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A course of androgen-deprivation therapy before and during radiotherapy prolonged 10-year survival by about 7% among men with intermediate-risk prostate cancer. The risk of erectile dysfunction from the addition of hormone therapy was also about 7% higher. In the 1980s, advances in both surgery and radiotherapy for clinically localized prostate cancer led to their acceptance as successful treatments, with considerable reductions in harmful side effects as compared with earlier treatments. 1 In the 1990s, reversible androgen suppression with the use of luteinizing hormone–releasing hormone analogues and oral antiandrogen agents was shown to induce apoptotic regression in androgen-responsive cancers, 2 potentially improving the prospects of local control and the duration of survival free of metastatic disease. Among patients with locally advanced disease, phase 3 clinical trials 3 , 4 showed that when added to radiotherapy, long-term treatment with these agents (≥2 years) . . .

A current standard treatment for locally advanced prostate cancer is external-beam radiotherapy combined with 3 years of androgen suppression. Adverse events, such as myocardial infarction, are associated with long-term androgen suppression. This trial examined survival after treatment with long-term (3 years) or short-term (6 months) androgen suppression, plus external-beam radiotherapy, in men with locally advanced prostate cancer. Overall and prostate-cancer–specific survival in the group receiving short-term androgen suppression was inferior to that in the group receiving long-term suppression. This trial examined survival after treatment with long-term (3 years) or short-term (6 months) androgen suppression, plus external-beam radiotherapy, in men with locally advanced prostate cancer. Overall and prostate-cancer–specific survival in the group receiving short-term androgen suppression was inferior. Overall survival among patients with locally advanced prostate cancer has improved with the use of external-beam radiotherapy combined with long-term androgen suppression (≥2 years) as compared with the use of external-beam radiotherapy and deferral of hormonal treatment until relapse. 1 – 5 However, long-term androgen suppression can reduce the quality of life and increase the risk of fatal myocardial infarction, 6 fractures, 7 and the metabolic syndrome. 8 These risks might be lowered by replacing long-term androgen suppression with short-term suppression (6 months), which has been found to reduce mortality from localized prostate cancer. 9 The European Organization for Research and Treatment of Cancer (EORTC) conducted . . .

Background Enzalutamide is an oral androgen receptor targeted agent that has been shown to improve survival in PREVAIL trials and has been approved for patients with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). Meanwhile, flutamide is a non-steroidal oral anti-androgen that was commonly used before the approval of bicalutamide. The objective of the OCUU-CRPC study is to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative anti-androgen therapy (AAT) after combined androgen blockade (CAB) therapy that included bicalutamide in patients with CRPC. Methods A total of 100 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day, 4 × 40 mg capsules once daily) and flutamide (375 mg/day; 3 × 125 mg tablets thrice daily) groups. The primary endpoint for the drug efficacy is the response rate of prostate-specific antigen (PSA) (i.e., the ratio of patients whose PSA declined by ≥50% from baseline) at 3 months. Meanwhile, the secondary endpoints are PSA progression rate at 3 and 6 months, PSA response rate at 6 months, change in quality of life, PSA progression-free survival, and safety. The patient registration started in January 2015 and will end in March 2018, and the follow-up period is 6 months after the last patient registration. The main result will be reported in March 2019. Discussion In the OCUU-CRPC study, we compare the efficacy and safety of enzalutamide or alternative AAT with flutamide in participants with CRPC who were previously treated with a CAB therapy with bicalutamide. The expected results of this study will be that enzalutamide is superior to flutamide in terms of PSA response. A longer time to disease progression with enzalutamide over flutamide may translate to better overall survival. However, flutamide may be more accessible for patients owing to its lower cost than enzalutamide. Trial registration The OCUU-CRPC study was prospectively registered at clinicaltrials.gov ( NCT02346578 , January 2015) and University Hospital Medical Information Network ( UMIN000016301 , January 2015).

The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment. The trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial. Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07–13·84) for all patients and 14·8 years (7·18–17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3–33·6) in the NHT plus WPRT group, 23·5% (18·7–28·3) in the NHT plus PORT group, 19·4% (14·9–24·0) in the WPRT plus AHT group, and 30·2% (25·0–35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group. In this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT. National Cancer Institute.

Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.

Rationale Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)‐induced stroke rats remain largely unknown. Methods We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular‐associated and apoptotic proteins in PT‐induced stroke rats treated with flutamide and seven consecutive days of PBM treatment (350 mW, 808 nM, 2 min/day). To gain further insights into the mechanism of PBM on testosterone synthesis, we used testosterone synthesis inhibitors to study their effects on bEND.3 cells. Results We showed that PT stroke caused a decrease in cerebrovascular testosterone concentration, which was significantly increased by 7‐day PBMT (808 nm, 350 mW/cm2, 42 J/cm2). Furthermore, PBMT significantly increased cerebral blood flow (CBF) and the expression of vascular‐associated proteins, while inhibiting vascular permeability and reducing endothelial cell apoptosis. This ultimately mitigated behavioral deficits in PT stroke rats. Notably, treatment with the androgen receptor antagonist flutamide reversed the beneficial effects of PBMT. Cellular experiments confirmed that PBMT inhibited cell apoptosis and increased vascular‐associated protein expression in brain endothelial cell line (bEnd.3) subjected to oxygen‐glucose deprivation (OGD). However, these effects were inhibited by flutamide. Moreover, mechanistic studies revealed that PBMT‐induced testosterone synthesis in bEnd.3 cells was partly mediated by 17β‐hydroxysteroid dehydrogenase 5 (17β‐HSD5). Conclusions Our study provides evidence that PBMT attenuates cerebrovascular injury and behavioral deficits associated with testosterone/AR following ischemic stroke. Our findings suggest that PBMT may be a promising alternative approach for managing cerebrovascular diseases. Photobiomodulation therapy mitigates cerebrovascular injury, including damage to the blood‐brain barrier, reduced cerebral blood flow, and decreased levels of vascular tight junction proteins, ameliorates the behavioral deficits associated with testosterone following an ischemic stroke.

The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c–T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76–82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50–82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87–92] vs 81% [78–85]; hazard ratio [HR] 1·88 [95% CI 1·12–3·15]; p=0·01). 5-year overall survival (95% [95% CI 93–97] vs 86% [83–89]; HR 2·48 [95% CI 1·31–4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92–96] vs 83% [80–86]; HR 2·31 [95% CI 1·23–3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3–4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. Spanish National Health Investigation Fund, AstraZeneca.

Several studies have shown the efficacy of endocrine therapy in combination with radiotherapy in high-risk prostate cancer. To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression. This randomised trial included men from 47 centres in Norway, Sweden, and Denmark. Between February, 1996, and December, 2002, 875 patients with locally advanced prostate cancer (T3; 78%; PSA<70; N0; M0) were centrally randomly assigned by computer to endocrine treatment alone (3 months of total androgen blockade followed by continuous endocrine treatment using flutamide; 439 patients), or to the same endocrine treatment combined with radiotherapy (436 patients). The primary endpoint was prostate-cancer-specific survival, and analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787. After a median follow-up of 7·6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23·9% in the endocrine alone group and 11·9% in the endocrine plus radiotherapy group (difference 12·0%, 95% CI 4·9–19·1%), for a relative risk of 0·44 (0·30–0·66). At 10 years, the cumulative incidence for overall mortality was 39·4% in the endocrine alone group and 29·6% in the endocrine plus radiotherapy group (difference 9·8%, 0·8–18·8%), for a relative risk of 0·68 (0·52–0·89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74·7% vs 25·9%, p<0·0001; HR 0·16; 0·12–0·20). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group. In patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone. In the light of these data, endocrine treatment plus radiotherapy should be the new standard. Schering-Plough, Abbott Scandinavia, Nordic Cancer Union, Swedish Cancer Society (070604), Norwegian Cancer Society, Lions Cancer Foundation, and Umeå University.

The g-C3N4/CS biosensor was designed, fabricated, and tested using compounds such as glucose, urine, lactose, and flutamide at a molarity of 10 µM, which could demonstrate a high sensitivity of 200 μm-1 for flutamide. Powerful effective medium theory and FDTD simulation were used to predict the most favorable mode and plasmonic properties of a graphite carbon nitride and chitosan nanocomposite. The research also explores the characteristics of surface plasmon resonance exhibited by the nanocomposite as the chitosan content is adjusted. Subsequent simulations are conducted on nanocomposites incorporating a thin layer and a modified gold structure. The intricate simulations ultimately reveal the optimal combination, tested under three different pH conditions (6.2, 7.2, and 8). In acidic conditions, the kinetic profile yielded a K D = 3.45 × 10 −7 , surpassing the K D value of a thin film. The Au significantly outperformed the alternative material. The biosensor demonstrated linear behavior across a wide concentration range from 1 to 150 µM, achieving a detection limit of 120 nM with its high sensitivity.

A novel particulate delivery matrix based on ionically crosslinked casein (CAS) nanoparticles was developed for controlled release of the poorly soluble anticancer drug flutamide (FLT). Nanoparticles were fabricated via oil-in-water emulsification then stabilized by ionic crosslinking of the positively charged CAS molecules below their isoelectric point, with the polyanionic crosslinker sodium tripolyphosphate. With the optimal preparation conditions, the drug loading and incorporation efficiency achieved were 8.73% and 64.55%, respectively. The nanoparticles exhibited a spherical shape with a size below 100 nm and a positive zeta potential (+7.54 to +17.3 mV). FLT was molecularly dispersed inside the nanoparticle protein matrix, as revealed by thermal analysis. The biodegradability of CAS nanoparticles in trypsin solution could be easily modulated by varying the sodium tripolyphosphate crosslinking density. A sustained release of FLT from CAS nanoparticles for up to 4 days was observed, depending on the crosslinking density. After intravenous administration of FLT-CAS nanoparticles into rats, CAS nanoparticles exhibited a longer circulation time and a markedly delayed blood clearance of FLT, with the half-life of FLT extended from 0.88 hours to 14.64 hours, compared with drug cosolvent. The results offer a promising method for tailoring biodegradable, drug-loaded CAS nanoparticles as controlled, long-circulating drug delivery systems of hydrophobic anticancer drugs in aqueous vehicles.