Cabazitaxel in the treatment of metastatic castration-resistant prostate cancer: patient selection and special considerations.

Cabazitaxel is an effective chemotherapeutic agent used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel. With the advent of new antiandrogen therapies, immune-based treatments, and radioactive-targeted therapy, there are now multiple effective and approved agents for this disease state. The optimal sequencing of these agents is unclear as there are no large-scale head-to-head comparisons. Clinicians must familiarize themselves with the most recent studies as well as drug toxicities to determine the best treatment option for their patients. In this review, we focus on the development of cabazitaxel for mCRPC, evaluate its efficacy, and highlight key strategies for toxicity management. Additionally, we summarize the studies that address cabazitaxel treatment sequencing and optimal dosing schedule

First Report of NRG Oncology/Radiation Therapy Oncology Group 0622: A Phase 2 Trial of Samarium-153 Followed by Salvage Prostatic Fossa Irradiation in High-Risk Clinically Nonmetastatic Prostate Cancer After Radical Prostatectomy.

PURPOSE: To investigate the utility of 153Sm lexidronam (Quadramet) in the setting of men with prostate cancer status post radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases. PATIENTS AND METHODS: Trial NRG Oncology RTOG 0622 is a single-arm phase 2 trial that enrolled men with pT2-T4, N0-1, M0 prostate cancer status post radical prostatectomy, who meet at least 1 of these biochemical failure criteria: (1) prostate-specific antigen (PSA) \u3e 1.0 ng/mL; (2) PSA \u3e 0.2 ng/mL if Gleason score 9 to 10; or (3) PSA \u3e 0.2 ng/mL if N1. Patients received 153Sm (2.0 mCi/kg intravenously × 1) followed by salvage external beam radiation therapy (EBRT) to the prostatic fossa (64.8-70.2 Gy in 1.8-Gy daily fractions). No androgen deprivation therapy was allowed. The primary objective was PSA response within 12 weeks of receiving 153Sm. The secondary objectives were to: (1) assess the completion rate for the regimen of 153Sm and EBRT; (2) evaluate the hematologic toxicity and other adverse events (AEs) at 12 and 24 weeks; and (3) determine the freedom from progression rate at 2 years. RESULTS: A total of 60 enrolled eligible patients were included in this analysis. Median follow-up was 3.97 years. A PSA response was achieved in 7 of 52 evaluable patients (13.5%), compared with the 25% hypothesized. The 2-year freedom from progression rate was 25.5% (95% confidence interval 14.4%-36.7%), and the biochemical failure rate was 64.4% (95% CI 50.5%-75.2%). Samarium-153 was well tolerated, with 16 (of 60) grade 3 to 4 hematologic AEs and no grade 5 hematologic AEs. Radiation therapy was also well tolerated, with no grade 3 to 5 acute radiation therapy-related AEs and 1 grade 3 to 4 and no grade 5 late radiation therapy-related AEs. CONCLUSIONS: Trial NRG Oncology RTOG 0622 did not meet its primary endpoint of PSA response, although the regimen of 153Sm and salvage EBRT was well tolerated. Although the toxicity profile supports study of 153Sm in high-risk disease, it may not be beneficial in men receiving EBRT

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

A Pilot Phase II Study of Digoxin in Patients with Recurrent Prostate Cancer as Evident by Rising PSA

Background: Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 – 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.Results: Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease 25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients. Conclusions: Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer

Summary from the NCI clinical trials planning meeting on next generation of clinical trials in non-muscle invasive bladder cancer

The National Cancer Institute organized a virtual Clinical Trials Planning Meeting (CTPM) on \u27Defining the next generation of clinical trials with combination therapies in non-muscle invasive bladder cancer (NMIBC)\u27 led by the Bladder Cancer Task Force of the NCI Genitourinary Cancers Steering Committee. The purpose of this meeting was to accelerate advances in clinical trials for patients with high-risk NMIBC. The meeting delivered a multidisciplinary expert consensus on optimal strategies for next-generation clinical trial designs in NMIBC with prioritization of combination therapies. Two clinical trial concepts were developed for potential implementation within the National Clinical Trials Network

Criterion and Construct Validity of the CogState Schizophrenia Battery in Japanese Patients with Schizophrenia

BACKGROUND: The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. CONCLUSIONS/SIGNIFICANCE: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease

Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies

Counterfactual Reasoning in Non-psychotic First-Degree Relatives of People with Schizophrenia

Counterfactual thinking (CFT) is a type of conditional reasoning that enables the generation of mental simulations of alternatives to past factual events. Previous research has found this cognitive feature to be disrupted in schizophrenia (Hooker et al., 2000; Contreras et al., 2016). At the same time, the study of cognitive deficits in unaffected relatives of people with schizophrenia has significantly increased, supporting its potential endophenotypic role in this disorder. Using an exploratory approach, the current study examined CFT for the first time in a sample of non-psychotic first-degree relatives of schizophrenia patients (N = 43), in comparison with schizophrenia patients (N = 54) and healthy controls (N = 44). A series of tests that assessed the "causal order effect" in CFT and the ability to generate counterfactual thoughts and counterfactually derive inferences using the Counterfactual Inference Test was completed. Associations with variables of basic and social cognition, levels of schizotypy and psychotic-like experiences in addition to clinical and socio-demographic characteristics were also explored. Findings showed that first-degree relatives generated a lower number of counterfactual thoughts than controls, and were more adept at counterfactually deriving inferences, specifically in the scenarios related to regret and to judgments of avoidance in an unusual situation. No other significant results were found. These preliminary findings suggest that non-psychotic first-degree relatives of schizophrenia patients show a subtle disruption of global counterfactual thinking compared with what is normally expected in the general population. Due to the potential impact of such deficits, new treatments targeting CFT improvement might be considered in future management strategies.This research was supported by the Spanish Ministry o fScience and Innovation,the Carlos III Health Institute (PI11/02221). AA was supported by a trainee research staff grant awarded by the University of Barcelona (APIF-UBgrants)