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1.
Artigo em Inglês | MEDLINE | ID: mdl-31789046

RESUMO

Infection with human immunodeficiency virus (HIV) is associated with substantially increased incidence of non-Hodgkin lymphoma (NHL). This risk may be driven in part by reduced immune control over viral infections in the setting of acquired immunodeficiency syndrome (AIDS), although the lymphomagenic mechanisms are not yet established. We used bead-based multiplex assays to measure antibody seroreactivity to 32 viral antigens representing 22 different viral infections (human herpesviruses 1-8, hepatitis B and C virus, human T-lymphotropic virus type-1 and human polyomaviruses) in two prospective HIV cohorts. Incident (n=28) and prevalent (n=38) AIDS-related NHL cases were matched by age, sex, race and CD4 count to 67 HIV-positive control individuals without AIDS-NHL. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of AIDS-NHL with the number of different viruses to which an individual was seropositive and seroreactivity to individual antigens. Seropositivity to an increasing number of viruses was inversely associated with AIDS-NHL (OR per virus=0.84, 95% CI=0.72-0.98). Seroreactivity to herpes simplex virus 2 mgG unique antigen (OR=0.47; 95% CI 0.23-0.97) and to WU polyomavirus viral capsid protein (OR=0.26, 95% CI 0.10-0.65) were significantly lower in AIDS-NHL cases compared to controls. In this evaluation of antibodies to multiple viruses, we observed an inverse association between seropositivity to a larger number of viruses and AIDS-NHL. While in need of further evaluation, our data raise the novel hypothesis that insufficient exposures or impaired humoral immune responses to viral infections may be associated with AIDS-related lymphomagenesis.

2.
Oral Oncol ; 101: 104522, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31881446

RESUMO

BACKGROUND: HPV-positive oropharynx squamous cell cancer (HPV-OPC) patients were initially described as younger, however incidence has increased among older age-groups. It is unknown why some patients present at a younger age and others at a later age. METHODS: Multi-institutional prospective study of HPV-OPC cases (n = 163) and matched controls (n = 345) with detailed behavioral survey, and serum tested for HPV antibodies by fluorescent bead-based technology. Age at diagnosis was used to stratify patients into younger (≤50 years), middle-age (51-65), and older (>65). RESULTS: By age, demographic characteristics were largely similar, but HPV biomarkers and sexual acts differed. Younger cases were more likely to be HPV16-positive than older cases (100% vs 77%, p = 0.009). Similarly, younger cases were more likely to be HPV16 E6 or E7 seropositive (100% vs 82%, p = 0.03). Younger cases had a higher number of oral sex partners per year, a marker of sexual intensity (sex-years, p = 0.003), but a similar number of lifetime oral sex partners (measure of cumulative sexual exposure), compared to older cases. While sex-years were higher for younger cases and controls, cases had significantly higher sex-years than matched controls in each age-group (p < 0.001). Younger patients were also more likely to perform oral sex at sexual debut, and were younger at sexual debut (each p < 0.03). CONCLUSIONS: Younger, middle-age and older HPV-OPC have distinct biomarker and behavioral profiles. Younger HPV-OPC cases have higher intensity of sexual exposure than older cases and controls, which may in part explain earlier disease onset. The distribution of HPV16-positive tumors among HPV-OPC differs by age group.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31719065

RESUMO

BACKGROUND: Epstein-Barr virus (EBV)-positive gastric cancers (GC) have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serological profiles may inform viral contribution to carcinogenesis. METHODS: We compared humoral responses of EBV-positive (n=67) and -negative (n=137) GC patients from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D) and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. Odds ratios (OR) of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in GC. RESULTS: Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and -negative tumors for anti-EA-D (97% vs. 67%, respectively, p<0.001) and anti-ZEBRA (97% vs. 85%, respectively, p=0.009). Adjusted ORs (vs. T1) for patients with EBV-positive vs. -negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR=0.16, p=0.021). Anti-p53 prevalence from the literature was 15%. CONCLUSIONS: These serological patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype. IMPACT: Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive GC for targeted therapies.

4.
Helicobacter ; : e12671, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746104

RESUMO

PURPOSE: To feasibly analyze associations of Helicobacter pylori (H. pylori) with disease in large cohort studies, assays are needed to assess H. pylori prevalence in existing biospecimens. However, serology has traditionally been unable to distinguish active from past infection. We sought to determine the sensitivity of seropositivity to H. pylori proteins to detect active infection. METHODS: We measured antibody responses to 13 H. pylori proteins using multiplex serology in serum samples of a training (n = 78) and validation set (n = 49) collected concurrently from patients undergoing urea breath test (UBT). To determine sensitivity of seropositivity to H. pylori proteins for active infection, a cutoff was applied to achieve 90% specificity. Antibody levels were retested in a subset of participants (n = 16) 6 months after baseline. RESULTS: With a specificity of 91%, seropositivity to H. pylori proteins VacA, GroEl, HcpC, and HP1564 ascertained active infection from 100% to 75% sensitivity. Positivity to a combination of these proteins (≥2 out of the 4) resulted in specificity of 90% and sensitivity of 100%. The validation set replicated results from the training set. Among those participants with successful H. pylori eradication after baseline, antibody levels decreased significantly for VacA, HcpC, and HP1564 when assessed 6 months later. CONCLUSION: Utilizing the cutoffs for seropositivity established through comparison with UBT, seropositivity to ≥2 of the H. pylori proteins VacA, GroEl, HcpC, and HP1564 determines active H. pylori infection at high specificity and sensitivity and may approximate the prevalence of active H. pylori infection in large cohorts.

5.
Int J Cancer ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31722114

RESUMO

Our aim was to describe HPV16E6 antibody kinetics prior to anal cancer in people living with HIV/AIDS (PLWHA) and evaluate the possible contribution of HPV16E6 serology to anal cancer risk prediction. For 91 persons diagnosed with anal cancer in the Swiss HIV Cohort Study (1989-2017), serial serum/plasma samples were tested for HPV16E6 antibodies using multiplex serology, supplemented with samples from 1,356 participants without anal cancer. Anal cancer incidence was estimated for PLWHA from 40 years-old in the cART era, stratified by HPV16E6 serostatus. HPV16E6 seroprevalence was 23.3% in samples <2 years prior to anal cancer diagnosis and decreased with increasing time prior to cancer: 16.7% at 2-4 years, 4.4% at 5-9, and 7.0% at ≥10 years. Of 25 individuals with anal cancer who were HPV16E6-seropositive at any time during follow-up, the majority (n = 18) remained seropositive in all samples after seroconversion, whereas for seven cases, seropositivity was transitory. Among individuals with anal cancer, HPV16E6 seroprevalence was marginally higher in women vs. men who have sex with men (adjusted OR = 4.3, 95% CI: 1.1, 17.2) and in older participants (adjusted OR = 6.2, 95% CI: 1.1, 34.8 for cases diagnosed at ≥55 vs. <45 years). Anal cancer incidence was 402/100,000 person-years in HPV16E6-positive vs. 82/100,000 in HPV16E6-negative PLWHA (incidence rate ratio = 4.9, 95% CI: 1.3, 13.1). In conclusion, HPV16E6 serology, despite its low sensitivity, allows characterization of a group of individuals with very high anal cancer incidence and may have a place in secondary prevention in groups at high risk for anal cancer such as PLWHA.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31597664

RESUMO

BACKGROUND: Human papillomavirus (HPV) infection is highly prevalent worldwide and may have a role, with sun exposure, in causing cutaneous squamous cell carcinoma. Little is known about the relationship of UV exposure and seroprevalence of cutaneous HPVs in the general population. METHODS: Using multiplex serology, we estimated the seroprevalence of 23 beta and 7 gamma HPVs and 7 other antigens (mu HPV1, HPV63, nu HPV41, alpha HPV16; polyomaviruses HPyV7 and MCV; p53) in a population-based sample of 1,161 Australian 45 and Up Study participants with valid data from blood specimens collected from 2010 to 2012. We calculated prevalence ratios (PR) for the association of each antigen with residential ambient solar UV and other UV-related variables. RESULTS: Seropositivity for at least one beta or gamma HPV was high at 88% (beta HPVs 74%, gamma HPVs 70%), and less in women than men [e.g., PR beta-2 HPV38 = 0.70; 95% confidence interval (CI), 0.56-0.87; any gamma = 0.90; 95% CI, 0.84-0.97]. A high ambient UV level in the 10 years before study enrollment was associated with elevated seroprevalence for genus beta (PRtertile3vs1 any beta = 1.17; 95% CI, 1.07-1.28), and beta-1 to beta-3 species, but not for gamma HPVs. Other UV-related measures had less or no evidence of an association. CONCLUSIONS: Seroprevalence of cutaneous beta HPVs is higher with higher ambient UV exposure in the past 10 years. IMPACT: The observed association between ambient UV in the past 10 years and cutaneous HPVs supports further study of the possible joint role of solar UV and HPV in causing skin cancer.

7.
Cancer Epidemiol Biomarkers Prev ; 28(9): 1552-1555, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481495

RESUMO

BACKGROUND: There is a lack of prospective data on the potential association of Fusobacterium nucleatum (F. nucleatum) and colorectal cancer risk. In this study, we assessed whether antibody responses to F. nucleatum are associated with colorectal cancer risk in prediagnostic serum samples in the European Prospective Investigation into Nutrition and Cancer (EPIC) cohort. METHODS: We applied a multiplex serology assay to simultaneously measure antibody responses to 11 F. nucleatum antigens in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: We observed neither a statistically significant colorectal cancer risk association for antibodies to individual F. nucleatum proteins nor for combined positivity to any of the 11 proteins (OR, 0.81; 95% CI, 0.62-1.06). CONCLUSIONS: Antibody responses to F. nucleatum proteins in prediagnostic serum samples from a subset of colorectal cancer cases and matched controls within the EPIC study were not associated with colorectal cancer risk. IMPACT: Our findings in prospectively ascertained serum samples contradict the existing literature on the association of F. nucleatum with colorectal cancer risk. Future prospective studies, specifically detecting F. nucleatum in stool or tissue biopsies, are needed to complement our findings.

8.
Int J Cancer ; 145(12): 3436-3444, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31407331

RESUMO

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1, -A3, -A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.

9.
Proc Natl Acad Sci U S A ; 116(34): 16955-16960, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31375628

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10-36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31427307

RESUMO

BACKGROUND: Accumulating evidence suggests that cutaneous viral infections are risk factors for the development of keratinocyte carcinomas. The Viruses in Skin Cancer (VIRUSCAN) Study, a prospective cohort study, was established in 2014 to investigate the risk of keratinocyte carcinoma associated with cutaneous human papillomavirus and polyomavirus infection and the possible interaction with ultraviolet radiation exposure (UVR). METHODS/RESULTS: VIRUSCAN incorporates repeated measures of viral infection using multiple markers of infection and quantitative measures of UVR using a spectrophotometer. Participants were recruited between July 14, 2014 and August 31, 2017 at the University of South Florida Dermatology Clinic in Tampa, FL. After excluding 124 individuals with prevalent keratinocyte carcinomas at baseline, 1,179 participants (53.2% women, 46.8% men, all ages 60 years and older) were followed for up to 4 years with routine skin exams occurring every 6 to 12 months. Here, we present the VIRUSCAN Study design, methods, and baseline characteristics, including demographics, sun exposure behavior, quantitative UVR exposure measurements, and cutaneous viral prevalence, for the full study cohort. CONCLUSIONS: The VIRUSCAN Study will provide critical temporal evidence needed to assess the causality of the role cutaneous viral infections play in the development of keratinocyte carcinomas, as well as the potential interaction between cutaneous viral infections and UVR exposure. IMPACT: Study findings will be valuable in future development of novel keratinocyte carcinoma prevention strategies.

11.
Clin Otolaryngol ; 44(6): 961-967, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31419373

RESUMO

OBJECTIVES: This paper aims to provide contemporary epidemiological data on squamous cell carcinoma (SCC) of the nasal cavity, which represents a rare type of head and neck cancer. DESIGN, SETTING & PARTICIPANTS: A descriptive analysis of people with nasal cavity SCC treated with curative intent from the Head and Neck 5000 study; a multicentre clinical cohort study of people from the UK with head and neck cancer. People with tumours of the nasopharynx, paranasal sinuses and other sub-sites of the head and neck were excluded. MAIN OUTCOME MEASURES: Demographic data and treatment details are presented for all participants. The main outcomes were overall survival and survival according to categories of characteristics (eg, smoker vs non-smoker); these were explored using Kaplan-Meier plots. RESULTS: Thirty people with nasal cavity SCC were included in the study, of which most were male (67%) and current or ex-smokers (70%). The majority (70%) presented with early-stage (T1/2, N0) tumours. Cervical lymph node metastases at presentation were rare, occurring in only one person. Nine people died during the follow-up period (30%). Worse survival outcomes were seen in people with moderate or severe co-morbidities. CONCLUSIONS: This paper provides epidemiological data on nasal cavity SCC in the UK. Patterns of disease and survival outcomes are described, identifying high-risk groups. Further studies should explore whether primary treatment modality alters survival.

12.
Cancer Prev Res (Phila) ; 12(10): 689-700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420362

RESUMO

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 "at-risk" people (screening) and 133 "high-risk" people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P < 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88% for DEIA, Cobas, and E6 antibodies, respectively), but specificity was reduced (93%-97%). Aptima had poor sensitivity (23%). Sensitivity decreased when cotesting HPV16 oral rinse DNA and E6 antibodies (37%-48%), or multiple E antibodies (69%-72%). HPV16 DNA were detected in ∼2% of the at-risk by either DEIA or Cobas and up to 15% of the high-risk population. HPV16 E6 seroprevalence was 2.3% and 2.4% in the at-risk and high-risk populations, respectively. Oral rinse HPV testing had moderate-to-poor sensitivity for HPV-OPC, suggesting many true positives would be missed in a potential screening scenario. HPV16 E6 serum antibody was the most promising biomarker evaluated.

13.
J Clin Microbiol ; 57(11)2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31434722

RESUMO

IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations.

14.
Clin Cancer Res ; 25(24): 7405-7412, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31444248

RESUMO

PURPOSE: The identification of high-risk patients within human papillomavirus (HPV)-positive and -negative head and neck squamous cell carcinoma (HNSCC) is needed for improved treatment and surveillance strategies. In this study, we set out to discover antibody responses (AR) with prognostic impact in HNSCC stratified by HPV status. EXPERIMENTAL DESIGN: A fluorescent bead-based multiplex serology assay on 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens, and 8 oncogenes) and 29 HPV antigens was performed in samples of 362 patients with HNSCC from five independent cohorts (153 HPV positive, 209 HPV negative). A multivariable Cox proportional hazard model with bootstrapping (M = 1000) was used for validation of prognostic antibody responses. RESULTS: Antibody response to any of the cancer antigens was found in 257 of 362 patients (71%). In HPV-negative patients, antibody responses to c-myc, MAGE-A1, -A4, and Rhodopsin E2 (combined as ARhigh risk) were significantly associated with shorter overall survival. In HPV-positive patients, antibody responses to IMP-1 were discovered as a negative prognostic factor. ARhigh risk (HR = 1.76) and antibody responses to IMP-1 (HR = 3.28) were confirmed as independent markers for a poor prognosis in a multivariable Cox proportional hazard model with bootstrapping (M = 1000). CONCLUSIONS: We identified antibody responses to cancer antigens that associate with a dismal prognosis in patients with HNSCC beyond HPV-positive status. ARhigh risk may be used to detect HPV-negative patients with an extraordinarily bad prognosis. Most importantly, antibody response to IMP-1 may serve as a marker for a subgroup of HPV-positive patients who present with a poor prognosis similar to that in HPV-negative patients.

15.
Cancer Prev Res (Phila) ; 12(10): 667-674, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31350279

RESUMO

Smoking is an established risk factor for gastric cancer development. In this study, we aimed to assess prospectively the association of smoking with gastric cancer risk in 1,446 non-cardia gastric cancer cases and 1,796 controls from China, Japan, and Korea with consideration of Helicobacter pylori infection as a potential effect modifier. Applying logistic regression models stratified by study and adjusted for age and sex we found that current, but not former, smoking was significantly associated with gastric cancer risk [OR = 1.33; 95% confidence interval (CI), 1.07-1.65]. However, the association was significant only in H. pylori sero-positive individuals determined by 3 different sero-markers: overall sero-positivity, sero-positivity to the onco-protein CagA, and sero-positivity to the gastric cancer associated sero-marker HP0305 and HP1564. Specifically, a significant interaction was found when stratifying by HP0305/HP1564 (P interaction = 0.01) with a 46% increased risk of gastric cancer among HP0305/HP1564 sero-positive current smokers (95% CI, 1.10-1.93) as opposed to no increased gastric cancer risk among HP0305/HP1564 sero-negative current smokers (OR = 0.93; 95% CI, 0.65-1.33). We confirmed that current smoking is associated with an increased gastric cancer risk, however, only among individuals that are simultaneously sero-positive for the leading causal factor for gastric cancer, H. pylori.

16.
Sci Rep ; 9(1): 10847, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350458

RESUMO

Antibodies to Streptococcus gallolyticus subspecies gallolyticus (SGG) have been associated with colorectal cancer (CRC). Because SGG may correlate with impaired gut epithelia, we assessed the association of antibodies to bacterial flagellin C (FliC), a measure potentially related to this impairment, with CRC and the CRC-specific interaction with antibodies to SGG proteins. Antibodies to FliC and SGG pilus proteins Gallo2178 and Gallo2179 were measured in two independent studies, a combined study from Nijmegen and Detroit (93 CRC cases, 74 controls) and a replication data set including 576 cases and 576 controls from the Spanish multicenter multicase-control study (MCC-Spain). Logistic regression was applied to assess whether antibodies to FliC were associated with CRC and modified the association of antibodies to SGG proteins with CRC. Antibodies to FliC were associated with those to SGG Gallo2178 among CRC cases, resulting in an interaction in the association of antibodies to Gallo2178 with CRC (p = 0.007). This association was only present among individuals with high antibody responses to FliC (OR: 2.42, 95% CI: 1.45-4.06). In conclusion, our findings suggest that colorectal tumorigenesis could be accompanied by an impaired integrity of the epithelium that could result in associated increased antibody responses to bacterial proteins.

17.
Int J Cancer ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269236

RESUMO

In cancer epidemiological studies, determination of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) typically depends on the availability of tumor tissue testing, and/or tumor tissue access. Identifying alternative methods for estimating HPV status can improve the quality of such studies when tissue is unavailable. We developed multiple predictive models for tumor HPV status and prognosis by combining both clinico-epidemiological variables and either serological multiplex assays of HPV or multiple imputation of HPV status (HPVmi ). Sensitivity, specificity and accuracy of these methods compared to either p16 immunostaining (p16 IHC) or survival were assessed. When compared to a reference of tumor tissue p16 IHC in 783 OPSCC patients, the clinic-HPVsero model incorporating a composite of 20 HPV serological antibodies (HPVsero ) and 4 clinical factors (c-index: 0.96) performed better than using HPVsero (c-index: 0.92) or HPVmi (c-index: 0.76) alone. However, the model that contained a single HPV16 E6 antibody combined with four clinical variables, performed extremely well (clinic-s1-16E6; c-index: 0.95). When defining HPV status by HPVsero , s1-16E6, HPVmi or through p16 IHC, each of these definitions demonstrated improved overall and disease-free survival in HPV-positive OPSCC patients, when compared to HPV-negative patients (adjusted hazard ratios between 0.25 and 0.63). Our study demonstrates that when blood samples are available, a model that utilizes a single s1-16E6 antibody combined with several clinical features has excellent test performance characteristics to estimate HPV status and prognosis. When neither blood nor tumor tissue is available, multiple imputation, calibrated on local population characteristics, remains a viable, but suboptimal option.

18.
BMJ Open ; 9(6): e025129, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31189673

RESUMO

INTRODUCTION: Human papillomaviruses (HPVs) are responsible for one-third of all cancers caused by infections. Most HPV studies focus on chronic infections and cancers, and we know little about the early stages of the infection. Our main objective is to better understand the course and natural history of cervical HPV infections in healthy, unvaccinated and vaccinated, young women, by characterising the dynamics of various infection-related populations (virus, epithelial cells, vaginal microbiota and immune effectors). Another objective is to analyse HPV diversity within hosts, and in the study population, in relation to co-factors (lifestyle characteristics, vaccination status, vaginal microbiota, human genetics). METHODS AND ANALYSIS: The PAPCLEAR study is a single center longitudinal study following 150 women, aged 18-25 years, for up to 2 years. Visits occur every 2 or 4 months (depending on HPV status) during which several variables are measured, such as behaviours (via questionnaires), vaginal pH, HPV presence and viral load (via qPCR), local concentrations of cytokines (via MesoScale Discovery technology) and immune cells (via flow cytometry). Additional analyses are outsourced, such as titration of circulating anti-HPV antibodies, vaginal microbiota sequencing (16S and ITS1 loci) and human genotyping. To increase the statistical power of the epidemiological arm of the study, an additional 150 women are screened cross-sectionally. Finally, to maximise the resolution of the time series, participants are asked to perform weekly self-samples at home. Statistical analyses will involve classical tools in epidemiology, genomics and virus kinetics, and will be performed or coordinated by the Centre National de la Recherche Scientifique (CNRS) in Montpellier. ETHICS AND DISSEMINATION: This study has been approved by the Comité de Protection des Personnes Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/AR1612278, decision number DR-2016-488) and by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007). Results will be published in preprint servers, peer-reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: NCT02946346; Pre-results.

19.
BMC Cancer ; 19(1): 545, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174492

RESUMO

BACKGROUND: Geospatial technology has facilitated the discovery of disease distributions and etiology and helped target prevention programs. Globally, gastric cancer is the leading infection-associated cancer, and third leading cause of cancer mortality worldwide, with marked geographic variation. Central and South America have a significant burden, particularly in the mountainous regions. In the context of an ongoing population-based case-control study in Central America, our aim was to examine the spatial epidemiology of gastric cancer subtypes and H. pylori virulence factors. METHODS: Patients diagnosed with gastric cancer from 2002 to 2013 in western Honduras were identified in the prospective gastric cancer registry at the principal district hospital. Diagnosis was based on endoscopy and confirmatory histopathology. Geospatial methods were applied using the ArcGIS v10.3.1 and SaTScan v9.4.2 platforms to examine regional distributions of the gastric cancer histologic subtypes (Lauren classification), and the H. pylori CagA virulence factor. Getis-Ord-Gi hot spot and Discrete Poisson SaTScan statistics, respectively, were used to explore spatial clustering at the village level (30-50 rural households), with standardization by each village's population. H. pylori and CagA serologic status was determined using the novel H. pylori multiplex assay (DKFZ, Germany). RESULTS: Three hundred seventy-eight incident cases met the inclusion criteria (mean age 63.7, male 66.3%). Areas of higher gastric cancer incidence were identified. Significant spatial clustering of diffuse histology adenocarcinoma was revealed both by the Getis-Ord-GI* hot spot analysis (P-value < 0.0015; range 0.00003-0.0014; 99%CI), and by the SaTScan statistic (P-value < 0.006; range 0.0026-0.0054). The intestinal subtype was randomly distributed. H. pylori CagA had significant spatial clustering only in association with the diffuse histology cancer hot spot (Getis-Ord-Gi* P value ≤0.001; range 0.0001-0.0010; SaTScan statistic P value 0.0085). In the diffuse gastric cancer hot spot, the lowest age quartile range was 21-46 years, significantly lower than the intestinal cancers (P = 0.024). CONCLUSIONS: Geospatial methods have identified a significant cluster of incident diffuse type adenocarcinoma cases in rural Central America, suggest of a germline genetic association. Further genomic and geospatial analyses to identify potential spatial patterns of genetic, bacterial, and environmental risk factors may be informative.


Assuntos
Saúde da População Rural , Neoplasias Gástricas/epidemiologia , Idoso , Estudos de Casos e Controles , América Central/epidemiologia , Suscetibilidade a Doenças , Feminino , Geografia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Helicobacter pylori , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Análise Espacial , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia
20.
Cancer Epidemiol ; 61: 79-88, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154081

RESUMO

BACKGROUND: In contrast to the recognized role of Helicobacter pylori in the etiology of non-cardia gastric cancer (GC), there is still insufficient epidemiological evidence for the involvement of Epstein-Barr virus (EBV) in gastric carcinogenesis. We aimed to evaluate the relation of antibody profile and antibody reactivity intensity against four individual EBV proteins to GC risk. METHODS: We used information from 281 GC cases and 2071 age and sex frequency matched controls recruited in the frame of the MCC-Spain multicase-control study, between 2008 and 2013. Sociodemographic, lifestyle and environmental factors were assessed in face-to-face interviews. Antibody responses to four EBV proteins (EBNA-1, ZEBRA, EA-D, and VCA-p18) were analyzed by multiplex serology. Odds ratios (OR) and 95% confidence intervals were calculated by using logistic regression mixed models to evaluate the association of seropositivity and antibody reactivity against EBV proteins with GC, adjusting for GC risk factors. Stratified analyses by tumor location (cardia vs. non-cardia) and morphology (intestinal vs. diffuse) were done. RESULTS: Among controls, seropositivity for EA-D, ZEBRA, EBNA-1 and VCA-p18 was 85%, 91%, 97% and 99%, respectively. Even though seropositivity for none of the studied proteins was associated with a higher GC risk, increasing antibody reactivity against EBNA-1 and VCA-p18 was associated with higher OR of GC. This association was present for cardia and non-cardia cancer cases, and for intestinal and diffuse types. CONCLUSION: Our results support the hypothesis that EBV may play a role in GC etiology, and highlight the importance of evaluating specific antibodies and the dose-response relations when studying widespread infections.

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