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Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer.We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 μg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment.Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups).The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient.None.

Summary: Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma. : Bankar et al. show that acylsulfonamides produce analgesic activity at low multiples of the IC50 for inhibition of NaV1.7, in contrast to studies with arylsulfonamides that required >10 times the IC50. The improvement correlates with longer residency time on the target channels. Keywords: pain, sodium channel, inherited erythromelalgia, diabetic neuropathy, residence time

Isothermal vapour-liquid data were measured for the krypton-xenon system at ten temperatures between 165 and 270 K and pressures to 6.7 MPa, using a vapour recirculating technique. The mixture critical line has been located in (P, T, x) space. Barker's method of data reduction has been used to test the thermodynamic consistency of isotherms below the critical temperature of krypton (209.4 K) and the excess Gibbs energy was evaluated, at the same temperatures, as a function of composition. The results of the experiments have been compared with predictions of the Peng-Robinson equation of state. With interaction parameter calculated by fitting the isotherm of 200.64 K, this equation predicts the liquid and vapour phase compositions to within about a few mole per cent over most of the experimental range.

The components of the renin-angiotensin system have been colocalized in many tissues suggesting that local generation of angiotensin II can regulate blood flow in specific organs or tissues. This in combination with the fact that proliferating tissues require angiogenesis and increased blood flow to develop have led us to study the relationship of angiotensinogen mRNA production to cell cycle regulation. Reuber H35 (H4IIE) cells were growth-arrested by serum deprivation. Cells were then treated with 10% fetal calf serum, depleted serum, or insulin. Insulin and serum were equally potent at increasing beta-actin mRNA levels, depressing angiotensinogen mRNA levels, and in increasing [3H]methyl thymidine incorporation. The half-maximal insulin effect occurred at 5 x 10(-9) M. Insulin-like growth factor I and II had no effect on any of the parameters measured. 12-O-tetradecanoyl phorbol 13-acetate (TPA) also induced beta-actin mRNA, decreased angiotensinogen mRNA, and caused an increase in [3H]methyl thymidine incorporation. The TPA effects were of shorter duration and of lower magnitude than those caused by insulin or serum. Inactivation of protein kinase C by preincubation with TPA did not block the insulin response. TPA has been shown to induce angiogenesis in vitro. Thus, these studies suggest that inhibition of angiotensinogen gene activity may be part of the proliferative or angiogenic process. Our experimental data may provide a model for further experimental dissection of the biochemical steps involved in angiogenesis.