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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.

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.

Objective To evaluate long-term oncological outcomes and the added value of sentinel lymph node sampling (SLN) compared to pelvic lymph node dissection (LND) in patients with endometrial cancer (EC). Methods During the evaluation phase of SLN for EC, we performed LND and SLN and retrospectively compared the oncologic outcome with the immediate non-overlapping historical era during which patients underwent LND. Results From 2007 to 2010, 193 patients underwent LND and from December 2010 to 2014, 250 patients had SLN mapping with completion LND. Both groups had similar clinical characteristics. During a median follow-up period of 6.9 years, addition of SLN was associated with more favorable oncological outcomes compared to LND with 6-year overall survival (OS) of 90% compared to 81% (p = 0.009), and progression free survival (PFS) of 85% compared to 75% (p = 0.01) respectively. SLN was associated with improved OS (HR 0.5, 95% CI 0.3–0.8, p = 0.004), and PFS (HR 0.6, 95% CI 0.4–0.9, p = 0.03) in a multivariable analysis, adjusted for age, ASA score, stage, grade, non-endometrioid histology, and LVSI. Patients who were staged with SLN were less likely to have a recurrence in the pelvis or lymph node basins compared to patients who underwent LND only (6-year recurrence-free survival 95% vs 90%, p = 0.04). Conclusion Addition of SLN to LND was ultimately associated with improved clinical outcomes compared to LND alone in patients with endometrial cancer undergoing surgical staging, suggesting that the data provided by the analysis of the SLN added relevant clinical information, and improved the decision on adjuvant therapy.

BACKGROUND: Existing literature provides contrasting data on statin use and bladder cancer (BC) outcome. OBJECTIVE: We evaluated whether (chronic) statin use was associated with clinical outcomes in patients with BC undergoing radical cystectomy (RC). METHODS: Using provincial health administrative databases, we retrospectively identified BC patients undergoing RC in Quebec province in 2000-2015, and collected data from two years before RC until December 2016 or death. We compared patients who chronically used statins before RC to never statin users. Survival analyses were conducted using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Covariates in multivariable analyses were age, sex, Charlson’s comorbidity index, year of RC, distance to hospital, hospital type, hospital’s and surgeon’s annual RC volume, and neoadjuvant chemotherapy. RESULTS: Our cohort contained 1406 chronic and 1754 never statin users. Five-year overall, BC-specific and recurrence-free survival rates were 40.5% (95% confidence interval (95% CI) 37.8–43.2%), 52.8% (95% CI 49.8–55.7%), and 50.1% (95% CI 47.2–53.0%) for chronic statin users, versus 34.9% (95% CI 32.5–37.2%), 45.5% (95% CI 42.9–48.1%), and 43.4% (95% CI 40.9–45.9%) for never statin users (p≤0.001). In multivariable analyses, hazard ratios (HR) for death, BC-specific deaths and recurrences were 0.83 (95% CI 0.75–0.91), 0.81 (95% CI 0.72–0.91), and 0.83 (95% CI 0.74–0.93) for chronic statin users, respectively. Similar observations were made in patients with diabetes and/or cardiovascular comorbidities (p≤0.001). Clinical outcome was not improved in patients who started statins in the year following surgery compared to never statin users (p > 0.4). CONCLUSIONS: Chronic statin use is associated with improved clinical outcome in BC patients undergoing RC in Quebec.

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 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.

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.

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.

BackgroundWe studied the association between human papillomavirus (HPV) viral load (VL) and HPV concordance.MethodsThe 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.ConclusionsPersistent HPV infections have limited VL fluctuations. VL between sex partners are correlated and seem predictive of transmission episodes.

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.

Summary Background Hand-to-genital contact is hypothesised to be a transmission mode of human papillomavirus (HPV) of the Alphapapillomavirus genus. We compared the relative importance of hand-to-genital and genital-to-genital HPV transmission between sexual partners. Methods In this prospective cohort study, we recruited and followed up female university students aged 18–24 years and their male sexual partners in Montreal, QC, Canada (2005–11). Participants were eligible if they had initiated sexual activity within the past 6 months. Women were examined at clinic visits at baseline and every 4–6 months for up to 24 months. Men had a baseline visit and a single follow-up visit approximately 4 months later. Partners provided hand and genital swab samples, which we tested for DNA of 36 HPV types using PCR. We assessed predictors of incident type-specific HPV detections using Cox proportional hazards models. Findings Participants were recruited between June 5, 2006, and April 4, 2013. 264 women and 291 men had valid hand samples. The hazard ratio (HR) of incident detection of HPV in genital samples from women was 5·0 (95% CI 1·5–16·4) when her partner was positive for the same HPV type on his hand versus negative, but adjustment for his genital HPV status reduced the HR to 0·5 (0·1–1·8). Similarly, the HR of incident detection of HPV on men's genitals was 17·4 (95% CI 7·9–38·5) when his partner was positive for the same HPV type on her hand versus negative, but adjustment for her genital HPV status reduced the HR to 2·3 (0·9–6·2). Conversely, the HR of type-specific incident detection of HPV in genital samples associated with partner genital HPV positivity was 19·3 (95% CI 11·8–31·8) for women and 28·4 (15·4–52·1) for men after adjustment for their hand HPV status. Interpretation Clinicians can reassure their patients that HPV transmission is unlikely to occur through hand-to-genital contact. The majority of genital HPV infections are likely to be caused by genital-to-genital sexual transmission. Funding Canadian Institutes for Health Research, National Institutes of Health, Fonds de la Recherche en Sante du Quebec, and Merck & Co.

Contains fulltext : 245492.pdf (Publisher’s version ) (Open Access) 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

Introduction/Background Nearly half of women diagnosed with endometrial cancer (EC) are 70 years old or older. Furthermore, elderly patients (>65 years) have been at risk for adverse perioperative outcomes throughout various surgical procedures and have a poorer prognosis which is related to both aggressive disease and under-treatment. We aimed to compare surgical and oncological outcomes between elderly (>65 year-old), intermediate to high risk, endometrial cancer patients undergoing staging with sentinel lymph node (SLN) staging and pelvic lymphadenectomy (LND). Methodology A prospective cohort study of elderly patients diagnosed with endometrial carcinoma between 2007 and 2017, treated in a single center in Montreal, comparing surgical and oncological outcomes of 3 endometrial cancer patients cohorts in non-overlapping eras, undergoing surgical staging including: LND, LND+SLN or SLN. 2-year progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) were analyzed using life tables, Kaplan-Meier survival curves and log-rank tests. Results Out of 278 patients with a median age of 73 (65–91) years, that were staged and met the study inclusion criteria, 84 patients underwent LND only, 120 underwent SLN followed by LND and 74 patients had only SLN. Patients in the SLN group had significantly less dissected nodes (mean of 5.4 nodes vs 10.4 and 10.0 in the SLN+LND and the LND cohorts, respectively, p Conclusion SLN based surgical staging is feasible, precise, affects adjuvant treatment and associated with better surgical and oncological outcomes in intermediate and high risk elderly patients. Disclosures We have no disclosures.

Introduction/Background Endometrial cancer (EC) is the most common gynecological malignancy worldwide, with an estimated 382,069 new cases and 89,929 deaths in 2018. Lymph node involvement represents one of the most important prognostic factors and guides better planning of post-operative adjuvant treatment. Whereas lymph node assessment has been included in surgical staging since 1988, the optimal procedure for lymph node evaluation is controversial, ranging from full pelvic and para-aortic lymph node dissection (LND) to complete omission of LND. We previously evaluated the oncologic outcomes of 472 cases of EC (SLN with LND vs. LND alone) and demonstrated significantly lower likelihood of pelvic side-wall recurrences in patients who underwent SLN. These data raised the possibility that addition of SLN biopsy may not just be equivalent to conventional staging but may actually increase the detection of metastatic disease, resulting in better stratification of patients into risk groups, optimal adjuvant therapy prescription and as a result, better oncologic outcomes. In this study, we investigated the long-term oncological outcome of adding SLN to pelvic LND in patients with EC. Methodology Retrospective study comparing survival outcomes (overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), recurrence-free survival) between endometrial cancer patients undergoing surgical staging, which included LND with or without SLN in non-overlapping contiguous eras. Hazard ratios (HR) and their respective 95% confidence intervals (95%CI) were calculated using Cox proportional hazard models. Results 193 patients underwent LND and 250 patients had SLN mapping prior to LND. Clinical characteristics, including adjuvant therapy use, were similar between groups. During a median follow-up period of 6.9 years, addition of SLN was associated with more favorable oncological outcomes compared to LND with 6-year OS of 90% compared to 81% (p=0.009), and PFS of 85% compared to 75% (p=0.01) respectively. SLN was associated with improved OS (HR 0.5, 95% CI 0.3–0.8, p=0.004), DSS (HR 0.5, 95%CI 0.2–1.0, p=0.05) and PFS (HR 0.6, 95% CI 0.4–0.9, p=0.03) in a multivariable analysis as well, adjusted for age, ASA score, stage, grade, non-endometrioid histology, and LVSI. Patients who were staged with SLN were less likely to have a recurrence in the pelvis or lymph node basins compared to patients who underwent LND only (6-year recurrence-free survival 95% vs 90%, p=0.04). Conclusion Addition of SLN was associated with improved clinical outcomes compared to LND alone in patients with endometrial cancer undergoing surgical staging. Disclosures We have no disclosures.

Objective To evaluate the impact of surgical wait times on outcome of patients with grade 3 endometrial cancer. Methods All consecutive patients surgically treated for grade 3 endometrial cancer between 2007 and 2015 were included. Patients were divided into two groups based on the time interval between endometrial biopsy and surgery: wait time from biopsy to surgery ≤12 weeks (84 days) vs more than 12 weeks. Survival analyses were conducted using log-rank tests and Cox proportional hazards models. Results A total of 136 patients with grade 3 endometrial cancer were followed for a median of 5.6 years. Fifty-one women (37.5%) waited more than 12 weeks for surgery. Prolonged surgical wait times were not associated with advanced stage at surgery, positive lymph nodes, increased lymphovascular space invasion, and tumor size (P = .8, P = 1.0, P = .2, P = .9, respectively). In multivariable analysis adjusted for clinical and pathological factors, wait times did not significantly affect disease-specific survival (adjusted hazard ratio [HR]: 1.2, 95% confidence interval [CI], 0.6-2.5, P = .6), overall survival (HR: 1.1, 95% CI, 0.6-2.1, P = .7), or progression-free survival (HR: 0.9, 95% CI, 0.5-1.7, P = .8). Conclusion Prolonged surgical wait time for poorly differentiated endometrial cancer seemed to have a limited impact on clinical outcomes compared to biological factors.

Study Objective To evaluate long-term oncological outcomes and the added value of sentinel lymph node sampling (SLN) compared to pelvic lymph node dissection (LND) in patients with endometrial cancer. Design During the evaluation phase of SLN for endometrial cancer, we performed LND and SLN and retrospectively compared the oncologic outcome with the immediate non-overlapping historical era during which patients underwent LND. Setting Tertiary gynecology oncology center. Patients or Participants From 2007 to 2010, 193 patients underwent LND and from December 2010 to 2014, 250 patients had SLN mapping with completion LND. Interventions Pelvic lymph node dissection (LND) versus sentinel lymph node sampling (SLN) followed by LND. Measurements and Main Results During a median follow-up period of 6.9 years, addition of SLN was associated with more favorable oncological outcomes compared to LND with 6-year overall survival (OS) of 90% compared to 81% (p=0.009), and progression free survival (PFS) of 85% compared to 75% (p=0.01) respectively. SLN was associated with improved OS (HR 0.5, 95% CI 0.3-0.8, p=0.004), and PFS (HR 0.6, 95% CI 0.4-0.9, p=0.03) in a multivariable analysis, adjusted for age, ASA score, stage, grade, non-endometrioid histology, and LVSI. Patients who were staged with SLN were less likely to have a recurrence in the pelvis or lymph node basins compared to patients who underwent LND only (6-year recurrence-free survival 95% vs 90%, p=0.04). Conclusion Addition of SLN to LND was ultimately associated with improved clinical outcomes compared to LND alone in patients with endometrial cancer undergoing surgical staging, suggesting that the data provided by the analysis of the SLN added relevant clinical information, and improved the decision on adjuvant therapy.

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

Objectives To assess risk factors for lymph node involvement in patients with endometrial cancer and a body-mass index (BMI) ≥30 kg/m2. Methods A retrospective analysis was performed of obese patients diagnosed with endometrial carcinoma between 2007 and 2015, treated in a single center in Montreal. Preoperative variables evaluated were age, BMI, parity, and preoperative ASA score, grade, CA-125 and histology. Odds ratios (OR) and hazard ratios (HR) and their respective 95% confidence intervals (95%CI) were calculated using multivariable logistic regression and Cox proportional hazard models. Results The study included 230 women with BMI >30, 223 (97.0%) had complete staging. Pelvic lymph node involvement was detected in 26 patients (11.3%). Sentinel node detection and pelvic lymph node dissection decreased with increasing BMI (adjusted OR 0.86, 95% CI 0.76–0.97 and 0.76, 95%CI 0.59–0.96, respectively, per 1 kg/m2 increment). Pelvic lymph node involvement was inversely correlated with BMI (adjusted OR 0.88, 95% CI 0.79–0.99) and present in 16/85 (18.8%), 6/56 (10.7%), and 4/82 (4.9%) of patients with a BMI of 30.0–34.9, 35.0–39.9, and ≥40.0 kg/m2, respectively. Preoperative CA-125 was associated with lymph node involvement (adjusted OR 2.77, 95%CI 1.62–4.73, per quartile increment). During a median follow-up of 72 months, a higher BMI was not associated with worse recurrence-free survival (adjusted HR 1.04, 95%CI 0.98–1.10), disease-specific survival (adjusted HR 0.97, 95%CI 0.88–1.06), or overall survival (adjusted HR 0.92, 95% CI 0.84–0.99). Conclusions Pelvic lymph node dissection might be omitted in selected cases of morbidly obese patients with failed sentinel nodes mapping and a low CA-125.

Objectives To determine whether surgical wait time impacts survival in patients with endometrial cancer (EC). Methods A retrospective analysis was performed, including all patients diagnosed with EC between 2008 and 2015 treated in a single centre in Montreal. Associations between surgery wait times and other variables were calculated using univariable linear regression models. In survival analysis, Cox proportional hazard models were used to calculate hazard ratios (HR); covariates included age, BMI, year of diagnosis, ECOG score, and tumor histology, grade and stage at surgery. Results The study included 358 patients with median follow-up of 5.9 years, categorized into four groups based on their wait time: 89, 87, 91, and 91 women with a median wait time of 37 days (8–49), 62 days (50–70), 91 days (71–103), and 91 days (104–869), respectively. Increased surgical wait time was associated with lymph-vascular space invasion and distant metastases. A surgery delay of 71 days or more (median) did not result in significantly worse overall (p=0.54) or EC specific survival (p=0.27), while known prognostic variables such as stage and grade at surgery did (p 30 (HR 1.43, 95% CI 1.00–2.03). Conclusions While surgery delay might predict outcome in specific subgroups, biological tumor determinants seems more important for survival outcome.

Introduction: Despite its proven benefit, studies have reported poor use of perioperative chemotherapy (POC) in bladder cancer (BC) 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

Introduction The sequential use of a number of new agents (NAs) have improved the overall survival (OS) of patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progresses after docetaxel (DOC) treatment. The aim of this study was to assess the cumulative survival outcomes of different sequencing strategies by evaluating the individual data from published studies of patients treated with a post-DOC sequence of two NAs. Patients and methods The patients’ Individual data were analysed in order to investigate whether different sequencing strategies lead to differences in OS. Results We analysed the data of 1,099 evaluable patients. Among the patients treated with a second-line new hormone agents (NHA), median OS from the start of third-line treatment was significantly longer in the patients treated with cabazitaxel (CABA) than in those treated with abiraterone acetate (AA) or enzalutamide (ENZA). Median cumulative OS from the start of second-line treatment (cumOS) was 21.1 months in the patients receiving NHA → NHA, 22.1 months in those receiving NHA → CABA, and 21.0 months in those receiving CABA → NHA. Among the patients with a second-line progression free survival of ≥6 months, median cumOS was significantly longer in patients receiving CABA-including sequences than in those treated with NHA → NHA sequences (29.5 vs 24.8 months; p = 0.03). Conclusions Our findings suggest that the sequential use of NAs with different mechanisms of action improves cumOS regardless of the order in which they are administered, thus supporting the hypothesis of cross-resistance between the two NHAs.

Objective To assess risk factors for lymph node involvement in patients with endometrial cancer and a body-mass index (BMI) ≥30 kg/m2. Materials and methods A retrospective analysis was performed of obese patients diagnosed with endometrial carcinoma between 2007 and 2015, treated in a single center in Montreal. Preoperative variables evaluated were age, BMI, parity, and preoperative ASA score, grade, CA-125 and histology. Odds ratios (OR) and hazard ratios (HR) and their respective 95% confidence intervals (95%CI) were calculated using multivariable logistic regression and Cox proportional hazard models. Results The study included 230 women with BMI ≥30, 223 (97.0%) had complete staging. Pelvic lymph node involvement was detected in 26 patients (11.3%). Sentinel node detection and pelvic lymph node dissection decreased with increasing BMI (adjusted OR 0.86, 95%CI 0.76–0.97 and 0.76, 95%CI 0.59–0.96, respectively, per 1 kg/m2 increment). Pelvic lymph node involvement was inversely correlated with BMI (adjusted OR 0.88, 95%CI 0.79–0.99) and present in 16/85 (18.8%), 6/56 (10.7%), and 4/82 (4.9%) of patients with a BMI of 30.0–34.9, 35.0–39.9, and ≥40.0 kg/m2, respectively. Preoperative CA-125 was associated with lymph node involvement (adjusted OR 2.77, 95%CI 1.62–4.73, per quartile increment). Conclusion Pelvic lymph node dissection might be omitted in selected cases of morbidly obese patients with failed sentinel nodes mapping and a low CA-125.

BACKGROUND AND OBJECTIVES We evaluated the short- and long-term outcome in bladder cancer (BC) patients treated with radical cystectomy (RC) in Quebec (Canada). METHODS Data were collected from provincial registries on all BC patients who underwent RC in Quebec 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

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 Quebec (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

Study Objective To evaluate the feasibility of sentinel lymph node (SLN) mapping in obese endometrial cancer patients. Design A retrospective study of obese patients (BMI ≥35 kg/m2), diagnosed with endometrial carcinoma between 2007 and 2017, comparing surgical and oncological outcomes of two patient's cohorts. Setting Tertiary gynecology oncology center. Patients or Participants 223 patients with median BMI of 40.6 kg/m2 including: 140 patients that underwent LND (with or without SLN) and 83 patients that underwent SLN. Interventions Lymph node dissection (LND) with or without SLN versus only SLN for endometrial cancer staging. Measurements and Main Results Patients that had only SLN seemed to have more metastatic pelvic nodal disease (13.3% vs. 7.1%), though this difference did not reach statistical significance (p=0.2). Patients from the SLN only group had significantly higher rate of successful mapping (92.8% vs. 78.4%, p=0.009), bilaterally detected SLN (80.7% vs. 54.5%, p Conclusion Omitting LND from surgical staging where SLN is performed was associated with shorter operative time and minimal bleeding without affecting survival. ICG should be the dye of choice in obese endometrial cancer patients.

To evaluate the five-tier Gleason grade group (GG) scoring of prostate cancers adopted by the International Society of Urology Pathology (ISUP) in 2014, and to propose modifications to optimize its performance.Data were obtained from PROCURE, a prospective cohort of patients with localized prostate cancer undergoing radical prostatectomy in Québec, 2006-2013. Surgical specimens were evaluated by genitourinary pathologists using 2014 ISUP criteria. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy. Analyses were conducted using Kaplan-Meier methods, log-rank tests, Cox proportional hazards models and Harrell's concordance indices.A total of 1 917 patients were included, with a median follow-up of 69 months. The 5-year treatment failure rates were 9.6%, 23.5%, 43.1%, 52.6% and 84.3% in GG1-5, respectively (P 0.001 when comparing GG2 with GG3). Treatment failure rates for patients in GG2 and GG3 with tertiary Gleason 5 pattern were higher than patients in the same group without a tertiary pattern (P 0.001), but were similar to rates for patients in GGs 3 or 4 without a tertiary pattern (P 0.3). Primary Gleason pattern (4/5) predicted treatment failure in GG5 (5-year failure rates 82.3% vs 97.1%, respectively; P = 0.001). The five-tier GG system had greater accuracy as a prognostic indicator compared with the four-tier system (Harrell's concordance index 0.716 vs 0.676). When upgrading patients in GG2/3 with tertiary Gleason 5 pattern to patients in GG3/4, and separating patients in GG5 by primary Gleason pattern, the Harrell's concordance index increased to 0.730.The five-tier GG system increased accuracy for predicting treatment failure compared with the previous grading systems, but can be further improved.

We evaluated whether an increased body-mass index (BMI) and decreased physical activity increase the risk of locally advanced or high-risk prostate cancer (PCa) at radical prostatectomy (RP), and treatment failure after surgery.Data were collected from the PROCURE Biobank, a prospective cohort of patients with localized PCa undergoing RP in four academic centers in Québec between 2006 and 2013. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy, and analyzed using the Kaplan-Meier method, log-rank tests, and Cox proportional-hazards models. Uni- and multivariate (ordered) logistic regression was used for time-independent variables.1813 patients were included. Median follow-up time was 69 months. Patients who reported a lower BMI were generally older, of Asian descent, and physically more active (p 0.05). Younger, black, and overweight/obese patients reported less physical activity (p 0.05). In multivariate analyses, a higher BMI increased the risk for locally advanced, high-risk PCa (defined as a pT3, N1 and/or Gleason 8-10 tumor; odds ratio 1.33, p 0.001), but increased physical activity did not predict high-risk disease (odds ratio 0.84, p = 0.39). Patients with a higher BMI also had a larger prostate at surgery (odds ratio 1.13, p = 0.03). BMI and physical activity were not associated with positive surgical margins or time to treatment failure (p 0.05).BMI was an independent predictor for locally advanced, high-risk disease in this cohort of PCa patients undergoing RP, but was unrelated to treatment failure. Physical activity was not related to locally advanced, high-risk PCa or treatment failure.

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.

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. Cancer 2014;120:3025–3032. © 2014 American Cancer Society.

Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10–30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1α, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386–99. ©2012 AACR.

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.Patients with localized, low-grade endometrial cancer who were aged45 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.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).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.

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

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, p0.001). 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.

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.

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.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.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%).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.

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.—Wissing, M. D., Mendonca, J., Kortenhorst, M. S. Q., Kaelber, N. S., Gonzalez, M., Kim E., Hammers, H., van Diest, P. J., Carducci, M. A., Kachhap, S. K. Targeting prostate cancer cell lines with polo-like kinase 1 inhibitors as a single agent and in combination with histone deacetylase inhibitors.

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.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.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.

In a recent article, Komlodi-Pasztor and colleagues argued that cancer researchers used a flawed rationale to develop inhibitors of mitotic enzymes, such as polo-like kinase 1 (PLK1) and aurora kinases ([1][1]). Scientists had been misled by the success of microtubule-targeting agents (MTA) by