the phosphoinositide-3-kinase (PI3K) pathway downstream of the epidermal growth factor receptor. Treatment of keratinocytes with epidermal growth factor results in an increase in Delta Np63 alpha expression at the mRNA level, which is abrogated by inhibition of PI3K but not mitogen-activated protein kinase signaling. Small interfering RNA-mediated knockdown of the p110 beta catalytic subunit of PI3K results in a decrease in Delta Np63 alpha protein levels in keratinocytes. The results presented herein suggest that regulation of Delta Np63 alpha expression by the PI3K pathway plays a critical role in the survival and proliferative capacity of squamous epithelia.
Among those women who have cervical cancer and have been screened, 14% to 33% of the cases represent failure to detect abnormalities that existed at the time of screening. New technologies intended to improve detection of cytologic abnormalities include liquid-based, thin-layer cytology (ThinPrep, AutoCyte), computerized rescreening (PAPNET), and algorithm-based computer rescreening (AutoPap). This report combines evidence reviews conducted for the U.S. Preventive Services Task Force and the Agency for Healthcare Research and Quality, in which we systematically identified articles on cervical neoplasia, cervical dysplasia, and screening published between January 1966 and March 2001. We note the challenges for improving screening methods, providing an overview of methods for collecting and evaluating cytologic samples, and examining the evidence about the diagnostic performance of new technologies for detecting cervical lesions. Using standard criteria for evaluation of the diagnostic tests, we determined that knowledge about the sensitivity, specificity, and predictive values of new technologies is meager. Only one study of liquid-based cytology used a reference standard of colposcopy, with histology as indicated, to assess participants with normal screening results. Lack of an adequate reference standard is the overwhelming reason that test characteristics cannot be properly assessed or compared. Most publications compare results of screening using the new technology with expert panel review of the cytologic specimen. In that case, the tests are not independent measures and do nothing to relate the screening test findings to the true status of the cervix, making determination of false-negatives, and thus sensitivity, specificity, and negative predictive value, impossible. We did not identify any literature about health outcomes or cost effectiveness of using these tools in a system of screening. For the purposes of guiding decision making about choice of screening tools, the current evidence is inadequate to gauge whether new technologies are "better" than conventional cytology..