Publications by authors named "Noemi Bender"

22 Publications

  • Page 1 of 1

Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

Cell 2021 Jul 1;184(14):3812-3828.e30. Epub 2021 Jul 1.

Zahedan University of Medical Sciences, 054 Zahedan, Iran.

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4 T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4 T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.
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http://dx.doi.org/10.1016/j.cell.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329841PMC
July 2021

Post-vaccination HPV seroprevalence among female sexual health clinic attenders in England.

Vaccine 2021 07 12;39(30):4210-4218. Epub 2021 Jun 12.

Blood Safety, Hepatitis, Sexually Transmitted Infections (STI) and HIV Service, Public Health England, London, UK.

Background: The National HPV Immunisation Programme was introduced in England in September 2008 using the HPV16/18 bivalent vaccine. We conducted serological surveillance to explore vaccination coverage levels. We also conducted a case-control study to investigate a hypothesised cross-protective effect of the HPV16/18 vaccine against genital warts.

Methods: Residual serum specimens from 16 to 20 year-old women attending six specialist sexual health services (SSHS) between 2011 and 2015 in England were tested for antibodies against HPV16 and HPV18 using a virus-like particle (VLP)-based multiplex serology assay. Patients were classified as having vaccine-induced seropositivity if they were seropositive for both HPV types and either had high antibody levels for at least one HPV type, or moderately high levels for both HPV types. Differences in vaccine-induced seropositivity by patient characteristics were investigated using logistic regression. Vaccine-induced seropositivity was then compared for patients with genital warts (cases) and matched patients without (controls).

Results: Of 3,973 serum specimens collected, 3,870 (97.4%) had a valid result. The proportion of women with vaccine-induced seropositivity decreased with age (from 78.1% in 16-year-olds to 52.6% in 20-year-olds). Vaccine-induced seropositivity was lower among women born outside the UK, from more deprived areas and with a history of chlamydia diagnosis. A difference in uptake by ethnic group was also seen but this was largely confounded by differences in deprivation and country of birth. Among 537 cases and 1,515 controls, there was little evidence of a protective effect of the bivalent HPV vaccine against genital warts (adjusted odds ratio 0.93; 95% CI: 0.74-1.18).

Discussion: Vaccine-induced seropositivity in this high-risk population was in line with vaccination coverage in the general population although was lower in some at-risk sub-groups. This study does not provide evidence to support a cross-protective effect of the HPV16/18 vaccine against genital warts.
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http://dx.doi.org/10.1016/j.vaccine.2021.05.018DOI Listing
July 2021

Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis-a presymptomatic case-control study.

Eur J Neurol 2021 Sep 27;28(9):3072-3079. Epub 2021 Jun 27.

Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.

Background And Purpose: Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology.

Methods: A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP).

Results: Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65).

Conclusions: Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity.
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http://dx.doi.org/10.1111/ene.14961DOI Listing
September 2021

Sustainability of neutralising antibodies induced by bivalent or quadrivalent HPV vaccines and correlation with efficacy: a combined follow-up analysis of data from two randomised, double-blind, multicentre, phase 3 trials.

Lancet Infect Dis 2021 May 28. Epub 2021 May 28.

Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany; FICAN-Mid, Pirkanmaan Sairaanhoitopiiri, Research, Development and Innovation Centre Nuorisotutkimusasema, Tampere, Finland; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Background: Quadrivalent and bivalent vaccines against oncogenic human papillomavirus (HPV) are used worldwide with different reported overall efficacies against HPV infections. Although protective concentrations of vaccine-induced antibodies are still not formally defined, we evaluated the sustainability of neutralising antibodies in vaccine trial participants 2-12 years after vaccination and the correlation with reported vaccine efficacy.

Methods: We did a follow-up analysis of data from the Finnish cohorts of two international, randomised, double-blind, phase 3 trials of HPV vaccines, PATRICIA (bivalent, HPV16 and 18) and FUTURE II (quadrivalent, HPV6, 11, 16, and 18). In 2002 and 2004-05, respectively, Finnish girls aged 16-17 years participated in one of these two trials and consented to health registry follow-up with the Finnish Cancer Registry. The cohorts were also linked with the Finnish Maternity Cohort (FMC) that collects first-trimester serum samples from nearly all pregnant Finnish women, resulting in 2046 post-vaccination serum samples obtained during up to 12 years of follow-up. We obtained serum samples from the FMC-based follow-up of the FUTURE II trial (from the quadrivalent vaccine recipients) and the PATRICIA trial (from corresponding bivalent vaccine recipients who were aligned by follow-up time, and matched by the number of pregnancies). We assessed neutralising antibody concentrations (type-specific seroprevalence) to HPV6, 16, and 18, and cross-neutralising antibody responses to non-vaccine HPV types 31, 33, 45, 52, and 58 from 2 to 12 years after vaccination.

Findings: Up to Dec 31, 2016, we obtained and analysed 577 serum samples from the quadrivalent vaccine recipients and 568 from the bivalent vaccine recipients. In 681 first-pregnancy serum samples, neutralising antibodies to HPV6, 16, and 18 were generally found up to 12 years after vaccination. However, 51 (15%) of 339 quadrivalent vaccine recipients had no detectable HPV18 neutralising antibodies 2-12 years after vaccination, whereas all 342 corresponding bivalent vaccine recipients had HPV18 neutralising antibodies.. In seropositive quadrivalent vaccine recipients, HPV16 geometric mean titres (GMT) halved by years 5-7 (GMT 3679, 95% CI 2377 to 4708) compared with years 2-4 (6642, 2371 to 13 717). Between 5 and 12 years after vaccination, GMT of neutralising antibodies to HPV16 and 18 were 5·7 times and 12·4 times higher, respectively, in seropositive bivalent vaccine recipients than in the quadrivalent vaccine recipients. Cross-neutralising antibodies to HPV31, 33, 45, 52, and 58 were more prevalent in the bivalent vaccine recipients but, when measurable, sustainable up to 12 years after vaccination with similar GMTs in both vaccine cohorts. Seroprevalence for HPV16, 31, 33, 52, and 58 significantly correlated with vaccine efficacy against persistent HPV infections in the bivalent vaccine recipients only (r=0·90, 95% CI 0·09 to 0·99, p=0·037, compared with r=0·62, 95% CI -0·58 to 0·97, p=0·27 for the quadrivalent vaccine recipients). Correlation of protection with prevalence of neutralising or cross-neutralising HPV antibodies was not significant in the quadrivalent vaccine recipients.

Interpretation: The observed significant differences in the immunogenicity of the two vaccines are in line with the differences in their cross-protective efficacy. Protective HPV vaccine-induced antibody titres can be detected up to 12 years after vaccination.

Funding: Academy of Finland and Finnish Cancer Foundation.
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http://dx.doi.org/10.1016/S1473-3099(20)30873-2DOI Listing
May 2021

Prospective investigation of polyomavirus infection and the risk of adult glioma.

Sci Rep 2021 05 5;11(1):9642. Epub 2021 May 5.

Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), 69120, Heidelberg, Germany.

Glioma is an aggressive primary tumor of the brain with a poorly understood etiology. We studied the association of 4 human polyomaviruses (HPyV)-JC virus (JCV), BK virus (BKV), human polyomavirus 6 (HPyV6), and Merkel cell polyomavirus (MCPyV) with glioma risk within the Cancer Prevention Study II in the US (CPS-II) and the Janus Serum Bank in Norway. Cohort participants subsequently diagnosed with glioma from the CPS-II (n = 37) and Janus Serum Bank (n = 323), a median of 6.9 and 15.4 years after blood collection, respectively, were matched to individual controls on age, sex, and date of blood draw. Serum antibodies to the major viral capsid protein (VP1) were used to establish infection history for each polyomavirus. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In the Janus Serum Bank, MCPyV infection was associated with a higher risk of glioma overall (OR: 1.56; 95% CI 1.10, 2.19). A modest, nonsignificant positive association with MCPyV infection was also observed in CPS-II (OR: 1.29; 95% CI 0.54, 3.08). In both cohorts, glioma risk was not significantly related to infection with JCV, BKV or HPyV6. The present study suggests that MCPyV infection may increase glioma risk.
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http://dx.doi.org/10.1038/s41598-021-89133-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100283PMC
May 2021

Toxoplasma gondii infection and the risk of adult glioma in two prospective studies.

Int J Cancer 2021 Jan 11. Epub 2021 Jan 11.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Toxoplasma gondii (T gondii) is a common parasite that shows affinity to neural tissue and may lead to the formation of cysts in the brain. Previous epidemiologic studies have suggested an association between glioma and increased prevalence of T gondii infection, but prospective studies are lacking. Therefore, we examined the association between prediagnostic T gondii antibodies and risk of glioma in two prospective cohorts using a nested case-control study design. Cases and matched controls were selected from the American Cancer Society's Cancer Prevention Study-II Nutrition Cohort (CPSII-NC) (n = 37 cases and 74 controls) and the Norwegian Cancer Registry's Janus Serum Bank (Janus) (n = 323 cases and 323 controls). Blood samples collected prior to diagnosis were analyzed for antibodies to two T gondii surface antigens (p22 and sag-1), with individuals considered seropositive if antibodies to either antigen were detected. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for each cohort. In both cohorts, a suggestive increase in glioma risk was observed among those infected with T gondii (OR: 2.70; 95% CI: 0.96-7.62 for CPSII-NC; OR: 1.32, 95% CI: 0.85-2.07 for Janus), particularly among participants with high antibody titers specific to the sag-1 antigen (CPSII-NC OR: 3.35, 95% CI: 0.99-11.38; Janus OR: 1.79, 95% CI: 1.02-3.14). Our findings provide the first prospective evidence of an association between T gondii infection and risk of glioma. Further studies with larger case numbers are needed to confirm a potential etiologic role for T gondii in glioma.
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http://dx.doi.org/10.1002/ijc.33443DOI Listing
January 2021

HPV cervical infections and serological status in vaccinated and unvaccinated women.

Vaccine 2020 12 7;38(51):8167-8174. Epub 2020 Nov 7.

Laboratoire MIVEGEC (UMR CNRS 5290, IRD 224, UM), Montpellier, France. Electronic address:

Understanding genital infections by Human papillomaviruses (HPVs) remains a major public health issue, especially in countries where vaccine uptake is low. We investigate HPV prevalence and antibody status in 150 women (ages 18 to 25) in Montpellier, France. At inclusion and one month later, cervical swabs, blood samples and questionnaires (for demographics and behavioural variables) were collected. Oncogenic, non-vaccine genotypes HPV51, HPV66, HPV53, and HPV52 were the most frequently detected viral genotypes overall. Vaccination status, which was well-balanced in the cohort, showed the strongest (protective) effect against HPV infections, with an associated odds ratio for alphapapillomavirus detection of 0.45 (95% confidence interval: [0.22;0.58]). We also identified significant effects of age, number of partners, body mass index, and contraception status on HPV detection and on coinfections. Type-specific IgG serological status was also largely explained by the vaccination status. IgM seropositivity was best explained by HPV detection at inclusion only. Finally, we identify a strong significant effect of vaccination on genotype prevalence, with a striking under-representation of HPV51 in vaccinated women. Variations in HPV prevalence correlate with key demographic and behavioural variables. The cross-protective effect of the vaccine against HPV51 merits further investigation.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.078DOI Listing
December 2020

Evaluation of serological assays to monitor antibody responses to single-dose HPV vaccines.

Vaccine 2020 08 24;38(38):5997-6006. Epub 2020 Jul 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Introduction: Whether existing serological assays are sufficiently robust to measure the lower antibody levels expected following single-dose HPV vaccination is unknown.

Methods: We evaluated seven assays measuring HPV-16/18 immunological responses overall and by number of doses in 530 serum samples from participants receiving varying doses of Cervarix or Gardasil up to 36-months post-vaccination. Serum was evaluated by simplex (HPV-16 ELISA, HPV-18 ELISA), multiplex (LIA-4, VLP-MIA, M9ELISA, GST-L1), and high-throughput pseudovirion-based neutralization assays (HT-PBNA), and results were compared to the gold standard HPV-16/18 secreted alkaline phosphatase neutralization assay (SEAP-NA). Reproducibility was assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Percent agreement, Pearson correlation, and weighted-kappa were used to assess validity. Determinants of seronegativity were evaluated by chi-squared test.

Results: HPV-16: Seropositivity range was 97.1-99.5% for single dose and 98.8-99.8% overall. CV range was 4.0-18.0% for single dose and 2.9-19.5% overall. ICC range was 0.77-0.99 for single dose and 0.74-0.99 overall. Correlation with SEAP-NA range was 0.43-0.85 for single dose and 0.51-0.90 overall. Weighted-kappa range was 0.34-0.82 for single dose and 0.45-0.84 overall. HPV-18: Seropositivity range was 63.9-94.7% for single dose and 86.2-97.9% overall. CV range was 8.1-18.2% for single dose and 4.6-18.6% overall. ICC range was 0.75-0.99 for single dose and 0.83-0.99 overall. Correlation with SEAP-NA range was 0.31-0.99 for single dose and 0.27-0.96 overall. Weighted-kappa range was 0.35-0.83 for single dose and 0.45-0.84 overall. HPV-16 seronegativity was <5% for all assays. HPV-18 seronegativity range was 5.5-17.3%. For LIA-4 and GST-L1 where the proportion of seronegativity was >10%, the strongest correlates of seronegativity were receiving a single vaccine dose and receiving Gardasil.

Conclusions: These results support the utility of existing serological assays to monitor antibody responses following single-dose HPV vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429278PMC
August 2020

Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.

Int J Cancer 2020 10 24;147(8):2042-2052. Epub 2020 Apr 24.

Clinical Microbiology, Department of Translational Medicine, Lund University, Malmö, Sweden.

A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.
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http://dx.doi.org/10.1002/ijc.32999DOI Listing
October 2020

Transcervical sonography and human papillomavirus 16 E6 antibodies are sensitive for the detection of oropharyngeal cancer.

Cancer 2020 06 4;126(11):2658-2665. Epub 2020 Mar 4.

Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Human papillomavirus 16 (HPV-16) E6 seropositivity is a promising early marker of human papillomavirus-driven oropharyngeal cancer (HPV-OPC), yet more sensitive imaging modalities are needed before screening is considered. The objective of this study was to determine the sensitivity of transcervical sonography (TCS) for detecting clinically apparent HPV-OPC in comparison with computed tomography (CT) and positron emission tomography (PET)/CT.

Methods: Fifty-one patients with known or suspected HPV-OPC without prior treatment underwent oropharyngeal TCS and blood collection (for HPV multiplex serology testing). Eight standard sonographic images were collected; primary-site tumors were measured in 3 dimensions if identified. Each patient underwent a full diagnostic workup as part of standard clinical care. The pathologic details, HPV status, final staging, and imaging findings were abstracted from the medical record. The sensitivity of each imaging modality was compared with the final clinical diagnosis (the gold standard).

Results: Twenty-four base of tongue cancers (47%), 22 tonsillar cancers (43%), and 2 unknown primary cancers (4%) were diagnosed; 3 patients (6%) had no tumors. All p16-tested patients were positive (n = 47). Primary-site tumors were correctly identified in 90.2% (95% confidence interval [CI], 78.6%-96.7%) with TCS, in 69.4% (95% CI, 54.6%-81.7%) with CT, and in 83.3% (95% CI, 68.6%-93.0%) with PET/CT. TCS identified tumors in 10 of 14 cases missed by CT and recognized the absence of tumors in 3 cases for which CT or PET/CT was falsely positive. The smallest sonographically identified primary-site tumor was 0.5 cm in its greatest dimension; the average size was 2.3 cm. Among p16-positive patients, 76.1% (95% CI, 61.2%-87.4%) were seropositive for HPV-16 E6.

Conclusions: TCS and HPV-16 E6 antibodies are sensitive for the diagnosis of HPV-OPC.
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http://dx.doi.org/10.1002/cncr.32799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829679PMC
June 2020

Peak neutralizing and cross-neutralizing antibody levels to human papillomavirus types 6/16/18/31/33/45/52/58 induced by bivalent and quadrivalent HPV vaccines.

NPJ Vaccines 2020 14;5(1):14. Epub 2020 Feb 14.

2Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany.

We performed an independent comparison of neutralizing and cross-neutralizing antibody (ab) levels seven months after initiation of three-dose, six-month vaccination schedules with the bivalent and quadrivalent human papillomavirus (HPV) vaccines in adolescent Finnish and Indian females, respectively. We used a semi-automated Pseudovirion-Based Neutralization Assay and observed significantly higher HPV16/18 peak ab-levels in bivalent as compared to quadrivalent vaccine recipients. Bivalent vaccine induced cross-neutralizing HPV31/33/45/52/58 antibodies significantly more frequently and to higher levels than the quadrivalent vaccine. The correlation of bivalent vaccine-induced HPV45 ab-levels with HPV16/18 ab-levels was stronger than that of corresponding quadrivalent vaccine-induced ab-levels, suggesting a qualitatively different cross-reactive response. Our findings on the comparison of the immunogenicity of two HPV vaccine tested in two different populations indicate that further head-to-head studies are warranted.
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http://dx.doi.org/10.1038/s41541-020-0165-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021830PMC
February 2020

Risk factors for human papillomavirus-positive nonoropharyngeal squamous cell carcinoma.

Head Neck 2020 08 26;42(8):1954-1962. Epub 2020 Feb 26.

Department of Otolaryngology Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer (HPV-OPC) is distinct from HPV-unassociated head and neck cancer. However, whether risk factors for HPV-positive oropharyngeal and nonoropharyngeal squamous cell cancer are the same is unclear.

Methods: Incident cases of HPV-positive head and neck cell cancer and matched non-cancer controls were enrolled in a multi-institutional, prospective study examining risk factors, biomarkers, and survival.

Results: HPV-nonOPC (n = 20) were more likely to be ever smokers than controls (n = 80, OR 3.49, 95%CI 1.11-10.9) and HPV-OPC (n = 185, OR 3.28, 95%CI 1.10-10.2). Compared with HPV-OPC, HPV-nonOPC were less likely to have had over 3 oral sexual partners (OR 0.29, 95%CI 0.06-0.9), more likely to have multimorbidity (OR 3.30, 95%CI 1.04-10.5), and less likely to have antibodies to HPV16 E6 (90% vs 28%, OR 0.05, 95%CI 0.02-0.2). HPV-nonOPC had worse 4-year OS (77% vs 96%, P = .001) and RFS (69% vs 94%, P < .001) than HPV-OPC.

Conclusions: HPV-positive nonoropharyngeal are distinct from HPV-positive oropharyngeal cancers.
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http://dx.doi.org/10.1002/hed.26116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369227PMC
August 2020

Distinct biomarker and behavioral profiles of human papillomavirus-related oropharynx cancer patients by age.

Oral Oncol 2020 02 24;101:104522. Epub 2019 Dec 24.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212394PMC
February 2020

Associations of Viral Seroreactivity with AIDS-Related Non-Hodgkin Lymphoma.

AIDS Res Hum Retroviruses 2020 05 2;36(5):381-388. Epub 2020 Mar 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

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 ( = 28) and prevalent ( = 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 2mgG 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) was 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.
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http://dx.doi.org/10.1089/AID.2019.0208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232664PMC
May 2020

Evaluating the Utility and Prevalence of HPV Biomarkers in Oral Rinses and Serology for HPV-related Oropharyngeal Cancer.

Cancer Prev Res (Phila) 2019 10 16;12(10):689-700. Epub 2019 Aug 16.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

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 < 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.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029397PMC
October 2019

Multiple imputation and clinico-serological models to predict human papillomavirus status in oropharyngeal carcinoma: An alternative when tissue is unavailable.

Int J Cancer 2020 04 23;146(8):2166-2174. Epub 2019 Jul 23.

Medical Biophysics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

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 (HPV ). 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-HPV model incorporating a composite of 20 HPV serological antibodies (HPV ) and 4 clinical factors (c-index: 0.96) performed better than using HPV (c-index: 0.92) or HPV (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 HPV , s1-16E6, HPV 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.
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http://dx.doi.org/10.1002/ijc.32548DOI Listing
April 2020

Progressive multifocal leukoencephalopathy in Zambia is caused by JC virus with prototype regulatory region.

J Neurovirol 2019 08 26;25(4):475-479. Epub 2019 Apr 26.

Department of Neurological Sciences, Rush University Medical Center, 1725 W. Harrison Street, Suite 1106, Chicago, IL, 60612, USA.

There are only few documented cases of progressive multifocal leukoencephalopathy (PML) in Africa. Whether this is caused by a lack of JC virus (JCV) spread or alteration in the JCV genome is unknown. We characterized the clinical presentation, laboratory findings, and JCV regulatory region (RR) pattern of the first documented PML cases in Zambia as well as JCV seroprevalence among HIV and HIV Zambians. We identified PML patients with positive JCV DNA PCR in their cerebrospinal fluid (CSF) among subjects enrolled in an ongoing tuberculous meningitis study from 2014 to 2016 in Lusaka. JCV regulatory region was further characterized by duplex PCR in patients' urine and CSF. Of 440 HIV patients, 14 (3%) had detectable JCV DNA in their CSF (age 18-50; CD4 T cells counts 15-155 × 10/μl) vs 0/60 HIV patients. The main clinical manifestations included altered mental status and impaired consciousness consistent with advanced PML. While prototype JCV was identified by duplex PCR assay in the CSF samples of all 14 PML patients, only archetype JCV was detected in their urine. All PML Zambian patients tested were seropositive for JCV compared to 46% in a control group of HIV and HIV Zambian patients without PML. PML occurs among HIV-infected individuals in Zambia and is caused by CNS infection with prototype JCV, while archetype JCV strains are present in their urine. JCV seroprevalence is comparable in Zambia and the USA, and PML should be included in the differential diagnosis of immunosuppressed individuals presenting with neurological dysfunction in Zambia.
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http://dx.doi.org/10.1007/s13365-019-00746-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750969PMC
August 2019

Sexually transmitted infections and risk of epithelial ovarian cancer: results from the Nurses' Health Studies.

Br J Cancer 2019 04 21;120(8):855-860. Epub 2019 Mar 21.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Sexually transmitted infections (STIs) are associated with pelvic inflammatory disease and tubal pathologies. Given the tubal origin of a proportion of ovarian cancers, STIs may be relevant in their aetiology.

Methods: Antibodies indicating past infection with Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus type 2, and against human papillomavirus oncogenes (L1 and E6+E7 oncoproteins of types 16, 18, 45) were measured in prediagnosis plasma samples in a nested case-control study in the Nurses' Health Studies (n = 337 cases 1:1 matched to controls). Logistic regression was used to estimate multivariable-adjusted relative risks (RRs) and 95% confidence intervals [CIs] comparing women seropositive vs. seronegative among all cases (invasive and borderline), invasive (n = 257), and invasive serous ovarian cancers; n = 170), and borderline ovarian tumours (n = 80).

Results: C. trachomatis seropositivity was associated with higher risk of ovarian cancer overall (RR = 2.07 [1.25-3.43]); results were similar for invasive, invasive serous, and borderline tumours. We observed no associations for the other STIs. Relative to women seronegative to all infections, strongest associations were observed for seropositivity to C. trachomatis plus another STI (2.74 [1.20-6.27]; C. trachomatis alone, 1.88 [1.03-3.42]; all cases); however, the RRs were not significantly different.

Conclusions: C. trachomatis infection may increase ovarian cancer risk; additional studies are required.
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http://dx.doi.org/10.1038/s41416-019-0422-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474309PMC
April 2019

Sex differences in HPV immunity among adults without cancer.

Hum Vaccin Immunother 2019 19;15(7-8):1935-1941. Epub 2019 Mar 19.

a Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, School of Medicine , Baltimore , MD , USA.

The incidence of human papillomavirus (HPV)-associated head and neck cancers is rising, particularly among men. Whether observed epidemiological differences in sex are explained by differences in sexual exposure and/or by immune response is unclear. In this cross-sectional, multi-institutional study, seroprevalence of antibodies to HPV L1 capsid antigen was compared by patient characteristics among 374 adult patients without cancer. A significantly higher seroprevalence was observed among women compared with men for HPV16 (OR = 2.96, 95% CI = 1.21-7.21) and HPV18 (OR = 2.84, 95% CI = 1.06-7.60) L1 antibodies. This difference persisted for HPV16 after controlling for lifetime and recent sexual behavior. After controlling for sex, HPV16 and HPV18 L1 seroprevalence was also significantly associated with higher number of lifetime (HPV16 OR = 1.05, 95% CI = 1.01-1.08; HPV18 OR = 1.04, 95% CI = 1.01-1.08) and recent (HPV16 OR = 1.54, 95% CI = 1.15-2.07; HPV18 OR = 1.40, 95% CI = 1.07-1.82) oral but not vaginal sexual partners. These findings potentially suggest a more robust immune response to HPV16/18 among women compared with men that may not be explained by differences in number of sexual partners, and thereby presumably HPV exposure. The independent association of HPV16/18 L1 seroprevalence with higher number of oral sexual partners suggests a possible role for site of mucosal exposure in the HPV immune response.
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http://dx.doi.org/10.1080/21645515.2019.1568157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746519PMC
March 2020

Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection.

Oncoimmunology 2016;5(10):e1204506. Epub 2016 Aug 9.

Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.

In tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing tumor macrophages in T-cell infiltration and tumor rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS macrophages in tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These results will be valuable for the development of strategies designed to overcome the paucity of T-cell infiltration into tumors that is a major obstacle in clinical cancer immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2016.1204506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087300PMC
August 2016

Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy.

Cancer Cell 2013 Nov 24;24(5):589-602. Epub 2013 Oct 24.

Division of Translational Immunology, German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT), 69120 Heidelberg, Germany.

Inefficient T cell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS⁺ M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors.
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http://dx.doi.org/10.1016/j.ccr.2013.09.014DOI Listing
November 2013

CD133/CD15 defines distinct cell subpopulations with differential in vitro clonogenic activity and stem cell-related gene expression profile in in vitro propagated glioblastoma multiforme-derived cell line with a PNET-like component.

Folia Neuropathol 2012 ;50(4):357-68

Division of Stereotactic Neurosurgery, Department of General Neurosurgery, University Medical Center Freiburg, Freiburg, Germany.

Glioblastoma multiforme (GBM), as many other solid tumours, contains a subpopulation of cells termed cancer stem-like cells responsible for the initiation and propagation of tumour growth. However, a unique immunophenotype/surface antigen composition for the clear identification of brain tumour stem cells (BTSC) has not yet been found. Here we report a novel code of cell surface markers for the identification of different cell subpopulations in neurospheres derived from a GBM with a primitive neuroectodermal tumour (PNET)-like component (GBM-PNET). These subgroups differ in their CD133/CD15 expression pattern and resemble cells with different stem-like genotype and developmental pathway activation levels. Strikingly, clonogenic analysis of cultures differentially expressing the investigated markers enabled the identification of distinct subpopulations of cells endowed with stem cell characteristics. High clonogenicity could be found in CD133(-)/CD15(-) and CD133(+)/CD15(+) but not in CD133(-)/CD15(+) cells. Moreover, cell subpopulations with pronounced clonogenic growth were characterized by high expression of stem cell-related genes. Interestingly, these observations were unique for GBM-PNET and differed from ordinary GBM cultures derived from tumours lacking a PNET component. This work elucidates the complex molecular heterogeneity of in vitro propagated glioblastoma-derived cells and potentially contributes to the development of novel diagnostic modalities aiming at the identification of the brain tumour stem-like cell population in a subgroup of GBMs.
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http://dx.doi.org/10.5114/fn.2012.32365DOI Listing
November 2013
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