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Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, affecting approximately one-fourth of adults worldwide, and is the leading cause of liver-related morbidity and mortality. MASLD is a sex-dimorphic disease, with a general higher prevalence in men. Women in fertile age exhibit a lower risk of MASLD than men. However, after menopause, their prevalence of MASLD becomes comparable to that of men. A complex interaction of gender-specific factors contributes to MASLD varying prevalence and severity. Sex is rarely considered as a biological variable in preclinical and clinical studies of MASLD. Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones. [ABSTRACT FROM AUTHOR]

To assess toxicity and patient quality of life after stereotactic body radiotherapy (SBRT) to oligoprogressive disease (OPD) in patients with metastatic castrate-resistant prostate cancer (CRPC) on androgen receptor targeted agents (ARTA). This phase II trial enrolled patients with metastatic CRPC with ≤ 2 oligoprogressive lesions in bone, lymph node, lung, or prostate. All patients were receiving systemic treatment with abiraterone or enzalutamide at the time of oligoprogression. All patients received SBRT to the OPD site(s) and continued the current ARTA. Patients received 30 Gy in 5 fractions (alternate days) to the OPD site. The primary endpoint of the trial is to assess if SBRT to OPD sites results in progression free survival of >6 months. The primary endpoint for this toxicity analysis is the rate of grade 3 or higher adverse events at any timepoint up to 6 months after SBRT. Secondary endpoints included comparing pre- and post-SBRT patient-related outcomes reported using visual analogue scale scores and EQ-5D health questionnaire. Forty enrolled patients had at least 6 months of follow-up at the time of analysis. Grade 3 or higher toxicity from any cause recorded using common terminology criteria for adverse events and radiation therapy oncology group was found in 8/40 (20%) of patients, but only 1/40 (2.5%) was deemed possibly related to SBRT. There was no significant difference in mean EQ5D visual analogue scale score from baseline to each timepoint after SBRT (p = 0.449). In this prospective phase II clinical trial for OPD whilst on ARTA in the CRPC setting, we report low grade ≥ 3 toxicity after SBRT. There is no discernible change in patient-reported quality of life due to SBRT treatment. The final results of progression-free survival and toxicity of SBRT treatment will be reported once further follow-up is complete. • Stereotactic radiotherapy to oligoprogressive disease in metastatic prostate cancer patients on targeted agents is feasible. • Stereotactic body radiotherapy is well tolerated in patients with castrate-resistant prostate cancer. • There is minimal treatment-related effect on quality of life and patient-reported outcomes. [ABSTRACT FROM AUTHOR]

To study prostate specific membrane antigen – positron emission tomography (Ga68PSMA-PETCT) based patterns of relapse at biochemical failure (BCF) after prostate-only radiotherapy (PORT) in high-risk (HR) prostate cancer and its implications on pelvic contouring recommendations. Patients with clinico-radiological high-risk node-negative prostate cancer treated with curative PORT and androgen deprivation therapy (ADT), either within the POP-RT randomised trial or off trial, who underwent a Ga68PSMA-PETCT upon BCF were included. Patterns of regional and distant recurrence on Ga68PSMA-PETCT were studied. Pelvic nodal recurrences were mapped with reference to the superior border of pubic symphysis. Pelvic lymph nodal caudal border (PLN cb) recommendations in the published contouring guidelines (RTOG cb , GETUG cb , PIVOTAL cb , NRG cb , GFRU cb) were evaluated. Of the total 262 patients screened, 68 eligible patients were included (POP-RT trial 35 patients; off-trial 33 patients). Median follow-up was 91 months (IQR, 72–117) and median time to BCF was 65 months (IQR, 49–83). Regional and distant recurrence was seen in 31 (46%) and 31 (46%) patients, respectively. Of the nodal recurrences, nearly half (46%, 14/31) had no distant metastases and 64% (20/31) had a failure in the common iliac nodal region. The lower-most nodal recurrence was 20 mm cranial to the top of pubic symphysis (RTOG cb , GETUG cb , GFRU cb) and 10 mm cranial to the PIVOTAL cb. The PLN cb recommended by NRG guideline (NRG cb) had an inter-patient variability of 32 mm, ranging from 16 mm above to 16 mm below the top of pubic symphysis, and the lower most nodal recurrence ranged from 4 mm to 36 mm cranial to NRG cb. Pelvic failures accounted for a major proportion of recurrences after prostate-only radiotherapy, with the caudal most nodal recurrence being 20 mm cranial to the top of pubic symphysis. This could have implications in defining the caudal border of contouring recommendations. • Roughly half of men with localised HRCaP have pelvic failures post prostate-only RT. • Pelvic nodal lower-border definition lacks consensus across existing guidelines. • Caudal-most nodal failure was mapped 20 mm superior to the top of pubic symphysis. [ABSTRACT FROM AUTHOR]

Hirsutism is the abnormal excessive growth of coarse terminal hair over androgen-sensitive body areas. It is a very common endocrine pathology, affecting up to 10% of young females and has been linked with multiple conditions. Polycystic ovary syndrome (PCOS) and Idiopathic hirsutism encompass 90% of the cases. Patients presenting with hirsutism may require additional investigations and a plan with options for treatment. Mechanical hair removal is first-line management, along with lifestyle changes. Laser and phototherapy have been gaining popularity. The combined contraceptive pill is the preferred initial medical treatment offered, if not contraindicated, followed by anti-androgen therapy. Other emerging therapeutic options are inositol and vitamin D, especially in patients with PCOS. Treatment options should be discussed with patients, irrespective of the clinical severity, as they could be addressing underlying psychosocial concerns. [ABSTRACT FROM AUTHOR]

Knowledge on survival probabilities is essential for determining optimal treatment strategies. We studied overall survival and associated prognostic factors in Dutch patients with localised prostate cancer (PCa) selected for external beam radiotherapy. For this single-centre retrospective cohort study, we identified all T1-T3 PCa patients (aged 55–80 years) in the radiotherapy planning database with a start date between January 2006 and December 2013, treated with 72–78 Gy in 2 Gy fractions to the prostate ± seminal vesicles (n = 1536). Long-term androgen deprivation therapy (ADT) was predominantly prescribed in the case of extracapsular disease (>T3). Overall survival was estimated using the Kaplan–Meier method. Prognostic factors were evaluated in Cox regression models for the intermediate-risk and high-risk groups. The median follow-up was 12 years for patients who were alive. Ten-year survival rates were 79.0% for low-risk (n = 120), 59.9% for intermediate-risk (n = 430) and 56.8% for high-risk patients (n = 986). A higher age, higher comorbidity score, active smoking and Gleason score ≥8 had a statistically significant negative impact on overall survival at multivariable analysis. ADT was associated with superior overall survival in the high-risk group translating into overall survival rates similar to the intermediate-risk group. Although PCa patients selected for external beam radiotherapy are typically in good health, their comorbidity score and smoking habits appeared to be dominant predictors for overall survival. Overall survival rates within the high-risk group varied, showing improved overall survival with ADT prescription and worse overall survival in the case of Gleason score ≥8. • Comorbidity score and smoking status are important predictors for overall survival. • Overall survival for T3 patients with adjuvant hormonal therapy was high. • Only the tumour characteristic Gleason score ≥8 was prognostic within risk groups. • 10-year survival rates within high-risk subgroups varied between 30 and 80%. [ABSTRACT FROM AUTHOR]

Introduction: While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration. Methods: We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all-and high-grade (grade = 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids. Results: Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC. Conclusions: The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling. [ABSTRACT FROM AUTHOR]

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that mainly affects the anogenital and axillary regions. Although its etiology has not been fully elucidated, there is evidence that androgen receptors (AR) are expressed in most cases of EMPD. However, the role of androgen signaling in the pathogenesis of EMPD remains unclear. To evaluate the role of androgen signaling in tumor growth of AR-positive EMPD. Patient-derived organoids were established and cultured from two AR-positive EMPD patients: one man and one woman. Cultured organoids were treated with androgen agonists and/or antagonists, then subjected to analysis of changes in organoid proliferation, as well as changes in androgen signaling pathway-specific genes. Organoid cultures were established from each EMPD sample. These organoids were immunohistologically and genetically identical to the original tumor. For each organoid sample, viable cell number increased in response to androgen exposure. The mRNA level of Fkbp5 , a known AR target gene, increased in a concentration-dependent manner in organoids exposed to the synthetic androgen R1881. Conversely, the AR inhibitor darolutamide suppressed the viable cell number in a concentration-dependent manner. The mRNA expression levels of MKI67 and Fkbp5 were also suppressed by darolutamide. Our results indicate that androgen signaling is a key pathway involved in the growth of AR-positive EMPD. Therefore, androgen signaling inhibition may be a novel treatment option for EMPD patients who require systemic therapy. • Androgen receptor (AR) has been shown to be expressed in vast majority of extramammary Paget's disease (EMPD). • Several tumor types, such as prostate cancer, are known to proliferate depending on the androgen signal. • EMPD organoids were established from two AR positive EMPD cases. • Proliferation of organoids was enhanced by androgens and inhibited by additional treatment with an androgen antagonist. • Inhibition of androgen signaling pathway will be a useful treatment option in metastatic EMPDs. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) has been considered for years the standard initial treatment for patients with metastatic prostate cancer (mPC). Recently published results support the use of taxanes, second-generation antiandrogens or radiotherapy to the primary tumor as part of the treatment in these patients, considering ADT alone as suboptimal. Metastasis-directed therapy (MDT) is used as part of the treatment for oligometastatic patients in different tumor types. In oligometastatic hormone-sensitive prostate cancer the role of MDT is being studied with promising results. In the present review we assess the available evidence for radiotherapy to the primary tumor in newly diagnosed mPC and for MDT in oligometastatic prostate cancer, as well as future directions in this clinical setting. [ABSTRACT FROM AUTHOR]

Gonadotropin-releasing hormone (GnRH) agonists and antagonists, critical medications for prostate cancer (PCa) treatment, may differ in cardiovascular safety. This prospective cohort study aimed to compare the long-term cardiovascular risks between GnRH agonists and antagonists. Patients with PCa receiving GnRH agonists or antagonists during 2013–2021 in Hong Kong were identified. Patients with <6 months' prescriptions, who were switching between drugs, had missing baseline prostate-specific antigen level or had a prior stroke or myocardial infarction were excluded. Patients were followed up until September 2021. The primary outcome was major adverse cardiovascular events (MACE) as in the PRONOUNCE trial (MACE PRONOUNCE), i.e. a composite of all-cause mortality, stroke and myocardial infarction. The secondary outcome was MACE CVM , i.e. a composite of cardiovascular mortality, stroke and myocardial infarction. Inverse probability treatment weighting was used to balance covariates between groups. The Log-rank test was used to compare the cumulative freedom from the primary outcome between groups. In total, 2479 patients were analysed (162 GnRH antagonist users and 2317 agonist users; median age 75.0 years, interquartile range 68.0–81.6 years). Inverse probability treatment weighting achieved good covariate balance between groups. Over a median follow-up duration of 3.0 years (interquartile range 1.7–5.0 years), 1115 patients (45.0%) had MACE PRONOUNCE and 344 (13.9%) had MACE CVM. GnRH agonist users had lower risks of MACE PRONOUNCE (Log-rank P < 0.001) and MACE CVM (Log-rank P = 0.027). However, no differences were observed within 1 year of follow-up (MACE PRONOUNCE : Log-rank P = 0.308; MACE CVM : Log-rank P = 0.357). Among patients without cardiovascular risk factors at baseline, GnRH agonist users had lower risks of MACE PRONOUNCE (Log-rank P < 0.001) and MACE CVM (Log-rank P = 0.001), whereas no differences were observed in those with such risk factor(s) (MACE PRONOUNCE : Log-rank P = 0.569; MACE CVM : Log-rank P = 0.615). GnRH antagonists may be associated with higher long-term, but not short-term, cardiovascular risks than agonists in Asian patients with PCa, particularly in those without known cardiovascular risk factors. • GnRH agents may differ in cardiovascular safety. • 2479 prostate cancer patients receiving GnRH agonists or antagonist were studied. • GnRH antagonist may be associated with higher long-term cardiovascular risks. • Short-term cardiovascular risks did not differ between GnRH agonists and antagonists. • Those without cardiovascular risk factors had a larger increase in long-term risks. [ABSTRACT FROM AUTHOR]

In this study, we investigated whether intense neoadjuvant therapy could increase the risk of complications in radical prostatectomy. After analyzing 124 patients we concluded that intense neoadjuvant therapy doesn't increase morbidity of radical prostatectomy and reduces positive surgical margins. The association of neoadjuvant therapy with extended pelvic lymphadenectomy may increase the risk of perioperative thromboembolic events. Introduction: Recent studies about intense neoadjuvant therapy followed by Radical Prostatectomy (RP) lack standardized cr iter ia regarding surgical complications and comparison to a group of patients who underwent RP without the use of neoadjuvant therapy. The aim of this study is to describe and compare the perioperative complication rates. Materials and Methods: This was a prospective, single-center phase II trial in patients with high-risk prostate cancer (HRPCa). The control group included HRPCa patients who underwent RP outside the clinical trial during the same study recruitment period. The interventional group was randomized (1:1) to receive neoadjuvant androgen deprivation therapy plus abiraterone with or without apalutamide followed by RP. Complications observed up to 30 days of surgery were classified based on the Clavien-Dindo classification. Uni- and multivariate analyses were carried out to assess predictive factors associated with perioperative complications. Results: In total, 124 patients with HRPCa were underwent to RP between May 27, 2019 and August 6, 2021, including 61 patients in the intervention group and 63 patients in the control group. The general and major complications in the intervention group reached 29.6% and 6.6%, respectively, and 39.7% and 7.9% in the control group, respectively. There was no significant difference between groups. We observed 4.9% of thromboembolic event in the neoadjuvant group. Conclusions: There was no significant increase in morbidity rate in RP after intense neoadjuvant therapy. The association of intense androgen deprivation neoadjuvant therapy with RP and extended pelvic lymphadenectomy may increase the risk of a perioperative thromboembolic events. [ABSTRACT FROM AUTHOR]

Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression. [ABSTRACT FROM AUTHOR]

Seahorses exhibit the unique characteristic of male pregnancy, which incubates numerous embryos in a brood pouch that plays an essential role in enhancing offspring survivability. The pot-belly seahorse (Hippocampus abdominalis) possesses the largest body size among seahorses and is a significant species in Chinese aquaculture. In this study, we revealed the cytological and morphological characteristics, as well as regulatory mechanisms, throughout the entire brood pouch development in H. abdominalis. The brood pouch originated from the abdominal dermis, extending towards the ventral midline. As the dermal layers thicken, the inner epithelium folds, the stroma loosens, and vascularization occurs, culminating in the formation of the brood pouch. Furthermore, through transcriptomic analysis of brood pouches at various developmental stages, 8 key genes (tgfb3 , fgf2 , wnt7a , pgf , mycn , tln2 , jund , ccn4) closely related to the development of brood pouch were identified in the MAPK, Rap1, TGF-β, and Wnt signaling pathways. These genes were highly expressed in the pseudoplacenta and dermal layers at the newly formed stage as examined by in situ hybridization (ISH). The angiogenesis, densification of collagen fibers, and proliferation of fibroblasts and endothelial cells in seahorse brood pouch formation may be regulated by these genes and pathways. Additionally, the expression of the androgen receptor gene (ar) was significantly upregulated during the formation of the brood pouch, and ISH confirmed the expression of the ar gene in the dermis and pseudoplacenta of the brood pouch, highlighting its role in the developmental process. Androgen and flutamide (androgen receptor antagonist) treatments significantly accelerated the formation of the brood pouch and completely inhibited its occurrence respectively, concomitant to the upregulated expression of differentially expressed genes involved above signaling pathways. These findings demonstrated that formation of the brood pouch is determined by androgen and the androgen receptor activates the above signaling pathways in the brood pouch through the regulation of fgf2 , tgfb3 , pgf , and wnt7a. Interestingly, androgen even induced the formation of the brood pouch in females. We firstly elucidated the formation of the seahorse brood pouch, demonstrating that androgens and their receptors directly induce the thickening, folding, and vascularization of the abdominal dermal layer into a placenta-like structure through multiple signaling pathways. These findings provide foundational insights to further exploring the evolution of male pregnancy and adaptive convergence in viviparity across vertebrates. [ABSTRACT FROM AUTHOR]

We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15–0.28) versus without concomitant statins (aHR: 0.31 [0.24–0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS. • Exposure to metformin or statins did not alter the efficacy of apalutamide. • Patients who received concomitant metformin or ACEI had improved MFS. • Patients who jointly received metformin, statins, and ACEI had improved MFS. [ABSTRACT FROM AUTHOR]

An optimal assessment of the therapeutic index is essential to manage patients with prostate cancer, especially in the geriatric age population. Our study showed strong evidence of activity in a larger (compared to our previous study) cohor t of patients who star ted enzalutamide at 50% or less of recommended dose. Lower dose could also be less costly to the healthcare system. Background: Enzalutamide is an important drug in the treatment of prostate cancer. Standard dosing often requires dose reduction because of side effects. There is no information on survival outcomes with lower doses. We investigated the impact of starting enzalutamide at ≥ 50% dose on metastatic prostate cancer outcomes including patients' longevity. Patients and Methods: Records of metastatic prostate cancer patients treated with enzalutamide at one center were retrospectively reviewed. Low-dose enzalutamide (≥80 mg/day) was compared with standard-dose (160 mg/day). The primary objective was to compute the restricted mean survival time (RMST - time scale) and restricted mean attained age (RMAA - age scale) using the Irwin method. Secondary objectives included overall survival (OS), progression-free survival (PFS), and PSA progression per PCWG3 cr iter ia (PSA PFS). We used the logrank test and the Δ difference between RMSTs for comparison. Results: Of 111 patients treated, 32 received a low-dose and 79 the standard-dose. Low-dose patients had less prior abiraterone or chemotherapy (28.1% vs. 65.8%, P < .001); more testosterone assessment (65.6% vs. 40.5%, P = .016); poorer ECOG performance status (48.3% score ≤2 vs. 26.6%; P = .040), more comorbidities (75.9% vs. 46.3%; P = .010)) including increased cardiovascular disease (51.7% vs. 21.4%, P = .004). Baseline PSA value and doubling time at start of enzalutamide and distribution of metastases were similar between the groups. OS and PFS did not differ between low-dose and standard-dose. Patients on low-dose had a better longevity with significantly longer RMAA, 89.1 years, versus standard-dose RMAA of 83.8 years (Δ = 5.3 years, P = .003, logrank P = .025). In a subgroup analysis by age at start of enzalutamide, < 75 versus ≤75 years old, longevity was also better with low-dose in younger patients (Δ = 2.9 years, P = .034, and older, Δ = 3.3 years, P = .011). Conclusion: The longevity advantage and reduced adverse events seen in patients with prostate cancer treated with low-dose enzalutamide warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Common iliac (CI) nodes are staged as (oligo)metastatic M1a for prostate cancer. Whether outcomes of pelvic node-positive (cN1) differ from CI node-positive (CI-M1a) prostate cancer after curative treatment is unclear. The present study compares outcomes in patients treated with radical whole pelvic radiation therapy (RT) and long-term androgen deprivation therapy (ADT).Methods and Materials: Patients with a node-positive adenocarcinoma prostate were identified, either CI-M1a or cN1, from a prospectively maintained database. More than 75% of patients were staged with Gallium (Ga) 68 prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) at the time of diagnosis. All patients received long-term ADT and moderately or extremely hypofractionated RT to the prostate and pelvis, including the CI region. At the time of biochemical failure (BCF), restaging was done with Ga68-PSMA-PET/CT to establish the patterns of failure. The CI-M1a cohort was classified as proximal or distal CI nodal location, and studied for outcomes.Results: Of the 130 patients analyzed, 87 had cN1 and 43 had CI-M1a stage disease. The median duration of ADT before RT was 7 months, and total duration was at least 24 months. The majority of patients (65%) had Gleason grade group IV to V, and 75% had ≥T3 disease. After a median follow up of 61 months, BCF in the 2 groups was similar (cN1: n = 21 of 87; 24.1%; CI-M1a: n = 11 of 43; 25.6%; P = .86). At the time of BCF, restaging Ga68-PSMA-PET/CT located distant metastases in 20 of 32 patients (63%; 57% in cN1 and 73% in CI-M1a; P = .47). In addition, the 5-year biochemical failure-free (cN1: 77.4%; CI-M1a: 70.4%; P = .43), distant metastasis-free (cN1: 86.9%; CI-M1a: 79.4%; P = .23), and overall (cN1: 92.6%; CI-M1a 90.1%; P = .80) survival were similar in the 2 groups. Outcomes within CI-M1a were similar for proximal versus distal CI nodal location and 5-year biochemical failure-free survival (73.6% vs 58.6%; P = .81).Conclusions: Patients with oligometastatic CI-M1a and cN1 prostate cancer showed similar outcomes when treated with curative whole pelvic RT and long-term ADT. The treatment for these oligometastatic patients should be prospectively evaluated. [ABSTRACT FROM AUTHOR]

Purpose: External beam radiation therapy (EBRT) to oligometastases may improve outcomes in patients with oligometastatic hormone-sensitive prostate cancer (oHSPC). Follow-up on this cohort has been limited to <5 years and prospective data on de novo patients with oHSPC are lacking. We reviewed the long-term outcomes of patients with oHSPC treated with EBRT and androgen deprivation therapy on a prospective trial.Methods and Materials: From 2006 to 2011, patients with oHSPC with 1 to 5 metastases received 36 weeks of androgen deprivation therapy (luteinizing hormone-releasing hormone agonist + bicalutamide) and up to 53 Gy to all visible metastases. When indicated, the primary tumor or prostate bed was treated with EBRT up to 78 or 66 Gy, respectively.Results: Twenty-nine patients were treated: 15 de novo, 14 oligorecurrent, and 21 patients (72.4%) had bone metastases. Median number of metastases per patient was 1 (range, 1-5). EBRT was administered to 52 lesions (38 bone, 12 pelvic lymph nodes [LNs], 2 nonpelvic LNs) up to 53 Gy (range, 47-66). Median follow-up was 9.9 years (years; range, 0.2-14.4). Median overall survival was 9.7 years (95% confidence interval [CI], 5.8-not reached). Median progression-free survival was 1.9 years (95% CI, 1.6-2.2). Patients who presented with prostate cancer-defined de novo metastases had significantly improved (P = .04) median progression-free survival (2.0 years; 95% CI, 1.3-6.0) compared with oligorecurrent patients (1.8 years; 95% CI, 1.0-2.0). Patients who presented with LN-only metastases had numerically improved (P = .13) median PFS (5.8 years; 95% CI, 1.2-not reached) compared with patients with bony metastases (1.8 years; 95% CI, 1.3-2.0). At last follow-up, 17 patients (58.6%) had local control of all EBRT-treated metastases. The metastases that locally progressed had previously been controlled for median 3.5 years (range, 1.7-10.5).Conclusions: Our results compare favorably with other reported studies of patients with oHSPC and provide new insights into their long-term outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To identify predictors of early artificial sphincter (AUS) erosion among a cohort of men with erosion, who underwent AUS placement by either university or community-based surgeons.Methods: The records of all patients with AUS erosions, including men who underwent AUS placement at outside facilities, were retrospectively reviewed. A Cox proportional-hazards model for time to erosion was performed with the predictors being the components of a fragile urethra (history of radiation, prior AUS, prior urethroplasty), androgen deprivation therapy (ADT), trans-corporal (TC), and 3.5 cm cuff, controlling for other risk factors. Kaplan-Meier survival curves and log-rank test compared "fragile" urethras with "not fragile" urethras. All statistical analysis was done using R version 3.5.2.Results: Of the 156 men included, 36% had undergone AUS placement in the community. Median time to erosion was 16.0 months (1.0-240.0 months), and 122 (78%) met at least one fragility criteria. Radiation (HR 2.36, 95% CI 1.52-3.64) and prior urethroplasty (HR 2.12, 95% CI 1.18-3.80) were independently associated with earlier time to erosion. The Kaplan-Meier estimates demonstrate 1- and 5-year survival rates of 76.5% and 50.0%, respectively, for "non-fragile" and 44.1% and 14.8% for "fragile" urethras (P < .0001).Conclusion: In a diverse cohort of men with AUS erosion, men with "fragile" urethras eroded sooner. Radiation and prior urethroplasty were independent risk factors for earlier time to erosion, but prior AUS, ADT, TC and 3.5 cm cuff were not. [ABSTRACT FROM AUTHOR]

The addition of either docetaxel or an androgen receptor signalling pathway inhibitor (ARSi) to androgen-deprivation therapy (ADT) has become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC) patients. Recent phase III data support even greater survival impact of a triplet regimen with ADT plus docetaxel plus an ARSi (abiraterone or darolutamide) compared to ADT plus docetaxel. To evaluate whether the addition of an ARSi to ADT improves outcomes of mCSPC patients treated with docetaxel. We searched MEDLINE/PubMed, the Cochrane Library, and ASCO Meeting abstracts for randomised clinical trials (RCTs) testing the combination of ARSi + ADT in mCSPC men who received docetaxel. Data extraction was conducted according to the PRISMA statement. Summary hazard ratio (HR) was calculated using random- or fixed-effects models. The statistical analyses were performed with RevMan software (v.5.2.3). Five RCTs were selected. Triplet therapy improved overall survival (OS) compared to ADT + docetaxel in mCSPC patients (HR = 0.73; p < 0.00001). This intensified strategy maintained the OS benefit when the ARSi was administered concomitant to chemotherapy (HR = 0.72; p < 0.00001), but no statistical effect was detected if the ARSi was sequential to docetaxel (p = 0.44). Moreover, in the subgroup of men with de novo mCSPC, triplets significantly improved OS (HR = 0.72, p < 0.0001). The lack of access to raw data was the main limit of our analysis. Our results support a clear survival advantage of adding an ARSi to ADT in mCSPC patients treated with docetaxel, mainly when the ARSi was administered concomitantly to chemotherapy and in the subgroup of de novo mCSPC. • Triplet (ADT + docetaxel + ARSi) improves OS compared to ADT + docetaxel in mCSPC. • The OS advantage is greater with ADT + docetaxel + ARSi administered concomitantly. • In the subgroup of de novo mCSPC the triplet significantly improves OS. [ABSTRACT FROM AUTHOR]

The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. Median rPFS was 5.5 months (95% CI 5.3–5.5). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2–not reached) and was significantly greater for AR-V7(−) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile. • 223Ra had a promising antitumour activity in patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases. • 223Ra showed an acceptable safety profile similar to that reported in other studies. • Overall survival of androgen receptor splice variant 7 (−) patients was significantly higher than androgen receptor splice variant 7 (+) patients. [ABSTRACT FROM AUTHOR]

Objective: To describe prostate-specific antigen (PSA) response and treatment adherence, overall and stratified by race, for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide.Methods: Electronic medical records representing 63 urology practices from the United States were used to conduct this study. Patients with ≥2 apalutamide prescription fills and ≥12 months of prior prostate cancer management were identified. Patients were followed from apalutamide initiation until a switch to another antineoplastic treatment, death, or end of data availability (October 4, 2019). PSA response (≥50% decline from baseline PSA) and apalutamide adherence rates are described for the overall nmCRPC population treated and also stratified by race (Black and non-Black cohorts).Results: Overall, 193 patients with nmCRPC were initiated on apalutamide. Thirty-three patients were Black (17.1%), 138 were non-Black (71.5%), and the remaining had an unknown racial background. The mean baseline PSA level for the overall, Black, and non-Black cohorts, was 7.0 ng/mL, 10.5 ng/mL, and 5.6 ng/mL, respectively. At 12 months of follow-up, PSA response was 86.0%, 93.1%, and 85.9% for the overall, Black, and non-Black cohorts, respectively. During a mean follow-up period of 333 days, 352 days, and 326 days, adherence was 93.6%, 90.1%, and 94.5% for the overall, Black and non-Black cohorts, respectively.Conclusion: This real-world study of patients with nmCRPC initiated on apalutamide showed that PSA response was robust and consistent with clinical trial data. Moreover, both Black and non-Black patients demonstrated high treatment adherence. [ABSTRACT FROM AUTHOR]

Purpose: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is increasingly used to guide salvage radiation therapy (sRT) in patients with prostate cancer and biochemical recurrence/persistence after prostatectomy. This work examined (1) metastasis-free survival (MFS) after PSMA-PET guided sRT and (2) the metastatic patterns on PSMA-PET images after sRT.Methods and Materials: This retrospective, multicenter (9 centers, 5 countries) study included patients referred for PSMA-PET due to recurrent/persistent disease after prostatectomy. Patients with distant metastases (DM) on PSMA-PET before sRT were excluded. Cox regression was performed to assess the effect of clinical parameters on MFS. The distribution of PSMA-PET detected DM after sRT and their respective risk factors were analyzed.Results: All (n = 815) patients received intensity modulated RT to the prostatic fossa. In the case of PET-positive pelvic lymph nodes (PLN-PET) (n = 275, 34%), pelvic lymphatics had been irradiated. Androgen deprivation therapy had been given in 251 (31%) patients. The median follow-up after sRT was 36 months. The 2-/4-year MFS after sRT were 93%/81%. In multivariate analysis, the presence of PLN-PET was a strong predictor for MFS (hazard ratio, 2.39; P < .001). After sRT, DM were detected by PSMA-PET in 128/198 (65%) patients, and 2 metastatic patterns were observed: 43% had DM in sub-diaphragmatic para-aortic LNs (abdominal-lymphatic), 45% in bones, 9% in supra-diaphragmatic LNs, and 6% in visceral organs (distant). Two distinct signatures with risk factors for each pattern were identified.Conclusions: MFS in our study is lower compared with previous studies, obviously due to the higher detection rate of DM in PSMA-PET after sRT. Thus, it remains unclear whether MFS is a surrogate endpoint for overall survival in PSMA PET-staged patients in the post-sRT setting. PLN-PET may be proposed as a new surrogate parameter predictive of MFS. Analysis of recurrence patterns in PET after sRT revealed risk factor signatures for 2 metastatic patterns (abdominal-lymphatic and distant), which may allow individualized sRT concepts in the future. [ABSTRACT FROM AUTHOR]

Enzalutamide and abiraterone acetate plus prednisone (AAP) have similar efficacy in metastatic castration-resistant prostate cancer (mCRPC). Herein, we compare fatigue, health-related quality-of-life (HRQoL) and metabolic changes in men with mCRPC treated with enzalutamide and AAP. In this single-centre, open-labelled, phase IV trial, patients with metastatic prostate cancer progressing on androgen deprivation therapy were randomly assigned to enzalutamide (160 mg daily) or AAP (1000 mg abiraterone acetate and 10 mg prednisone daily) as first-line mCRPC treatment. The primary outcome was the difference in changed fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire). The secondary outcomes were differences in changed HRQoL (Functional Assessment of Cancer Therapy-Prostate questionnaire), body composition, weight, glucose homeostasis, lipid profile and blood pressure. All outcomes were assessed at baseline and at 12-week follow-up. Trial registration: clinicaltrialsregister.eu (2017-000099-27). 170 patients were randomised (1:1) to enzalutamide or AAP. The primary outcome was positive with a clinically meaningful difference in fatigue, favouring AAP (3.4 points, 95% CI 1.2; 5.6, P = 0.003). The group difference in changed HRQoL did not reach clinical significance. The most important metabolic finding was a higher increase in glycated haemoglobin (HbA1c) for AAP than enzalutamide (3.4 mmol/mol, 95% CI 2.1; 4.8, P = 0.001). Eight patients developed type 2 diabetes (T2D) in the AAP group and none in the enzalutamide group. No treatment-related serious adverse event was observed. AAP resulted in less fatigue than enzalutamide in a randomised setting. This was at the expense of a higher HbA1c increase and incidence of T2D. • Abiraterone results in clinically important less fatigue than enzalutamide. • The treatment difference in quality-of-life favoured AAP but did not reach clinical significance. • Abiraterone results in a higher incidence of type 2 diabetes than enzalutamide. [ABSTRACT FROM AUTHOR]

Objective: To present a recent clinical case of Skene's gland carcinoma and review all published literature of Skene's gland malignancy with associated treatment and outcomes.Methods: We review a new case of metastatic Skene's gland adenocarcinoma. We then performed a systematic search of PubMed and Ovid-Medline through December 2021 and retrieved English language articles for review. Peer-reviewed articles were deemed eligible if they included patients with Skene's gland malignancy. Reports were reviewed for pathologic accuracy, patient characteristics, clinical presentation, tumor pathology, treatment and outcome.Results: We reviewed 211 articles and included 15 cases from 1974 to 2022. The median patient age was 71 years (range 46-88). The most common presentation was an asymptomatic periurethral or urethral lesion in five cases (33.3%), followed by hematuria or vaginal bleeding in three patients (20.0%). In eight cases, a prostate-specific antigen was measured and found to be elevated, range 0.8-60.8 ng/mL. Treatment approaches varied and included local excision in eight cases, radical surgical resection in two cases, radiation therapy in two cases, and adjunctive androgen deprivation therapy in one case. Pathology was consistent with adenocarcinoma resembling prostate in all cases. In all cases tested, prostate-specific antigen normalized after definitive therapy of any type. Median follow up was 11.5 months, and there were no cases of recurrence or mortality secondary to Skene's gland adenocarcinoma.Conclusion: There are 15 published cases of a Skene's gland malignancy, all adenocarcinoma resembling prostate. Local excision is most often utilized for treatment, with androgen deprivation therapy emerging as a new treatment consideration. [ABSTRACT FROM AUTHOR]

• Testosterone recovery after androgen deprivation therapy is highly variable. • Younger age and GnRH antagonist use are associated with testosterone recovery. • Many men prescribed GnRH agonists may never recover their testosterone. • Strategies to limit treatment duration of androgen ablation should be considered. Finite courses of androgen deprivation therapy (ADT) are often utilized in men undergoing treatment for prostate cancer. Previous evidence suggests that timing of testosterone (T) recovery can be variable after ADT. Recently, an oral gonadotropin releasing-hormone (GnRH) antagonist, relugolix, has demonstrated more rapid T recovery than injectable GnRH agonists such as leuprolide. In this study, we sought to evaluate patient characteristics associated with T recovery in patients undergoing ADT of defined duration. The Northwestern Enterprise Data Warehouse was queried for men with prostate cancer who completed a course of ADT and subsequently had a testosterone lab performed. Testosterone recovery was evaluated for levels that reached above castrate (T > 50 ng/dl), partial recovery (T > 150 ng/dl), and full recovery (T ≥ 300 ng/dl). 388 men who received finite courses of ADT were identified (348 receiving leuprolide, 36 receiving relugolix, and 4 receiving degarelix). In multivariable Cox regression analysis, men who were prescribed GnRH antagonists (HR = 3.74, CI = 2.53–5.53, P ≤ 0.001) and who were younger (HR for 1 year increase in age = 0.96, CI = 0.95–0.98, P < 0.001) were more likely to achieve partial recovery. In a subgroup analysis, men who received extended ADT courses (>12 months) with a GnRH agonist had lower rates of partial T recovery (HR = 0.58, CI = 0.41–0.81, P = 0.001). T recovery after ADT is variable with roughly one sixth of men remaining castrate. GnRH antagonist use and younger age are associated with higher rates of T recovery after ADT. Longer ADT courses were associated with worse T recovery rates. [ABSTRACT FROM AUTHOR]

• Two novel sets of thiohydantoin derivatives were designed and synthesized with expected cytotoxicity and androgen antagonists based on the binding pattern of enzalutamide to the androgen receptor. • The dicyanide derivatives 3a showed the best LNCaP inhibition demonstrating IC 50 of 2.64 µM with a potential to inhibit its S-phase reducing the natural DNA transactivation of androgens. • In vivo evaluation of 3a significantly ameliorated the testosterone-induced increase in the prostate index and weight as compared to finasteride. • Apoptosis initiation was observed in the early phase with 22.74 % in contrast to 9.06 % at the late phase with respect to 0.44 % and 0.13 % of the control cells at early and late stages, respectively. Novel thiohydantoin derivatives were designed as androgen antagonists based on the binding pattern of enzalutamide to the androgen receptor that avoided the bifurcated activation pattern of dihydrotestosterone. Twelve thiohydantoin derivatives were synthesized following Michael-type addition which were fully characterized. The dicyanide derivatives 3a showed the best LNCaP inhibition demonstrating IC 50 of 2.64 µM with a potential to inhibit its S-phase reducing the natural DNA transactivation of androgens. Moreover, apoptosis initiation was observed in the early phase with 22.74 % in contrast to 9.06 % at the late phase with respect to 0.44 % and 0.13 % of the control cells at early and late stages, respectively. In vivo evaluation of 3a significantly ameliorated the testosterone-induced increase in the prostate index and weight as compared to finasteride. This was confirmed by the histopathological examinations of prostatic tissues that demonstrated a reduction in the accompanied histopathological changes as well as lowering the immunohistochemical up-regulation of androgen receptors induced by testosterone. Moreover, molecular docking simulation justified the achieved biological activity. [Display omitted] [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy is a common treatment for men with advanced prostate cancer. They have experienced many complex symptoms that affect their quality of life. However, qualitative reviews that synthesize the symptom experience for men with prostate cancer are lacking. To explore the men's symptom experience throughout androgen deprivation therapy for prostate cancer. A qualitative evidence synthesis using meta-aggregation. Published and unpublished literature between January 2001 and August 2023 were identified from PubMed, Embase (Ovid), Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, ProQuest, Google Scholar, China National Knowledge Infrastructure (CNKI), Wang Fang, and VIP. Two reviewers independently conducted screening, study selection and data extraction, and quality appraisal was performed using the Joanna Briggs Institutes Critical Appraisal Checklist for Qualitative Research. Data synthesis was conducted using meta-aggregative approach. 24 articles of moderate to high methodological quality were included. A total of 98 findings were extracted with 59 unequivocal or equivocal findings eligible for meta-aggregation, aggregated into nine categories, and developed four synthesized findings: (1) production of symptoms: unrecognized and underestimated, (2) perception of symptoms: varied and complicated, (3) meaning of symptoms: threatened and affected, and (4) response to symptoms: push and pull. Men throughout androgen deprivation for prostate cancer experience the four crisis-packed stages in their symptomatic journey. Health care provider need to understand the men's thoughts whether in the process of shared decision-making or in the course of the chosen therapy. Future research should develop individual suitable interventions and offer practical strategies for managing symptom. PROSPERO registration: CRD42023449129. [ABSTRACT FROM AUTHOR]

Caffeine exerts a biphasic effect on zebrafish behavior. High doses of caffeine have been associated with increased stress and anxiety, whereas low doses have been found to enhance performance on tasks requiring focus and attention. However, the sex-specific nature of these biphasic effects on behavior and physiology remains unclear. This study assessed the behavioral responses and hormone levels in male and female zebrafish after acute exposure to caffeine ranging from 0.3 to 600 mg/L. The results showed no significant difference in caffeine intake between males and females after acute exposure at each concentration. Caffeine-induced behavioral and physiological responses indicated a threshold dosage existed between 30 and 300 mg/L. Female fish displayed increased anxiety-like behavioral phenotypes, i.e., latency to upper and freezing, whereas males exhibited more erratic movement following acute exposure to a high-dose treatment. In addition, females exhibited a significant increase in whole-body cortisol levels, while males experienced a testosterone elevation at 300 mg/L of caffeine acute exposure. There was a significant decrease in the duration of erratic movements in males treated with the androgen receptor antagonist flutamide compared to the control group. The transcriptome analysis uncovered 511 and 592 up-regulated and 761 and 922 down-regulated differential expression genes in males and females, respectively, compared to the control. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis revealed that caffeine has the potential to impact various pathways in zebrafish, including phototransduction and steroid hormone biosynthesis. Our findings demonstrate that testosterone and cortisol play a combined role in regulating stress responses in both behavior and physiology. Furthermore, our study highlights the significance of encompassing both male and female zebrafish as a model system. • Zebrafish showed sex-specific behavior and physiology in response to caffeine. • Females showed signs of freezing, while males displayed erratic movements. • Cortisol and testosterone levels were higher in females and males, respectively. • Caffeine may affect steroid hormone production. [ABSTRACT FROM AUTHOR]

PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0–2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTEN IHC status were pre-planned. Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI −12.8 to 13.6, p = 0.58), with similar results in the PTEN IHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTEN IHC loss (10.1 months [95 %CI: 4.6–13.9] vs 14.8 months [95 %CI: 10.8–18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC. • RE-AKT is a multicentre, randomized, double-blinded phase II trial in mCRPC. • Combined capivasertib and enzalutamide did not increase enzalutamide's antitumour activity in mCRPC. • Albeit well tolerated, capivasertib exposure is reduced when enzalutamide is given. [ABSTRACT FROM AUTHOR]

Epitestosterone is a stereoisomer of the active androgen testosterone and its circulating concentrations are similar to those of testosterone in women and children. However, its biological function and pathways of metabolism remain unknown. The structural similarity to testosterone suggests a potential function in the modulation of androgen receptor signalling. It is well established that the conversion of testosterone to 5α-dihydrotestosterone enhances local androgen receptor signalling. In this study, we show that epitestosterone is metabolized to 5α-dihydroepitestosterone by both human steroid 5α-reductase isoforms, SRD5A1 and SRD5A2. Using two different variations of a reporter assay for transactivation of the human androgen receptor, we show that epitestosterone is a partial AR agonist and that the 5α-reduction of epitestosterone increases its androgenic activity. In line with this, we show that 5α-reduction of epitestosterone reduces its ability to antagonize 5α-dihydrotestosterone-induced androgen receptor transactivation. In conclusion, we provide evidence that steroid 5α-reductases regulate the modulatory effect of epitestosterone on androgen receptor signalling. • Epitestosterone is a partial androgen receptor agonist. • Epitestosterone is efficiently 5α-reduced by SRD5A1 and SRD5A2. • 5α-reduction of epitestosterone increases its efficacy as androgen receptor agonist. • 5α-reduction of epitestosterone reduces its activity as an androgen receptor antagonist. [ABSTRACT FROM AUTHOR]

Purpose: CHHiP is a randomized trial evaluating moderately hypofractionated radiation therapy for treatment of localized prostate cancer. Of all participants, 97% of them had concurrent short-course hormone therapy (HT), either luteinizing hormone-releasing hormone analog (LHRHa) or 150 mg of bicalutamide daily. This exploratory analysis compares efficacy and side effects in a nonrandomized comparison.Methods and Materials: In our study, 2700 patients received LHRHa and 403 received bicalutamide. The primary endpoint was biochemical/clinical failure. Groups were compared with Cox regression adjusted for various prognostic factors and stratified by radiation therapy dose. A key secondary endpoint was erectile dysfunction (ED) assessed by clinicians (using scores from Late Effects on Normal Tissues: Subjective/Objective/Management [LENT-SOM] subjective erectile function for vaginal penetration) and patients (single items within the University of California-Los Angeles Prostate Cancer Index [UCLA PCI] and Expanded Prostate Cancer Index Composite [EPIC]-50 questionnaires) at 2 years and compared between HT regimens by χ2 trend test.Results: Bicalutamide patients were significantly younger (median 67 vs 69 years LHRHa). Median follow-up was 9.3 years. There was no difference in biochemical or clinical failure with an adjusted hazard ratio or 0.97 (95% confidence interval, 0.77-1.23; P = .8). At 2 years, grade ≥2 LENT-SOM ED was reported in significantly more LHRHa patients (313 out of 590; 53%) versus bicalutamide (17 out of 68; 25%) (P < .0001). There were no differences in ED seen with UCLA-PCI and EPIC-50 questionnaires.Conclusions: In this nonrandomized comparison, there was no evidence of a difference in efficacy according to type of HT received. Bicalutamide preserved clinician assessed (LENT-SOM) erectile function at 2 years but patient-reported outcomes were similar between groups. [ABSTRACT FROM AUTHOR]

Purpose: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.Methods and Materials: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.Results: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.Conclusions: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity. [ABSTRACT FROM AUTHOR]

The benefits of neoadjuvant androgen deprivation therapy (nADT) in the management of intermediate- and high-risk prostate cancer patients have been well-established. The aim of this study was to identify radiomic prognostic features derived from routine anatomic magnetic resonance imaging (MRI) sequences that can predict the response of the prostate cancer to nADT. Patients with intermediate- and high-risk prostate cancer (with one of clinical stage ≥ T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) who received 3 months of ADT prior to radical external beam radiotherapy were enrolled into this study. The relative blood volume and the relative blood flow were used as dynamic MRI kinetic parameters to quantify vascular changes as responses to nADT. For all pre- and post-nADT data sets, a combination of T2-weighted and contrast-enhanced T1-weighted anatomic images were used to define regions of interest (ROI) as the dominant malignant nodules (DMNs) and the benign prostate (the entire prostate with the summed DMNs being subtracted). MRI textural radiomic features associated with prostate cancer response in the literature of energy and homogeneity were selected. Pyradiomics was used to extract textural features of the ROIs. A Wilcoxon signed-rank test was carried out to investigate if there were statistically significant differences in values of radiomic features between: (i) benign prostate ROI and DMN pre-nADT; (ii) pre- and post-nADT of benign prostate ROI; (iii) pre- and post-nADT of DMN. Changes in radiomic features and dynamic MRI kinetic parameters were correlated using the Spearman correlation test. Twenty prostate cancer patients were recruited into the study. The median time between the first baseline scan and the first on-treatment scan was 91.5 days (range 82–105). One patient had no discernible tumour visible, leaving 19 patients with evaluable data for the analysis. Baseline homogeneity and energy values differed significantly between benign and malignant tissue (P < 0.01). In response to nADT, homogeneity and energy showed reciprocal changes, significantly increased in benign prostate while decreasing in the DMN. The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and tumour blood volume induced by androgen deprivation as derived from dynamic MRI parameters. Energy and homogeneity radiomic features derived from MRI of benign and malignant prostate showed significant reciprocal changes in response to nADT. This study confirms the potential of these radiomic features to act as surrogate markers of tumour androgen sensitivity due to their strong association with ADT-induced physiological effects in prostate tumours. • This study identified radiomic features derived from anatomic magnetic resonance imaging that can predict the physiological response of prostate cancer to neoadjuvant androgen deprivation therapy (nADT). • Baseline homogeneity and energy radiomic features differed significantly between benign and malignant tissue. • In response to nADT, homogeneity and energy showed reciprocal changes, significantly increasing in benign prostate while decreasing in malignant nodules. • The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and blood volume induced by ADT. [ABSTRACT FROM AUTHOR]

Objectives: To assess the cost-effectiveness of systemic treatments for metastatic castration-sensitive prostate cancer from the US healthcare sector perspective with a lifetime horizon.Methods: We built a partitioned survival model based on a network meta-analysis of 7 clinical trials with 7287 patients aged 36 to 94 years between 2004 and 2018 to predict patient health trajectories by treatment. We tested parameter uncertainties with probabilistic sensitivity analyses. We estimated drug acquisition costs using the Federal Supply Schedule and adopted generic drug prices when available. We measured cost-effectiveness by an incremental cost-effectiveness ratio (ICER).Results: The mean costs were approximately $392 000 with androgen deprivation therapy (ADT) alone and approximately $415 000, $464 000, $597 000, and $959 000 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. The mean quality-adjusted life-years (QALYs) were 3.38 with ADT alone and 3.92, 4.76, 3.92, and 5.01 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. As add-on therapy to ADT, docetaxel had an ICER of $42 069 per QALY over ADT alone; abiraterone acetate had an ICER of $58 814 per QALY over docetaxel; apalutamide had an ICER of $1 979 676 per QALY over abiraterone acetate; enzalutamide was dominated. At a willingness to pay below $50 000 per QALY, docetaxel plus ADT is likely the most cost-effective treatment; at any willingness to pay between $50 000 and $200 000 per QALY, abiraterone acetate plus ADT is likely the most cost-effective treatment.Conclusions: These findings underscore the value of abiraterone acetate plus ADT given its relative cost-effectiveness to other systemic treatments for metastatic castration-sensitive prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT).Methods and Materials: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis.Results: The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%.Conclusions: The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial.Methods: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36).Findings: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed.Interpretation: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process.Funding: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca. [ABSTRACT FROM AUTHOR]

Purpose: We report efficacy of a prospective phase 2 trial (NCT00450411) of salvage low-dose-rate (LDR) prostate brachytherapy (BT) for local failure (LF) after prior external beam radiation therapy (EBRT) with minimum 5-years' follow-up.Methods and Materials: Eligible patients had low/intermediate risk prostate cancer (PCa) before EBRT and biopsy-proven LF >30 months after EBRT, with prostate-specific antigen <10 ng/mL and no regional/distant disease. The primary endpoint, late gastrointestinal and genitourinary adverse events (Common Terminology Criteria for Adverse Events v3.0) grade ≥3 were 14%. With minimum 5-year follow-up after salvage BT, secondary clinical outcomes including disease-free survival (DFS; includes death from any cause), disease-specific survival, and overall survival (OS) were estimated using the Kaplan-Meier method and modelled using Cox proportional hazards regression. Local tumor progression (ie, LF), distant failure (DF), and biochemical failure (BF) were estimated using cumulative incidence. Time to LF, DF, and BF were modeled by cause-specific Cox proportional hazards regression.Results: From May 2007 to January 2014, 20 centers registered 100 patients (92 analyzable). Median follow-up is 6.7 years (range, 0.3-11.2); median age 70 years (range, 55-82); median prior EBRT dose 74 Gy [interquartile range (IQR):70 - 76] at a median of 85 months prior (IQR 60-119 months). Androgen deprivation was combined with salvage BT in 16%. Ten-year OS is 70% [95% confidence interval (CI) 58% - 83%]. Nineteen patients died (5 PCa, 10 other, 4 unknown). Ten-year failure rates are local 5% (95% CI, 1-11), distant 19% (95% CI, 10-29), and biochemical 46% (95% CI, 34-57). DFS is 61% at 5 years and 33% at 10 years. No baseline characteristic was significantly associated with any clinical outcome.Conclusions: This is the first prospective multicenter trial reporting outcomes of salvage LDR BT for LF after EBRT. Five-year freedom from BF is 68%, comparable to other salvage modalities. Although further LF is rare (5%), BF climbs to 46% by 10 years. [ABSTRACT FROM AUTHOR]

Purpose: Guidelines from the American Society of Clinical Oncology and Cancer Care Ontario recommend brachytherapy boost for patients with intermediate-risk or high-risk prostate cancer. SABR is an emerging technique for prostate cancer, but its use in high-risk disease is limited. Efficacy, toxic effects, and quality of life (QoL) were compared in patients treated on 2 prospective protocols that used SABR boost or magnetic resonance-guided high-dose-rate brachytherapy (HDR-BT) boost with 6 to 18 months of androgen deprivation therapy (ADT).Methods and Materials: In SATURN study (study 1), patients received 40 Gy to the prostate and 25 Gy to the pelvis in 5 weekly fractions. In SPARE (study 2), patients received HDR-BT (15 Gy × 1) to the prostate and ≤22.5 Gy to the magnetic resonance imaging nodule, followed by 25 Gy in 5 weekly fractions to the pelvis. All patients received between 6 and 18 months of ADT.Results: Thirty patients (7% unfavorable intermediate risk and 93% high risk, per National Comprehensive Cancer Network [NCCN] criteria) completed study 1, and 31 patients (3% favorable intermediate risk, 47% unfavorable intermediate risk, and 50% high risk) completed treatment as per study 2. The median follow-up times were 72 and 62 months, respectively. In study 2, 6 patients had biochemical failure, and all 6 developed metastatic disease. Actuarial 5-year biochemical failure was 0% for study 1 and 18.2% for study 2 (P = .005). There was no significant difference in the worst acute or late gastrointestinal or genitourinary toxicity. Grade 3 late genitourinary toxicity was noted in 3% of the patients in study 2 (HDR-BT boost). There was either no significant difference or minimal clinically important change in QoL.Conclusions: In the context of 5-fraction pelvic radiation therapy and ADT, there did not appear to be a significant difference in toxicity or QoL between SABR and HDR-BT boost. Although efficacy favored the SABR boost cohort, this should be viewed in the context of limitations and biases associated with comparing 2 sequential phase 2 studies. [ABSTRACT FROM AUTHOR]

Background: Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane.Methods: In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0-2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436.Findings: Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6-13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7-46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment.Interpretation: Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations.Funding: Janssen Research & Development. [ABSTRACT FROM AUTHOR]

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups.Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855.Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group.Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended.Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among men in western countries. Androgen deprivation therapy (ADT) is considered the standard therapy for recurrent prostate cancer; however, this therapy may lead to ADT resistance and tumor progression, which seems to be regulated by epithelial-mesenchymal transition (EMT) and/or neuroendocrine differentiation (NED). In addition, recent data suggested the involvement of either adaptive or innate infiltrated immune cells in the initiation, progression, metastasis, and treatment of prostate cancer. In this review, we outlined the characteristics and roles of these immune cells in the initiation, progression, metastasis, and treatments of prostate cancer. We also summarized the current therapeutic strategies in targeting immune cells of the prostate tumor microenvironment. [ABSTRACT FROM AUTHOR]

To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer – 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml – in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database. All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan–Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan–Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups. The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5–18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4–99.6), 89.0% (82.4–96.1), 81.5% (70.5–94.2) and 41.8% (29.7–58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6–96.7), 92.1% (87.6–96.9) and 75.9% (67.8–84.9), respectively. Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies. • 15-year follow-up data following LDR brachytherapy for prostate cancer • 97.5% of patients with 4-year PSA ≤ 0.2 ng/ml disease free 10 years post-implant • 4-year PSA ≤ 0.2 ng/ml equates to cure for these patients; safe to discharge to GP • 10-year DFS > 90% for patients with low and favourable-intermediate risk prostate cancer • 75.9% 10-year DFS for unfavourable-intermediate risk [ABSTRACT FROM AUTHOR]

There is a paucity of long-term data on outcomes of high-risk prostatic adenocarcinoma after moderately hypofractionated radiotherapy with elective nodal treatment and long-term androgen deprivation therapy (ADT). We report long-term control and toxicity outcomes and analyse the predictors of failure and toxicity. The records of 120 consecutive high-risk prostate cancer patients treated in a single institution between February 2012 and December 2016 were retrospectively analysed. A moderately hypofractionted radiotherapy (HypoRT) regimen of 60 Gy in 20 fractions over 4 weeks with simultaneous elective pelvic irradiation to 44 Gy in 20 fractions with intensity-modulated radiotherapy was used, together with long-term ADT with either orchiectomy or medical castration for a total duration of 2–3 years. We analysed biochemical control, metastasis-free survival and late toxicities and their predictive factors using survival analysis. Patients had locally advanced cancers (cT3 77.5%, median pretreatment prostate-specific antigen 30 ng/ml, Gleason score 8–10 in 45.8%). The median follow-up time was 70 months. The 3- and 5-year probability of freedom from biochemical progression was 93% and 80%, respectively. The 5-year probability of freedom from local relapse/intra-pelvic nodal relapse/distant metastases as the site of first failure was 96%/97%/86%, respectively. Gleason score 8–10 and medical ADT for 2–3 years (as opposed to orchidectomy) were independent risk factors for distant metastases. A total of 18 grade 2 and above late gastrointestinal toxicity events and a total of 23 grade 2 and above late genitourinary toxicity events were documented. Patients who underwent a transurethral resection of prostate prior to radiotherapy had worse urological toxicity. HypoRT with elective nodal treatment results in excellent pelvic control. Distant metastases are the primary mode of failure. Risk of metastases is associated with Gleason score and the duration of ADT. Late urinary toxicities are more common in those with prior transurethral resection of prostate. • Moderate hypofractionation is implementable in high-risk localised prostate cancer. • Pelvic control is excellent, and most failures manifest as distant metastases. • Metastasis-free survival is longer with orchidectomy versus 2–3 years of medical castration. • Metastasis-free survival is longer in patients with Gleason 6–7 versus Gleason 8–10. [ABSTRACT FROM AUTHOR]

Taxanes - docetaxel and cabazitaxel - are the most active chemotherapy drugs currently used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, despite a good initial response and survival benefit, nearly all patients eventually develop resistance, which is an important barrier to long-term survival. Resistance to taxanes is also associated with cross-resistance to androgen receptor signaling inhibitors (ARSIs). Unfortunately, other than platinum-based treatments, which have demonstrated some benefit in a subset of patients with Aggressive Variant Prostate Cancer (AVPC), few therapeutic options are available to patients progressing to taxanes. Hence, more research is required to determine whether platinum-based chemotherapy will confer a survival benefit in mCRPC, and the identification of predictive biomarkers and the clinical evaluation of platinum compounds in molecularly selected patients is an urgent but unmet clinical need. The present review focuses on the current status of chemotherapy treatments in mCRPC, interactions with androgen deprivation therapy (ADT) and novel ARSIs, and the main mechanisms of resistance. We will examine the impact of platinum-based treatments in mCRPC and summarize the known predictive biomarkers of platinum response. Finally, future approaches and avenues will be discussed. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a leading cause of cancer mortality in the male population commonly treated with androgen deprivation therapy (ADT) and relapsing as aggressive and androgen-independent castration-resistant prostate cancer (CRPC). In PCa the FGF/FGFR family of growth factors and receptors represents a relevant mediator of cancer growth, tumor-stroma interaction, and a driver of resistance and relapse to ADT. In the present work, we validate the therapeutic efficacy the FDA-approved FGFR inhibitor pemigatinib, in an integrated platform consisting of human and murine PCa cells, and the transgenic multistage TRAMP model of PCa that recapitulates both androgen-dependent and CRPC settings. Our results show for the first time that pemigatinib causes intracellular stress and cell death in PCa cells and prevents tumor growth in vivo and in the multistage model. In addition, the combination of pemigatinib with enzalutamide resulted in long-lasting tumor inhibition and prevention of CRPC relapse in TRAMP mice. These data are confirmed by the implementation of a stochastic mathematical model and in silico simulation. Pemigatinib represents a promising FDA-approved FGFR inhibitor for the treatment of PCa and CRPC alone and in combination with enzalutamide. [ABSTRACT FROM AUTHOR]

Les données et recommandations actuelles relatives à la prise en charge des auteurs de violences sexuelles concernent essentiellement les adultes de sexe masculin. Il existe à ce jour peu de structures spécialisées et de professionnels formés à la prise en charge des adolescents auteurs de violences sexuelles (AAVS). Or, une meilleure connaissance des dispositifs de soin proposés aux AAVS permettrait une meilleure prise en charge par les professionnels de santé. Cet article a pour but de présenter les principaux modèles de prise en charge pédopsychiatriques des AAVS proposés en France. Une revue narrative de la littérature sur la prise en charge pédopsychiatrique proposée aux AAVS âgés de dix à dix-neuf ans en France, incluant des articles publiés entre 2006 et 2019, a été menée. Cette revue de la littérature permet de constater que les dispositifs existants sont rares et hétérogènes (prises en charge individuelles, groupales, familiales, avec un éventuel recours aux traitements médicamenteux). Il n'existe pas d'harmonisation des pratiques ni de recommandations au niveau national. Cependant, un travail autour de la gestion émotionnelle et des relations interpersonnelles semble être un axe de travail commun à ces approches. Il serait intéressant de réaliser une comparaison des différents dispositifs pédopsychiatriques existants afin d'harmoniser les pratiques, de mieux former les professionnels de santé, de potentialiser l'efficience du suivi et de promouvoir la santé psychique et sexuelle des AAVS. Le recours à des prises en charge multimodales semble ainsi une voie prometteuse. Most of data and current recommendations relating to the treatment of sex offenders in France concern adults, and particularly adult males. To date, there are very few specialized structures and health professionals trained in the care of juvenile sex offenders. We assume that a better knowledge of the care models offered to this specific population would allow health professionals to provide and to think better care. The aim of this article is to describe the main care models existing in France. A narrative review of the French literature was conducted, investigating the child psychiatric care offered to juvenile sex offenders aged from ten to nineteen years old. We included articles published between 2006 and 2019. This review of the literature shows that the existing care models in France remain rare and heterogenous. Indeed, they consist in individual, group or family psychotherapy carried out under different conditions, involving in some cases the use of drug treatments such as antidepressants or antiandrogens. Therefore, this review shows that there are neither consensus on practices that should be used, nor recommendations at the national level. However, working on emotional regulation and interpersonal relationships seems to be a common goal of these care models proposed to juvenile sex offenders. We suggest a comparison of the different care models, so as to standardize practices, to ensure better training of health professionals and to promote juvenile sex offenders' psychological and sexual health. The use of multimodal approaches should be encouraged as a basis for improving the care of juvenile sex offenders. [ABSTRACT FROM AUTHOR]