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Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing. Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0–25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4–24·8) in the radium-223 group and 26·0 months (21·8–28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917–1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3–4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia). The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination. Bayer.

In this study, the androgen-receptor inhibitor enzalutamide improved progression-free and overall survival in men with castration-resistant metastatic prostate cancer who had not received chemotherapy. Prostate cancer is the most commonly diagnosed cancer and the sixth leading cause of cancer-related death among men worldwide. 1 Strategies to block androgen-receptor signaling have formed the backbone of prostate-cancer therapy since the first description of the hormonal dependence of this cancer in 1941. 2 Advances in endocrine therapies have improved survival in men with high-risk locoregional prostate cancer. 3 , 4 However, new hormonal agents have been shown to extend survival in men with metastatic castration-resistant disease. 5 – 9 In most patients who are treated for advanced recurrent prostate cancer with androgen-deprivation therapy (comprising a luteinizing hormone–releasing hormone [LHRH] analogue or orchiectomy with . . .

Deep learning algorithms have been successfully used in medical image classification. In the next stage, the technology of acquiring explainable knowledge from medical images is highly desired. Here we show that deep learning algorithm enables automated acquisition of explainable features from diagnostic annotation-free histopathology images. We compare the prediction accuracy of prostate cancer recurrence using our algorithm-generated features with that of diagnosis by expert pathologists using established criteria on 13,188 whole-mount pathology images consisting of over 86 billion image patches. Our method not only reveals findings established by humans but also features that have not been recognized, showing higher accuracy than human in prognostic prediction. Combining both our algorithm-generated features and human-established criteria predicts the recurrence more accurately than using either method alone. We confirm robustness of our method using external validation datasets including 2276 pathology images. This study opens up fields of machine learning analysis for discovering uncharted knowledge. Technologies for acquiring explainable features from medical images need further development. Here, the authors report a deep learning based automated acquisition of explainable features from pathology images, and show a higher accuracy of their method as compared to pathologist based diagnosis of prostate cancer recurrence.

BackgroundIn the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan.MethodsPatients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints.ResultsThe Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred.ConclusionsEfficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.

Accurate prostate cancer screening is imperative for reducing the risk of cancer death. Ultrasound imaging, although easy, tends to have low resolution and high inter-observer variability. Here, we show that our integrated machine learning approach enabled the detection of pathological high-grade cancer by the ultrasound procedure. Our study included 772 consecutive patients and 2899 prostate ultrasound images obtained at the Nippon Medical School Hospital. We applied machine learning analyses using ultrasound imaging data and clinical data to detect high-grade prostate cancer. The area under the curve (AUC) using clinical data was 0.691. On the other hand, the AUC when using clinical data and ultrasound imaging data was 0.835 ( p  = 0.007). Our data-driven ultrasound approach offers an efficient tool to triage patients with high-grade prostate cancers and expands the possibility of ultrasound imaging for the prostate cancer detection pathway.

Background/Objectives: S-892216 is a poorly water-soluble drug developed as a novel oral treatment for COVID-19, although its oral absorption is low. For Phase 1 (Ph1) studies and commercial use, both oral solution and solid dispersion technologies are evaluated to enhance drug solubility. Methods: The solubility enhancement technology was selected by considering physicochemical factors such as stability and oral absorption, along with patient and customer acceptability. Results: Pharmacokinetics study in rats revealed that both the polyethylene glycol 400 oral solution and polyvinylpyrrolidone-vinyl acetate (PVPVA) amorphous solid dispersion powder suspension showed almost 100% oral bioavailability. Therefore, they can be proposed as clinical formulations for Ph1 studies. PVPVA solid dispersion tablets were developed as a to-be-marketed formulation showed higher bioavailability in dogs than the anhydrous crystal formulation. Additionally, the stability of the developed solid dispersion tablet was acceptable. Conclusions: This study demonstrates that multiple solubility enhancement technologies can be adopted for S-892216 development, and amorphous solid dispersion technology was selected for commercialization.

Background In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. Patients and Methods In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. Results No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (–2.5; 95% CI –5.2 to 0.1), EORTC QLQ-C30 physical functioning (–0.87; 95% CI –2.7 to 1.0), and FKSI-DRS (–0.7; 95% CI –1.2 to –0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). Conclusions Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. Trial Registration Clinicaltrials.gov Identifier: NCT03142334 Patient-reported outcomes provide an important measure of health-related quality of life and can complement efficacy and safety results. This article presents analyses of health-related quality of life in patients enrolled in the KEYNOTE-564 trial.

We investigated the role of pharmacists in adverse event (AE) management during renal cell carcinoma (RCC) drug therapy by surveying patients, physicians, and pharmacists. We identified the types of AEs for which pharmacist involvement is beneficial and explored measures to promote pharmacist intervention. This was an ad hoc analysis of a questionnaire-based cross-sectional web survey conducted from May to June 2022 among patients undergoing RCC drug therapy, physicians prescribing RCC treatments, and pharmacists involved in oncology care in Japan. A total of 83 patients with metastatic RCC, 165 physicians, and 218 pharmacists were included. Among patients, 28.9% reported experiencing AEs or symptoms requiring pharmacist intervention. Most physicians (78.2%) and pharmacists (96.3%) supported pharmacist involvement in AE management. Notably, 35.6% of patients who reported no AEs or symptoms requiring pharmacist intervention acknowledged difficulty in communicating AEs to their physicians. Regarding desired pharmacist interventions for AEs, patients prioritized rash/pruritus, fatigue, and diarrhea; physicians emphasized stomatitis and anorexia; pharmacists identified constipation, stomatitis, and diarrhea. The most common reason patients valued pharmacist involvement was the reassurance of support from multiple healthcare providers. Physicians and pharmacists valued pharmacists' greater familiarity with AE management, particularly considering physicians' limited time. Raising awareness among patients and healthcare professionals, patient requests, and improving institutional support were strategies to enhance pharmacist involvement. Over 86% of healthcare professionals considered pharmaceutical outpatient clinics necessary to strengthen interdisciplinary collaboration. This study highlights widespread support among patients, physicians, and pharmacists for pharmacist involvement in managing AEs during RCC drug therapy.

Background/Objectives: The Vesical Imaging-Reporting and Data System (VI-RADS) provides high diagnostic accuracy for muscle-invasive bladder cancer; however, its prognostic value remains limited. We propose serum cytokeratin 19 fragment (CYFRA 21-1) and tumor contact length (TCL) as complementary prognostic factors. We aimed to construct a composite risk score integrating VI-RADS, CYFRA 21-1, and TCL for prognostic stratification. Methods: We retrospectively analyzed data from 101 patients with bladder cancer (BC) who underwent transurethral resection of bladder tumor (TURBT), magnetic resonance imaging, and postoperative serum CYFRA 21-1 measurement. For each factor, cut-off values were determined using receiver operating characteristic (ROC) analysis; meeting each threshold contributed one point (score range, 0–3). Overall survival (OS) was assessed using Kaplan–Meier and Cox regression analyses. Results: ROC analysis identified cut-offs of VI-RADS ≥ 3 (area under the curve [AUC] 0.779), TCL ≥ 40 mm (AUC 0.817), and CYFRA 21-1 ≥ 2.1 ng/mL (AUC 0.875). Based on these, patients were stratified into low- (0–1, n = 81), intermediate- (2, n = 12), and high-risk (3, n = 8) groups with 3-year OS rates of 95.1%, 75.0%, and 25.0%, respectively (p < 0.001). In univariate Cox regression, all factors significantly predicted poor OS: VI-RADS ≥ 3 (hazard ratio [HR], 6.51; p = 0.015), TCL ≥ 40 mm (HR, 8.36; p < 0.001), and CYFRA 21-1 ≥ 2.1 ng/mL (HR, 14.02; p < 0.001). In multivariate analysis, only CYFRA 21-1 remained independently significant (HR, 11.80; p < 0.001). Conclusions: A composite risk score combining VI-RADS, TCL, and CYFRA 21-1 effectively stratified patients with BC into distinct groups using minimally invasive, peri-TURBT assessments. Prospective multicenter validation is warranted.