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. Methods: Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm. Results: Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients. Conclusions: Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.

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. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade ≥3 non-haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty-six (65%) patients had ≥1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression-free survival was 3·9 months. Median overall survival was 16·3 months and the 1-year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre-treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM.

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. The primary endpoint was single-dose elotuzumab pharmacokinetics. RESULTS: A total of 26 patients (median age, 63 years) were treated (NRF, n = 8; SRI, n = 9; ESRD, n = 9). The median baseline CrCl was 105 mL/min (range, 84-146 mL/min) for those with NRF and 26 mL/min (range, 15-33 mL/min) for those with SRI. Twenty-three patients (89%) had received previous therapy (median, 2 regimens; range, 1-7). Treatment was discontinued in 6 patients with NRF, 4 with SRI, and 5 with ESRD, primarily because of disease progression. The mean elotuzumab serum concentrations were comparable across groups (n = 23). No statistically significant differences were observed in the maximum observed serum concentration, area under the concentration-time curve from time 0 to the last quantifiable serum concentration, or area under the concentration-time curve from time 0 to infinity when the SRI and ESRD groups were compared with the NRF group (P > .05). All patients had ≥ 1 adverse event (AE). Of the 8 patients with NRF, 9 with SRI, and 9 with ESRD, 7, 8, and 7 experienced grade 3 to 4 AEs. The overall response rates were 75% in the NRF, 67% in the SRI, and 56% in the ESRD groups. CONCLUSION: The results of the present study support the use of elotuzumab for the treatment of patients with MM and renal dysfunction without dose adjustment.

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. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 µmol/mol creatinine vs ≥60 µmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. FINDINGS: Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]). INTERPRETATION: The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. FUNDING: Bristol-Myers Squibb.

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. This brief report discusses in detail follow-up data on two patients who remain alive after >2.5 years on dasatinib single-agent therapy after discontinuing docetaxel treatment.

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. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied. RESULTS: Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months. CONCLUSIONS: The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study. Cancer 2012;. © 2011 American Cancer Society.

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. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase). RESULTS: The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia. CONCLUSIONS: Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.

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. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks. RESULTS: Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved > or =40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate. CONCLUSIONS: This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC.

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). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients. CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.

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. Total sleep time, sleep efficiency and overnight motor learning were the main outcome measures. Cocaine dependent men compared to women exhibited deteriorations in sleep time, sleep efficiency, and overnight learning as abstinence progressed from 3 to 20 days. At abstinence day 3, cocaine dependent men and women were no different than control participants in the main outcomes. However, there were significant differences between cocaine men at abstinence day 20 and controls in sleep time and sleep-dependent learning, but no differences between controls and cocaine dependent women. There is growing evidence that sleep disturbances are associated with cocaine abuse and abstinence and have functional consequences that may be relevant to the development of effective treatments. The absence of sleep disturbances in women suggests a need to understand the mechanisms underlying these differences, as such knowledge could lead to novel therapies in cocaine dependence.

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. Other studies have also related these regional activations to postconflict/error behavioral adjustment. However, very few studies have directly explored the neural correlates of postconflict/error behavioral adjustment. Here we employed an SST to elicit errors in approximately half of the stop trials despite constant behavioral adjustment of the observers. Using functional magnetic resonance imaging, we showed that prefrontal loci including the ventrolateral prefrontal cortex are involved in post-error slowing in reaction time. These results delineate the neural circuitry specifically involved in error-associated behavioral modifications.

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. METHOD: Daily salivary samples of cortisol, progesterone, and estradiol were collected at waking across 28 days from 12 cocaine-dependent females receiving inpatient treatment and 10 healthy females. Participants also completed mood-rating scales each week corresponding to four phases of the menstrual cycle and cocaine craving was monitored in cocaine patients at each phase. RESULTS: Cocaine-dependent females in their first month of abstinence demonstrated significantly higher levels of both cortisol and progesterone across the menstrual cycle and significantly lower estradiol/progesterone (E2/P) ratios compared to healthy controls. They also showed significantly increased negative mood compared with controls, but no variation in cocaine craving across the menstrual cycle. CONCLUSIONS: Findings indicate altered stress and sex hormones suggestive of an overactive stress system during the first month of cocaine abstinence after chronic cocaine abuse. These increased levels of cortisol and progesterone could impact both abstinence-related symptoms such as negative mood and susceptibility to drug-seeking behavior in cocaine-dependent 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. RESULTS: Current (daily, occasional) and prior smoking significantly increased odds of having current or prior major depression. These associations varied as a function of gender. Women with prior smoking were at significantly higher risk of current and past depression than men (OR: 1.53 vs 1.36; 1.72 vs 1.36), as was true for current occasional (OR: 1.92 vs 1.39; 1.90 vs 1.30) and daily smoking (OR: 2.52 vs 1.95; 1.84 vs 1.48). CONCLUSIONS: The association between smoking and current or past depression is not necessarily limited to smoking that meets criteria for nicotine dependence, and is more potent in women. Smoking cessation interventions for this population should consider the role that depression may play in failure to quit and smoking relapse, particularly in women.

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. Severity of emotional abuse, sexual abuse, and overall childhood trauma was associated with the number of days cocaine was used during follow-up in women, as was the association of severity of physical abuse and overall childhood trauma with the average amount of cocaine used per occasion. No associations between childhood trauma and cocaine relapse outcomes were found in men. These findings demonstrate that childhood trauma increases the likelihood of cocaine relapse and drug use escalation after initial relapse in women but not in men. Comprehensive assessments of childhood trauma and specialized treatments that address trauma-related pathophysiology could be of benefit in improving cocaine treatment outcomes in women.

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. Data were analyzed using Pearson's correlation, Cox proportional hazards regression, and multiple regression. FINDINGS: The CCQ-Brief demonstrated good internal consistency and construct and concurrent validity. Both the CCQ-Now and the CCQ-Brief summary scores predicted time to cocaine relapse. In addition, the anticipation of a positive outcome from cocaine use, and intent and planning to use cocaine subscales of the CCQ-Now also predicted time to cocaine relapse. CONCLUSIONS: The CCQ-Brief was found to be a reliable and valid measure in a mixed gender sample, and both the CCQ-Now and CCQ-Brief were predictive of cocaine relapse risk. Craving assessments that go beyond desire and take into account intent and planning to use cocaine and the patient's anticipation of a positive outcome from using cocaine are likely to provide a sensitive index of cocaine relapse susceptibility. However, fear of social and clinical consequences could impact accurate reporting of cocaine craving and intent to use cocaine.

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. Bernstein & L. Fink, 1998; D. P. Bernstein et al., 2003), the Perceived Stress Scale (S. Cohen, T. Kamarck, & R. Mermelstein, 1983), and the COPE Questionnaire (C. S. Carver, M. R. Scheier, & J. K. Weintraub, 1989). Simple and multiple linear regression analyses were used to analyze relationships while adjusting for relevant covariates. Findings indicate that overall childhood maltreatment severity was significantly associated with greater perceived stress and greater use of avoidance stress-coping strategies. These findings suggest that having a history of childhood maltreatment may influence how recently abstinent cocaine dependent individuals experience and cope with stress. Stress and stress-coping focused interventions may be particularly indicated for cocaine dependent individuals with histories of childhood maltreatment.

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. Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions (N = 42,565). Relationships between smoking status and DSM-IV current alcohol and drug use diagnoses by gender were assessed in terms of odds ratios using regressions. The presence of current alcohol or drug diagnoses increased the odds of being a daily, occasional, or former smoker, and gender was found to moderate these associations. Overall, women with a current alcohol use disorder had greater odds of being a daily or occasional smoker compared with men (odds ratio [OR], 3.52 versus 2.93; 5.22 versus 3.56). Women with a drug use diagnosis had greater odds of being a daily smoker compared with men (OR, 6.54 versus 4.63) and similar odds of being an occasional smoker (OR, 4.48 versus 4.51). The results of this study highlight gender-specific patterns of comorbidity, which may contribute to more focused primary and secondary prevention efforts.

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. RESULTS: There were no group differences in progesterone, 5alpha-DHP, or DHEA levels. The PTSD group ALLO levels were < 39% of healthy group levels. The ALLO/DHEA ratio correlated negatively with PTSD re-experiencing symptoms (n = -.82, p < 008; trend) and with Profile of Mood State depression/dejection scores (n = -0.70, p < 0008). CONCLUSION: Low CSF ALLO levels in premenopausal women with PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, resulting in increased PTSD re-experiencing and depressive symptoms.

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. We discuss graphical and model-based ways to estimate, summarize, and compare SROC curves, and we present an example from a meta-analysis of data on techniques for staging cervical cancer. We also present a brief survey of the methodologic literature for addressing heterogeneity, correlated data, multiple thresholds per study, and systematic reviews of ROC studies. We conclude with a discussion of the significant methodologic challenges that continue to face investigators in this area of diagnostic medicine research. CONCLUSION: Systematic reviews of diagnostic performance are a rigorous approach to examining and synthesizing evidence in the evaluation of diagnostic and screening tests. The information from such reviews is needed by clinicians, health policy makers, researchers in diagnostic medicine, developers of diagnostic techniques, and the general public. However, despite progress in study quality and reporting and in methodologic development, major challenges confront investigators undertaking these reviews.

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. MATERIALS AND METHODS: Subjects were healthy non-medicated men and women, aged 39+/-12 years, who smoked, on average, 22 cigarettes per day. Depressive symptoms, smoking withdrawal symptoms, and plasma steroid levels were measured before and after 8 days of verified smoking abstinence. Relapse status at day 15 was then determined. RESULTS: In the full sample (n=63), there was a trend for changes in depressive symptoms to be associated with relapse. In the subset of 25 subjects with plasma neuroactive steroid data, there was a significant interaction between the change in the plasma DHEA/cortisol ratio from day 0 to day 8 and relapse status at day 15. This ratio was similar before abstinence, but lower at day 8 in relapsed, compared to abstinent, subjects. Changes in the DHEA/cortisol ratio tended to predict changes in depressive symptoms in the women only. CONCLUSION: A decrease in the plasma DHEA/cortisol ratio during 8 days of smoking abstinence was associated with relapse over the following week. Further research is needed to fully characterize sex-specific relationships between abstinence-induced changes in neuroactive steroid levels, depressive or withdrawal symptoms, and relapse. Such research may lead to new interventions for refractory smoking dependence.