Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint

Background: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. Objective: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. Design, setting, and participants: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. Intervention: Cabozantinib 60 mg once daily orally versus mitoxantrone 12 mg/m2 every 3 wk plus prednisone 5 mg twice daily orally. Outcome measurements and statistical analysis: The primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power. Results and limitations: Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N =61; mitoxantrone-prednisone: N = 58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15%versus 17%,a −2%difference(95%confidenceinterval:−16%to11%, p = 0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. Conclusions: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. Patient summary: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases

Impact of model improvements on 80 m wind speeds during the second Wind Forecast Improvement Project (WFIP2)

During the second Wind Forecast Improvement Project (WFIP2; October 2015&ndash;March 2017, held in the Columbia River Gorge and Basin area of eastern Washington and Oregon states), several improvements to the parameterizations used in the High Resolution Rapid Refresh (HRRR &ndash; 3&thinsp;km horizontal grid spacing) and the High Resolution Rapid Refresh Nest (HRRRNEST &ndash; 750&thinsp;m horizontal grid spacing) numerical weather prediction (NWP) models were tested during four 6-week reforecast periods (one for each season). For these tests the models were run in control (CNT) and experimental (EXP) configurations, with the EXP configuration including all the improved parameterizations. The impacts of the experimental parameterizations on the forecast of 80&thinsp;m wind speeds (wind turbine hub height) from the HRRR and HRRRNEST models are assessed, using observations collected by 19 sodars and three profiling lidars for comparison. Improvements due to the experimental physics (EXP vs. CNT runs) and those due to finer horizontal grid spacing (HRRRNEST vs. HRRR) and the combination of the two are compared, using standard bulk statistics such as mean absolute error (MAE) and mean bias error (bias). On average, the HRRR 80&thinsp;m wind speed MAE is reduced by 3&thinsp;%&ndash;4&thinsp;% due to the experimental physics. The impact of the finer horizontal grid spacing in the CNT runs also shows a positive improvement of 5&thinsp;% on MAE, which is particularly large at nighttime and during the morning transition. Lastly, the combined impact of the experimental physics and finer horizontal grid spacing produces larger improvements in the 80&thinsp;m wind speed MAE, up to 7&thinsp;%&ndash;8&thinsp;%. The improvements are evaluated as a function of the model's initialization time, forecast horizon, time of the day, season of the year, site elevation, and meteorological phenomena. Causes of model weaknesses are identified. Finally, bias correction methods are applied to the 80&thinsp;m wind speed model outputs to measure their impact on the improvements due to the removal of the systematic component of the errors. </div

I may not like you, but I still care: Children differentiate moral concern from other constructs. (advance online)

In industrialized societies, adults exhibit stable preferences for the types of people, animals, and entities they feel moral concern for (Crimston et al., 2016). Only one published study to date has utilized the moral circles paradigm to examine these preferences in children, finding that as children age, their preferences shift to become more similar to adults’ (Neldner et al., 2018). However, it is currently unclear whether children’s conceptualization of moral concern differs from that of other related social constructs. The aim of the current study was twofold: first, to test the moral circles paradigm in a new sample of children to see whether published patterns of moral concern could be replicated and, second, to investigate whether children distinguish moral concern from the related constructs of liking and familiarity. Australian children aged 4 to 10 years old (N = 281; 143 boys, 138 girls; predominantly middle class) placed 24 pictures of human, animal, and environmental entities on a stratified circle according to how much they cared, liked, or knew about the targets. We found similar patterns of moral prioritization to previous research (Neldner et al., 2018), replicating both stable preferences and age-related changes in children’s moral concern for others. Crucially, we extend these findings by showing that children distinguish how much they care about entities from their levels of liking and knowing about them. This suggests children differentiate between moral concern and other social constructs early in development and display distinct patterns of prioritization when evaluating everyday entities according to these judgments

Cabozantinib versus mitoxantrone-prednisone in symptomatic metastatic castration-resistant prostate cancer : a randomized phase 3 trial with a primary pain endpoint

Background: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. Objective: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. Design, setting, and participants: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. Intervention: Cabozantinib 60 mg once daily orally versus mitoxantrone 12 mg/m2 every 3 wk plus prednisone 5 mg twice daily orally. Outcome measurements and statistical analysis: The primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power. Results and limitations: Enrollment was terminated early because cabozantinib did not demonstrate a survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N = 61; mitoxantrone-prednisone: N = 58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a −2% difference (95% confidence interval: −16% to 11%, p = 0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. Conclusions: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. Patient summary: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases. Control of debilitating pain is an unmet need for men with metastatic castration-resistant prostate cancer (mCRPC). This phase 3 trial failed to show an improved pain response for cabozantinib compared with mitoxantrone-prednisone in patients with previously treated, symptomatic mCRPC