Clinical Outcomes In Men Research Articles

A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The ‘Thr’ PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Early clinical outcomes in men and women undergoing proximal thoracic aortic surgery: A Swedish population-based cohort study

ObjectiveThe study objective was to investigate the association between female sex and 30-day mortality and postoperative complications in patients undergoing scheduled proximal thoracic aortic surgery in Sweden. MethodsIn a nationwide population-based cohort study, all patients who underwent scheduled proximal thoracic aortic surgery in Sweden between 2016 and 2020 were included. The primary outcome measure was 30-day mortality. Secondary outcome measures included a combined end point including 30-day all-cause mortality, postoperative new-onset dialysis, perioperative stroke, or a prolonged need of postoperative ventilation (>48 hours). Logistic regression models and propensity score matching were used to estimate the association between female sex and primary and secondary outcomes adjusted for differences in baseline characteristics. ResultsA total of 2000 patients (29% women) were analyzed. The crude 30-day all-cause mortality rate was higher in women compared with men (3.1% vs 1.4%, P < .001). Women were older at the time of surgery (65.6 vs 60.2 years, P < .001) and had more comorbidities and a larger maximum indexed aortic diameter (cm/m body height) at the time of surgery (3.4 ± 0.56 vs 3.0 ± 0.48, P < .001). The adjusted risk for 30-day mortality for women compared with men was not significant (odds ratio, 1.41; 95% CI, 0.70-2.83), and neither was the secondary composite end point (odds ratio, 0.89; 95% CI, 0.62-1.27). The propensity score–matched analysis showed similar results. ConclusionsWomen who underwent proximal thoracic aortic surgery had a 2-fold higher unadjusted 30-day mortality risk, but the mortality risk was not significantly higher when age and comorbidities was taken into consideration.

Neuroendocrine challenges and clinical outcomes in men with chronic traumatic brain injury: a cross-sectional study.

Marked changes in the hypothalamic-pituitary axis have been documented in patients with traumatic brain injury (TBI). These enduring endocrine challenges could significantly influence the physical and psychological outcomes thereby impacting overall recovery. This study aimed to determine the prevalence and types of endocrine dysfunction in men with chronic TBI and to determine the association of endocrine dysfunction with clinical outcomes. A cross-sectional study that included male participants of 25-45 years (N = 66) with moderate to severe TBI within 6-24 months of injury. Serum Cortisol, Free T4, TSH, Luteinizing hormone, Testosterone, ACTH, Prolactin and IGF-1 were assessed. Glasgow Outcome Scale Extended (GOS-E) and Modified Barthel Index (MBI) scores were also assessed in them. The study cohort comprised male patients with a mean ± age of 32.8 ± 5.7 years. Low IGF-1 levels were most commonly encountered, followed by hypogonadism. Hypopituitarism was present in 56.1%. The proportion of hypogonadism was significantly higher in the group with moderate-total dependence (13/26) as compared to the functionally independent (8/40) group (50% vs. 20%; P = 0.011). Univariate and multivariate logistic regression analysis was used to determine the factors associated with hypopituitarism, revealing that severity of injury (OR = 2.6;) and GOS-E (OR = 3.1) were significant (P < 0.10) on univariate analysis. This study emphasizes the need to screen TBI patients for neuroendocrine dysfunction during the chronic phases and to establish screening criteria.

Correlates and predictors of sarcopenia among men with metastatic castrate-resistant prostate cancer.

Sarcopenia is a predictor of clinical outcomes in men with metastatic castrate-resistant prostate cancer (mCRPC); however, correlates and predictors of sarcopenia are poorly understood in this population. The aim of this study was to examine correlates and predictors of sarcopenia in men with mCRPC prior to treatment. A secondary analysis of an observational study was performed. Participants were receiving care for mCRPC at the Princess Margaret Cancer Centre. Sarcopenia was assessed prior to treatment and was defined as the combination of low grip strength (<35.5 kg), low gait speed (<0.8 m/s), and computed tomography-derived low muscle mass or density. Participants' sociodemographic and clinical characteristics, comorbidity information, and clinically relevant blood markers were collected prior to treatment and were used to identify correlates and predictors of sarcopenia through Spearman correlations and multivariable logistic regression, respectively. In total, 110 men had complete data on sarcopenia measures and were included in the analysis. Sarcopenia was identified in 30 (27.3%) participants. Pre-treatment sarcopenia was moderately correlated with dependence in one or more instrumental activities of daily living (IADLs) (r=0.412), Vulnerable Elders Survey-13 (r=0.404), and a lower hemoglobin (r=0.407 per 10 g/L decrease). In adjusted logistic regression, dependence in one or more IADLs (odds ratio [OR] 4.37, 95% confidence interval [CI] 1.37-13.86, p=0.012), and a 10 g/L decrease in hemoglobin (OR 1.70, 95% CI 1.13-2.57, p=0.012) were significantly associated with sarcopenia. In settings where assessment of sarcopenia is not feasible, evaluation of IADLs and hemoglobin may be used to identify high-risk patients that can benefit from supportive care strategies aiming to improve muscle mass and function.

Salvage Radiotherapy PSMA PET/CT-guided in Men With PSA Recurrence.

To evaluate the clinical outcome in men with recurrent prostate cancer (PCa) treated by salvage radiotherapy (sRT) prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT)-guided. From January 2021 to January 2023, 33 patients who previously underwent definitive/systemic therapy were submitted to sRT PSMA PET/CT-guided for PCa recurrence: 16 (48.5%) on the prostate bed (PB), 12 (36.4%) on the lymph node (LN) and five (15.1%) on the bone. The median PSA value was 3.3 ng/ml (range=0.3-15.5 ng/ml): 0.2-0.5 ng/ml (18.2% cases), 0.51-1 ng/ml (39.4% cases) and >1 ng/ml (42.4% cases). Median 18F PSMA PET/CT standardized uptake value (SUVmax) was evaluated on PB, vs. LN vs. bones PCa recurrences and was equal to 12.5 vs. 19.0 vs. 30.1, respectively. Overall, at a median follow up of 12 months, 23/33 patients (69.7%) had local control without distant progression (PSA and SUVmax evaluation): 14/16 (87.5%) vs. 7/12 (58.3%) vs. 2/5 (40%) underwent sRT on the PB vs. LN vs. bone metastases, respectively. PSMA PET/CT allows to perform sRT early in men with PCa recurrence and low PSA values obtaining a complete clinical response in approximately 70% of the cases one year from treatment.

Association of resistance training and moderate-to-vigorous physical activity with clinical outcomes in men with airflow limitation: a nationwide population-based study

Aerobic moderate-to-vigorous physical activity (MVPA) is recommended for individuals with chronic diseases. However, the association between resistance training (RT) in addition to moderate to vigorous physical activity (MVPA) and sleep duration, as well as respiratory symptoms, in patients with chronic obstructive pulmonary disease has not been thoroughly investigated. This population-based cross-sectional study used data from the Korea National Health and Nutrition Examination Survey between 2014 and 2019. A total of 61,754 individuals were identified and men with airflow limitation (FEV1/FVC < 0.7) who engaged in aerobic MVPA were selected (n = 794). Weighted percentages and odds ratio (OR) of sleep problems (≤ 5 or ≥ 9 h), chronic cough, and chronic sputum were estimated. A multivariate-adjusted complex sample logistic regression model was used to calculate ORs and 95% confidence intervals (CI). Subgroup analyses were conducted using the forced expiratory volume (FEV1) % of the predicted value (%pred) ≥ 80 vs. < 80. The percentages of sleep problems, chronic cough, and chronic sputum production were lower in men who underwent aerobic MVPA + RT than in those who underwent aerobic MVPA alone. The multivariable-adjusted OR of sleep problems was 0.44 (95% CI 0.25–0.77) in individuals undergoing aerobic MVPA + RT compared to aerobic MVPA alone. The ORs of chronic cough and sputum were 0.35 (95% CI 0.13–0.94) and 0.51 (95% CI 0.30–0.87), respectively. These associations were only significant in individuals with FEV1 < 80% pred. Compared with aerobic MVPA alone, aerobic MVPA + RT was associated with appropriate sleep duration and a decrease in chronic cough and sputum in male with airflow limitation. This was more pronounced in individuals with a FEV1 < 80% pred.

Serum Testosterone Concentration Influences the Response to Extracorporeal Shock Wave Treatment in Men With Peyronie's Disease

To assess the relationship between baseline total serum testosterone (T) and clinical outcomes in men affected by Peyronie's disease (PD) stable stage and treated by extra corporeal shockwave therapy (ESWT). In this study, 168 patients affected by PD in stable stage (≥12months) and treated with ESWT, were divided into 2 groups. Group 1 (G1) counted 71 patients with low T levels (≤ 300ng/dL); group 2 (G2) consisted of 97 patients with normal T that received ESWT with the same protocol of G1 for 6weeks. There were assessed at baseline and follow-up: Erectile dysfunction (ED), presence and severity of painful erections, penile plaque size, and penile curvature degree. The results were evaluated at baseline and 3, 6, 12, months after the treatment. Not statistically significant differences emerged between the 2 groups at baseline, except for higher presence of patients with ED in G1 (90%) vs G2 (52%). Three months after the treatment in G2 pain was resolved completely in 80.4% of the patients, compared with G1 (54.9%). G2 had a reduction of curvature degree after the 3-month treatment (P<.001). Mean plaque size decreased in both groups without statistically differences with baseline values. Mean±SD International Index of Erectile Function-5 score progressively improved significantly in the eugonadal men. This study demonstrated greater efficacy for the treatment of PD in men with normal T concentrations compared with men with low T concentrations. The results obtained from this study suggest that may be valuable in considering T therapy in men with PD prior to ESWT.

Associations between sarcopenia and clinical outcomes in men with metastatic castrate-resistant prostate cancer.

12056 Background: Understanding the impact of sarcopenia on clinical outcomes in patients with metastatic cancer will assist clinicians with risk stratification, treatment decision-making, and inform the need for targeted supportive care strategies. Our objective was to comprehensively assess sarcopenia using measures of muscle mass (radiographically) and function (i.e., muscle strength and walking speed) and examine its impact on severe treatment toxicity, time to first emergency room (ER) visit, prostate-specific antigen (PSA) progression, radiographic progression, and overall mortality in men initiating androgen receptor-axis targeted therapy (ARAT) or chemotherapy for mCRPC. Methods: This was a secondary analysis of a prospective observational study of older men with mCRPC at the Princess Margaret Cancer Centre. Sarcopenia was defined as the combination of low muscle strength (grip strength &lt; 35.5kg), slowness (walking speed &lt; 0.8m/s), and low muscle quantity or quality prior to treatment initiation. The skeletal muscle index and skeletal muscle density were assessed through computed tomography scans prior to ARAT or chemotherapy initiation to determine muscle quantity and quality, respectively, using published cut-offs. Severe treatment toxicity, unplanned healthcare use, and disease progression were assessed from treatment initiation until treatment termination or loss to follow up. The associations between sarcopenia and severe treatment toxicity (i.e., grade 3+ toxicity) were assessed using multivariable logistic regression. Survival analyses were used to assess the impact of sarcopenia on the time to first ER visit, PSA progression, radiographic progression, and overall mortality. An interaction term for sarcopenia by treatment was introduced in all multivariable models and when necessary, an analysis by treatment was performed. Results: In total, 110 men participated, of whom 30 (27.3%) had sarcopenia prior to initiating treatment. Sarcopenia was associated with severe treatment toxicity (adjusted odds ratio (aOR) = 6.26, 95%CI = 1.17-33.58, P = 0.032) and time to first ER visit (adjusted hazard ratio (aHR) = 4.41, 95%CI = 1.26-15.43, p = 0.020) in the group that was initiating ARAT but not chemotherapy. Sarcopenia was a significant predictor of radiographic progression (aHR = 2.39, 95%CI = 1.06-5.36, p = 0.035) and overall mortality (aHR = 2.44, 95%CI = 1.17-5.08, p = 0.018) in the entire cohort. Conclusions: Sarcopenia may predict severe treatment toxicity and emergency room visits in men starting ARAT for mCRPC. Additionally, sarcopenia predicts radiographic progression and overall mortality regardless of treatment type in men with mCRPC. Confirmation is needed from large-scale studies. Assessment of sarcopenia can assist clinicians in treatment decision making while identifying high-risk patients that require targeted supportive care strategies.

The impact of circulating tumor cell HOXB13 RNA detection in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide.

5060 Background: It has been shown that HOXB13 is an important androgen receptor (AR) coregulator. The primary objective of this analysis was to correlate HOXB13 expression with clinical outcomes in men with mCRPC. Methods: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (n=118) treated abiraterone (abi) or enzalutamide (enza). CTC detection and specific HOXB13 cDNA detection and expression was measured using a modified Adnatest using appropriate controls. CTC HOXB13 status was categorized into 3 groups: undetectable CTCs (CTC=0 based on CTC PSMA &amp; PSA=0); CTC+ but HOXB13 CTC negative (&lt;4 copies) or positive (≥4 copies) where the HOXB13 cutoff point was determined by the maximally selected rank statistic for prognostic associations. The association between HOXB13 and overall survival (OS) and radiographic progression-free survival (rPFS) were explored using the proportional hazards model. We also explored the association between the two endpoints and multigroup of HOXB13 at cutoff 0 and CellSearch CTC at cutoff 1 and 5. Results: 102 men who had sufficient CTC cDNA sample for HOXB13 detection. Of those men with detectable CTCs, 19% (n=19) had no detectable HOXB13, while the majority of men at 67% (n=58) had both CTC and HOXB13 detection. The proportion of patients with CTC=0, CTC+ HOXB13-, and CTC+ HOXB13+ using the optimal HOXB13 threshold were 25%, 31% and 44%, respectively. Men with HOXB13- CTCs were more likely to have low PSA (median 3 vs 79 copies), low CTC PSMA (0 vs 99 copies), low AR-FL (47 vs. 89 copies) and CTC AR-V7 (5.9 vs. 42 copies), and more likely to have liver/lung metastases (41% vs 25%). Median OS were 25.7, 25 and 12.1 months while the median rPFS of the three groups were 9.0, 7.2 and 4.7 months, respectively. Compared to CTC=0, men with HOXB13- CTCs did not have a worse hazard rate for OS (HR: 0.9, 95% CI: 0.4-1.9), while HOXB13+ CTC patients had a worse hazard for OS (HR: 2.0, 95% CI: 1.0-3.9), adjusting for prior abi/enza treatment and Halabi clinical risk score. The positive HOXB13 had also statistically significant increased hazard for progression/death (HR: 2.31, 95% CI: 1.24-4.30). Compared to the group with both HOXB13=0 and CellSearch CTC=0, men with HOXB13&gt;0 and CellSearch CTC≥5 had increased hazard on both OS and rPFS (OS: HR:2.39, 95% CI: 1.06-5.4; rPFS: HR: 2.78, 95% CI: 1.38-5.59). Conclusions: Higher CTC HOXB13 expression is associated with AR dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC, and this assay could be useful to select for patients appropriate for AR or future HOXB13 targeted therapies. Clinical trial information: NCT02269982 .

Androgen Drives the Expression of SARS-CoV-2 Entry Proteins in Sinonasal Tissue.

Men have higher morbidity and mortality from COVID-19 than women, possibly due to androgen receptor-regulated viral entry protein expression. This led to a clinical trial of androgen deprivation therapy (ADT), which has not shown a significant benefit in the outcomes among hospitalized male COVID-19 patients. The aim of this study was to explore biological explanations for the failure of ADT to mitigate clinical outcomes in men with severe COVID-19 by assessing the role of androgen in regulating viral entry protein expression in the upper and lower respiratory tract. Immunohistochemistry was used to assess the expression of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and how it correlated to androgen receptor expression in the sinonasal epithelium, minor salivary glands of the sinus, lacrimal glands, and lungs from mice pretreated with and without castration and ADT as well as the sinonasal epithelium obtained from healthy human donors and hospitalized COVID-19 patients. In murine models, castration and ADT treatment downregulated the expression of TMPRSS2 and ACE2 in the sinonasal epithelium, minor salivary glands of the sinus, and lacrimal glands, but not in the lungs. Correlative analyses using human tissue also showed a potential role of ADT in men during the early sinonasal phase but not in the later lung phase of SARS-CoV-2 infection. Our study suggests a potential benefit of ADT in male patients with early COVID-19 when the virus enters the nasopharynx, but not in those with advanced disease. The downregulation of viral entry proteins in the upper respiratory system following androgen blockade may be a key mechanism for this effect.

Abstract PD6-10: PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies

Abstract Background/Rationale: Male breast cancer accounts for less than 1 percent of all cancer diagnoses in men. Because it is rare, it does not lend itself to large, randomized trials. In general, the approach to the treatment of early, non-metastatic male breast cancer has largely been extrapolated from female breast cancer trials. Specifically, the data on early-stage post mastectomy radiation therapy (PMRT) is limited, and its benefits remain unclear. Objectives: We conducted this meta-analysis to determine the impact of PMRT on clinical outcomes of men with breast cancer. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of invasive non-metastatic male breast cancer (MBC), comparative studies of PMRT versus none, and studies that reported the incidence of local and distant recurrences as well as survival data in the compared arms. A meta-analysis using the Mantel-Haenszel method for calculating the weighted pooled relative risk (RR) under the fixed effects model. Subsequently, the heterogeneity statistic gets incorporated to calculate the summary RR under the random effects model. Results: Ten retrospective comparative studies with 3912 patients were included and analyzed. Eight studies reported survival data. Six and three studies reported local and distant recurrence incidence, respectively. PMRT did not have an impact on overall survival or distant recurrences. However, PMRT significantly lowered the RR of locoregional recurrences (RR=0.53, 95%CI 0.31-0.92). In addition, when survival was analyzed by TNM stage and N status, PMRT was found to have a significant reduction in RR of death in stage III (RR=0.85, 95%CI 0.75-0.97), N1 (RR=0.77, 95%CI 0.61-0.98), and N2 (RR=0.61, 95%CI 0.49-0.78) disease. Conclusions: This is the first meta-analysis to show that PMRT is associated with a lower relative risk of death in stage III MBC as well as N1 and N2 disease. It also demonstrates a significant reduction in RR of locoregional recurrences. In the absence of randomized clinical trials, it represents the most compelling data supporting the use of PMRT in this MBC patient population. Citation Format: Philip A. Haddad, Usman Zaheer. PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-10.

Nadir Prostate-specific Antigen as an Independent Predictor of Survival Outcomes: A Post Hoc Analysis of the PROSPER Randomized Clinical Trial.

This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.

Performance of a blood-based liquid biopsy test to detect PSMA expression on circulating tumor cells in men with metastatic prostate cancer.

256 Background: PSMA-targeted radioligand therapy has dramatically improved clinical outcomes in men with mCRPC. A blood-based liquid biopsy assay to detect PSMA expression on circulating tumor cells (CTCs) could be helpful to optimize therapeutic decisions and identify patients most likely to benefit from PSMA-targeted therapies. Here we describe the development of this PSMA blood-based assay and the application of the single cell sequencing (SCS) pipeline to identify copy number alterations and further characterize heterogeneity in late-stage disease. Methods: A 4-color immunofluorescence (IF) assay was developed to detect PSMA expression on CTCs on the Epic Sciences liquid biopsy platform. CTCs were identified as DAPI+, cytokeratin (CK)+, and CD45- with appropriate cell morphology. Cells were plated onto glass slides and subjected to IF staining followed by CTC identification using a high throughput scanning platform with digital pathology machine learning algorithms. Cell line cells (LNCaP, PC3s, 22Rv1) of varying PSMA expression levels were spiked into normal blood (CLC/WBC; 1:10000) to create laboratory derived slides. Assay specificity, sensitivity, limit of detection (LOD), precision, and overall accuracy, as well as subcellular localization of biomarker expression were reported. Clinical validation was performed in a cohort of high-risk mCRPC patients (N=24) with previously demonstrated PSMA expression by tissue biopsy, utilizing 3ml of blood. Additionally, a subset of CTCs (36 cells from 11 patients) underwent single-cell low-pass whole genome sequencing to identify copy number alterations. Results: The PSMA CTC assay (Epic Sciences) achieved analytical specificity, sensitivity, and overall accuracy of over 99%. Precision was evaluated using intra-class correlation (ICC) (0.98). The assay showed an LOD of 1 CLC/technical replicate. PSMA expression was specific to staining outside the nucleus and distinguished from CK cytoplasmic staining. Analysis of 24 mCRPC samples revealed that 21/24 (88%) had at least one conventional CTC/mL (range: 0-30 CTCs/mL), of which 16/21 (76%) were PSMA positive (range: 0-27 CTCs/mL) with considerable tumor heterogeneity. 36 sequenced CTCs (N=11 pts) exhibited genomic heterogeneity and frequent AR (3/11), MYC (7/11), and MYCN (5/11) gains or losses of PTEN (4/11), TP53 (7/11), BRCA2 (5/11), CHD1 (6/11), and/or RB1(5/11 pts). Conclusions: The PSMA CTC assay analytical results firmly support its feasibility to detect PSMA expression in CTCs from mCRPC patient samples. The assay demonstrates high sensitivity, specificity, and overall accuracy. Many ongoing trials are designed to target PSMA-positive tumors, positioning this assay as a robust research tool to identify and longitudinally monitor PSMA expression and explore heterogeneity, response, and resistance in these patient populations.

Adrenal Steroids and Resistance to Hormonal Blockade of Prostate and Breast Cancer.

Prostate cancer and breast cancer are sex-steroid-dependent diseases that are driven in major part by gonadal sex steroids. Testosterone (T) is converted to 5α-dihydrotestosterone, both of which stimulate the androgen receptor (AR) and prostate cancer progression. Estradiol is the major stimulus for estrogen receptor-α (ERα) and proliferation of ERα-expressing breast cancer. However, the human adrenal provides an alternative source for sex steroids. A number of different androgens are produced by the adrenals, the most abundant of which is dehydroepiandrosterone (DHEA) and DHEA sulfate. These precursor steroids are subject to metabolism by peripherally expressed enzymes that are responsible for the synthesis of potent androgens and estrogens. In the case of prostate cancer, the regulation of one of these enzymatic steps occurs at least in part by way of a germline-encoded missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which regulates potent androgen biosynthesis and clinical outcomes in men with advanced prostate cancer treated with gonadal T deprivation. The sex steroids that drive prostate cancer and breast cancer require a common set of enzymes for their generation. However, the pathways diverge once 3-keto, Δ4-androgens are generated and these steroids are either turned into potent androgens by steroid-5α-reductase, or into estrogens by aromatase. Alternative steroid receptors have also emerged as disease- and treatment-resistance modifiers, including a role for AR in breast cancer and glucocorticoid receptor both in breast and prostate cancer. In this review, we integrate the commonalities of adrenal steroid physiology that regulate both prostate and breast cancer while recognizing the clear distinctions between these diseases.

Co-administration of sodium hydrosulfide and tadalafil modulates hypoxia and oxidative stress on bladder dysfunction in a rat model of bladder outlet obstruction.

This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCL(p<0.001), carbachol(p<0.01), electrical field stimulation(p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine β-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.

Preoperative Circulating 11-Oxygenated Androgens Are Associated With Metastasis-free Survival in Localized Prostate Cancer.

Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized prostate cancer. We studied 1,793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors in the prospective PROCURE cohort, for which preoperative plasma samples were obtained prior to radical prostatectomy. Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7), were quantified using liquid chromatography-tandem mass spectrometry. Circulating levels were evaluated in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models. At a median follow-up of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease, and 168 deceased. Higher levels of 11-hydroxytestosterone and 11-ketotestosterone were observed in men with PSA >20 ng/mL and positive nodal status (P < .05). In multivariable analyses, no significant association between 11-oxygenated androgens and disease-free survival was observed. Adrenal 11β-hydroxyandrostenedione, the predominant androgenic 11-ketotestosterone, and its metabolite 11-ketoandrosterone, modeled as quartiles, were associated with metastasis-free survival (P = .06, P = .03, and P = .008, respectively). Significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in patients on 5α-reductase inhibitors (P < .001). Preoperative circulating 11-oxygenated androgen levels are associated with metastasis-free survival in men with localized prostate cancer undergoing radical prostatectomy and are affected by 5α-reductase inhibitor treatment.

UGT2B28 accelerates prostate cancer progression through stabilization of the endocytic adaptor protein HIP1 regulating AR and EGFR pathways

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28.In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors.

Perceived frailty and clinical outcomes in men and women with atrial fibrillation treated with edoxaban: insights from the 2-year follow-up of ETNA-AF-Europe

Abstract Background/Introduction Many clinicians estimate the frailty of patients solely using their clinical expertise instead of validated scores. Previous reports show that women are more often perceived as frail than men. It is uncertain whether the same trend is observed in patients with atrial fibrillation (AF) and if the association between perceived frailty and adverse clinical outcomes is affected by sex. Purpose To assess whether sex affects the association between frailty status and adverse clinical outcomes in patients with AF. Methods ETNA-AF-Europe is an ongoing, post-authorisation, prospective cohort study conducted in 825 centres enrolling patients with AF treated with edoxaban in 10 European countries. In this substudy on the first 2-years of follow-up, patients were categorised in four subgroups based on sex and clinician-perceived frailty at baseline. We calculated incidence rates (per 100 patient-years) of the composite endpoint of any stroke or systemic embolic event (SEE), of major bleeding, and of all-cause death for the four subgroups; and determined the unadjusted association between perceived frailty (frail vs non-frail) and each outcome, stratified by sex, using Cox proportional hazards models. To assess for consistency in our findings, we tested the same associations by sex category but using objective risk factors: age (&amp;gt;74 vs &amp;lt;65 years) and CHA2DS2-VASc score (≥4 vs &amp;lt;4). Results Information about frailty-status was recorded for 12,254 (93.3%) patients, of whom 8.5% of men and 15.4% of women were perceived as frail by their clinician (p&amp;lt;0.0001) (Table 1). For both sex categories calculated separately, the risk of any stroke or SEE, major bleeding, or all-cause death was higher in the frail than in the non-frail patients (Figure 1A). However, the difference in risks of stroke or SEE between frail and non-frail patients was greater for men (HR 3.77, 95% confidence interval [CI] 2.25–6.31) than for women (HR 2.18, 95% CI 1.34–3.55) and a similar trend toward a greater risk-difference for men was seen for the risk of all-cause death (HR 4.58, 95% CI 3.76–5.59 vs HR 3.63, 95% CI 2.94–4.49). There was no marked difference between sex categories in the association between frailty-status and major bleeding (HR 2.86, 95% CI 1.81–4.50 vs HR 2.56, 95% CI 1.68–3.90) (Figure 1A). The association of age or CHA2DS2-VASc subgroups with clinical outcomes were either similar between sexes or suggested a possible lower risk-difference for men (Figure 1B and 1C). Conclusion In our cohort, differences in the risks of clinical outcomes between those who were perceived as frail and those who were not is more pronounced for men than women. Because we did not observe similar trends in the associations between age or CHA2DS2-VASc score subgroups and clinical outcomes, our results indicate that clinicians perceive the extent of frailty differently in men than in women. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer.

Loss of the histone demethylase KDM5D (lysine-specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP-seq) of the LNCaP cell line (androgen-sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2-binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone-sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)-positive hormone-sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line-specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone-sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone-sensitive prostate cancer.

Clinical outcomes for men with positive surgical margins after radical prostatectomy—results from the South Australian Prostate Cancer Clinical Outcomes Collaborative community-based registry

ObjectivePositive surgical margins (PSMs) after radical prostatectomy (RP) indicate failure of surgery to completely clear cancer. PSMs confer an increased risk of biochemical recurrence (BCR), but how more robust outcomes are affected is unclear. This study investigated factors associated with PSMs following RP and determined their impact on clinical outcomes (BCR, second treatment [radiotherapy and/or androgen deprivation therapy], and prostate cancer-specific mortality [PCSM]). MethodsThe study cohort included men diagnosed with prostate cancer (pT2-3b/N0/M0) between January 1998 and June 2016 who underwent RP from the South Australian Prostate Cancer Clinical Outcomes Collaborative database. Factors associated with risk of PSMs were identified using Poisson regression. The impact of PSMs on clinical outcomes (BCR, second treatment, and PCSM) was assessed using competing risk regression. ResultsOf the 2827 eligible participants, 28% had PSMs—10% apical, 6% bladder neck, 17% posterolateral, and 5% at multiple locations. Median follow-up was 9.6 years with 81 deaths from prostate cancer recorded. Likelihood of PSM increased with higher pathological grade and pathological tumor stage, and greater tumour volume, but decreased with increasing surgeon volume (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.88–0.98, per 100 previous prostatectomies). PSMs were associated with increased risk of BCR (adjusted sub-distribution hazard ratio [sHR] 2.5; 95% CI 2.1–3.1) and second treatment (sHR 2.9; 95% CI 2.4–3.5). Risk of BCR was increased similarly for each PSM location, but was higher for multiple margin sites. We found no association between PSMs and PCSM. ConclusionOur findings support previous research suggesting that PSMs are not independently associated with PCSM despite strong association with BCR. Reducing PSM rates remains an important objective, given the higher likelihood of secondary treatment with associated comorbidities.