A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer.

BACKGROUND: Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. METHODS: Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). RESULTS: There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. CONCLUSIONS: Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

Pembrolizumab in the treatment of advanced urothelial cancer.

Pembrolizumab is a humanized monoclonal antibody that targets PD-1. In the Phase III trial KEYNOTE-045, pembrolizumab was associated with a significant overall survival benefit when compared with docetaxel, paclitaxel and vinflunine in second line metastatic urothelial carcinoma (UC). Additionally, in the first line, early results from an interim analysis of the Phase II trial Keynote-052 study indicated that pembrolizumab is efficacious for cisplatin-ineligible patients. Based on data from these trials, pembrolizumab was the most recent among the five checkpoint inhibitors tested in UC to be approved by the US FDA in May 2017. It was granted regular approval for patients with advanced-stage UC who progress after receiving platinum-based chemotherapy and accelerated approval in the first line for patients who are ineligible to receive cisplatin.

Death of a Child Prior to Midlife, Dementia Risk, and Racial Disparities.

OBJECTIVES: This study considers whether experiencing the death of a child prior to midlife (by parental age 40) is associated with subsequent dementia risk, and how such losses, which are more common for black than for white parents, may add to racial disparities in dementia risk. METHODS: We use discrete-time event history models to predict dementia incidence among 9,276 non-Hispanic white and 2,182 non-Hispanic black respondents from the Health and Retirement Study, 2000-2014. RESULTS: Losing a child prior to midlife is associated with increased risk for later dementia, and adds to disparities in dementia risk associated with race. The death of a child is associated with a number of biosocial variables that contribute to subsequent dementia risk, helping to explain how the death of child may increase risk over time. DISCUSSION: The death of a child prior to midlife is a traumatic life course stressor with consequences that appear to increase dementia risk for both black and white parents, and this increased risk is explained by biosocial processes likely activated by bereavement. However, black parents are further disadvantaged in that they are more likely than white parents to experience the death of a child, and such losses add to the already substantial racial disadvantage in dementia risk.

Identification of Affective State Change in Adults With Aphasia Using Speech Acoustics.

Purpose: The current study aimed to identify objective acoustic measures related to affective state change in the speech of adults with post-stroke aphasia. Method: The speech of 20 post-stroke adults with aphasia was recorded during picture description and administration of the Western Aphasia Battery-Revised (Kertesz, 2006). In addition, participants completed the Self-Assessment Manikin (Bradley & Lang, 1994) and the Stress Scale (Tobii Dynavox, 1981-2016) before and after the language tasks. Speech from each participant was used to detect a change in affective state test scores between the beginning and ending speech. Results: Machine learning revealed moderate success in classifying depression, minimal success in predicting depression and stress numeric scores, and minimal success in classifying changes in affective state class between the beginning and ending speech. Conclusions: The results suggest the existence of objectively measurable aspects of speech that may be used to identify changes in acute affect from adults with aphasia. This work is exploratory and hypothesis-generating; more work will be needed to make conclusive claims. Further work in this area could lead to automated tools to assist clinicians with their diagnoses of stress, depression, and other forms of affect in adults with aphasia.

Immunotherapy in Urothelial Cancer: Recent Results and Future Perspectives.

Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12-14 months for patients with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently. Immune-checkpoint inhibitors targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have shown significant anti-tumor activity, tolerable safety profiles and durable, long-term responses in clinical trials. Atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs under investigation that will redefine the standard of care for bladder cancer. CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab, approved in May 2016, and nivolumab, approved in February 2017, are the first Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in bladder cancer for platinum-pretreated patients based on phase II data. On March 16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that survival was significantly longer in patients treated with pembrolizumab when compared with the standard second-line chemotherapy. Research into biomarkers such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load and gene signature expression will be crucial to determining why some patients respond to immunotherapy and others do not. This review article describes the advances in immunotherapy since the development of BCG, presents results from clinical trials investigating immune-checkpoint inhibitors and discusses biomarkers and prognostic factors associated with response to these new drugs.

Stress and depression scales in aphasia: relation between the aphasia depression rating scale, stroke aphasia depression questionnaire-10, and the perceived stress scale.

BACKGROUND: Assessment and diagnosis of post-stroke depression (PSD) among patients with aphasia presents unique challenges. A gold standard assessment of PSD among this population has yet to be identified. OBJECTIVES: The first aim was to investigate the association between two depression scales developed for assessing depressive symptoms among patients with aphasia. The second aim was to evaluate the relation between these scales and a measure of perceived stress. METHOD: Twenty-five (16 male; 9 female) individuals with history of left hemisphere cerebrovascular accident (CVA) were assessed for depression and perceived stress using the Stroke Aphasic Depression Questionnaire-10 (SADQ-10), the Aphasia Depression Rating Scale (ADRS), and the Perceived Stress Scale (PSS). RESULTS: SADQ-10 and ADRS ratings were strongly correlated with each other (r = 0.708, p < 0.001). SADQ-10 ratings were strongly correlated with PSS ratings (r = 0.620, p = 0.003), while ADRS ratings were moderately correlated (r = 0.492, p = 0.027). Item analysis of each scale identified items which increased both inter-scale correlation and intra-scale consistency when excluded. CONCLUSIONS: The SADQ-10 and ADRS appear to be acceptable measures of depressive symptoms in aphasia patients. Measurements of perceived stress may also be an important factor in assessment of depressive symptoms.

Upper Tract Urothelial Carcinomas: Prognostic Factors and Outcomes in Patients With Non-Lymph Node Distant Metastasis.

BACKGROUND: Upper tract urothelial carcinomas (UTUCs) are increasingly recognized as separate malignancies. Additional insight into clinical outcomes and key prognostic factors are needed. OBJECTIVES: To detail outcomes of patients with UTUCs recurring after radical nephroureterectomy (RNU) and to determine a risk score that predicts outcomes of patients with non-lymph node distant metastasis. DESIGN, SETTING, AND PARTICIPANTS: Chart review of all patients who had an extraurothelial recurrence after RNU for UTUC at Dana-Farber Cancer Institute between 2009 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median overall survival defined as time from chemotherapy for distant relapse to death. Prognostic relevance of performance status, hemoglobin, and receipt of cisplatin were assessed by Cox regression model. RESULTS AND LIMITATIONS: A total of 102 patients were identified, 57 of whom had non-lymph node distant metastases at relapse; 45 received chemotherapy. Median follow-up was 29.8 months; median overall survival was 14.7 months. Objective response rate to any chemotherapy in the first-line setting was only 22%. Hemoglobin > 11 g/dL and receipt of cisplatin was associated with numerically longer median survival but did not reach statistical significance in univariate and multivariate analysis. Prognostic risk score scale including hemoglobin < 11 g/dL and receipt of cisplatin was inversely associated with survival, with scores of 0, 1, and 2 leading to median survival of 19.0, 14.9, and 7.2 months (P = .38), respectively. CONCLUSIONS: Advanced UTUC portends a poor prognosis, and most patients cannot receive cisplatin-based chemotherapy. A risk score that includes anemia and receipt of cisplatin helps stratify patients with distant metastasis for inclusion into eventual clinical trials. More studies are needed to validate these findings. PATIENT SUMMARY: Metastatic UTUC is an aggressive disease, where anemia and ineligibility to receive cisplatin are adverse features associated with shorter survival.

Unexpected resistance to external cardiac compression may signal pericardial tamponade.

Pericardial tamponade associated with central catheters is often lethal, unless promptly identified. We report our experience with two infants who suffered this complication but were successfully resuscitated. In each case, associated radiographs showed the tip of the central catheter beyond the superior vena cava-right atrium (SVC-RA) junction. Identifying the clinical triad of (1) sudden cardiovascular collapse unresponsive to usual resuscitative measures, (2) thoracic transillumination not suggestive of air leak, and (3) unexpected resistance to external cardiac compression led to the working diagnosis of pericardial tamponade and therapeutic pericardiocentesis. Prompt recovery followed. Central catheters within the RA seem prone to cause pericardial tamponade.