Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143.

Background: Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported.

Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.

Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7-expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50-200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade ≥3 non-haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy.

Pharmacokinetics and Safety of Elotuzumab Combined With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma and Various Levels of Renal Impairment: Results of a Phase Ib Study.

Introduction: The present study evaluated the pharmacokinetics and safety of elotuzumab, a humanized IgG1 monoclonal antibody against signaling lymphocyte activation molecule-F7, combined with lenalidomide and dexamethasone, in patients with multiple myeloma (MM) and renal impairment.

Patients And Methods: Patients with MM and normal renal function (NRF) (creatinine clearance [CrCl] ≥ 90 mL/min), severe renal impairment (SRI) (CrCl < 30 mL/min, not requiring dialysis), or end-stage renal disease (ESRD) (requiring dialysis) were enrolled in this open-label, phase Ib study. Elotuzumab (10 mg/kg), lenalidomide (5-25 mg), and dexamethasone (40 mg) were administered in 28-day cycles until disease progression or unacceptable toxicity developed.

Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial.

Background: Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer.

Long-term use of dasatinib in patients with metastatic castration-resistant prostate cancer after receiving the combination of dasatinib and docetaxel.

Dasatinib is a potent oral tyrosine kinase inhibitor which targets several kinases, including the SRC family kinases. SRC family kinases have been implicated in androgen therapy resistance that often develops in metastatic castration-resistant prostate cancer (mCRPC), which drives the need for non-androgen targeting therapies. This article describes the preclinical rationale for the use of combination dasatinib and docetaxel therapy in mCRPC, and highlights the results of a phase I-II trial in which 46 patients with mCRPC, treated with a regimen of dasatinib and docetaxel, demonstrated improvements in bone scans, high rates of soft tissue responses, and modulation of markers of bone turnover.

Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study.

Background: To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.

Methods: In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m(2) every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m(2) every 21 days.

Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer.

Objectives: To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.

Methods: Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD.

Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer.

Purpose: Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC).

Experimental Design: Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily.

Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors.

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists.

Experimental Design: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing.

Results: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34).

Sex differences in sleep and sleep-dependent learning in abstinent cocaine users.

Sleep and sleep-dependent learning are impaired in male cocaine users during abstinence, but for female users little is known. Cocaine dependent men (n=12) and women (n=14), and control participants (n=19) participated in this study of sleep and sleep-dependent learning. Cocaine users were assessed at 3, 10 and 20 days of abstinence and controls were studied over one night.

Neural correlates of post-error slowing during a stop signal task: a functional magnetic resonance imaging study.

The ability to detect errors and adjust behavior accordingly is essential for maneuvering in an uncertain environment. Errors are particularly prone to occur when multiple, conflicting responses are registered in a situation that requires flexible behavioral outputs; for instance, when a go signal requires a response and a stop signal requires inhibition of the response during a stop signal task (SST). Previous studies employing the SST have provided ample evidence indicating the importance of the medial cortical brain regions in conflict/error processing.

Craving predicts time to cocaine relapse: further validation of the Now and Brief versions of the cocaine craving questionnaire.

Background: The 10-item version of the cocaine craving questionnaire (CCQ-Brief) has not been validated in a mixed-gender sample, and predictive validity of the CCQ-Now and CCQ-Brief in terms of their relationship with cocaine relapse has not been demonstrated.

Objective: To further validate the CCQ-Brief in a mixed gender sample and to determine the predictive validity of the CCQ-Now and CCQ-Brief.

Method: Seventy-two men and 51 women (Total N=123) seeking inpatient cocaine dependence treatment were administered assessments upon admission, and a prospective design was employed to assess cocaine relapse outcomes during a 90-day follow-up period after discharge from inpatient treatment.

Severity of childhood trauma is predictive of cocaine relapse outcomes in women but not men.

We prospectively examined the gender-specific effects of childhood trauma on cocaine relapse outcomes in an inpatient sample of treatment engaged cocaine dependent adults. Cocaine dependent men (n=70) and women (n=54) participating in inpatient treatment for cocaine dependence were assessed on severity of childhood trauma and followed for 90 days after discharge from treatment. Greater severity of childhood emotional abuse was associated with an increased risk of relapse in women.

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females.

Rationale: There is growing evidence of alterations in brain stress and reward circuits associated with cocaine dependence. Sex differences are also documented and sex steroid hormones have been linked to cocaine reinforcement.

Objectives: The current study therefore assessed daily fluctuations in stress and sex hormones in cocaine-dependent females compared with healthy females.

Gender differences in the comorbidity of smoking behavior and major depression.

Objective: The present investigation sought to determine whether smoking behavior was associated with current or lifetime major depression and whether this association was greater in women.

Methods: Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Wave 1, 2001-2002, n=42,565). Relationships between smoking status (daily, occasional, prior) and DSM-IV major depression (current or lifetime) by gender were assessed in terms of odds ratios using logistic regressions.

Gender differences in association with substance use diagnoses and smoking.

Alcohol and drug use disorders are highly comorbid with tobacco use. Given the substantial health risks associated with concurrent substance use and smoking, there is a clinical need to identify factors that confer heightened risk for their cause. This investigation examined gender-specific associations between smoking behaviors with current alcohol and drug use diagnoses.

Childhood maltreatment, perceived stress, and stress-related coping in recently abstinent cocaine dependent adults.

The authors examined associations between a personal history of childhood maltreatment and the perceived stress and stress-coping styles of recently abstinent and treatment-engaged cocaine dependent adults. Fifty men and 41 women at an inpatient treatment and research facility were administered the short form of the Childhood Trauma Questionnaire (D. P.

Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder.

Background: Alterations in the gamma-amino-butyric acid (GABA) neurotransmitter system have been identified in some populations with posttraumatic stress disorder (PTSD).

Methods: To further investigate factors of relevance to GABAergic neurotransmission in PTSD, we measured cerebrospinal fluid (CSF) levels of allopregnanolone and pregnanolone combined (ALLO: congeners that potently and positively modulate effects of GABA at the GABA(A) receptor), 5alpha-dihydroprogesterone (5alpha-DHP: the immediate precursor for allopregnanolone), dehydroepiandrosterone (DHEA: a negative modulator of GABA(A) receptor function), and progesterone with gas chromatography, mass spectrometry in premenopausal women with (n = 9) and without (n = 10) PTSD. Subjects were free of psychotropic medications, alcohol, and illicit drugs; all were in the follicular phase of the menstrual cycle except three healthy and four PTSD subjects receiving oral contraceptives.

Meta-analysis of diagnostic and screening test accuracy evaluations: methodologic primer.

Objective: Interest in evidence-based diagnosis is growing rapidly as diagnostic and screening techniques proliferate. In this article we provide an overview of systematic reviews of diagnostic performance and discuss in detail statistical methods for the most common variant of the problem: meta-analysis of studies in which a pair of estimates of sensitivity and specificity is reported. The need to account for possible variations in threshold for test positivity across studies led to the formulation of the Summary ROC (SROC) curve method.

A decrease in the plasma DHEA to cortisol ratio during smoking abstinence may predict relapse: a preliminary study.

Rationale: Increases in depressive symptoms during smoking cessation have been associated with risk for relapse. Several studies have linked plasma levels of cortisol and dehydroepiandrosterone (DHEA) or DHEA-sulfate (DHEAS) to depressive symptoms.

Objectives: To determine whether changes in plasma cortisol, DHEA, or DHEAS levels and emergence of depressive symptoms during smoking cessation are associated with smoking relapse.

Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.

Background: Cocaine dependence is associated with high rates of relapse. Stress and drug cue exposure are known to increase cocaine craving and stress arousal, but the association between these responses and cocaine relapse has not been previously studied.

Objective: To examine whether stress-induced and drug cue-induced cocaine craving and hypothalamic-pituitary-adrenal axis responses evoked in the laboratory are associated with subsequent cocaine relapse.

Examining accuracy of screening mammography using an event order model.

Screening mammography is a widely used method for breast cancer detection. For each mammogram we propose a performance model based on order of outcomes. That is, we envision an initial assessment, a follow up assessment if the initial one is positive and, eventually, a determination of whether cancer was present or not.

Estimating measures of diagnostic accuracy when some covariate information is missing.

Many biomedical data sets are concerned with relating the result of screening procedure(s) for a clinical event to the occurrence of that event. The effect of risk factors on measures of accuracy such as positive predictive value and negative predictive value is of great interest for clinicians. In this paper we propose a generic approach to estimate these measures of accuracy in the setting where an explanatory model has been fitted to the joint screening and event outcome data but information on one or more risk factors in the model is not available.

The association between obesity and screening mammography accuracy.

Background: Obesity is increasing among American women, especially as they age. The influence of obesity on the accuracy of screening mammography has not been studied extensively.

Methods: We analyzed 100 622 screening mammography examinations performed on members of a nonprofit health plan.