Search

ABSTRACT Given low seroconversion rates following human papillomavirus (HPV) infection, fixed external cutoffs may lead to errors in estimating HPV seroprevalence. We evaluated finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) among unvaccinated, sexually active, HPV-exposed women to determine study-specific HPV16 and HPV18 seropositivity thresholds. We included 399 women (aged 18–24 years) enrolled in the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study between 2005 and 2011 in Montreal, Canada. Participants’ blood samples from up to six visits spanning 2 years were tested by multiplex serology for antibodies [median fluorescence intensity (MFI)] specific to bacterially expressed HPV16 and HPV18 L1 glutathione S-transferase fusion proteins. We applied FMM and GBTM to baseline and longitudinal antibody titer measurements, respectively, to define HPV type-specific seronegative and seropositive distributions. Study-specific thresholds were generated as five standard deviations above the mean seronegative antibody titers, mimicking cutoffs (HPV16: 422 MFI; HPV18: 394 MFI) derived from an external population of sexually inactive, HPV DNA-negative Korean women (aged 15–29 years). Agreement (kappa) of study-specific thresholds was evaluated against external cutoffs. Seroprevalence estimates using FMM (HPV16: 27.5%–43.2%; HPV18: 21.7%–49.5%) and GBTM (HPV16: 11.8%–11.8%; HPV18: 9.9%–13.4%) thresholds exceeded those of external cutoffs (HPV: 10.2%; HPV18: 9.7%). FMM thresholds showed slight-to-moderate agreement with external cutoffs (HPV16: 0.26%–0.46%; HPV18: 0.20%–0.56%), while GBTM thresholds exhibited high agreement (HPV16: 0.92%–0.92%; HPV18: 0.82%–0.99%). Kappa values suggest that GBTM, used for longitudinal serological data, and otherwise FMM, for cross-sectional data, are robust methods for determining the HPV serostatus without prior classification rules.IMPORTANCEWhile human papillomavirus (HPV) seropositivity has been employed as an epidemiologic determinant of the natural history of genital HPV infections, only a fraction of women incidentally infected with HPV respond by developing significant antibody levels. HPV seropositivity is often determined by a dichotomous fixed cutoff based on the seroreactivity of an external population of women presumed as seronegative, given the lack of evidence of HPV exposure. However, considering the variable nature of seroreactivity upon HPV infection, which arguably varies across populations, such externally defined cutoffs may lack specificity to the population of interest, causing inappropriate assessment of HPV seroprevalence and related epidemiologic uses of that information. This study demonstrates that finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) can be used to independently estimate seroprevalence or serve as the basis for defining study-specific seropositivity thresholds without requiring prior subjective assumptions, consequently providing a more apt internally valid discrimination of seropositive from seronegative individuals.

Abstract Background Studies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients. Methods This is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000–2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson’s comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone). Results Of 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55–0.82), DSS (HR 0.58, 95%CI 0.45–0.76), and RFS (HR 0.61, 95%CI 0.47–0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07–1.55), DSS (HR 1.38, 95%CI 1.10–1.72), and RFS (HR 1.41, 95%CI 1.13–1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95–1.27), 1.24 (95%CI 1.03–1.48), and 1.22 (95%CI 1.03–1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too. Conclusions In our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.

Background: The treatment paradigm for locally advanced cervical cancer (LACC) has shifted from two-dimensional-brachytherapy (2D-BT) to three-dimensional-image-guided adaptive BT (3D-IGABT). In this retrospective study, we report our experience with the change from 2D-BT to 3D-IGABT. Methods: We reviewed 146 LACC patients (98 3D-IGABT and 48 2D-BT) who received chemoradiation between 2004 and 2019. The multivariable odds ratio (OR) for treatment-related toxicities and hazard ratios (HR) for locoregional control (LRC), distant control (DC), failure-free survival (FFS), cancer-specific survival (CSS) and overall survival (OS) are reported. Results: The median follow-up was 50.3 months. There was a significant decrease in overall late toxicities in the 3D-IGABT group compared to the 2D-BT group (OR 0.22[0.10–0.52]), late gastrointestinal (OR 0.31[0.10–0.93]), genitourinary (OR 0.31[0.09–1.01]) and vaginal toxicities (0% vs. 29.6%). Grade ≥ 3 toxicity was low in both groups (2D-BT: 8.2% acute, 13.3% late vs. 3D-IGABT: 6.3% acute, 4.4% late, NS). The five-year LRC, DC, FFS, CSS and OS for 3D-IGABT were 92.0%, 63.4%, 61.7%, 75.4% and 73.6%, compared to 87.3%, 71.8%, 63.7%, 76.3% and 70.8% for 2D-BT (NS). Conclusions: 3D-IGABT for the treatment of LACC is associated with a decrease in overall late gastrointestinal, genitourinary and vaginal toxicities. The disease control or survival outcomes were comparable to contemporary 3D-IGABT studies.

Objectives: This study aimed to evaluate dynamics of antibody levels after exposure to SARS-CoV-2 for 12 months in Dutch non-vaccinated hairdressers and hospitality staff. Methods: In this prospective cohort study, blood samples were collected every 3 months for 1 year and analyzed using a qualitative total antibody enzyme-linked immunosorbent assay (ELISA) and a quantitative immunoglobulin (Ig)G antibody ELISA. Participants completed questionnaires, providing information on demographics, health, and work. Differences in antibody levels were evaluated using Mann–Whitney U and Wilcoxon signed-rank tests. Beta coefficients (β) and 95% confidence intervals (CIs) were calculated using linear regression. Results: Ninety-five of 497 participants (19.1%) had ≥1 seropositive measurement before their last visit using the qualitative ELISA. Only 2.1% (2/95) seroreverted during follow-up. Of 95 participants, 82 (86.3%) tested IgG seropositive in the quantitative ELISA too. IgG antibody levels significantly decreased in the first months (P

Abstract Prostate cancer (PCa) clinical heterogeneity underscores tumor heterogeneity, which may be best defined by cell subtypes. To test if cell subtypes contributing to progression can be assessed noninvasively, we investigated whether 14 genes representing luminal, neuroendocrine, and stem cells are detectable in whole blood RNA of patients with advanced PCa. For each gene, reverse transcription quantitative polymerase chain reaction assays were first validated using RNA from PCa cell lines, and their traceability in blood was assessed in cell spiking experiments. These were next tested in blood RNA of 40 advanced PCa cases and 40 healthy controls. Expression in controls, which was low or negative, was used to define stringent thresholds for gene overexpression in patients to account for normal variation in white blood cells. Thirty‐five of 40 patients overexpressed at least one gene. Patients with more genes overexpressed had a higher risk of death (hazard ratio 1.42, range 1.12–1.77). Progression on androgen receptor inhibitors was associated with overexpression of stem (odds ratio [OR] 7.74, range 1.68–35.61) and neuroendocrine (OR 13.10, range 1.24–142.34) genes, while luminal genes were associated with taxanes (OR 2.7, range 1.07–6.82). Analyses in PCa transcriptomic datasets revealed that this gene panel was most prominent in metastases of advanced disease, with diversity among patients. Collectively, these findings support the contribution of the prostate cell subtypes to disease progression. Cell‐subtype specific genes are traceable in blood RNA of patients with advanced PCa and are associated with clinically relevant end points. This opens the door to minimally invasive liquid biopsies for better management of this deadly disease.

COVID-19 has made a global impact since early 2020, requiring characterization of the SARS-CoV-2 virus, including transmission risk. The COco-study aims to evaluate the risk for COVID-19 infections in two non-medical contact-intensive professions. COco is a prospective cohort study evaluating SARS-CoV-2 antibodies in hairdressers and hospitality personnel in the province of North-Brabant in the Netherlands, using a total antibody enzyme-linked immunosorbent assay. Baseline data from June/July 2020 were analyzed. Participants filled out a questionnaire, providing information on demographics, health, work situation, and risk factors for COVID-19. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using logistic regression. In June/July 2020, 497 participants were enrolled: 236 hairdressers, 259 hospitality employees, and two participants worked in both industries. Hospitality staff was more frequently seropositive than hairdressers (14.2% versus 8.0%, respectively; OR 1.9, 95% CI 1.1–3.4). Furthermore, a high education level (OR 3.0, 95% CI: 1.7–5.6) and increased alcohol use (OR, 7 glasses per week increment: 1.3, 95% CI: 1.1–1.5) were associated with seropositivity. Of the 56 seropositive participants, 18 (32%) had not experienced any COVID-19 symptoms. The symptoms anosmia/ageusia differed most evidently between seropositive and seronegative participants (53.6% versus 5.7%, respectively; P

Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process.Applying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs.Our study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics.