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In the United States, 6.5 million children experience food insecurity. The purpose of this project was to evaluate the Building Blocks for Healthy Kids summer nutrition education program for low-income children. Twenty-six children ages 6–11 years participated in the six-lesson program that included snacks incorporating gleaned produce. Plate waste data indicated 55-80% of the served snack was consumed. Knowledge related to nutrition and food systems increased between pre- and post-intervention (p <.0001). At post-intervention, children reported practicing more mindful and sustainable eating practices. Overall, the program increased knowledge and improved food-related behaviors in low-income children. [ABSTRACT FROM AUTHOR]

Background: In a European cohort, it was previously reported that 35% of oropharyngeal cancer (OPC) patients were human papillomavirus type-16 (HPV16) seropositive up to 10 years before diagnosis vs 0.6% of cancer-free controls. Here, we describe the kinetics of HPV16-E6 antibodies prior to OPC diagnosis.Methods: We used annual serial prediagnostic blood samples from the PLCO Cancer Screening Trial. Antibodies to HPV were initially assessed in prediagnostic blood drawn at study enrollment from 198 incident head and neck cancer patients (median years to cancer diagnosis = 6.6) and 924 matched control subjects using multiplex serology, and subsequently in serial samples (median = 5/individual). Available tumor samples were identified and tested for HPV16 RNA to define HPV-driven OPC.Results: HPV16-E6 antibodies were present at baseline in 42.3% of 52 OPC patients and 0.5% of 924 control subjects. HPV16-E6 antibody levels were highly elevated and stable across serial blood samples for 21 OPC patients who were seropositive at baseline, as well as for one OPC patient who seroconverted closer to diagnosis. All five subjects with HPV16-driven OPC tumors were HPV16-E6-seropositive, and the four subjects with HPV16-negative OPC tumors were seronegative. The estimated 10-year cumulative risk of OPC was 6.2% (95% confidence interval [CI] = 1.8% to 21.5%) for HPV16-E6-seropositive men, 1.3% (95% CI = 0.1% to 15.3%) for HPV16-E6-seropositive women, and 0.04% (95% CI = 0.03% to 0.06%) among HPV16-E6-seronegative individuals.Conclusions: Forty-two percent of subjects diagnosed with OPC between 1994 and 2009 in a US cohort were HPV16-E6 seropositive, with stable antibody levels during annual follow-up for up to 13 years prior to diagnosis. Tumor analysis indicated that the sensitivity and specificity of HPV16-E6 antibodies were exceptionally high in predicting HPV-driven OPC. [ABSTRACT FROM AUTHOR]

Using the 1988 Child Health Supplement to the National Health Interview Survey, we analysed the association between child-care characteristics and frequent ear infections among children under 6 years attending child care. We observed strong associations for 1- to 2-year-old children for variables involving exposure to many different children, including number of children in the main setting and one or more changes in child-care arrangement in the past year. No significant effects were observed for the children under 1 year, but sample sizes were small. Likewise, no strong associations were observed for the 3- to 5-year-old children, but they may have outgrown the detrimental effects of repeated respiratory tract infections. [ABSTRACT FROM AUTHOR]

Background: The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial. Methods and Results: We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67–75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1–30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8–11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5–39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III–IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death. Conclusions: A TRV≥3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531 [ABSTRACT FROM AUTHOR]

Background: Analogous to the geographic distribution of variants of human papillomavirus (HPV) types, the distribution and persistence of these variants among infected individuals may be related to the racial composition of a population living in one geographic region. Methods: We studied 1114 women in the United States participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 and/or HPV18 at enrollment. Race was self-reported. HPV samples were characterized by sequencing the E6 gene and part of the long control region and classified as variants according to established lineages. Subjects were examined for HPV every 6 months for 2 years. All statistical tests were two-sided. Results: HPV18 African variants were predominant in the 97 HPV18-infected African American women (i.e., 62 women or 63.9%, 95% confidence interval [CI] = 53.5% to 73.4%), and European variants were common in the 168 HPV18-infected white women (i.e., 91 women or 54.2%, 95% CI = 46.3% to 61.9%). HPV16 African variants accounted for 43 (26.5%, 95% CI = 19.9% to 34.0%) of the infections in the 162 HPV16-infected African American women but for only 25 (4.3%, 95% CI = 2.8% to 6.3%) in the 584 HPV16-infected white women. The likelihood of remaining HPV18 positive was statistically significantly higher in white women infected with European than in white women infected with African variants (P = .04); the reverse was observed in African American women (P = .03). A similar pat- tern was observed for persistence of HPV16 variants, with the likelihood of remaining positive being higher for white women, but lower for African American women, infected with an European variant than with an African variant (P = .03 and P= .16, respectively). Conclusions: Variants of HPV16 and HPV18 appear to persist longer in a host whose race indicates an ancestral geographic distribution that was once shared with that of the variant-i.e., European variants persist longer in white women, and African variants persist longer in African American women. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions ( n = 365) and cytologically normal population controls ( n = 681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in >5% of US Caucasians but in <1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in <1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes. [ABSTRACT FROM AUTHOR]

Use of human papillomavirus (HPV) testing in cervical cancer prevention is increasing rapidly. A DNA test for 13 HPV types that can cause cervical cancer is approved in the United States for co-screening with cytology of women ≥30 years old and for tri- age of women of all ages with equivocal cytology. However, most infections with HPV are benign. We evaluated trade-offs between specificity and sensitivity for approximately 40 HPV types in predicting cervical intraepithelial neoplasia 3 and cancer in two prospective studies: a population-based screening study that followed 6196 women aged 30–94 years from Costa Rica for 7 years and a triage study that followed 3363 women aged 18–90 years with equivocal cytology in four U.S. centers for 2 years. For both screening and triage, testing for more than about 10 HPV types decreased specificity more than it increased sensitivity. The minimal increases in sensitivity and in negative predictive value achieved by adding HPV types to DNA tests must be weighed against the projected burden to thousands of women falsely labeled as being at high risk of cervical cancer. [ABSTRACT FROM AUTHOR]

In the 1980s, a case–control epidemiologic study was conducted in Iowa (USA) to analyze the association between exposure to disinfection by-products (DBPs) and bladder cancer risk. Trihalomethanes (THMs), the most commonly measured and dominant class of DBPs in drinking water, served as a primary metric and surrogate for the full DBP mixture. Average THM exposure was calculated, based on rough estimates of past levels in Iowa. To reduce misclassification, a follow-up study was undertaken to improve estimates of past THM levels and to re-evaluate their association with cancer risk. In addition, the risk associated with haloacetic acids, another class of DBPs, was examined. In the original analysis, surface water treatment plants were assigned one of two possible THM levels depending on the point of chlorination. The re-assessment considered each utility treating surface or groundwater on a case-by-case basis. Multiple treatment/disinfection scenarios and water quality parameters were considered with actual DBP measurements to develop estimates of past levels. The highest annual average THM level in the re-analysis was 156 μg/L compared to 74 μg/L for the original analysis. This allowed the analysis of subjects exposed at higher levels (> 96 μg/L). The re-analysis established a new approach, based on case studies and an understanding of the water quality and operational parameters that impact DBP formation, for determining historical exposure. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Studies have suggested that polymorphisms in genes involved in immune recognition and antigen presentation are associated with cervical cancer risk. We sought to replicate a recent study which reported an association between specific SNPs on CD83 and cervical cancer and to further explore whether effects varied by age, clinical stage (in situ versus invasive), and histology (squamous carcinomas versus adenocarcinomas). Methods: We evaluated the association between SNPs on CD83 and cervical cancer in a multicenter case-control study of cervical cancer conducted in the Eastern United States (263 cases, 307 controls), focusing on the five SNPs (RS9296925, RS853360, RS9230, RS9370729, RS750749) previously found to be associated with cervical cancer. We also pooled data from the Eastern U.S. (263 cases) with those from the original report (377 cases) to assess the effects of CD83 on the age at diagnosis, disease stage, and histology. Risk estimates (ORs) and 95% confidence intervals were estimated using logistic regression; trend tests were performed under an additive model. Results: Consistent with the original report, carriers of the CT or CC genotypes for one of the five CD83 SNPs evaluated (rs750749) demonstrated a 30% and 50% reduction in disease risk, relative to carriers of the more common TT genotype (p-trend=0.02). Two additional SNPs also resulted in consistent findings (rs9296925: p-trend=0.07 and rs9370729: p-trend=0.08), although the effects observed did not reach statistical significance at the 0.05 level. Pooled evaluation of cases from the two aforementioned studies suggested differences in the distribution of susceptibility alleles by histology; adenocarcinoma cases were more likely to be carriers of the susceptibility alleles for SNP rs9370729 (p-trend=0.02) and SNP rs750749 (p-trend=0.09). No differences were observed in the age or stage of diagnosis of carriers for CD83 susceptibility alleles relative to non-carriers. Conclusions: We confirm an association between CD83 polymorphisms and cervical cancer and suggest the possibility that CD83-disease associations might be heterogenous by tumor histology. [Copyright &y& Elsevier]

Cancer of the oropharynx has attracted considerable attention in recent years given: (1) an increasing incidence in selected populations over the past three decades; (2) the discovery of human papillomavirus (HPV) infection as the driver of the increase, as opposed to the traditional risk factors such as tobacco (smoking and chewing) and alcohol; and (3) the promise of new prevention and treatment strategies. As a result of such developments, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI), convened the fourth Cancer Seminar meeting in November 2018 to focus on this topic. This report summarizes the proceedings: a review of recent science on the descriptive epidemiology, etiology, biology, genetics, early detection, pathology and treatment of HPV-positive oropharyngeal cancer, and the formulation of key research questions to be addressed. [ABSTRACT FROM AUTHOR]

Background: Burden of cancer mortality is often measured by death counts or mortality rates, but potential years of life lost (PYLL) and PYLL per death may be more useful to estimate the impact of cancer-related deaths occurring at younger ages., Methods: We used U.S. national death certificate data. A total of 45 categories of common cancers were grouped for cancer-specific calculations of PYLL and PYLL per death. PYLL was defined as the sum of the total years of life lost prior to age 75 years., Results: The largest number of PYLL in 2017 was due to deaths from cancers of the lung/bronchus (891,313; 20.8%), colon/rectum (409,538; 9.6%), and breast (400,643; 9.4%). Cancers with the highest PYLLs generally also caused the largest number of deaths and had the highest mortality rates, with the exception of prostate cancer (5.1% of deaths, 2.0% of PYLL). In contrast, PYLLs per death were greatest for deaths due to cancers of testis (mean = 34.0 years), bones/joints (26.4), and other endocrine sites including thymus (25.2)., Conclusions: Although PYLLs generally reflect mortality rates, they more heavily weigh cancers that occur at younger ages. In contrast, PYLL per death, which is an average quantification of life years lost for individual patients with cancer, shows a different pattern., Impact: Mortality rates, PYLL, and PYLL per death are complementary measures of the burden of deaths due to cancer that should be considered in tandem to prioritize public health interventions focused on preventing premature mortality., (©2020 American Association for Cancer Research.)

Background: Prevalence of Helicobacter pylori ( H. pylori ) infection, the main risk factor for gastric cancer, has been decreasing in the United States; however, there remains a substantial racial disparity. Moreover, the time-trends for prevalence of CagA-positive H. pylori infection, the most virulent form, are unknown in the U.S., Population: We sought to assess prevalence of CagA-positive H. pylori infection over time by race in the United States., Methods: We utilized multiplex serology to quantify antibody responses to H. pylori antigens in 4,476 participants across five cohorts that sampled adults from 1985 to 2009. Using log-binomial regression models, we calculated prevalence ratios and 95% confidence intervals for the association between H. pylori -CagA sero-prevalence and birth year by race., Results: African Americans were three times more likely to be H. pylori -CagA sero-positive than Whites. After adjustment, H. pylori -CagA sero-prevalence was lower with increasing birth year among Whites ( P trend = 0.001), but remained stable for African Americans. When stratified by sex and education separately, the decline in H. pylori < 0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex; furthermore, sero-prevalence increased with increasing birth year among those with a high school education or less ( P trend < 0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex; furthermore, sero-prevalence increased with increasing birth year among those with a high school education or less ( P = 0.006)., Conclusions: Among individuals in the United States born from the 1920s to 1960s, H. pylori -CagA sero-prevalence has declined among Whites, but not among African Americans., Impact: Our findings suggest a widening racial disparity in the prevalence of the most virulent form of H. pylori , the main cause of gastric cancer., (©2020 American Association for Cancer Research.)

Background & Aims: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States., Methods: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression., Results: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007)., Conclusions: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains, including many primary isolates, have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1, and the BART microRNA (miRNA) cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction. A novel classification of EBNA1 DNA binding domains, named QCIGP, results from phylogeny analysis of their protein sequences but is not linked to the type 1/type 2 classification. The BART cluster 2 miRNA region is classified into three major variants through single-nucleotide polymorphisms (SNPs) in the primary miRNA outside the mature miRNA sequences. These SNPs can result in altered levels of expression of some miRNAs from the BART variant frequently present in Chinese and Indonesian nasopharyngeal carcinoma (NPC) samples. The EBV genetic variants identified here provide a basis for future, more directed analysis of association of specific EBV variations with EBV biology and EBV-associated diseases. IMPORTANCE Incidence of diseases associated with EBV varies greatly in different parts of the world. Thus, relationships between EBV genome sequence variation and health, disease, geography, and ethnicity of the host may be important for understanding the role of EBV in diseases and for development of an effective EBV vaccine. This paper provides the most comprehensive analysis so far of variation in specific EBV genes relevant to these diseases and proposed EBV vaccines. By focusing on variation in LMP1, Zp, gp350, EBNA1, and the BART miRNA cluster 2, new relationships with the known type 1/type 2 strains are demonstrated, and a novel classification of EBNA1 and the BART miRNAs is proposed., (Copyright © 2017 Correia et al.)

Background: Epidemiologic studies of the carcinogenic stomach bacterium Helicobacter pylori have been limited by the lack of noninvasive detection and genotyping methods. We developed a new stool-based method for detection, quantification, and partial genotyping of H. pylori using droplet digital PCR (ddPCR), which allows for increased sensitivity and absolute quantification by PCR partitioning., Materials and Methods: Stool-based ddPCR assays for H. pylori 16S gene detection and cagA virulence gene typing were tested using a collection of 50 matched stool and serum samples from Costa Rican volunteers and 29 H. pylori stool antigen-tested stool samples collected at a US hospital., Results: The stool-based H. pylori 16S ddPCR assay had a sensitivity of 84% and 100% and a specificity of 100% and 71% compared to serology and stool antigen tests, respectively. The stool-based cagA genotyping assay detected cagA in 22 (88%) of 25 stools from CagA antibody-positive individuals and four (16%) of 25 stools from CagA antibody-negative individuals from Costa Rica. All 26 of these samples had a Western-type cagA allele. Presence of serum CagA antibodies was correlated with a significantly higher load of H. pylori in the stool., Conclusions: The stool-based ddPCR assays are a sensitive, noninvasive method for detection, quantification, and partial genotyping of H. pylori. The quantitative nature of ddPCR-based H. pylori detection revealed significant variation in bacterial load among individuals that correlates with presence of the cagA virulence gene. These stool-based ddPCR assays will facilitate future population-based epidemiologic studies of this important human pathogen., (© 2015 John Wiley & Sons Ltd.)

Background: We conducted two independent nested case-control studies to identify circulating inflammation markers reproducibly associated with lung cancer risk and to investigate the utility of replicated markers for lung cancer risk stratification., Methods: Nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the previously published discovery study included 526 lung cancer patients and 592 control subjects and the replication study included 526 lung cancer case patients and 625 control subjects. Control subjects were matched by sex, age, smoking, study visit, and years of blood draw and exit. Serum levels of 51 inflammation markers were measured. Odds ratios (ORs) were estimated with conditional logistic regression. All statistical tests were two-sided., Results: Of 11 markers identified in the discovery study, C-reactive protein (CRP) (odds ratio [OR] [highest vs. lowest category] = 1.77, 95% confidence interval [CI] = 1.23 to 2.54), serum amyloid A (SAA) (OR = 1.88, 95% CI = 1.28 to 2.76), soluble tumor necrosis factor receptor-2 (sTNFRII) (OR = 1.70, 95% CI = 1.18 to 2.45), and monokine induced by gamma interferon (CXCL9/MIG) (OR = 2.09, 95% CI = 1.41 to 3.00) were associated with lung cancer risk in the replication study (P trend < .01). In pooled analyses, CRP, SAA, and CXCL9/MIG remained associated with lung cancer more than six years before diagnosis (P trend < .05). The incorporation of an inflammation score combining these four markers did not improve the sensitivity (77.6% vs 75.8%, P = .33) or specificity (56.1% vs 56.1%, P = .98) of risk-based lung cancer models., Conclusions: Circulating levels of CRP, SAA, sTNFRII, and CXCL9/MIG were reproducibly associated with lung cancer risk in two independent studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, underscoring an etiologic role for inflammation in lung carcinogenesis, though replication is needed in other populations. Markers did not improve lung cancer risk stratification beyond standard demographic and behavioral characteristics., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received., Methods: Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase., Findings: We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group., Interpretation: 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine., Funding: US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven prevention methods. We aimed to establish the natural history of oral HPV infection in men., Methods: To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method., Findings: 1626 men aged 18-73 years and with a median follow-up of 12·7 months (IQR 12·1-14·7) were included in the analysis. During the first 12 months of follow-up, 4·4% (95% CI 3·5-5·6; n=115 incident infections) of men acquired an incident oral HPV infection, 1·7% (1·2-2·5; n=53 incident infections) an oral oncogenic HPV infection, and 0·6% (0·3-1·1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6·9 months (95 % CI 6·2-9·3; n=45 cleared infections) for any HPV, 6·3 months (6·0-9·9; n=18 cleared infections) for oncogenic HPV, and 7·3 months (6·0-not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits., Interpretation: Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts., Funding: US National Cancer Institute, Merck Sharp & Dohme., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera., Methods: We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression., Results: HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative., Conclusion: HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

Carcinogenic human papillomavirus (HPV) infections are very common after sexual debut and nearly all become undetectable ("clear") within a few years. Following clearance, the long-term risks of type-specific HPV re-appearance and subsequent risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are not well defined. In the 7-year, population-based cohort study in Guanacaste, Costa Rica, we studied how often type-specific carcinogenic HPV infections re-appeared after clearance and how often re-appearance led to CIN2+. We considered 1,740 carcinogenic HPV infections detected by MY09/11 PCR among 2,805 women (18-91 years old, median 34) who were actively followed at 6- or 12-month intervals. We identified women with one or more type-specific HPV infections that cleared and re-appeared and further defined a subgroup of "definite clearance and re-appearance" (≥2 intervening negative results over a period of ≥1 year). We determined the absolute risk of CIN2+ among the different groups. p values are two-sided. Only 7.7% (81/1,052) of HPV-infected women had intervening negative results. Very few (3.7%, 39/1,052) had "definite clearance and re-appearance", of which 5.1% (2/39) subsequently persisted to a diagnosis of CIN2. There were zero CIN3+ lesions. Extremely few women (2/2,805 of women in our cohort) had a type-specific carcinogenic HPV infection clear, re-appear and lead to CIN2+. If confirmed, this argues against vaccination to avoid re-appearance that leads to precursor lesions and against the need of frequent HPV screening after initial negative results., (Copyright © 2011 UICC.)

Background: Oral human papillomavirus type-16 (HPV16) infection is a risk factor for oropharyngeal cancer. We examined oral HPV infection among healthy men., Methods: Oral rinse/gargle specimens and questionnaire data were collected from 1,688 healthy men aged 18 to 74 (median = 31 years), from the United States, Mexico, and Brazil. HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59, and noncarcinogenic HPV types were detected using Roche Linear Array., Results: Oral HPV DNA was detected in 67 of 1,680 (4.0%, 95% CI = 3.1%-5.0%) β-globin-positive specimens; carcinogenic HPVs were detected in 1.3% (95% CI = 0.8%-2.0%; n = 22) and HPV16 was the most commonly detected carcinogenic HPV type (0.6%, 95% CI = 0.2%-1.1%; n = 10). The prevalence of oral HPV infection was similar by country except for HPV55, which had notably higher prevalence in Mexico (3.0%) than Brazil (0%) or the United States (0.2%). Oral HPV prevalence nonsignificantly increased over increasing age categories (P(trend) = 0.096). The strongest predictor of oral HPV was current tobacco use, which increased the odds 2.5-fold (95% CI = 1.4-4.4). Oral sexual behaviors were not associated with oral HPV infection., Conclusions: Oral HPV16 infection was rare in healthy men, especially at younger ages, and was positively associated with current tobacco use., Impact: Oral HPV appears to be about 10-fold less prevalent than infection at genital sites in men (4% vs. ∼40%, respectively). It remains unclear whether this reflects reduced exposure or if the oral region is more resistant to HPV infection compared with anogenital sites., (©2011 AACR.)

Background: Cofactors might affect the risk of the rare progression from infection with carcinogenic human papillomavirus (HPV) to cervical premalignancy to invasive cancer. Some studies have observed that Chlamydia trachomatis infection is associated with increased risk for cervical cancer. In a large prospective cohort, we assessed the role of C trachomatis in cervical premalignancy and addressed confounding by HPV., Methods: We identified 182 women with prevalent and 132 women with incident histological cervical intraepithelial neoplasia grade 2 (CIN2), grade 3 (CIN3), or cervical cancer (CIN2+) in the Costa Rica HPV Natural History Study. Control subjects were 995 (approximately 10% of the 10 049) subjects who were randomly selected from the same study. Cervical HPV status at enrollment was determined by MY09/MY11 polymerase chain reaction amplification and dot-blot hybridization. The presence of C trachomatis DNA in cervical exfoliated cells at enrollment was determined by a novel serovar-specific polymerase chain reaction-based C trachomatis detection and genotyping assay. Plasma drawn at enrollment from each subject was used to determine C trachomatis immunoglobulin G (IgG) status. Logistic regression was used to examine the association between C trachomatis and CIN2+, taking into account possible confounding by HPV., Results: C trachomatis positivity at enrollment was associated with CIN2+ and concurrent and subsequent carcinogenic HPV infection. To account for confounding by HPV status, we restricted the analysis to women positive for carcinogenic HPV DNA at enrollment and found no association between C trachomatis status (as assessed by DNA or IgG) at enrollment and combined prevalent and/or incident CIN2+ (for C trachomatis DNA positivity, odds ratio = 0.77, 95% confidence interval = 0.42 to 1.41; for C trachomatis seropositivity, odds ratio = 1.09, 95% confidence interval = 0.85 to 1.41)., Conclusions: We found no association between C trachomatis status, as assessed by DNA or IgG, and risk of cervical premalignancy, after controlling for carcinogenic HPV-positive status. Previous positive associations between C trachomatis and cervical premalignancy could have been caused, in part, by an increased susceptibility to HPV infection.

Background: Although the variant lineages of human papillomavirus (HPV) types 16 and 18 are well established, their individual associations with high-grade cervical intraepithelial neoplasia (CIN) have not been extensively evaluated., Methods: Study subjects were women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 or HPV18 at enrollment. These women were followed every 6 months for 2 years. Viral isolates from enrollment samples were characterized by DNA sequencing and classified as variant lineages., Results: Over a 2-year study period, CIN3 was histologically diagnosed in 291 of the 779 HPV16-positive women and 47 of the 275 HPV18-positive women. Among women without CIN2-3 at enrollment, the risk of subsequent CIN3 was 2.7-fold greater for those with HPV16 African-2 [95% confidence interval (95% CI), 1.0-7.0] and 3.1-fold greater for those with HPV16 Asian American (95% CI, 1.6-6.0), compared with European variants. Relative to infection with HPV18 African variants, the risk associating subsequent CIN3 was 3.8 (95% CI, 0.9-17.2) for infection with HPV18 European variants and 4.8 (95% CI, 1.0-23.6) for infection with HPV18 Asian American variants. Similar associations were observed when the 2-year prevalence of CIN3 was used as the end point. Further, for those with HPV16 European variants, the 2-year prevalence of CIN3 was higher in White women than in African American women (P = 0.01); this trend was reversed for those with HPV16 African-1 variants (P = 0.22). A similar pattern was present for infections with HPV18 European versus African variants., Conclusions: The lineages of HPV16 and HPV18 variants are associated with differing risks for high-grade CIN.

Objective: Difficulties in detecting cervical adenocarcinoma early are well known. We report a detailed pathology review of cervical adenocarcinoma subtypes, comparing growth patterns and appearance of non-neoplastic epithelium to inform possible clues for disease progression and early detection., Methods: This analysis includes 154 women aged 18-69 years and diagnosed with incident in situ or invasive adenocarcinoma (AC), adenosquamous (AS), or other rare cervical glandular tumors from 1992-1996 in six U.S. medical centers. A pathology review panel evaluated histological features from original diagnostic slides., Results: Higher tumor grade (P < 0.001) and vascular invasion (P = 0.002) were more common in AS compared to AC. Adenocarcinoma in situ (AIS) was also more common among AC than AS (P = 0.002). Among AC with cervical intraepithelial carcinoma (CIN), AIS and cribriform patterns were more common than AC without CIN (P = 0.01). Further, non-endometrioid AC had higher tumor grade (P = 0.01) and stromal responses (P = 0.02) than endometrioid AC. Finally, although microglandular hyperplasia is historically thought to be related to oral contraceptive (OC) use, our data do not support this notion., Conclusion(s): AS appears to be either diagnosed later or histologically more aggressive than AC, and among AC subtypes, there are distinct histologic characteristics. Further research is needed to identify precursor lesions for early detection of AC and particularly for AS where AIS may not be a common precursor.

To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.

Background: Analogous to the geographic distribution of variants of human papillomavirus (HPV) types, the distribution and persistence of these variants among infected individuals may be related to the racial composition of a population living in one geographic region., Methods: We studied 1114 women in the United States participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 and/or HPV18 at enrollment. Race was self-reported. HPV samples were characterized by sequencing the E6 gene and part of the long control region and classified as variants according to established lineages. Subjects were examined for HPV every 6 months for 2 years. All statistical tests were two-sided., Results: HPV18 African variants were predominant in the 97 HPV18-infected African American women (i.e., 62 women or 63.9%, 95% confidence interval [CI] = 53.5% to 73.4%), and European variants were common in the 168 HPV18-infected white women (i.e., 91 women or 54.2%, 95% CI = 46.3% to 61.9%). HPV16 African variants accounted for 43 (26.5%, 95% CI = 19.9% to 34.0%) of the infections in the 162 HPV16-infected African American women but for only 25 (4.3%, 95% CI = 2.8% to 6.3%) in the 584 HPV16-infected white women. The likelihood of remaining HPV18 positive was statistically significantly higher in white women infected with European than in white women infected with African variants (P = .04); the reverse was observed in African American women (P = .03). A similar pattern was observed for persistence of HPV16 variants, with the likelihood of remaining positive being higher for white women, but lower for African American women, infected with an European variant than with an African variant (P = .03 and P = .16, respectively)., Conclusions: Variants of HPV16 and HPV18 appear to persist longer in a host whose race indicates an ancestral geographic distribution that was once shared with that of the variant-i.e., European variants persist longer in white women, and African variants persist longer in African American women.

Previous work suggests that cervical cancer may aggregate in families. We evaluated the association between a family history of gynecological tumors and risk of squamous cell and adenocarcinomas of the cervix in 2 studies conducted in Costa Rica and the United States. The Costa Rican study consisted of 2,073 women (85 diagnosed with CIN3 or cancer, 55 diagnosed with CIN2 and 1,933 controls) selected from a population-based study of 10,049 women. The U.S. study consisted of 570 women (124 with in situ or invasive adenocarcinomas, 139 with in situ or invasive squamous cell carcinomas of the cervix and 307 community-based controls) recruited as part of a multicentric case-control study in the eastern part of the United States. Information on family history of cervical and other cancers among first-degree relatives was ascertained via questionnaire. Information on other risk factors for cervical cancer was obtained via questionnaire. Human papillomavirus (HPV) exposure was assessed in both studies using broad spectrum HPV L1-based PCR testing of exfoliated cervicovaginal cells and in Costa Rica by additional testing of plasma collected from participants for antibodies against the L1 protein of HPV types 16, 18, 31 and 45 by ELISA. A family history of cervical cancer in a first-degree relative was associated with increased risk of squamous tumors in both studies (odds ration [OR] = 3.2 for CIN3/cancer vs. controls; 95% confidence interval [CI] = 1.1-9.4 in Costa Rica; OR = 2.6 for in situ/invasive squamous cell carcinoma cases vs. controls, 95% CI = 1.1-6.4 in the Eastern United States study). These associations were evident regardless of whether the affected relative was a mother, sister or daughter of the study participant. Furthermore, observed effects were not strongly modified by age. In Costa Rica, the effect persisted in analysis restricted to HPV-exposed individuals (OR = 3.0; 95% CI = 1.0-9.0), whereas in the Eastern United States study there was evidence of attenuation of risk in analysis of squamous carcinoma cases restricted to HPV positive women (OR = 1.4; 95% CI = 0.29-6.6). No significant association was observed between a family history of cervical cancer in a first-degree relative and adenocarcinomas (OR = 1.3; 95% CI = 0.43-3.9). History of gynecological tumors other than cervical cancer in a first-degree relative was not significantly associated with risk of disease in either study. These results are consistent with a role of host factors in the pathogenesis of squamous cell cervical cancer, although familial aggregation due to shared environmental exposures cannot be ruled out., ((c) 2005 Wiley-Liss, Inc.)

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor-ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.

Background: Although cervical carcinoma incidence and mortality rates have declined in the U.S. greatly since the introduction of the Papanicolaou smear, this decline has not been uniform for all histologic subtypes. Therefore, the authors assessed the differential incidence rates of squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the cervix by race and disease stage for the past 25 years., Methods: Data from nine population-based cancer registries participating in the U.S. Surveillance, Epidemiology, and End Results (SEER) Program were used to compute incidence rates for cervical carcinoma diagnosed during 1976-2000 by histologic subtype (SCC and AC), race (black and white), age, and disease stage (in situ, localized, regional, or distant)., Results: In black women and white women, the overall incidence of invasive SCC declined over time, and the majority of tumors that are detected currently are in situ and localized carcinomas in young women. The incidence of in situ SCC increased sharply in the early 1990s. AC in situ (AIS) incidence rates increased, especially among young women. In black women, invasive AC incidence rose linearly with age., Conclusions: Changes in screening, endocervical sampling, nomenclature, and improvements in treatment likely explain the increased in situ cervical SCC incidence in white women and black women. Increasing AIS incidence over the past 20 years in white women has not yet translated into a decrease in invasive AC incidence. Etiologic factors may explain the rising invasive cervical AC incidence in young white women; rising cervical AC incidence with age in black women may reflect either lack of effective screening or a differential disease etiology., (Copyright 2004 American Cancer Society.)

The distributions of human papillomavirus (HPV) types detected in cervical adenocarcinomas and squamous cell tumors differ. However, whether the distributions of intratypic HPV variants seen in these two histological forms of cervical disease differ is unknown. Our objective was to compare the distribution of HPV intratypic variants observed in squamous cell carcinomas (SCC) and cervical tumors of glandular origin (e.g., adenocarcinomas; AC) for two HPV types commonly observed in cervical tumors, HPV16 and HPV18. Participants in a multicenter case-control study of AC and SCC conducted in the eastern United States were studied. A total of 85 HPV16 and/or HPV18 positive individuals (31 diagnosed with AC, 43 diagnosed with SCC, and 11 population controls) were included. For HPV16-positive individuals, both the noncoding long control region and the E6 open reading frame were sequenced, and classified into phylogenetic-based lineage groups (European, Asian-American, African1, and African2). For HPV18-positive individuals, the long control region region only was sequenced and classified into known intratypic lineages (European, Asian-Amerindian, and African). The distribution of these different intratypic lineages among AC cases, SCC cases, and population controls was compared using standard methods. Non-European HPV16 and/or HPV18 intratypic variants were observed in 42% of ACs compared with 16% of SCCs and 18% of population controls (P = 0.04). Intratypic variants from the Asian-American lineage of HPV16 accounted for the differences seen between histological groups. The differences observed between AC and SCC cases were strongest for HPV16, and persisted in analysis restricted to Caucasian women, suggesting that the effect cannot be explained by differences in the ethnic make-up of AC versus SCC cases. Cervical AC and SCC differ not only with respect to the distribution of HPV types detected but also with respect to intratypic variants observed. Non-European HPV16 and/or HPV18 variants are commonly seen in AC. A possible hormonal mechanism is suggested to explain the observed findings.

The role of host immunity in the development of virus-induced cancers has been difficult to elucidate, in part because of our inability to effectively measure multiple immune parameters using available amounts of biological material. The objective of the present study was to validate the use of a newly developed multiplex assay, the LINCOplex assay, for the simultaneous measurement of multiple cytokines [interleukin/(IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, and tumor necrosis factor-alpha]. Supernatants obtained from peripheral blood mononuclear cell cultures stimulated with various different mitogens and antigens (including phytohemagglutinin, influenza, tetanus, HPV16 E6 and E7 peptides, and media alone) were selected for study. In total, 750 specimens obtained from 26 participants were tested in replicate using the 8-plex LINCOplex assay (25 micro l of specimen required per well). Every specimen was included in duplicate in a blinded fashion. For some specimens, multiple 2-fold dilutions of the same specimen were included to evaluate the linearity of results. The availability of independently obtained IL-2 and IFN-gamma results from standard single cytokine (simplex) assays allowed for a direct comparison between the LINCOplex results and those obtained from the simplex assays. Spearman correlation coefficients for continuous results, and exact agreement rates and weighted kappa statistics for quartiled variables, were computed to evaluate intra- and interassay agreement. IL-4 levels were consistently below the detectable level of the assay (3 pg/ml) whereas IL-6 and IL-8 levels were consistently above the highest detectable level of the assay (10,000 pg/ml), and these three cytokines were, therefore, not evaluated further. For the remaining five cytokines, excellent intra-assay reproducibility was observed, with Spearman correlation coefficients consistently above 0.90 for all five cytokines. Exact agreement rates ranging from 77.6-90.3% and weighted kappas ranging from 0.81-0.92 were observed. Similar results were observed when analysis was restricted to supernatants obtained from cultures that had been stimulated with HPV16 peptides and when analysis was restricted to supernatants obtained from cultures containing no antigen or mitogen, suggesting that the LINCOplex assay is applicable under conditions where moderate or weak cytokine responses/levels are expected. Linearity of results was observed when dilutions of a single specimen were blindly tested, with the exception of IL-2 and IL-10, where deviations from linearity were sometimes observed. For IL-2 and IFN-gamma, where results from simplex assays were available for comparison, the LINCOplex assay and the simplex assay results agreed well. Spearman correlation coefficients were 0.86 and 0.93 for IL-2 and IFN-gamma, respectively. Exact agreement and weighted kappa values were 68.5% and 0.72 (95% confidence interval, 0.65-0.79), respectively, for IL-2 and 67.3% and 0.73 (95% confidence interval, 0.67-0.80), respectively, for IFN-gamma. These results indicate the applicability of the LINCOplex assay for the simultaneous measurement of multiple cytokines using small amounts of biological material.

Objectives: Few studies of smoking and cervical carcinoma have addressed the rare cervical adenocarcinomas or used DNA-based tests to control for human papillomavirus (HPV) infection., Methods: This multicenter case-control study included 124 adenocarcinoma cases, 307 community controls (matched on age, race, and residence to adenocarcinoma cases), and 139 squamous carcinoma cases (matched on age, diagnosis date, clinic, and disease stage to adenocarcinoma cases). Participants completed risk-factor interviews and volunteered cervical samples for PCR-based HPV testing. Polychotomous logistic regression generated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for both histologic types., Results: Eighteen percent of adenocarcinoma cases, 43% of squamous carcinoma cases, and 22% of controls were current smokers. After control for HPV and other questionnaire data, adenocarcinomas were consistently inversely associated with smoking (e.g. current: OR = 0.6, 95% CI 0.3-1.1; > or = 1 pack per day: OR = 0.7, 95% CI 0.4-1.3), while squamous carcinomas were positively associated with smoking (e.g. current: OR = 1.6, 95% CI 0.9-2.9; > or = 1 pack per day: OR = 1.8, 95% CI 1.0-3.3). Results in analyses restricted to HPV-positive controls were similar., Conclusion: Smoking has opposite associations with cervical adenocarcinomas and squamous carcinomas. Although both histologic types are caused by HPV and arise in the cervix, etiologic co-factors for these tumors may differ.

The host immune response to human papillomaviruses (HPVs) is believed to be an important determinant of progression of HPV-associated cervical neoplasia. Human leukocyte antigens (HLAs) are important in the presentation of foreign antigens to the immune system. Previous studies have suggested a possible association between HLA and cervical neoplasia, but the specific alleles found to be associated with disease have varied between studies. To further evaluate this issue, we conducted a nested case-control study within a 24,000-woman cohort study in the United States. A total of 711 women were selected for the study: 141 women diagnosed with high-grade squamous intraepithelial lesions (HSILs) of the cervix; 202 women diagnosed with low-grade SILs (LSILs); 166 women with no history of cervical neoplasia, but evidence of HPV-16 infection; and 202 women with no history of cervical abnormalities and who were HPV negative during follow-up as part of our cohort. Cervicovaginal lavage samples collected from participants were used for HPV testing by L1 consensus primer PCR and the Hybrid Capture tube test methods. DNA extracted from these same lavage samples were used for PCR-based HLA genotyping. Our results suggest a positive association between HLA B7 and HLA DQB1*0302 and disease. A negative association with disease was observed for HLA DRB1*1501-DQB1*0602 and DRB1*13. Associations were strongest when analyses were restricted to HPV-16-positive cases as follows. Compared with women who were cytologically normal and HPV negative, HLA B7 was associated with a 1.5-fold increased risk of HPV/LSIL [95% confidence interval (CI) = 0.95-2.5] and a 2.5-fold increased risk of HSIL (95% CI = 1.2-5.1). HLA DQB1*0302 was associated with a 1.5-fold increased risk of HPV/LSIL (95% CI = 0.94-2.4) and a 1.7-fold increased risk of HSIL (95% CI = 0.84-3.5). HLA DRB1*1501-DQB1*0602 was associated with a decreased risk of HSIL [relative risk (RR) = 0.21; 95% CI = 0.07-0.62]. HLA DRB1*13 was associated with a decreased risk of HPV/LSIL (RR = 0.78; 95% CI = 0.51-1.2) and HSIL (RR = 0.63; 95% CI = 0.30-1.3). Individuals who were either homozygous for DQB1*0302 or carriers of both B7 and DQB1*0302 were found to be at highest risk of disease (RR = 4.5, 95% CI = 1.5-14 for HPV/LSIL; and RR = 9.0, 95% CI = 2.4-34 for HSIL). No synergistic effect was observed for the alleles found to be associated with reduced risk of cervical neoplasia. Our findings support previous studies that have found HLA B7 and DQB1*0302 to be positively associated with cervical neoplasia and are consistent with those that have suggested that DRB1*13 is negatively associated with disease, but do not confirm previous assertions that DRB1*1501-DQB1*0602 increases the risk of cervical disease.

Background: Automated cytology devices have utility in quality assurance applications, but the effectiveness of these devices in primary screening is unknown., Methods: Enrollment smears obtained from 7323 women participating in a population-based study sponsored by the National Cancer Institute were screened manually in Costa Rica and then evaluated independently in the U.S. with the PAPNET system (Neuromedical Systems, Inc., Suffern, NY), a semiautomated, neural network-based device. Smears with abnormal PAPNET images were microscopically rescreened and then diagnosed by a U.S. cytopathologist. ThinPrep slides (Cytyc Corporation, Boxborough, MA), prepared from rinses of the cytologic sampler, and cervigrams (National Testing Laboratories, Fenton, MO) were also evaluated. Women with any abnormal cytologic diagnosis or a positive cervigram were referred for colposcopy with biopsy and definitive therapy if indicated., Results: Based on the U.S. cytotechnologist's review of the PAPNET images, 1017 (13.9%) of 7323 smears were selected for manual screening, resulting in the selection of 492 (6.7%) possibly abnormal slides for referral to the U.S. pathologist. Ultimately, 312 smears (4.3% of the total) were diagnosed as containing squamous cells of undetermined significance or a more severe abnormality (> or =ASCUS), resulting, hypothetically, in the referral of 66.5% of women with a final diagnosis of a squamous intraepithelial lesion or a more severe abnormality (> or =SIL) and 86.0% of patients with > or =high grade SIL. Conventional microscopic screening performed in Costa Rica resulted in the hypothetical referral of 6.5% of patients with > or =ASCUS for colposcopy, including 69.5% of patients with > or =SIL and 79.8% of those with > or =high grade SIL., Conclusions: In this study, PAPNET-assisted cytologic screening accurately identified smears obtained from women with high grade SIL or carcinoma. Determination of the clinical cost-effectiveness of PAPNET-assisted screening in routine practice awaits future study.

Background: Breast cancer incidence rates have historically been 4-7 times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, breast cancer risk rises over several generations and approaches that among U.S. Whites., Purpose: Our objective was to quantify breast cancer risks associated with the various migration patterns of Asian-American women., Methods: A population-based, case-control study of breast cancer among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, was conducted during 1983-1987 in San Francisco-Oakland, California, Los Angeles, California, and Oahu, Hawaii. We successfully interviewed 597 case subjects (70% of those eligible) and 966 control subjects (75%)., Results: A sixfold gradient in breast cancer risk by migration patterns was observed. Asian-American women born in the West had a breast cancer risk 60% higher than Asian-American women born in the East. Among those born in the West, risk was determined by whether their grandparents, especially grandmothers, were born in the East or the West. Asian-American women with three or four grandparents born in the West had a risk 50% higher than those with all grandparents born in the East. Among the Asian-American women born in the East, breast cancer risk was determined by whether their communities prior to migration were rural or urban and by the number of years subsequently lived in the West. Migrants from urban areas had a risk 30% higher than migrants from rural areas. Migrants who had lived in the West for a decade or longer had a risk 80% higher than more recent migrants. Risk was unrelated to age at migration for women migrating at ages less than 36 years. Ethnic-specific incidence rates of breast cancer in the migrating generation were clearly elevated above those in the countries of origin, while rates in Asian-Americans born in the West approximated the U.S. White rate., Conclusions: Exposure to Western lifestyles had a substantial impact on breast cancer risk in Asian migrants to the United States during their lifetime. There was no direct evidence of an especially susceptible period, during either menarche or early reproductive life., Implications: Because heterogeneity in breast cancer risk in these ethnic populations is similar to that in international comparisons and because analytic epidemiologic studies offer the opportunity to disentangle correlated exposures, this study should provide new insights into the etiology of breast cancer.

The attributable risk for invasive cervical cancer in the US and Italian populations has been estimated in relation to main 'aetiological' factors (number of sexual partners, age at first intercourse, parity, oral contraceptive use and smoking) and history of Pap smear using data from two case-control studies conducted in the US (466 cases and 788 controls) and Italy (528 cases and 456 controls). The risk of cervical cancer increased in both studies with multiple sexual partners, decreasing age at first intercourse, higher parity, oral contraceptive use and smoking. Levels of exposure to various risk factors were markedly different in the two countries (ie number of sexual partners, frequency of oral contraceptive use and smoking were greater in the US). Multiple Pap smears and a short interval since last Pap smear strongly reduced risk of cervical cancer in both populations, although screening was much more widespread in the US study population, with only 9% of controls reporting no previous smear versus 38% of the Italian control series. The combined population attributable risk for the five 'aetiological' risk factors was slightly greater in the US study (76%) than in the Italian one (69%), chiefly because of a higher prevalence of exposure to sexual factors in US study women. A substantially larger proportion of Italian cases were due in part to deficiency in screening (46% in US and 84% in Italy). Thus, further inclusion of the effect of screening programmes (number of Pap smears and time since last Pap) led to an overall proportion of cases attributable to the examined risk factors of 87% in the US and 95% in Italy.