Androgen Deprivation Research Articles

SABR tolerance after prostatectomy: pushing the boundaries of ultrahypofractionation.

To evaluate the feasibility and tolerance of ultra-hypofractionated SABR (stereotactic ablative radiation therapy) protocol following radical prostatectomy. We included patients undergoing adjuvant or salvage SABR between April 2019 and April 2023 targeting the surgical bed and pelvic lymph nodes up to a total dose of 36.25 Gy (7.25 Gy/fraction) and 26 Gy (5.2 Gy/fraction), respectively, in 5 fractions on alternate days with an urethra sparing protocol. Acute and late adverse effects were assessed using the CTCAE v5.0. Pearson's chi-square test for categorical variables was used to compare characteristics and possible associations among different subgroups. Adjuvant radiation therapy (ART) was administered to 40 high-risk patients (detectable post-surgery PSA, Grade Group 4/5, nodal involvement, R1/R2 resection margin), while salvage radiotherapy (SRT) was delivered to 60 patients with rising PSA levels post-undetectable values. Elective nodal irradiation was performed in 57 patients, with 11 additional patients receiving a simultaneous integrated boost (total dose: 40 Gy in 5 fractions) for macroscopic nodal disease. Twenty-four high-risk patients underwent 24-months androgen deprivation therapy (ADT). Treatment was well-tolerated with minimal toxicity. The maximum grade of SABR-related toxicity observed was grade 3. Acute gastrointestinal (GI) toxicity included seven cases of grade 2 and one of grade 3, while acute genitourinary (GU) events were limited to grade 2 in eight patients. Early-late toxicity included two cases of grade 3 and seven of grade 2 for GI, and 11 cases of grade 2 for GU. No toxicity above grade 3 was reported. With a median follow-up of 24 months (6-60 months), 14 patients experienced disease recurrence. Ultra-hypofractionated adjuvant/salvage SABR appears feasible and safe. Longer follow-up is needed to validate observed outcomes.

An AI-Digital Pathology Algorithm Predicts Survival after Radical Prostatectomy from the PLCO Trial.

Clinical variables alone have limited ability to determine which patients will have recurrence after radical prostatectomy (RP). We evaluated the ability of locked multimodal artificial intelligence (MMAI) algorithms trained on prostate biopsy specimens to predict prostate cancer specific mortality (PCSM) and overall survival (OS) among patients undergoing radical prostatectomy with digitized RP specimens. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Randomized Controlled Trial randomized subjects from 1993-2001 to cancer screening or control. A subset of patients who underwent RP with available digitized histopathological images and subsequent survival data were identified. Distant metastasis (DM) and PCSM MMAIs originally trained on biopsy slides for patients undergoing radiation were evaluated for prediction of PCSM and OS. Cox proportional hazards modeling and Kaplan Meier survival curve analysis were utilized. 1032 patients who underwent RP with median follow up of 17 years (IQR 14.3, 19.3 years) were identified. MMAI algorithms for PCSM and DM both predicted PCSM (HR 2.31, 95% confidence interval [CI] 1.6-3.35, p<0.001, and HR 1.96, 95% CI 1.35-2.85, p<0.001, respectively). Similarly, DM and PCSM MMAI predicted OS (HR 1.22, 95% CI 1.01-1.47, p=0.04 and HR 1.19, 95% CI 1.02-1.4, p=0.03). Locked MMAI algorithms previously developed and validated on biopsy specimens from patients undergoing radiation for prostate cancer successfully predicted clinical outcomes when applied to RP specimens from patients treated with surgery. MMAI models and other biomarkers may help select patients who may benefit from post-operative treatment intensification with androgen deprivation therapy or radiation.

Integrative Bioinformatics and Experimental Validation Reveal the Mechanistic Action of Patchouli Alcohol in Prostate Cancer Treatment.

Prostate cancer is an androgen-dependent malignancy, and the use of androgen deprivation therapies frequently results in treatment resistance, relapse, and the development of aggressive castration-resistant tumors. Patchouli alcohol, a tricyclic sesquiterpene derived from Pogostemon cablin of the Labiatae family, has demonstrated potential in modulating inflammatory responses and tumor progression. This study aimed to investigate the mechanisms through which patchouli alcohol influences inflammatory pathways associated with prostate cancer using bioinformatics and experimental validation. Differentially Expressed Genes (DEGs) were identified from the GSE46602 dataset, containing 36 prostate cancer and 14 normal prostate biopsy samples, using the GEO2R tool (adjusted P < 0.05). Functional annotation was performed using GO and KEGG databases, while PPI networks were constructed via STRING and Cytoscape. Key hub genes were identified. To validate the bioinformatics findings, qPCR and Western blotting were employed to confirm the differential expression of selected hub genes in DU145 prostate cancer cells treated with patchouli oil. Bioinformatic analysis revealed 71 DEGs, including 35 upregulated and 36 downregulated genes. Thirteen hub genes were identified (DCK, APRT, ADK, KCNK9, ADSL, PKM, KCNK3, S100A10, ENTPD2, PKLR, ARHGEF38, TPK1, and AK5), which were enriched in pathways, such as MAPK, PI3K-Akt, Ras, and Rap1. Experimental validation confirmed the upregulation of DCK, APRT, KCNK9, ADSL, PKM, S100A10, ENTPD2, PKLR, ARHGEF38, and AK5, and the downregulation of ADK, KCNK3, and TPK1 at both the mRNA and protein levels. Patchouli alcohol appears to influence multiple hub genes associated with prostate cancer progression through its modulation of key cellular signaling and metabolic pathways. These findings support its potential role as a therapeutic agent for prostate cancer.

Clinical Manifestations and Challenges in Adolescent and Adult Females With Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a rare genetic condition that results in cortisol deficiency and excess production of adrenal androgens. While the introduction of newborn screening for CAH has reduced morbidity and mortality, management of CAH remains challenging. Lifelong treatment with glucocorticoids is required to replace the endogenous cortisol deficiency and reduce excess adrenal androgens. Undertreatment or overtreatment with glucocorticoids can lead to multiple disease- and treatment-related comorbidities, including impaired growth and compromised final height, menstrual irregularities and reduced fertility in females, and long-term cardiometabolic complications. In addition to avoiding adrenal crisis and sudden death, treatment goals in adolescent females with CAH are to obtain normal growth and bone maturation and normal timing of puberty. Management of adolescents is particularly challenging due to changes in growth and sex hormone levels that can lead to inadequate suppression of adrenal androgens and increasing independence that can affect treatment adherence. During the transition to adult care, treatment goals focus on preventing symptoms of hyperandrogenism, preserving menstrual regularity and fertility, and providing education and support for issues related to sexuality, atypical genitalia, and/or complications from previous surgical treatment. In addition, patients must be monitored continuously to prevent long-term complications such as decreased bone mineral density, obesity, diabetes, and hypertension. In this review, we discuss the challenges faced by adolescent and adult females with CAH and provide guidance to health-care professionals to help patients to navigate these challenges.

« Augmented radiotherapy » in the management of high-risk prostate cancer (PCa): A systematic review.

In patients with high-risk (HR) prostate cancer (PCa) treated with radiotherapy and androgen deprivation therapy (ADT), intensification with androgen receptor pathway inhibitor (ARPI) improves overall survival (OS), at the cost of significant side-effects. We hypothesized that "augmented RT" schedules (defined as either dose-escalation on the prostate gland over 78 Gy and/or addition of whole pelvic radiotherapy (WPRT)), combined with long-term ADT can reach excellent prostate cancer specific survival (PCSS) in this population with little detrimental impact on quality of life. We searched Pubmed database until February 8, 2024. Studies reporting both oncological and toxicity outcomes after "augmented RT" were deemed eligible. Studies without ADT or with ARPI intensification were deemed ineligible. Dose-escalation within the prostate gland at doses over 78 Gy halved the risk of biochemical recurrence at 5 years, with however no impact on PCSS. The addition of WPRT provides a 5-year disease-free survival (DFS) reaching 89.5 % at 5 years, with no significant increase in late grade≥ 2 genito-urinary (GU) or gastrointestinal (GI) toxicity. Combined approaches result in 9-year PCSS ranging between 96.1 % and 100 %. Most approaches demonstrated excellent safety profiles. "Augmented RT" reached excellent oncological outcomes, with minimal additional toxicity. The development of biomarkers might lead to further treatment personalization, in the rapidly evolving landscape of systemic therapies.

The real prevalence and clinical courses of non-metastatic castration-resistant prostate cancer: a retrospective single-institutional study.

Non-metastatic castration-resistant prostate cancer (PCa) has become clinically important in PCa management, with treatments aiming to delay metastasis. However, limited data exist on its prevalence and patient characteristics in real-world settings. We retrospectively investigated the clinical records of 1929 patients who were treated for localized PCa between 2005 and 2018. From this population, we counted patients who progressed to non-metastatic castration-resistant PCa, and summarized the characteristics of the patients. Among patients who underwent radical prostatectomy (796 patients), radiation therapy (1021 patients), or primary androgen deprivation therapy (ADT) (112 patients), 0.9%, 0.9%, and 5.4%, respectively, were diagnosed with non-metastatic castration-resistant PCa over a median follow-up of 5.5years. Including referred cases, a total of 45 non-metastatic castration-resistant PCa patients were analyzed. The median age at non-metastatic castration-resistant PCa diagnosis was 76years, with a median time of 4.8years from the initiation of ADT to non-metastatic castration-resistant PCa development. From the initial PCa diagnosis, the median time to non-metastatic castration-resistant PCa was 5.9years. Median metastasis-free survival was 5.2years, while overall survival was 6.3years. This study reports the prevalence of non-metastatic castration-resistant PCa at our institution and provides clinical findings of non-metastatic castration-resistant PCa patients by analyzing consecutive localized PCa cases through comprehensive medical chart reviews for every patient.

Perceived cognitive impairment and occupational functioning in prostate cancer survivors: an exploratory cross-sectional analysis.

Perceived cancer-related cognitive impairment (CRCI) has been reported in prostate cancer survivors. Little is known about how CRCI impacts occupational functioning in working-aged prostate cancer survivors (PCS). This study aimed to investigate the association between CRCI and occupational functioning in PCS. Data from 51 PCS, who were employed at the time of diagnosis, undergoing hormonal treatments (e.g., androgen deprivation therapy) or 'watchful waiting'/ 'active surveillance', were analysed. An online survey assessed CRCI using the FACT-Cog Perceived Cognitive Impairments (PCI20) subscale, the EORTC-QLQ-30 two-item cognitive functioning scale, and a single 'Yes/No' CRCI item (i.e., were 'changes in thinking (e.g., memory, attention)' experienced as a treatment side effect). PCS also indicated 'Yes/No' to changes to their ability to work, performance of work duties, and decreased work hours. Logistic regression analyses examined the relationship between CRCI measures and occupational outcomes. Of the 51 PCS, 19 (37%) endorsed experiencing cognitive side effects from treatment. The single 'Yes/No' CRCI question was significantly associated with perceived changes in work ability and ability to perform work duties at the same level. PCI20 and the EORTC-QLQ-30 cognitive functioning scale were not significantly associated with any occupational outcomes. Perceived CRCI is associated with adverse changes to occupational functioning and is important to consider when PCS are making plans to return-to-work following treatment. Prostate cancer survivors may experience cognitive changes, which may impact their work ability.

Development of Novel Nomograms to Predict 5- and 7-Year Biochemical-Recurrence-Free Survival in High-Risk Prostate Cancer Patients After Carbon-Ion Radiotherapy and Androgen Deprivation Therapy

Background: The aim of this study was to develop nomograms predicting 5- and 7-year biochemical-recurrence (BCR)-free survival in high-risk prostate cancer (PCa) patients treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). Methods: We retrospectively evaluated 785 high-risk PCa patients treated with CIRT and ADT. Based on the least absolute shrinkage and selection operator model, two nomograms predicting 5- and 7-year BCR-free survival were developed and internally validated. The ability of each nomogram to predict BCR-free survival was determined by calculating the area under the survival curve (AUC). Results: The 5- and 7-year BCR-free survival rates were 92.1% and 89.3%, respectively. Age, prostate-specific antigen level, clinical T stage, and Gleason score were incorporated into the nomogram predicting 5-year BCR-free survival. In addition to these variables, the percentage of positive biopsy cores was also added to the nomogram predicting 7-year BCR-free survival. The AUC value of each nomogram showed suboptimal-to-good discrimination. Conclusions: We developed the first nomograms accurately predicting BCR-free survival in high-risk PCa patients treated with CIRT and ADT. These nomograms will enable adequate understanding and explanation of BCR-free survival to patients when clinicians use them.

Unraveling the bidirectional link between cancer and dementia and the impact of cancer therapies on dementia risk: A systematic review and meta-analysis.

Observational studies on the cancer-dementia relationship have yielded controversial results. This study systematically reviews the evidence to clarify this association. We searched Embase, Global Health, Ovid Medline, and APA PsycInfo. Colorectal and lung cancers showed the greatest risk reduction for all-cause dementia (ACD) and Alzheimer's disease (AD), respectively, while melanoma and colorectal cancers had the largest reduction in vascular dementia (VaD). Prostate cancer survivors on androgen deprivation therapy (ADT) had a higher risk of ACD/AD, while breast cancer patients on tamoxifen had a lower AD risk. Chemotherapy was linked to a reduced AD risk. ACD patients saw a 30% risk reduction for bladder, colorectal, and lung cancers, while AD patients had a ≈ 35% reduction for bladder and lung cancers. Our study urges clinicians to monitor cognitive function in cancer patients, especially those on ADT, tamoxifen, or chemotherapy and highlights the need for research into cancer-dementia mechanisms. HIGHLIGHTS: Cancer survivors have an 8% to 14% lower risk of dementia, while those with dementia have a 25% lower cancer risk. Colorectal and non-melanoma skin cancers were associated with reduced risks of all-cause dementia (ACD; 16%/9%), Alzheimer's disease (AD; 13%/5%), and vascular dementia (VaD; 24%/9%). Lung cancer reduced AD risk by 17%, and melanoma reduced VaD risk by 27%. ACD and AD patients had lower risks of lung (30%/36%), bladder (32%/34%), breast (26%/20%), and colorectal (31%/28%) cancers. Tamoxifen and chemotherapy reduced AD risk, while androgen deprivation therapy increased ACD risk.

Prognostic significance of the mEPE score in intermediate-risk prostate cancer patients undergoing ultrahypofractionated robotic SBRT.

This study aimed to evaluate the prognostic significance of magnetic resonance imaging (MRI) parameters on biochemical failure-free survival (BFS) in patients diagnosed with intermediate-risk prostate cancer and treated with robotic ultrahypofractionated stereotactic body radiotherapy (SBRT) without androgen deprivation therapy (ADT). Aretrospective analysis was conducted in patients with intermediate-risk prostate cancer undergoing robotic SBRT delivered in five fractions with atotal radiation dose of 35-36.25 Gy. The primary endpoint was biochemical failure as defined by the Phoenix criteria. Among other clinicopathological data, Tstage, Prostate Imaging-Reporting and Data System (PI-RADS) score, and multiparametric magnetic resonance imaging-based extra-prostatic extension (mEPE) score were collected and analyzed using the log-rank test. Atotal of 74patients were eligible for analysis. Median age at treatment was 68.8 years and median prostate volume was 47.8cm3. Fifty-four and 14patients were diagnosed with Gleason scores 7a and 7b, respectively. In total, 40patients were classified as having unfavorable intermediate-risk prostate cancer according to American Urological Association/American Society for Radiation Oncology/ Society of Urologic Oncology (AUA/ASTRO/SUO) guidelines. The median follow-up was 30months (range: 4-91.2 months; interquartile range (IQR): 18.5-48months). The 3‑year BFS was 92%. Atotal of 12(16.2%) biochemical failures were reported. In univariate analysis, an mEPE score of 5, the delivered total radiation dose (35 Gy vs. 36.25 Gy), and aprostate-specific antigen (PSA) nadir >1 ng/ml were associated with lower BFS (mEPE-BFS: p < 0.001, total radiation dose-BFS: p = 0.04, PSAnadir-BFS: p =< 0.001). Patients diagnosed with intermediate-risk prostate cancer with ahigh mEPE score are more likely to experience biochemical failure after SBRT. Treatment intensification measures, such as administration of concomitant ADT, should be considered.

Androgen Receptor Pathway Inhibitor Therapy for Advanced Prostate Cancer

The open-label randomized phase 2 LACOG0415 trial evaluated 3 treatment strategies for patients with advanced castration-sensitive prostate cancer (CSPC): androgen deprivation therapy (ADT) plus abiraterone acetate and prednisone (AAP), apalutamide (APA) alone, or APA plus AAP. To investigate the association of ADT plus AAP, APA alone, or APA plus AAP with health-related quality of life (HRQOL) in patients with advanced CSPC in the LACOG0415 trial. The LACOG0415 randomized clinical trial comprised 128 patients with advanced CSPC who were randomized (1:1:1) to 1 of 3 treatment arms from October 16, 2017, to April 23, 2019. Statistical analysis was conducted from March to September 2022. Patients were randomized (1:1:1) to 1 of 3 treatment arms: ADT plus AAP, APA alone, or APA plus AAP. Health-related quality of life was evaluated using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, including its subscales, completed at baseline and every 4 weeks until week 25. FACT-P scores range from 0 to 156, and higher scores indicate better HRQOL. Mean changes in score from baseline to week 25 were adjusted by baseline score and were calculated to evaluate whether there was a difference according to the treatment arm using a mixed-effect model for repeated measures. Time to deterioration was estimated by Kaplan-Meier curves and compared by stratified log-rank test. Analysis was performed on an intention-to-treat basis. A total of 128 patients with advanced CSPC were randomized to receive ADT plus AAP (n = 42; median age, 69.8 years [IQR, 58.9-71.6 years]), APA alone (n = 42; median age, 69.5 years [IQR, 59.8-72.6 years]), or APA plus AAP (n = 44; median age, 71.0 years [IQR, 63.0-72.3 years]). Metastatic disease was present in 95 patients (74.2%), high-risk biochemical recurrence disease in 22 (17.2%), and locally advanced disease in 11 (8.6%). There was no significant difference in baseline mean (SD) FACT-P total scores and subscales among the 3 treatment arms (FACT-P total score: ADT plus AAP arm, 118.5 [24.3]; APA alone arm, 116.1 [23.9]; AAP plus APA arm, 114.9 [18.1]; P = .69). Health-related quality of life was maintained during treatment period, and there were no statistically significant differences at 25 weeks in mean (SD) FACT-P total scores or subscales between treatment arms (FACT-P total score: ADT plus AAP arm, 122.3 [20.4]; APA alone arm, 119.5 [16.4]; AAP plus APA arm, 119.9 [20.3]). The APA alone and AAP plus APA arms were not associated with meaningful improvements in HRQOL compared with the ADT plus AAP arm, except in time to deterioration of the emotional well-being score, which was more favorable in the APA alone arm (reference arm: ADT plus AAP arm; APA alone arm: hazard ratio, 0.37 [0.15-0.85]; P = .02; ADT plus AAP arm: hazard ratio, 0.56 [0.26-1.19]; P = .13). Limitations include short follow-up period and the absence of other questionnaires to capture differences between therapies. In this prespecified secondary analysis of a randomized clinical trial of ADT plus AAP, APA alone, or APA plus AAP for patients with advanced CSPC, HRQOL was not statistically different between treatments with APA alone or APA plus AAP as compared with ADT plus AAP. Larger studies with longer follow-up and more specific questionnaires are needed to further evaluate HRQOL with these treatment strategies. ClinicalTrials.gov Identifier: NCT02867020.

Early Versus Delayed Androgen Deprivation Therapy for Biochemical Recurrence After Local Curative Treatment in Non-Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review of the Literature.

The ideal timing of androgen deprivation therapy (ADT) for patients with biochemical recurrence (BCR) of prostate cancer (PCa) remains controversial due to its side effects and uncertain impact on survival outcomes. We performed a review of the current literature by comprehensively searching the PubMed, Embase, and Cochrane databases to determine the optimal timing of ADT initiation after biochemical recurrence. We selected 26 studies including systematic reviews, randomized controlled trials (RCTs), and retrospective studies, while also reviewing practice guidelines. Not all patients with BCR cancer experience clinical or radiological progression. While early ADT may delay progression, evidence of its effect on PCa-specific mortality remains inconclusive. The PSA thresholds for initiating ADT vary, complicating decision-making. Key predictors of progression include a short PSA doubling time (PSADT), a high Gleason score (GS), and a brief interval to BCR of PCa post-radiotherapy (RT). Combining ADT with androgen receptor pathway inhibitors (ARPIs) has been shown to improve metastasis-free survival in high-risk patients. The ideal timing of ADT initiation in BCR PCa remains uncertain. Early ADT can help control the progression, but its effect on PCa-specific mortality is unclear. Stratifying patients by their risk factors, such as their PSADT, GS, and time to BCR can guide individualized treatment. In high-risk patients, delaying ADT should be avoided, while combining ADT with an androgen receptor pathway inhibitor (ARPI) may further improve outcomes.

An Updated Systematic Review and Network Meta-Analysis of First-Line Triplet vs. Doublet Therapies for Metastatic Hormone-Sensitive Prostate Cancer.

Purpose: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies. Methods: We conducted a systematic search for RCTs on systemic therapies for mHSPC using MEDLINE, Embase, and the Web of Science Core Collection in September 2024. An NMA utilizing random-effects models was performed to compare progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence (PROSPERO: CRD42024591458). Results: A total of 12 RCTs (n = 11,954) were included in our NMAs. Triplet therapies were associated with significant improvements in PFS compared to ARPI-based doublet therapies (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59-0.93; p = 0.01), but the difference did not reach the conventional levels of statistical significance for OS (HR: 0.82; 95% CI: 0.67-1.01; p = 0.059). In a subset analysis, compared to ARPI-based doublet therapies, triplet therapies showed a significant improvement in PFS in patients with high-volume disease (HR: 0.64; 95% CI: 0.47-0.88; p < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; p = 0.7). No significant difference in grade ≥ 3 AEs was observed between triplet therapies and ARPI-based doublet therapies. The main limitations include patient heterogeneity and limited follow-up in some studies. Conclusions: Triplet therapies can improve the oncologic outcomes of patients with mHSPC compared to ARPI-based doublet therapies, without significantly increasing severe AEs. These findings warrant further confirmation in a head-to-head trial powered for overall survival.

Sulfur dioxide (SO2) donors, a new gasotransmitter, improve erectile dysfunction after castration in a rat model.

Androgen deprivation is associated with erectile dysfunction (ED). In different animal models, sulfur dioxide (SO2) donors Na2SO3 and NaHSO3 reduced oxidative stress, fibrosis, and inflammation which contribute to the pathogenesis of androgen deprivation-induced ED, however the effect of SO2 donors on ED in castrated rats were not known. To investigate the therapeutic effect of SO2 donors, Na2SO3/NaHSO3, on ED in castrated rat model. Sprague-Dawley male rats (n=30) were divided into four groups; control, control-treated with Na2SO3/NaHSO3, castrated, and castrated-treated with Na2SO3/NaHSO3. Castration was induced by bilateral scrotal incisions. Four weeks after castration, rats were treated with Na2SO3/NaHSO3 (0.54/0.18mmol/kg) intraperitoneally (i.p.) for 4 weeks. Intracavernosal pressure/mean arterial pressure ratio (ICP/MAP) and total ICP were measured to evaluate in vivo erectile responses in cavernosal tissue. In vitro relaxant and contractile responses were measured in all groups. Endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), PI3 kinase p85 alpha + gamma (PI3K), protein kinase B (AKT 1/2/3), cysteine dioxygenase-1 (CDO), and aspartate aminotransferase (AAT) expressions and localizations were evaluated by Western blotting and immunohistochemical staining. The smooth muscle/collagen ratio was evaluated by Masson's trichrome staining. Prostate (p<0.001) and penis weight (p<0.001), total serum testosterone (T) level (p<0.001), and in vivo erectile responses (p<0.001 at 7.5 and 5V, p<0.05 at 2.5V for ICP/MAP and total ICP) of castrated rats were decreased compared with control. SO2 donors improved reduced ICP/MAP ratio and total ICP (p<0.01 at 7.5, 5, and 2.5V for ICP/MAP and total ICP) nitrergic (p<0.05 at 20Hz), and endothelium-independent relaxation (p<0.05 at 1nM, p<0.01 at 10µM and 100µM) in the castrated group. Decreased eNOS (p<0.01) and AKT (p<0.001) protein expressions in the castrated group were normalized by SO2. SO2 donors partially restored the reduced smooth muscle/collagen ratio in the castrated group (p<0.001). The expressions and locations of nNOS, PI3K, CDO, and AAT proteins in penile tissue did not alter among all groups (p>0.05). SO2 donors significantly improve erectile functions and relaxation responses in a castrated rats via ameliorating endothelial damage and fibrosis. Androgen deprivation inhibits the AKT/eNOS signaling while SO2 activates this pathway. SO2 donors may be promising for the treatment of ED in hypoandrogenic men.

Evaluation of clinical risk stratification to determine benefit from long-term versus short-term androgen deprivation in high-risk localized prostate cancer.

Patients treated with RT and long-term androgen deprivation therapy (ltADT) for high-risk localized prostate cancer (HRLPC) with 1 high-risk factor (any of Gleason ≥8, PSA > 20 ng/mL, ≥cT3; "high-risk") have better outcomes than those with 2-3 factors and/or cN1 disease ("very high risk"). We evaluated whether this risk stratification could determine benefit from ltADT versus short-term (stADT). The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) repository of randomized trials was queried to identify eligible patients and trials. The key outcomes of interest were metastasis-free survival (MFS), overall survival (OS), time to metastasis (TTM) and prostate cancer-specific mortality (PCSM). Stratified Cox and Gray's regression were used to obtain the overall treatment effect for outcomes and risk groups, and the Wald interaction test to estimate whether treatment benefit differed by risk group or trial. Heterogeneity of studies was assessed by Cochran's Q and I2. 2780 patients from 3 trials were included. Patients with very-high risk disease had greater benefit with ltADT compared to high-risk disease (MFS HR 0.77 [0.68-0.88] vs. 0.89 [0.76-1.03]; TTM 0.61 [0.51-0.74] vs. 0.77 [0.59-0.99]; PCSM 0.71 [0.56-0.90] vs. 0.82 [0.59-1.14]; OS 0.87 [0.76-1.00] vs. 0.93 [0.79-1.08]), but there was no statistically significant difference in treatment effect by risk group (p-interaction >0.1). Heterogeneity for treatment effect across trials was low in the very high-risk group and moderate in the high-risk group. Clinical risk stratification merits further evaluation in clinical trials to identify which patients with HRLPC may benefit from ltADT versus stADT.

Osteoporosis in Older Men: Informing Patient Management and Improving Health-Related Outcomes.

Osteoporosis has been usually considered a female disease, generally causing more fracture risk and complications in adult and older women compared to older men. While vertebral fractures occur in a small proportion of men during middle age, men generally fracture about 10years later than women, with significant increases in fracture risk after about age 75. Independent of age, men experiencing fragility fractures have a higher risk of life-threatening events compared to women, but the risk of secondary fragility fracture overlaps between men and women. Often, male osteoporosis recognizes the overlap between secondary causes and primary osteoporosis risk factors. Assessment through physical examination, history, and laboratory tests is recommended, with dual-energy X-ray absorptiometry of bone density being the preferred diagnostic test for osteoporosis in men. A treatment program should include awareness of diet and vitamin D status, fall risk reduction, and pharmaceutical therapy. Medications that are fracture-reducing in older women should also achieve fewer fractures in older men; however, there is a paucity of studies in men with the primary outcome of fracture risk reduction. Most older men with osteoporosis should be treated with oral or intravenous bisphosphonates, denosumab especially when on androgen deprivation therapy, and initial anabolic treatment should be considered for men at very high risk of fracture. This review summarizes the main features of osteoporosis and fragility fractures in men and reports findings from the available pharmacological and non-pharmacological studies conducted in men.

Angelica gigas Nakai (Korean Dang-gui) Root Alcoholic Extracts in Health Promotion and Disease Therapy - active Phytochemicals and In Vivo Molecular Targets.

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extracts have been marketed as dietary supplements in the United States for memory health and pain management. We have recently reviewed the pharmacokinetics (PK) and first-pass hepatic metabolism of ingested AGN supplements in humans for the signature pyranocoumarins decursin (D, Cmax 1x), decursinol angelate (DA, Cmax ~ 10x) and their common botanical precursor and hepatic metabolite decursinol (DOH, Cmax ~ 1000x). Here we update in vivo medicinal activities of AGN and/or its pyranocoumarins and furanocoumarin nodakenin in cancer, pain, memory loss, cerebral ischemia reperfusion stroke, metabolic syndrome and vascular endothelial dysfunctions, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, osteoporosis and osteoarthritis. Given their polypharmacology nature, the pertinent mechanisms of action are likely misrepresented by many cell culture studies that did not consider the drug metabolism knowledge. We report here Rho-associated protein kinases (ROCK1/2) as novel targets for DA and DOH. Combining with published inhibitory activity of DOH on acetylcholinesterase, agonist activity of DOH and antagonist/degrader activity of DA/D on androgen and estrogen receptors, D/DA promoting activity for glutamic acid decarboxylase (GAD)- gamma-aminobutyric acid (GABA) inhibitory axis and inhibition of glutamate dehydrogenase (GDH), monoamine oxidase-A (MAO-A) and transient receptor potential vanilloid 1 (TRPV1), we postulate their contributions to neuro-cognitive, metabolic, oncologic, vascular and other beneficial bioactivities of AGN extracts. A clinical trial is being planned for an AGN extract to manage side effects of androgen deprivation therapy in prostate cancer patients.

The prognostic value of serum testosterone to BMI ratio in Chinese males with prostate cancer treated by androgen deprivation therapy: a single-center study.

To investigate the prognostic value of serum testosterone combining with body mass index (BMI) on the prostate cancer (PCa) after androgen deprivation therapy (ADT). In this study, we included the patients from June, 2017 to June, 2022 who were diagnosed with PCa and received ADT. The data of these patients were reviewed and analyzed. The ratio of serum testosterone to BMI (T/BMI) was calculated and the patients were divided into high T/BMI and low T/BMI group based on the optimal T/BMI cutoff value. A total of 84 patients were screened and divided into high T/BMI group (> 0.244) (n = 35) and low T/BMI group (≤ 0.244) (n = 49). Higher possibility of metastasis occurred in low T/BMI than high T/BMI group (P < 0.001) and the PFS in low T/BMI group was significantly lower (P < 0.001) compared to high T/BMI group. Serum testosterone in the high BMI group was significantly lower than that in the non-high BMI group. Testosterone, BMI, and T/BMI were significantly different in the tumor progression group than that in non-tumor progression group (P < 0.05). The result from univariate Cox regression analysis demonstrated that BMI (HR = 1.247, P = 0.001), testosterone (HR = 0.936, P = 0.009), T/BMI(HR = 1.036, P = 0.017), and the metastasis (HR = 1.593, P = 0.025) were significantly correlated with PFS. The result from multivariate Cox regression analysis demonstrated that T/BMI (HR = 1.037, P = 0.015) was significantly correlated with PFS. T/BMI has a certain predicting value for the prognosis and correlated with PFS of the PCa patients. Higher level of BMI and lower level of testosterone are more associated with poor outcomes than those with low BMI and high testosterone.

Exploring B7-H4's role in prostate cancer dormancy post-androgen deprivation therapy: extracellular matrix interactions and therapeutic opportunities.

Prostate cancer (PCa) is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique PCa patient-derived xenograft (PDX) dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of PCa patients treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during PCa dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.

A Personalized Approach for Oligometastatic Prostate Cancer: Current Understanding and Future Directions.

Oligometastatic prostate cancer (OMPC) represents an intermediate state in the progression from localized disease to widespread metastasis when the radiographically significant sites are limited in number and location. With no clear consensus on a definition, its diagnostic significance and associated optimal therapeutic approach remain controversial, posing a significant challenge for clinicians. The current standard of care for metastatic disease is to start systemic therapy; however, active surveillance and targeted radiotherapy have become attractive options to mitigate the long-term effects of androgen deprivation therapy (ADT). Furthermore, evolving biomarker methodologies may further define optimal treatment selection. In this review, we summarize the current understanding that guides the treatment of OMPC, with a focus on how host response can be an important contributing factor. Evolving scientific understanding and clinical development will continue to shape the landscape of treatment strategies for this distinct disease state.