Publications by authors named "Tim Waterboer"

283 Publications

Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer.

Nat Commun 2021 Oct 12;12(1):5945. Epub 2021 Oct 12.

Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italy.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
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http://dx.doi.org/10.1038/s41467-021-26151-9DOI Listing
October 2021

Reply to Peluso, et al.

Clin Infect Dis 2021 Oct 7. Epub 2021 Oct 7.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1093/cid/ciab892DOI Listing
October 2021

Reduced Endometrial Ascension and Enhanced Reinfection Associated with IgG Antibodies to Specific Chlamydia trachomatis Proteins in Women at Risk for Chlamydia.

J Infect Dis 2021 Oct 5. Epub 2021 Oct 5.

Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Previous research revealed antibodies targeting Chlamydia trachomatis (CT) elementary bodies was not associated with reduced endometrial or incident infection in CT-exposed women. However, data on the role of CT protein-specific antibodies in protection are limited.

Methods: A whole-proteome CT array screening serum pools from CT-exposed women identified 121 immunoprevalent proteins. Individual sera were probed using a focused array. IgG antibody frequencies and endometrial or incident infection relationships were examined using Wilcoxon Rank sum test. The impact of breadth and magnitude of protein-specific IgGs on ascension and incident infection were examined using multivariable stepwise logistic regression. Complementary RNA-sequencing quantified CT gene transcripts in cervical swabs from infected women.

Results: IgG to Pgp3 and CT005 were associated with reduced endometrial infection; anti-CT443, -CT486 and -CT123 were associated with increased incident infection. Increased breadth of protein recognition did not however predict protection from endometrial or incident infection. mRNAs for immunoprevalent CT proteins were highly abundant in the cervix.

Conclusions: Protein-specific CT antibodies are not sufficient to protect against ascending or incident infection but broad recognition of CT proteins by IgG correlates with cervical CT gene transcript abundance, suggesting CT protein abundance correlates with immunogenicity and signifies their potential as vaccine candidates.
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http://dx.doi.org/10.1093/infdis/jiab496DOI Listing
October 2021

Associations between markers of social functioning and depression and quality of life in survivors of head and neck cancer: Findings from the Head and Neck Cancer 5000 study.

Psychooncology 2021 Sep 30. Epub 2021 Sep 30.

Population Health Sciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK.

Objective: To investigate associations between markers of social functioning (trouble with social eating and social contact), depression and health-related quality of life (QOL) among head and neck cancer survivors.

Methods: This cross-sectional analysis included individuals with oral cavity, oropharynx, larynx, salivary gland and thyroid cancers from Head and Neck 5000 alive at 12 months. Trouble with social eating and social contact were measured using items from EORTC QLQ-H&N35 and QOL using EORTC QLQ-C30; responses were converted into a score of 0-100, with a higher score equalling more trouble or better QOL. A HADS subscale score of ≥8 was considered significant depression. Associations between tertiles of trouble with social eating and social contact and depression and QoL were assessed using multivariable logistic and linear regression (with robust errors), respectively.

Results: Of 2561 survivors, 23% reported significant depression. The median QOL score was 75.0 (interquartile range 58.3-83.3). For trouble with social eating, after confounder adjustment, those in the intermediate and highest tertiles had higher odds of depression (intermediate: OR = 4.5, 95% CI 3.19-6.45; high: OR = 21.8, 15.17-31.18) and lower QOL (intermediate:β = -8.7, 95% CI -10.35 to -7.14; high: β = -24.8, -26.91 to -22.77). Results were similar for trouble with social contact.

Conclusion: We found strong clinically important associations between markers of social functioning and depression and QOL. More effective interventions addressing social eating and contact are required. These may help survivors regain their independence, reduce levels of isolation and loneliness, and depression, and improve QOL outcomes generally.
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http://dx.doi.org/10.1002/pon.5830DOI Listing
September 2021

Low sun exposure acts synergistically with high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels in multiple sclerosis etiology.

Eur J Neurol 2021 Aug 26. Epub 2021 Aug 26.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk.

Methods: We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP).

Results: Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01 status.

Conclusions: Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.
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http://dx.doi.org/10.1111/ene.15082DOI Listing
August 2021

Ornithine decarboxylase (ODC1) gene variant (rs2302615) is associated with gastric cancer independently of Helicobacter pylori CagA serostatus.

Oncogene 2021 Oct 10;40(40):5963-5969. Epub 2021 Aug 10.

UAB Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham (UAB), Birmingham, AL, USA.

The primary cause of gastric cancer is chronic infection with Helicobacter pylori (H. pylori), particularly the high-risk genotype cagA, and risk modification by human genetic variants. We studied 94 variants in 54 genes for association with gastric cancer, including rs2302615 in ornithine decarboxylase (ODC1), which may affect response to chemoprevention with the ODC inhibitor, eflornithine (difluoromethylornithine; DFMO). Our population-based, case-control study included 1366 individuals (664 gastric cancer cases and 702 controls) from Western Honduras, a high incidence region of Latin America. CagA seropositivity was strongly associated with cancer (OR = 3.6; 95% CI: 2.6, 5.1). The ODC1 variant rs2302615 was associated with gastric cancer (OR = 1.36; p = 0.018) in a model adjusted for age, sex, and CagA serostatus. Two additional single nucleotide polymorphisms (SNPs) in CASP1 (rs530537) and TLR4 (rs1927914) genes were also associated with gastric cancer in univariate models as well as models adjusted for age, sex, and CagA serostatus. The ODC1 SNP association with gastric cancer was stronger in individuals who carried the TT genotype at the associating TLR4 polymorphism, rs1927914 (OR = 1.77; p = 1.85 × 10). In conclusion, the ODC1 variant, rs2302615, is associated with gastric cancer and supports chemoprevention trials with DFMO, particularly in individuals homozygous for the T allele at rs1927914.
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http://dx.doi.org/10.1038/s41388-021-01981-5DOI Listing
October 2021

Biologic and behavioral associations of estrogen receptor alpha positivity in head and neck squamous cell carcinoma.

Oral Oncol 2021 Oct 22;121:105461. Epub 2021 Jul 22.

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

Objectives: Tumor HPV status is an established independent prognostic marker for oropharynx cancer (OPC). Recent studies have reported that tumor estrogen receptor alpha (ERα) positivity is also associated with prognosis independent of HPV. Little is known about the biologic and behavioral predictors of ERα positivity in head and neck squamous cell cancer (HNSCC). We therefore explored this in a multicenter prospective cohort study.

Materials And Methods: Participants with HNSCC completed a survey and provided a blood sample. Tumor samples were tested for ERα using immunohistochemistry. ERα positivity was defined as ≥1%, standardized by the American Society of Clinical Oncology/College of American Pathologists in breast cancer. Characteristics were compared with χ and Fisher's exact test. Odds ratios (OR) were calculated using logistic regression.

Results: Of 318 patients with HNSCC, one third had ERα positive tumors (36.2%, n = 115). Odds of ERα expression were significantly increased in those with HPV-positive tumors (OR = 27.5, 95% confidence interval[CI] 12.1-62), smaller tumors (≤T2, OR = 3.6, 95% CI 1.9-7.1), male sex (OR = 2.0, 95% CI 1.1-3.6), overweight/obesity (BMI ≥ 25, OR = 1.9, 95% CI 1.1-3.3), and those married/living with a partner (OR = 1.7, 95% CI 1.0-3.0). In a multivariate model, HPV-positivity (aOR = 27.5, 95% CI 11.4-66) and small tumor size (≤T2, aOR = 2.2, 95% CI 1.0-4.8) remained independently associated with ERα status. When restricted to OPC (n = 180), tumor HPV status (aOR = 17.1, 95% CI 2.1-137) and small tumor size (≤T2, aOR = 4.0 95% CI 1.4-11.3) remained independently associated with ERα expression.

Conclusion: Tumor HPV status and small tumor size are independently associated with ERα expression in HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448948PMC
October 2021

Cutaneous Human Papillomaviruses and the Risk of Keratinocyte Carcinomas.

Cancer Res 2021 Sep 15;81(17):4628-4638. Epub 2021 Jul 15.

International Agency for Research on Cancer, WHO, Lyon, France.

Cutaneous human papillomavirus (cuHPV) infections may be novel targets for skin cancer prevention and treatment, but critical information regarding the development of virus-positive skin cancers following cuHPV infection has been lacking. In this study, baseline cuHPV infection was measured by serology and viral DNA detection in eyebrow hairs (EBH) and forearm skin swabs (SSW) among 1,008 individuals undergoing routine skin cancer screening exams and followed for incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC). Baseline β-HPV detection, particularly in SSW, significantly predicted cuSCC (HR = 4.32; 95% confidence interval, 1.00-18.66), whereas serologic evidence of past β-HPV infection was not associated with cuSCC. Less than 5% of baseline β-HPV types detected in SSW were present in subsequent cuSCC tumors, and cuHPV detected in SSW with higher mean fluorescence intensity values were more likely to be present in cuSCC compared with those with lower levels ( < 0.001). β-HPV-positive cuSCC occurred more often in areas of highly sun-damaged skin than did β-HPV-negative cuSCC. Overall, no clear patterns were observed between baseline β-HPV detection and subsequent development of BCC, or between baseline γ-HPV detection and either cuSCC or BCC. Collectively, these results demonstrate that β-HPV detection in SSW is a significant predictor of cuSCC risk, although evidence suggests only a small subset of cuSCC is etiologically linked to β-HPV infection. SIGNIFICANCE: β-HPV positivity may be a useful biomarker for identifying individuals who could benefit from increased screening or novel cutaneous squamous cell carcinoma prevention strategies.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416805PMC
September 2021

Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.

Clin Infect Dis 2021 Jul 5. Epub 2021 Jul 5.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

Background: Long COVID is defined as the persistence of symptoms beyond 3 months after SARS-CoV-2 infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of COVID-19 patients prospectively.

Methods: Patients were included at 5 months after acute COVID-19 in this prospective, non-interventional follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n=96, 32.3% hospitalised, 55.2% females) were included in this analysis of symptoms, quality of life (based on a SF-12 survey), laboratory parameters including antinuclear antibodies (ANA), and SARS-CoV-2 antibody levels.

Results: At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnoea (37.5%), concentration problems (39.6%), problems finding words (32.3%), and sleeping problems (26.0%). Females showed significantly more neurocognitive symptoms than males.ANA titres were ≥1:160 in 43.6% of patients at 12 months post COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titre ≥1:160 compared to <1:160. Compared to patients without symptoms, patients with at least one long COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2-antibody levels, but had a significantly reduced physical and mental life quality compared to patients without symptoms.

Conclusions: Neurocognitive long COVID symptoms can persist at least for one year after COVID-19 symptom onset, and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titre elevations. This may indicate autoimmunity as cofactor in aetiology of long COVID.
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http://dx.doi.org/10.1093/cid/ciab611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394862PMC
July 2021

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

Sensitivity and Specificity of Human Papillomavirus (HPV) 16 Early Antigen Serology for HPV-Driven Oropharyngeal Cancer: A Systematic Literature Review and Meta-Analysis.

Cancers (Basel) 2021 Jun 16;13(12). Epub 2021 Jun 16.

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

Antibodies against HPV16 early proteins have been shown to be promising biomarkers for the identification of HPV-driven oropharyngeal cancer (HPV-OPC) among OPC cases in multiple studies. A systematic literature search was performed to identify original research articles comparing HPV early antigen serology with established reference methods to determine molecular HPV tumor status. Random-effects models were used to calculate summary estimates for sensitivity and specificity of HPV16 E2, E6 and E7 serology for HPV-OPC. Subgroup analyses were performed to explore heterogeneity across studies and describe variables associated with test performance. We identified = 23 studies meeting all eligibility criteria and included these in the meta-analysis. E6 serology showed the best performance with pooled sensitivity and specificity estimates of 83.1% (95% confidence interval (CI) 72.5-90.2%) and 94.6% (95% CI 89.0-97.4%), respectively, while E2 and E7 serological assays were highly specific (E2: 92.5% (95% CI 79.1-97.6%); E7: 88.5% (95% CI 77.9-94.4%)) but moderately sensitive (E2: 67.8% (95% CI 58.9-75.6%); E7: 67.0% (95% CI 63.2-70.6%)). Subgroup analyses revealed increased pooled sensitivity for bacterially (89.9% (95% CI 84.5-93.6%)) vs. in vitro expressed E6 antigen (55.3% (95% CI 41.0-68.7%)), while both showed high specificity (95.2% (95% CI 93.0-96.7%) and 91.1% (95% CI 46.6-99.2%), respectively). Pooled specificity estimates for HPV16 E2, E6 and E7 serology were significantly lower in studies utilizing HPV DNA PCR as the only molecular reference method compared to those using a combination of any two reference methods (HPV DNA, RNA, in situ hybridization (ISH), p16 immunohistochemistry (IHC)), or histopathological reference methods (ISH or p16 IHC) as stand-alone marker. In conclusion, HPV16 E6 seropositivity is a highly sensitive and specific biomarker for HPV-OPC. However, its performance differs between serological assays and depends on molecular reference methods.
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http://dx.doi.org/10.3390/cancers13123010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234521PMC
June 2021

Association between Human Polyomaviruses and Keratinocyte Carcinomas: A Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 Sep 29;30(9):1761-1764. Epub 2021 Jun 29.

Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.

Background: A positive association between Merkel cell polyomavirus (MCPyV) infection and cutaneous squamous cell carcinoma (cuSCC) has been observed in at least one previous case-control study. To evaluate this association in a prospective context, we investigated infections with human polyomaviruses (HPyV), including MCPyV, as predictors of keratinocyte carcinomas, including cuSCC and basal cell carcinoma (BCC), among a cohort of immunocompetent individuals enrolled in the Viruses in Skin Cancer (VIRUSCAN) Study.

Methods: Associations between markers of baseline HPyV infection (serum antibodies and viral DNA in eyebrow hairs and skin swabs) and incident keratinocyte carcinomas were modeled using Cox proportional hazards regression. Proportions of baseline HPyV infections that were concordant with a subsequent tumor positive for the same HPyV type were assessed.

Results: No significant associations were observed between baseline markers of MCPyV or other HPyV infections and cuSCC or BCC. Less than 4.5% of baseline MCPyV infections were also detected in subsequently developed keratinocyte carcinoma tumors.

Conclusions: HPyV infection was not a predictor of keratinocyte carcinoma risk in this prospective cohort.

Impact: Cancer-associated infections represent attractive targets for cancer prevention; however, HPyV infections have limited potential as novel targets for cuSCC prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419098PMC
September 2021

Seroprevalence of Chlamydia trachomatis, herpes simplex 2, Epstein-Barr virus, hepatitis C and associated factors among a cohort of men ages 18-70 years from three countries.

PLoS One 2021 22;16(6):e0253005. Epub 2021 Jun 22.

Center for Infection Research in Cancer, Moffitt Cancer Center, Tampa, Florida, United States of America.

Objectives: To estimate the seroprevalence of Chlamydia trachomatis (CT), herpes simplex type-2 (HSV2), hepatitis C (HCV), Epstein-Barr virus (EBV) and nine human papilloma virus (HPV) types, and investigated factors associated with the seropositivity among men from three countries (Brazil, Mexico and U.S).

Methods: Archived serum specimens collected at enrollment for n = 600 men were tested for antibodies against CT, HSV2, HCV, EBV, and 9-valent HPV vaccine types (6/11/16/18/31/33/45/52/58) using multiplex serologic assays. Socio-demographic, lifestyle and sexual behavior data at enrollment were collected through a questionnaire.

Results: Overall, 39.3% of the men were seropositive for CT, 25.4% for HSV2, 1.3% for HCV, 97.3% for EBV, 14.0% for at least one of the seven oncogenic HPV (types: 16/18/31/33/45/52/58), and 17.4% for HPV 6/11. In the unadjusted models, age, race, smoking, sexual behavior variables, and seropositivity for high-risk HPV were significantly associated with the seropositivity for CT. In multivariable analyses, self-reported black race, higher numbers of lifetime female/male sexual partners, current smoking, and seropositivity to high-risk HPV were significantly associated with increased odds of CT seropositivity. Odds of HSV2 seroprevalence were elevated among older men and those seropositive for high risk HPV.

Conclusion: Exposure to STIs is common among men. Prevention and screening programs should target high-risk groups to reduce the disease burden among men, and to interrupt the disease transmission to sexual partners.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253005PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219163PMC
June 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

High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development.

Mult Scler 2021 Jun 14:13524585211022011. Epub 2021 Jun 14.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied.

Methods: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale.

Results: High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4-1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1-0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1-0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0-0.6).

Conclusion: High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.
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http://dx.doi.org/10.1177/13524585211022011DOI Listing
June 2021

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

Eur J Neurol 2021 09 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 Oct 31;21(10):1458-1468. Epub 2021 May 31.

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
October 2021

Trends in, and predictors of, swallowing and social eating outcomes in head and neck cancer survivors: A longitudinal analysis of head and neck 5000.

Oral Oncol 2021 07 20;118:105344. Epub 2021 May 20.

Population Health Sciences Institute, Newcastle University Centre for Cancer, Newcastle University, United Kingdom. Electronic address:

Objective: To investigate the recovery trajectory and predictors of outcome for swallowing difficulties following head and neck cancer treatment in a large prospective cohort.

Materials And Methods: Data from 5404 participants of the Head and Neck 5000 study were collected from 2011 to 2014. Patient-reported swallowing was measured using the EORTC HN35, recorded at baseline (pre-treatment) and 4 and 12 months post-baseline. Mixed-effects linear multivariable regression was used to investigate time trends, compare cancer sites, and identify associations between clinical, socio-demographic and lifestyle variables.

Results: 2458 participants with non-recurrent oral (29%) oropharyngeal (46%) and laryngeal (25%) cancer were included in the analysis. There was a clinically significant deterioration in scores between baseline and four months for swallowing (11.7 points; 95% CI 10.7-12.8) and trouble with social eating (17.9 points; 95% CI 16.7-19.2), but minimal difference between baseline and 12 months. Predictors of better swallowing and social eating were participants with larynx cancer, early-stage disease, treatment type, age, gender, co-morbidity, socio-economic status, smoking behaviour and cohabitation.

Conclusion: Swallowing problems persist up to a year after head and neck cancer treatment. These findings identify disease and demographic characteristics for particularly vulnerable groups, supporting the need for holistic interventions to help improve swallowing outcomes. People diagnosed with head and neck cancer at risk of severe eating and drinking problems following treatment can be identified earlier in the pathway, receive more accurate information about early and late post-treatment side-effects, which can inform shared decision-making discussions.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105344DOI Listing
July 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

From Multiplex Serology to Serolomics-A Novel Approach to the Antibody Response against the SARS-CoV-2 Proteome.

Viruses 2021 04 24;13(5). Epub 2021 Apr 24.

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

The emerging SARS-CoV-2 pandemic entails an urgent need for specific and sensitive high-throughput serological assays to assess SARS-CoV-2 epidemiology. We, therefore, aimed at developing a fluorescent-bead based SARS-CoV-2 multiplex serology assay for detection of antibody responses to the SARS-CoV-2 proteome. Proteins of the SARS-CoV-2 proteome and protein N of SARS-CoV-1 and common cold Coronaviruses (ccCoVs) were recombinantly expressed in or HEK293 cells. Assay performance was assessed in a COVID-19 case cohort ( = 48 hospitalized patients from Heidelberg) as well as = 85 age- and sex-matched pre-pandemic controls from the ESTHER study. Assay validation included comparison with home-made immunofluorescence and commercial enzyme-linked immunosorbent (ELISA) assays. A sensitivity of 100% (95% CI: 86-100%) was achieved in COVID-19 patients 14 days post symptom onset with dual sero-positivity to SARS-CoV-2 N and the receptor-binding domain of the spike protein. The specificity obtained with this algorithm was 100% (95% CI: 96-100%). Antibody responses to ccCoVs N were abundantly high and did not correlate with those to SARS-CoV-2 N. Inclusion of additional SARS-CoV-2 proteins as well as separate assessment of immunoglobulin (Ig) classes M, A, and G allowed for explorative analyses regarding disease progression and course of antibody response. This newly developed SARS-CoV-2 multiplex serology assay achieved high sensitivity and specificity to determine SARS-CoV-2 sero-positivity. Its high throughput ability allows epidemiologic SARS-CoV-2 research in large population-based studies. Inclusion of additional pathogens into the panel as well as separate assessment of Ig isotypes will furthermore allow addressing research questions beyond SARS-CoV-2 sero-prevalence.
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http://dx.doi.org/10.3390/v13050749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147094PMC
April 2021

Heterogeneous associations of polyomaviruses and herpesviruses with allergy-related phenotypes in childhood.

Ann Allergy Asthma Immunol 2021 08 23;127(2):191-199.e3. Epub 2021 Apr 23.

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.

Background: Evidence suggests a complex interplay between infections and allergic diseases.

Objective: To explore the association of 14 common viruses with eczema, asthma, and rhinoconjunctivitis in childhood.

Methods: We used cross-sectional (n = 686) and prospective (n = 440) data from children participating in the Rhea birth cohort. Immunoglobulin G to polyomaviruses (BK polyomavirus, JC polyomavirus, KI polyomavirus [KIPyV], WU polyomavirus [WUPyV], human polyomavirus 6, human polyomavirus 7, Trichodysplasia spinulosa polyomavirus, Merkel cell polyomavirus, human polyomavirus 9, and human polyomavirus 10) and herpesviruses (Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus-1, Herpes simplex virus-2) were measured at age 4 years by fluorescent bead-based multiplex serology. Definitions of eczema, asthma, and rhinoconjunctivitis at ages 4 and 6 years were based on questionnaires. Mediation of the associations by immune biomarkers was tested.

Results: Less likely to have eczema at age 4 years were KIPyV-seropositive (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.27-0.82) and human polyomavirus 6 (OR, 0.44; 95% CI, 0.26-0.73) compared with their seronegative counterparts. Seropositivity to Epstein-Barr virus was negatively associated with eczema at age 4 years (OR, 0.39; 95% CI, 0.22-0.67) and 6 years (OR, 0.50; 95% CI, 0.25-0.99). Children with a higher burden of herpesviruses or of skin polyomaviruses had the lowest odds of eczema at age 4 years. Higher odds for asthma at age 4 years were found for WUPyV-seropositive children (OR, 3.98; 95% CI, 1.38-11.51), and for children seropositive to both respiratory polyomaviruses (KIPyV and WUPyV) (OR, 7.35; 95% CI, 1.66-32.59) compared with children seronegative to both. No associations were observed for rhinoconjunctivitis. There was no evidence of mediation by immune biomarkers.

Conclusion: A heterogeneous pattern of infections and allergic diseases was observed with common infections associated with a decreased eczema risk and an increased asthma risk in children.
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http://dx.doi.org/10.1016/j.anai.2021.04.019DOI Listing
August 2021

Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort.

Gut Microbes 2021 Jan-Dec;13(1):1-14

Department of Medical Biosciences, Pathology, Umeå University, Ireland.

Experimental evidence has implicated genotoxic () and enterotoxigenic (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to and ETBF with CRC.The IgA-positivity of any of the tested antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (= 0.095). Sero-positivity to and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.
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http://dx.doi.org/10.1080/19490976.2021.1903825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078709PMC
April 2021

Prediagnostic Antibody Responses to Proteins Are Not Associated with Risk of Colorectal Cancer in a Large U.S. Consortium.

Cancer Epidemiol Biomarkers Prev 2021 06 18;30(6):1279-1282. Epub 2021 Mar 18.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Background: The association between prediagnostic antibody responses to () and subsequent risk of colorectal cancer is not established.

Methods: We conducted a nested case-control study of 8,126 participants in a consortium of 10 prospective cohorts in the United States.

Results: Higher seroprevalence of any antibody was observed among non-White participants (51.1%) compared with White participants (31.2%). We did not find any statistically significant association between seropositivity to any of the eight proteins and colorectal cancer risk.

Conclusions: Prediagnostic antibody responses to proteins were not associated with the risk of colorectal cancer.

Impact: Future studies may consider a more specific detection of the immunoglobulin isotypes or focus on examining in stool or tissue samples.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172443PMC
June 2021

Survival advantage in patients with human papillomavirus-driven oropharyngeal cancer and variation by demographic characteristics and serologic response: Findings from Head and Neck 5000.

Cancer 2021 Jul 15;127(14):2442-2452. Epub 2021 Mar 15.

Infections and Cancer Epidemiology; Infection, Inflammation and Cancer Program, German Cancer Research Center, Heidelberg, Germany.

Background: Patients with human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) experience better survival than those with HPV-negative OPC. It is unclear whether this benefit varies by demographic characteristics and serologic response.

Methods: Records from 1411 patients with OPC who had HPV serology data were analyzed. HPV status was based on HPV type 16 (HPV16) E6 serology. Participants were followed for a median of 5.9 years, and Cox proportional hazards models were used to estimate hazard ratios (HRs). The association between HPV status and overall survival was analyzed by age group, sex, smoking status, tumor site, HPV antibody levels, and HPV antibody pattern. Models were adjusted for age, sex, smoking status, and comorbidity.

Results: For the overall association between HPV status and survival, the fully adjusted HR was 0.43 (95% CI, 0.33-0.56). The HR was 0.19 (95% CI, 0.10-0.35) for participants aged ≤54 years, 0.38 (95% CI, 0.25-0.56) for those aged 55 to 64 years, and 0.73 (95% CI, 0.47-1.13) for those aged ≥65 years (P for interaction = .023). There was no clear evidence for an interaction by sex, smoking status, or tumor site. Survival did not differ according to E6 antibody levels in those who were seropositive. All seropositivity patterns were associated with increased survival compared with a pattern of seronegativity for all antibodies. Patients who are positive for E1, E2, E6, and E7 may experience better survival.

Conclusions: HPV status confers a survival advantage across all groups. This survival advantage is more marked for younger patients. The HPV antibody pattern, but not the antibody level, may also affect survival.
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http://dx.doi.org/10.1002/cncr.33505DOI Listing
July 2021

DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies.

J Neurol Neurosurg Psychiatry 2021 Jul 9;92(7):717-722. Epub 2021 Mar 9.

Karolinska Institute, Stockholm, Sweden.

Objective: We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for .

Methods: Using population-based case-control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.

Results: The effect of each allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between and each assessed environmental factor was of similar magnitude regardless of the number of alleles, although ORs were affected. When any of the environmental factors were present in carriers without the protective allele, a three-way interaction occurred and rendered high ORs, especially among homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).

Conclusions: The strikingly increased MS risk among homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.
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http://dx.doi.org/10.1136/jnnp-2020-325676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223646PMC
July 2021

Elimination of HPV-associated oropharyngeal cancers in Nordic countries.

Prev Med 2021 03 4;144:106445. Epub 2021 Mar 4.

FICAN-MID, Tampere, Finland; Department of Health Security, Finnish Institute for Health and Welfare, Helsinki, Finland; Infections and Cancer Epidemiology, Deutsches Krebsforschungzentrum, Heidelberg, Germany; Department of Lab Medicine, Karolinska Institute, Stockholm, Sweden.

Incidence of human papillomavirus (HPV, most notably HPV type 16) associated oropharyngeal squamous cell carcinoma (OPSCC) among middle-aged (50-69 year-old) males has tripled in four high income Nordic countries (Denmark, Finland, Norway and Sweden) over the last 30 years. In Finland and Sweden, this increase was preceded by an HPV16 epidemic in fertile-aged populations in the 1980's. The recent implementation of school-based prophylactic HPV vaccination in early adolescent boys and girls will gradually decrease the incidence, and eventually eliminate the HPV-associated OPSCCs (especially tonsillar and base of tongue carcinomas) in the Nordic countries. However, beyond the adolescent and young adult birth cohorts vaccinated, there are approximately 50 birth cohorts (born in 1995 or before) that would benefit from screening for HPV-associated OPSCC. This article reviews the need, prerequisites, proof-of-concept trial and prospects of preventing HPV-associated OPSCC in the Nordic countries.
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http://dx.doi.org/10.1016/j.ypmed.2021.106445DOI Listing
March 2021

Overweight/obesity in young adulthood interacts with aspects of EBV infection in MS etiology.

Neurol Neuroimmunol Neuroinflamm 2021 01 15;8(1). Epub 2020 Dec 15.

From the Department of Clinical Neuroscience (A.K.H., J.H., T.O., L.A.), Karolinska Institutet, Stockholm, Sweden; Infections and Cancer Epidemiology (N.B., J.B., T.W.), German Cancer Research Center (DKFZ), Heidelberg; Center for Molecular Medicine (J.H., T.O.), Karolinska Institutet at Karolinska University Hospital, Solna, Sweden; and Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm, Sweden.

Objective: Because obesity affects the cellular immune response to infections, we aimed to investigate whether high body mass index (BMI) in young adulthood and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels interact with regard to MS risk. We also aimed at exploring potential 3-way interactions between BMI at age 20 years, aspects of Epstein-Barr virus (EBV) infection (high EBNA-1 antibody levels and infectious mononucleosis [IM] history, respectively) and the human leukocyte antigen allele.

Methods: Using Swedish population-based case-control studies (5,460 cases and 7,275 controls), we assessed MS risk in relation to interactions between overweight/obesity at age 20 years, IM history, EBNA-1 levels, and status by calculating ORs with 95% CIs using logistic regression. Potential interactions were evaluated on the additive scale.

Results: Overweight/obesity, compared with normal weight, interacted significantly with high (>50th percentile) EBNA-1 antibody levels (attributable proportion due to interaction 0.2, 95% CI 0.1-0.4). The strength of the interaction increased with higher category of EBNA-1 antibody levels. Furthermore, 3-way interactions were present between overweight/obesity at age 20 years, and each aspect of EBV infection.

Conclusions: With regard to MS risk, overweight/obesity in young adulthood acts synergistically with both aspects of EBV infection, predominantly among those with a genetic susceptibility to the disease. The obese state both induces a chronic immune-mediated inflammation and affects the cellular immune response to infections, which may contribute to explain our findings.
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http://dx.doi.org/10.1212/NXI.0000000000000912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803338PMC
January 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

Timing, number, and type of sexual partners associated with risk of oropharyngeal cancer.

Cancer 2021 Apr 11;127(7):1029-1038. Epub 2021 Jan 11.

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

Background: Case-control studies from the early 2000s demonstrated that human papillomavirus-related oropharyngeal cancer (HPV-OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV-OPC.

Methods: HPV-OPC patients and frequency-matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi-square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression.

Results: A total of 163 HPV-OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV-OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8-6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1-3.2]) and oral sex intensity (>5 sex-years: aOR, 2.8 [95% CI, 1.1-7.5]) remained associated with significantly increased odds of HPV-OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1-2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1-2.4]) was associated with HPV-OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122-670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70-378]) was associated with increased odds of HPV-OPC.

Conclusion: Number of oral sex partners remains a strong risk factor for HPV-OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV-OPC.
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http://dx.doi.org/10.1002/cncr.33346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035131PMC
April 2021

Inequality in survival of people with head and neck cancer: Head and Neck 5000 cohort study.

Head Neck 2021 04 8;43(4):1252-1270. Epub 2021 Jan 8.

School of Medicine, Dentistry, and Nursing, University of Glasgow, Glasgow, UK.

Background: Explanations for socioeconomic inequalities in survival of head and neck cancer (HNC) patients have had limited attention and are not well understood.

Methods: The UK Head and Neck 5000 prospective clinical cohort study was analyzed. Survival relating to measures of socioeconomic status was explored including area-based and individual factors. Three-year overall survival was determined using the Kaplan-Meier method. All-cause mortality was investigated via adjusted Cox Proportional Hazard models.

Results: A total of 3440 people were included. Three-year overall survival was 76.3% (95% CI 74.9, 77.7). Inequality in survival by deprivation category, highest education level, and financial concerns was explained by age, sex, health, and behavioral factors. None of the potential explanatory factors fully explained the inequality associated with annual household income or the proportion of income of benefits.

Conclusion: These results support the interventions to address the financial issues within the wider care and support provided to HNC patients.
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http://dx.doi.org/10.1002/hed.26589DOI Listing
April 2021
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