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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., Competing Interests: E.L.F. has served as an occasional advisor to companies involved with human papillomavirus (HPV) diagnostics (Roche, BD, Qiagen, and Gen-Probe) and HPV vaccines (Merck and GSK). His institution has received unconditional grants from Merck in aid of investigator-initiated studies. M.Z. and E.L.F. hold a patent related to the discovery "DNA methylation markers for early detection of cervical cancer", registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October 2018). F.C. has received grants or free reagents through his institution from Merck Sharp and Dohme, Becton Dickinson and Roche, as well as honoraria from Merck and Roche for lectures on HPV. T.W. serves on advisory boards for MSD (Merck) Sharp & Dohme. All other authors report no potential conflicts of interest. None of the work presented in this manuscript was paid for or influenced by any of the aforementioned companies.

Background: Human papillomavirus (HPV) infection contributes to approximately 5% of the worldwide cancer burden. The three-dose HPV vaccine has demonstrated immunogenicity and efficacy. Humoral responses may be critical for preventing, controlling, and/or eliminating HPV infection. Using data from the HITCH cohort, we analysed humoral immune response to HPV vaccination among women in relation to the phylogenetic relatedness of HPV genotypes., Methods: We included 96 women aged 18-24 years attending college or university in Montreal, Canada. Participants provided blood samples at enrolment and five follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase fusion proteins of multiple Alphapapillomavirus types, and to virus-like particles (VLP-L1) of HPV16 and HPV18 were measured using multiplex serology. We assessed correlations between antibody seroreactivities using Pearson correlations (r)., Results: At enrolment, 87.7% of participants were unvaccinated, 2.4% had received one, 3.2% two, and 6.7% three doses of HPV vaccine. The corresponding L1 seropositivity to any HPV was 41.2%, 83.3%, 100%, and 97.0%. Between-type correlations for L1 seroreactivities increased with the number of vaccine doses, from one to three. Among the latter, the strongest correlations were observed for HPV58-HPV33 (Pearson correlation [r] = 0.96; α9-species); HPV11-HPV6 ( r  = 0.96; α10-species); HPV45-HPV18 ( r  = 0.95; α7-species), and HPV68-HPV59 ( r  = 0.95; α7-species)., Conclusions: Correlations between HPV-specific antibody seroreactivities are affected by phylogenetic relatedness, with anti-L1 correlations becoming stronger with the number of vaccine doses received.

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., (© 2023. The Author(s).)

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.

Background: Humoral immune responses may be critical for preventing, controlling, and/or eliminating human papillomavirus (HPV) infection. We analyzed humoral response to natural HPV infection considering phylogenetic relatedness among unvaccinated women., Methods: We included 399 young women attending university/college in Montreal, Canada who were participants of the HITCH cohort. Participants provided blood samples at baseline and 5 follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase (GST) fusion proteins, and virus-like particles (VLP-L1) of Alphapapillomavirus types were measured using multiplex serology. We assessed correlations and associations between HPV types at baseline using Pearson correlation coefficients (r) and univariable linear regressions., Results: At baseline, > 40% were seropositive for GST-L1 antibodies of at least 1 HPV type. Strong correlations between GST-L1 were observed for α9 HPV types: 58-52 (r = 0.86), 58-33 (r = 0.75), 33-52 (r = 0.72), and between GST-E6: 52-11 (r = 0.84), 52-18 (r = 0.79), 58-33 (r = 0.78), 35-11 (r = 0.76). HPV16 VLP-L1 moderately explained variability in HPV16 GST-L1 (regression coefficient [b] = 0.38, R2 = 43.1%), and HPV45 GST-L1 in HPV18 GST-L1 (b = 0.68, R2 = 42.8%). GST-E6 antibodies accounted for a low to moderate proportion of variability in HPV16 and HPV18 GST-E6 (R2 = 6.4%-62.2%)., Conclusions: Associations between naturally induced HPV-specific antibodies depend on phylogenetic relatedness., Competing Interests: Potential conflicts of interest . E. L. F. has served as an occasional advisor to companies involved with human papillomavirus (HPV) diagnostics (Roche, BD, Qiagen, Gen-Probe) and HPV vaccines (Merck, GSK); and his institution has received unconditional grants from Merck in aid of investigator-initiated studies. M. Z. and E. L. F. hold a patent related to the discovery “DNA methylation markers for early detection of cervical cancer”, registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October 2018). F. C. has received grants or free reagents through his institution from Merck Sharp and Dohme, Becton Dickinson, and Roche; and honoraria from Merck and Roche for lectures on HPV. T. W. serves on advisory boards for MSD (Merck) Sharp & Dohme. M. D. W. is currently a senior medical writer at Certara Synchrogenix consulting services. None of the work presented in this manuscript was paid for or influenced by Certara Synchrogenix. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 <0.01) but remained detectable for up to 12 months in all participants. Older age (β, 10-years increment: 24.6, 95% CI: 5.7-43.5) and higher body mass index (β, 5kg/m² increment: 40.0, 95% CI: 2.9-77.2) were significantly associated with a higher peak of antibody levels., Conclusion: In this cohort, SARS-CoV-2 antibodies persisted for up to 1 year after initial seropositivity, suggesting long-term natural immunity., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Previous studies examining the association between male circumcision (MC) and human papillomavirus (HPV) infections have reported inconsistent results. We used data from the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study to examine the association between MC and HPV infections in males and their female sexual partners., Methods: We enrolled monogamous couples in a longitudinal study between 2005 and 2011 in Montreal, Canada. We used logistic and Poisson regression models with propensity score adjustment to estimate odds ratios (ORs) and rate ratios for the association between MC and the prevalence, transmission, and clearance of HPV infections., Results: Four hundred thirteen couples were included in our study. The prevalence OR for the association between MC and baseline infections was 0.81 (95% confidence interval [CI], .56-1.16) in males and 1.05 (95% CI, .75-1.46) in females. The incidence rate ratio for infection transmission was 0.59 (95% CI, .16-2.20) for male-to-female transmission and 0.77 (95% CI, .37-1.60) for female-to-male transmission. The clearance rate ratio for clearance of infections was 0.81 (95% CI, .52-1.24)., Conclusions: We found little evidence of an association between MC and HPV infection prevalence, transmission, or clearance in males and females. Further longitudinal couple-based studies are required to investigate this association., Competing Interests: Potential conflicts of interest. E. L. F. and M. Z. hold a patent related to the discovery “DNA methylation markers for early detection of cervical cancer,” registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October 2018). F. C. has received grants through his institution from Merck, Becton Dickinson, and Roche, as well as honoraria from Merck and Roche for lectures on HPV. All other authors report no potential conflicts of interest.. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 < 0.001 (chi-squared test)). In conclusion, four months after the first identified COVID-19 patient in the Netherlands, employees in the hospitality industry had significantly more frequently detectable SARS-CoV-2 antibodies than hairdressers., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: Existing literature suggests that bladder cancer (BC) outcome may be improved when patients use 5α-reductase inhibitors and/or α 1 -blockers, but such a conclusion may be subject to publication bias. We evaluated whether preoperative use of 5α-reductase inhibitors or α 1 -blockers was associated with improved clinical outcomes in a cohort of patients with BC undergoing radical cystectomy (RC)., Patients and Methods: Using provincial health administrative databases, we retrospectively identified male BC patients undergoing RC in Quebec province between 2000 and 2015, and we collected data from 2 years before RC until December 2016 or death. Survival analyses were conducted using Kaplan-Meier curves, log-rank tests, propensity score matching, and uni- and multivariable Cox proportional hazards models. Covariates included age, Charlson's comorbidity index, region of residence, year of RC, distance to hospital, hospital type, annual RC volume of each hospital and surgeon, neoadjuvant chemotherapy use, and type of bladder diversion., Results: Of the 2822 patients included, 284 patients used 5α-reductase inhibitors and 1001 patients used α 1 -blockers prior to surgery. Median follow-up time was 7.7 years. Patients who used 5α-reductase inhibitors or α 1 -blockers were generally older, had more comorbidities, and were treated more recently in academic centers. Overall, bladder cancer-specific and recurrence-free survival did not differ significantly between those using 5α-reductase inhibitors prior to surgery and controls who never used 5α-reductase inhibitors. Adjusted hazard ratios were 1.03 (95% confidence interval [CI], 0.88-1.21) for overall survival, 1.12 (95% CI, 0.92-1.36) for bladder cancer-specific survival, and 1.19 (95% CI, 0.99-1.42) for recurrence-free survival. The aforementioned outcomes were significantly worse in patients who used α1-blockers prior to surgery compared to controls, with respective adjusted hazard ratios of 1.15 (95% CI, 1.04-1.27), 1.19 (95% CI, 1.05-1.35), and 1.18 (95% CI, 1.05-1.33)., Conclusion: Preoperative use of 5α-reductase inhibitors and α 1 -blockers did not improve clinical outcome in our cohort of male patients undergoing radical cystectomy for bladder cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Serum antibody levels can be used to measure the humoral immune response against human papillomaviruses (HPV). We developed and validated a rapid, technically simple and relatively inexpensive multiplex non-competitive Luminex-based immunoassay (ncLIA) to measure total IgG antibody levels against four HPV types. For the assay's solid phase, virus-like particles (VLPs) of HPV6, 11, 16 and 18 were bound to heparin-coated beads. HPV serum antibody levels binding to the VLPs were quantified using a phycoerithrin-conjugated secondary polyclonal donkey anti-human IgG antibody. Standardization and validation of the ncLIA were performed using 96 paired serum and genital samples from participants in the HITCH cohort study, including young women (aged 18-24 years) and their male sexual partners (aged 18+) in Montreal, Canada. Results from the ncLIA were compared to a validated Luminex immunoassay from PPD laboratories using Pearson's correlation coefficients, receiver operating characteristic curves and logistic regression. Our assay had good inter- and intra-assay variability. The correlation of serum antibody levels between the ncLIA and validation assay was highest for HPV16 and HPV11 ( r =0.90), followed by HPV6 ( r =0.86) and HPV18 ( r =0.67). The ncLIA was better able to predict HPV DNA positivity in genital samples than the validation assay for HPV16 [area under the curve (AUC) 0.65 versus 0.52, P =0.001] and HPV18 [AUC 0.71 versus 0.57, P =0.024]. AUCs for HPV6 and HPV11 were similar between the two assays (0.70 versus 0.71, P =0.59, and 0.88 versus 0.96, P =0.08, respectively). The developed ncLIA is useful for measuring total IgG antibody response following natural infection or vaccination against four HPV VLPs included in the quadrivalent vaccine.

Guidelines for the treatment of tubo-ovarian cancer patients beyond third line are lacking. We aimed to evaluate the effect of response in each line on patient's outcome as well as identify variables that predict response for additional line of chemotherapy. A cohort study was performed including all patients with advanced high-grade ovarian cancer. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Odds ratios and hazard ratios were calculated using multilevel, mixed-effects logistic regression and Cox regression, adjusting for repeated measures within individual patients. Two-hundred thirty-eight patients were included and underwent up to 10 lines of chemotherapy. The median progression-free survival was 15.6 and overall survival (OS) was 55.6 months. Response rates dropped with each additional line and by line 5, most patients (61%) became refractory and only 16% had any type of response (complete 4% or partial 12%). By line 2, whether a patient had partial disease (PR), stable disease (SD) or progressive disease (PD) did not have an effect on the OS. From line 2, whether a patient had PR, SD or PD did not have an effect on chemotherapy-free interval. Number of previous lines and time from previous line were the only variables that significantly correlated with both outcome of patients and response to the next line. In conclusion, time interval from the previous line of chemotherapy is the major clinical factor that predicts beneficial effect of another line of treatment in patients with ovarian cancer., (© 2020 Union for International Cancer Control.)

Introduction: The objective was to assess whether an early response to neoadjuvant chemotherapy in women with advanced ovarian cancer may predict short- and long-term clinical outcome., Material and Methods: This is a retrospective study of all women with stage III-IV tubo-ovarian cancer treated with neoadjuvant chemotherapy at a single center in Montreal between 2003 and 2014. Logistic regression models were used to evaluate the association between cancer antigen 125 (CA-125) levels during neoadjuvant chemotherapy and debulking success. Cox proportional hazard models were used to estimate hazard ratios and their respective 95% CI for death and recurrence. Harrell's concordance indices were calculated to evaluate which variables best predicted the chemotherapy-free interval and overall survival in our population., Results: In all, 105 women were included. Following the first, second, and third cycles of neoadjuvant chemotherapy, CA-125 levels had a median reduction of 43.2%, 85.4%, and 92.9%, respectively, compared with CA-125 levels at diagnosis. As early as the second cycle, CA-125 was associated with overall survival (hazard ratio 1.03, 95% CI 1.01-1.05, per 50 U/mL increment). By the third cycle, CA-125 did not only predict overall survival (hazard ratio 1.04, 95% CI 1.01-1.08), but it predicted overall survival better than the success of debulking surgery (Harrell's concordance index 0.646 vs 0.616). Both absolute CA-125 levels and relative reduction in CA-125 levels after 2 and 3 cycles predicted the chance to achieve complete debulking (P < .05)., Conclusions: Reduction of CA-125 levels during neoadjuvant chemotherapy provides an early predictive tool that strongly correlates with successful cytoreductive surgery and long-term clinical outcome in women with advanced high-grade serous and endometrioid ovarian cancer., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Despite its proven benefit, studies have reported poor use of perioperative chemotherapy (POC) in bladder cancer patients undergoing radical cystectomy (RC). We evaluated POC use in Quebec between January 2000 and September 2016., Methods: Using provincial health administrative databases, data were retrospectively collected from patients from two years before RC until December 2016 or death. Logistic regression was used to identify variables predicting POC use. Survival analyses were conducted using Cox regression. Analyzed covariates were age, sex, comorbidities, year of RC, residence and hospital region, distance to hospital, hospital type and size, and hospital's and surgeon's RC volume., Results: A total of 790/4656 patients (17.0%) received POC. Neoadjuvant chemotherapy (NAC) use increased in recent years: 3.5% (2009), 11.2% (2012), and 20.7% (2015). POC use was increased in patients with recent surgery, a younger age, less comorbidities, residing closer to the hospital of surgery, and a high surgeon's RC volume (p<0.05). For patients treated between 2013 and 2016, a younger age (odds ratio [OR] 0.71; 95% confidence interval [CI] 0.64-0.80 per five years), shorter distance to the hospital (OR 0.88; 95% CI 0.77-0.99 per 50 km), surgery in an academic hospital (OR 1.86; 95% CI 1.06-3.29), and recent surgery (OR 1.34; 95% CI 1.14-1.58 per year) independently predicted NAC use. These NAC users had a significantly higher overall survival rate than patients without POC (hazard ratio 0.73; 95% CI 0.55-0.97). Limitations include missing data on pathological staging., Conclusions: NAC/POC use increased in Quebec but was lower compared to most developed countries. Its use was lower in patients residing further from the hospital and in those treated in non-academic hospitals.

Objective: Scleroderma renal crisis (SRC) is a severe life-threatening manifestation in patients with systemic sclerosis (SSc). However, the knowledge about risk factors for SRC is limited. We determined here the frequency of SRC and identified risk factors for the prediction of SRC., Methods: Based on regular followup data from the German Network for Systemic Scleroderma, we used univariate and multivariate generalized estimating equations to analyze the association between clinical variables, SSc subsets, therapy [i.e., angiotensin-converting enzyme inhibitors (ACEi), corticosteroids], and the occurrence of SRC., Results: Data of 2873 patients with 10,425 visits were available for analysis with a mean number of registry visits of 3.6 ± 2.8 and a mean time of followup of 3.6 ± 3.8 years. In total, 70 patients developed SRC (70/2873, 2.4%). Of these patients, 57.1% (40/70) were diagnosed with diffuse cutaneous SSc, 31.4% (22/70) with limited cutaneous SSc, and 11.4% (8/70) with SSc-overlap syndromes. Predictive independent factors with the highest probability for SRC were positive anti-RNA polymerase antibodies (RNAP), a history of proteinuria prior to SRC onset, diminished DLCO, and a history of hypertension. Interestingly, positive antitopoisomerase autoantibodies did not predict a higher risk for SRC. Further, patients with SRC were significantly more frequently treated with ACEi and corticosteroids without being independently associated with SRC., Conclusion: In this cohort, SRC has become a rare complication. By far the highest risk for SRC was associated with the detection of anti-RNAP and proteinuria.

Background: Vaccination against human papillomaviruses (HPV) prevents HPV infections and, consequently, cervical lesions. However, the effect of vaccination on HPV transmission within couples is unknown., Methods: We used data from HITCH, a prospective cohort study of heterosexual couples (women ages 18-24 years) in Montreal, 2005 to 2013. Vaccination history was self-reported. Genital samples were tested for HPV DNA by PCR (linear array). Type-specific viral loads were quantified using real-time PCR. OR and HR were estimated using multilevel mixed-effects logistic regression and a parametric model for interval- censored survival-time data, respectively. Differences in viral loads were evaluated using the Friedman ANOVA test., Results: Among 497 couples, 12, 16, and 35 women received 1, 2, or 3 vaccination doses at baseline, respectively. Median age at vaccination was 18 years. Most women (92.1%) had their first coitus before vaccination. At baseline, partner concordance of persistent HPV6/11/16/18 infections was lower in vaccinated than unvaccinated women [adjusted OR = 0.10; 95% confidence interval (CI), 0.01-0.65] but not for non α7/α9/α10-HPV types (adjusted OR = 1.00; 95% CI, 0.44-2.29). Incidence of persistent α7/α9/α10 HPV types in women was inversely associated with vaccination status at baseline (adjusted HR = 0.12; 95% CI, 0.03-0.47). Likewise, male partners of vaccinated women had a lower incidence of α7/α9/α10 HPV infections (adjusted OR = 0.22; 95% CI, 0.05-0.95). Vaccinated women with HPV 6/11/16/18 infections had lower viral loads ( P = 0.001) relative to unvaccinated women., Conclusions: Vaccination of sexually active women significantly reduced transmission of α7/α9/α10 HPV types in heterosexual couples., Impact: These results underscore and quantify the positive effect of HPV vaccination on HPV transmission within heterosexual couples., (©2019 American Association for Cancer Research.)

Background: We studied the association between human papillomavirus (HPV) viral load (VL) and HPV concordance., Methods: The HITCH cohort study included young, heterosexual, recently formed, sexually active couples. Questionnaires and genital samples were collected at 0 and 4 months. Samples were tested for HPV DNA by polymerase chain reaction (PCR; Linear Array). VLs of HPV6/11/16/18/31/42/51 were quantified using type-specific real-time PCR. Correlations between VL and type-specific HPV prevalence and incidence were evaluated using multilevel, mixed-effects linear/logistic regression models., Results: We included 492 couples. VLs were higher in penile than vaginal samples. VL at subsequent visits correlated significantly within men (r, 0.373), within women (r, 0.193), and within couples (r range: 0.303-0.328). Men with high VL had more type-specific persistent HPV infections (odds ratio [OR], 4.6 [95% confidence interval {CI}, 2.0-10.5]). High VL in men was associated with prevalent (OR, 5.3 [95% CI, 2.5-11.2]) and incident (OR, 6.7 [95% CI, 1.5-30.7]) type-specific HPV infections in their partner. Women's VL was associated with type-specific HPV prevalence in their partner at the same (OR, 5.9) and subsequent (OR, 4.7) visit., Conclusions: Persistent HPV infections have limited VL fluctuations. VL between sex partners are correlated and seem predictive of transmission episodes., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background and Objectives: We evaluated the short- and long-term outcome in bladder cancer (BC) patients treated with radical cystectomy (RC) in Québec (Canada)., Methods: Data were collected from provincial registries on all BC patients who underwent RC in Québec province in 2000-2015. Outcomes were hospitalization rates and survival. Survival analyses were conducted using log-rank tests and Cox proportional hazards models., Results: In total, 4450 patients were included in our analysis. RC was increasingly conducted by higher-volume surgeons in larger, higher-volume, academic hospitals. Comparing patients treated in 2010-2015 to 2000-2009, recently treated patients had shorter postoperative hospital stays (absolute difference, 0.9 days, P < 0.001) but also a higher readmission rate (25.0% vs 21.1% in the 30 days following discharge, P = 0.003). Overall (5-year rates 50.9% vs 42.7%, P < 0.001) and BC-specific survival (61.3% vs 55.5%, P < 0.001) had significantly improved. In multivariable analyses, overall survival was significantly better in recently treated patients (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.60-0.73), younger patients (HR, 1.16; 95% CI, 1.14-1.19), patients residing closer to the hospital (HR, 1.03; 95% CI, 1.01-1.06), and patients treated by high-volume surgeons (HR, 0.88; 95% CI, 0.82-0.94)., Conclusions: Survival in BC patients after RC has improved in recent years. Other predictors for survival are younger age, shorter distance between patients' residences and hospitals, and higher surgeon's RC loads., (© 2019 Wiley Periodicals, Inc.)

Objective: The psychosocial impact of a prostate cancer diagnosis significantly affects a patient's quality of life. We studied patient communication at the time of diagnosis and its impact on psychosocial adjustment of patients., Methods: This is a cross-sectional data analysis from self-administered questionnaires in the PROCURE biobank study, consisting of a cohort of patients with localized prostate cancer undergoing radical prostatectomy in Québec (Canada), 2006 to 2013. Odds ratios (OR) and their respective 95% confidence intervals (95% CI) were calculated using binary or ordered logistic regression models., Results: Data from 1841 patients were analyzed. The median age of patients was 62 years (range 41-80 years), the majority was French-Canadian (68.3%) and married (79.6%). Most patients (90.1%) considered conversations with their treating physician a useful information source. Patients were dissatisfied on the communication when receiving their diagnosis by telephone (OR = 0.19, 95% CI, 0.11-0.33). Younger patients were also more dissatisfied. Most patients preferred to receive information on prostate cancer (89.5%) and radical prostatectomy (88.0%) at the time of diagnosis, while only 58.8% and 52.4% of patients received this information at this stage. Patients who were dissatisfied with the communication of the diagnosis had more negative responses, such as increased worries and fear (P < 0.05). The five most useful coping mechanisms were physical activity (62.3%), breathing exercises (44.5%), music (32.8%), faith (30.3%), and muscle relaxation (30.1%), but varied by demographics., Conclusions: This study highlights the importance of physicians communicating a prostate cancer diagnosis well to their patients. Patients may benefit from individually tailored interventions to facilitate their overall coping., (© 2019 John Wiley & Sons, Ltd.)

Population-based registries are increasingly used in cancer research. In such studies, cancer-specific mortality or survival is frequently used as the primary outcome. To determine whether a putative cancer was part of the causal chain of events leading to death, cancer registries primarily rely on death certificates. Hence, they depend on the subjective interpretation of information available to medical examiners at the time of death. Misclassification may occur: studies report misclassification of cancer as a cause of death in 15%-35% of death certificates based on evaluation by expert panels and/or autopsy reports. Further misclassification may occur when coding death causes in the cancer registry. Researchers should be aware of potential misclassification bias when using cancer registry data. Differential misclassification may bias the results towards or away from the null hypothesis, depending on whether there is relative over- or under-reporting of cancer-related deaths in one group. Strategies to improve reporting of cancer-specific survival/mortality include (1) describing the procedure used to identify cancer-specific deaths; (2) considering the use of multiple definitions of cancer-related deaths (strict/liberal definitions of cancer-specific deaths, and/or addition of relative survival as an outcome); and (3) reporting cancer-specific survival/mortality together with the objectively measured parameters overall survival or all-cause mortality., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The incidence of endometrial cancer among young women is increasing. Some patients with low-grade endometrial cancer receive hormone therapy (HT) before surgery to preserve fertility. It is unclear whether this adversely affects survival., Methods: Patients with localized, low-grade endometrial cancer who were aged <45 years were selected from the Surveillance, Epidemiology, and End Results database between 1993 and 2012. Propensity score matching was used to select comparable groups receiving HT or primary surgery. Cancer-specific and overall survival were measured using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (95% CIs) were estimated using Cox models adjusted for age, period of diagnosis, marital status, race, tumor grade, morphology, and previous radiotherapy., Results: A total of 6339 women were included in the current study cohort, 161 of whom initially received HT and 6178 of whom received primary surgery. After 15 years of follow-up, all-cause mortality did not differ between the groups (HT group: 14.1% [95% CI, 6.7%-28.4%] and propensity score-matched primary surgery group: 9.3% [95% CI, 4.1%-20.5%]). Cancer-specific mortality appeared higher in patients treated with HT compared with those treated with primary surgery (9.2% [95% CI, 3.4%-24.0%] vs 2.1% [95% CI, 1.5%-2.8%]). However, this difference was driven by 3 late deaths in the HT group. Sensitivity analyses using a broader definition of cancer-specific mortality provided no statistical evidence of a survival difference between the treatment groups. The hazard ratio for the overall risk of death was 1.45 (95% CI, 0.44-4.74)., Conclusions: Based on this population-based cohort, young patients with low-grade endometrial cancer appear to have excellent survival, regardless of the primary therapy chosen (HT vs primary surgery). The current selection of patients for HT to preserve fertility, which is managed carefully by experienced clinicians, does not appear to significantly worsen clinical outcomes. Cancer 2017;123:1545-1554. © 2017 American Cancer Society., (© 2016 American Cancer Society.)

It is estimated that bone loss occurs in 70 % of all patients dying from cancer, causing a significant disease burden in cancer patients. Bone loss is caused by cancer itself and its metastases, but also by cancer therapies. Of the cancer therapy-induced bone loss, hormone therapies are best known for their bone damaging abilities. However, chemo- and radiotherapy may result in bone loss too. In this review, direct and indirect effects of various chemotherapies (such as methotrexate, imatinib, and taxanes) that cause bone loss are discussed. Furthermore, we discuss bone loss caused by radiotherapy and radionuclides, of which the latter may be reduced with the introduction of the alpha-emitter Radium-223. Finally, agents preventing chemotherapy- or radiotherapy-induced bone loss, in particular denosumab and bisphosphonates, are being reviewed for their efficacy in preventing chemotherapy- and irradiation-induced bone loss in cancer patients.

Cabazitaxel and abiraterone have both received approval for treating metastatic castrate-resistant prostate cancer (mCRPC) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population., (© 2014 UICC.)

Background: US Food and Drug Administration (FDA) approval of new drugs depends on results from clinical trials that must be generalized to the US population. However, racial minorities are frequently under-represented in clinical studies. The enrollment of racial minorities was compared in key clinical studies submitted to the FDA in the last 10 years in support of potential marketing approval for prostate cancer (PCa) prevention or treatment., Methods: Patient demographic data were obtained from archival data sets of large registration trials submitted to the FDA to support proposed PCa indications. Six countries/regions were analyzed: the United States, Canada, Australia, Europe, the United Kingdom, and Eastern Europe. Background racial demographics were collected from national census data., Results: Seventeen key PCa clinical trials were analyzed. These trials were conducted in the past 20 years, comprising 39,574 patients with known racial information. Most patients were enrolled in the United States, but there appeared to be a trend toward increased non-US enrollment over time. In all countries, racial minorities were generally under-represented. There was no significant improvement in racial minority enrollment over time. The United States enrolled the largest nonwhite population (7.1%)., Conclusions: Over the past 20 years, racial minorities were consistently under-represented in key PCa trials. There is a need for effective measures that will improve enrollment of racial minorities. With increased global enrollment, drug developers should aim to recruit a patient population that resembles the racial demographics of the patient population to which drug use will be generalized upon approval., (© 2014 American Cancer Society.)

Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs. We used in vitro and in vivo xenograft models of prostate cancer (PCA) to test whether combination of HDACIs with the pan-aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACIs synergistically decreased cell proliferation activity and clonogenic survival in DU-145, LNCaP, and PC3 PCA cell lines compared to single-agent treatment. Cellular senescence, polyploidy, and apoptosis was significantly increased in all cell lines after combination treatment. In vivo xenograft studies indicated decreased tumor growth and decreased aurora B kinase activity in mice treated with low-dose AMG 900 and vorinostat compared to either agent alone. Pharmacodynamics was assessed by scoring for phosphorylated histone H3 through immunofluorescence. Our results indicate that combination treatment with low doses of AMG 900 and HDACIs could be a promising therapy for future clinical trials against PCA., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Novel biomarkers predicting prostate cancer (PCa) aggressiveness and docetaxel therapy response of PCa patients are needed. In this study the correlation between nuclear Eg5-expression, PCa docetaxel response and PCa aggressiveness was assessed. Immunohistochemical staining for nuclear Eg5 was performed on 117 archival specimens from 110 PCa patients treated with docetaxel between 2004 and 2012. Samples were histologically categorized as positive/negative. Median follow-up time from diagnosis was 11.6 years. Nuclear Eg5-expression was significantly related to docetaxel response (p=0.036) in tissues acquired within three years before docetaxel initiation. Nuclear Eg5-expression was not related to Gleason-score (p=0.994). Survival of patients after docetaxel initiation did not differ based on nuclear Eg5-expression (p=0.540). Analyzing samples taken before hormonal therapy, overall survival and time to docetaxel use were significantly decreased in patients with nuclear Eg5-expressing tumors (p<0.01). Eg5-positive nuclei were found more frequently in T4-staged tumors (p=0.04), Gleason 8-10 tumors (p=0.08), and in metastasized tumors (p<0.01). Multivariate analyses indicated that nuclear Eg5-expression may be an independent parameter for tumor aggressiveness. Limitations of a retrospective analysis apply. In conclusion, nuclear Eg5-expression may be a predictive biomarker for docetaxel response in metastatic castrate-resistant PCa patients and a prognostic biomarker for hormone-naive PCa patients. Prospective validation studies are needed.

Cyclin-dependent kinase 5 (CDK5) is a potential target for prostate cancer treatment, the enzyme being essential for prostate tumor growth and formation of metastases. In the present study, we identified agents that target prostate cancer cells based on CDK5 expression. CDK5 activity was suppressed by transfection of PC3 prostate cancer cells with a dominant-negative construct (PC3 CDK5dn). PC3 CDK5dn and PC3 control cells were screened for compounds that selectively target cells based on CDK5 expression, utilizing the Johns Hopkins Drug Library. MTS proliferation, clonogenic and 3D growth assays were performed to validate the selected hits. Screening of 3,360 compounds identified rutilantin, ethacridine lactate and cetalkonium chloride as compounds that selectively target PC3 control cells and a tilorone analog as a selective inhibitor of PC3 CDK5dn cells. A PubMed literature study indicated that tilorone may have clinical use in patients. Validation experiments confirmed that tilorone treatment resulted in decreased PC3 cell growth and invasion; PC3 cells with inactive CDK5 were inhibited more effectively. Future studies are needed to unravel the mechanism of action of tilorone in CDK5 deficient prostate cancer cells and to test combination therapies with tilorone and a CDK5 inhibitor for its potential use in clinical practice.

The treatment scope for patients with metastatic castrate-resistant prostate cancer (mCRPC) is rapidly expanding. On May 15, 2013, the U.S. Food and Drug Administration (FDA) approved radium-223 chloride ((223)RaCl2) for the treatment of mCRPC patients whose metastases are limited to the bones. Radium-223 is an α-emitting alkaline earth metal ion, which, similar to calcium ions, accumulates in the bone. In a phase III study (ALSYMPCA), mCRPC patients with bone metastases received best standard-of-care treatment with placebo or (223)RaCl2. At a prespecified interim analysis, the primary endpoint of median overall survival was significantly extended by 3.6 months in patients treated with radium-223 compared with placebo (P < 0.001). The radioisotope was well tolerated and gave limited bone marrow suppression. (223)RaCl2 is the first bone-targeting antitumor therapy that received FDA approval based on a significant extended median overall survival. Further studies are required to optimize its dosing and to confirm its efficacy and safety in cancer patients.

Combinations of anticancer therapies with high efficacy and low toxicities are highly sought after. Therefore, we studied the effect of polo-like kinase 1 (Plk1) inhibitors on prostate cancer cells as a single agent and in combination with histone deacetylase (HDAC) inhibitors valproic acid and vorinostat. IC50s of Plk1 inhibitors BI 2536 and BI 6727 were determined in prostate cancer cells by MTS assays. Morphological and molecular changes were assessed by immunoblotting, immunofluorescence, flow cytometry, real-time RT-PCR, and pulldown assays. Efficacy of combination therapy was assessed by MTS and clonogenic assays. IC50 values in DU145, LNCaP, and PC3 cells were 50, 75, and 175 nM, respectively, for BI 2536 and 2.5, 5, and 600 nM, respectively, for BI 6727. Human prostate fibroblasts and normal prostate epithelial cells were unaffected at these concentrations. While DU145 and LNCaP cells were solely arrested in mitosis on treatment, PC3 cells accumulated in G2 phase and mitosis, suggesting a weak spindle assembly checkpoint. Combining Plk1 inhibitors with HDAC inhibitors had synergistic antitumor effects in vitro. DMSO-treated prostate cancer cells were used as controls to study the effect of Plk1 and HDAC inhibition. Plk1 inhibitors decreased proliferation and clonogenic potential of prostate cancer cells. Hence, Plk1 may serve as an important molecular target for inhibiting prostate cancer. Combining HDAC inhibitors with BI 2536 or BI 6727 may be an effective treatment strategy against prostate cancer.

Background: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of the Dutch CUP, detailing the safety and efficacy of cabazitaxel in a routine clinical practice setting., Patients and Methods: Safety and efficacy data of all 5 Dutch centers participating in the cabazitaxel CUP were collected. Safety data were collected prospectively using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Overall survival (OS) and progression-free survival (PFS), time to PSA progression (TTPP), and best clinical response were evaluated retrospectively., Results: Fifty-one patients were registered in the CUP; 49 received cabazitaxel. Forty-two of 49 patients [85.7%], 42 patients had ≥ 2 metastatic sites. Patients received on average 6 cabazitaxel cycles (range, 1-21). A dose reduction or dose delay occurred in 13 and 20 patients [26.5% and 40.9%] respectively. Prophylactic granulocyte colony-stimulating factor (G-CSF) was used in 8 patients [16.3%]. Grade ≥ 3 adverse events were observed in 25 patients [51.0%]; 16 patients [32.7%] discontinued treatment because of treatment-emergent adverse events (TEAEs). Serious adverse events (SAEs) occurred in 16 (32.7%) patients; the most frequent SAEs were hematuria (4 patients [8.3%]) and urosepsis (3 patients [6.3%]). Febrile neutropenia occurred twice; no patient had grade ≥ 3 neuropathy. No toxicity-related mortality occurred. Median follow-up was 24.1 months. Median OS was 8.7 months (interquartile range [IQR], 6.0-15.9 months); median TTPP was 2.8 months (IQR, 1.7-5.9 months)., Conclusion: In the Dutch CUP, patients with advanced mCRPC had delayed tumor progression with acceptable toxicities using cabazitaxel treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal's website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients.

The N-myc downstream regulated gene 1 (NDRG1) has been identified as a metastasis-suppressor gene in prostate cancer (PCa). Compounds targeting PCa cells deficient in NDRG1 could potentially decrease invasion/metastasis of PCa. A cell based screening strategy was employed to identify small molecules that selectively target NDRG1 deficient PCa cells. DU-145 PCa cells rendered deficient in NDRG1 expression by a lentiviral shRNA-mediated knockdown strategy were used in the primary screen. Compounds filtered from the primary screen were further validated through proliferation and clonogenic survival assays in parental and NDRG1 knockdown PCa cells. Screening of 3360 compounds revealed irinotecan and cetrimonium bromide (CTAB) as compounds that exhibited synthetic lethality against NDRG1 deficient PCa cells. A three-dimensional (3-D) invasion assay was utilized to test the ability of CTAB to inhibit invasion of DU-145 cells. CTAB was found to remarkably decrease invasion of DU-145 cells in collagen matrix. Our results suggest that CTAB and irinotecan could be further explored for their potential clinical benefit in patients with NDRG1 deficient PCa.

Introduction: Metastatic castrate-resistant prostate cancer (mCRPC) is the second deadliest cancer in men. The group of taxanes, which target microtubules of mitotic cells, is currently the only chemotherapy which has proven to increase overall survival in mCRPC patients. Other mitotic inhibitors are being explored for their clinical potential in mCRPC treatment., Areas Covered: In this review, we summarize recent developments in the application of mitotic inhibitors for mCRPC from a clinical perspective. The four main groups of mitotic inhibitors currently being tested in clinical trials are microtubule-inhibitors, polo-like kinase 1 inhibitors, aurora kinase inhibitors and kinesin-spindle protein inhibitors. Compounds of these groups of inhibitors that are in clinical development for mCRPC are discussed. For this extensive overview, relevant literature was searched in PubMed and retrieved from clinicaltrials.gov and presentations at ASCO/AACR meetings., Expert Opinion: In general, mitotic inhibitors are clinically well tolerated but exert limited antitumor activity compared to preclinical study results. However, efficacy of mitotic inhibitors is improving, either by personalizing treatment, by introducing more active compounds, by decreasing resistance of cancer cells against mitotic inhibitors or by using mitotic inhibitors in combination therapies.

Background: 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., Methodology/principal Findings: 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., Conclusions/significance: 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.