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Introduction Fluctuations in ovarian hormones have been associated with changes in cigarette smoking behavior, which can be measured through both serum or less invasive salivary procedures. The primary aim of this exploratory study is to characterize the progesterone profiles of salivary progesterone measurements and to compare that with the profiles estimated from a previously measured serum sample. Aims and Methods Nontreatment-seeking, cigarette smoking women (n = 82; ages 18–45 years) provided daily salivary hormone samples every morning for 14 consecutive days. Time-dependent random effects functions were used to approximate daily salivary progesterone (ng/mL) levels over the course of a standardized menstrual cycle. Serum measures of progesterone from a previous study of female cigarette smokers were examined for consistency with established profiles and compared with the salivary profile using the same methodology. Results The salivary model fit exhibits relative stability during the follicular phase and a clear unimodal peak during the luteal phase. Parameter estimates from the non-linear function show correspondence to serum data. Although the profiles estimated from salivary and serum data agree in functional form, we observed larger between-subject heterogeneity both in the follicular level and the peak luteal level in salivary measures. Conclusions The pattern of salivary and serum progesterone measured across the menstrual cycle is similar in form, which is noteworthy given that the saliva and serum samples were drawn from independent sample of female smokers. Inter- and intra-individual variation in salivary measures may be greater than in serum measures. Implications Measuring progesterone level variation across the menstrual cycle via saliva samples has several benefits relative to serum sampling methods in that they are easily obtained, noninvasive, and low-cost. Inter- and intra-individual variation in measurements may be greater than those in serum measurements. However, the functional form of the salivary progesterone profile is isomorphic to serum progesterone.

Introduction: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT). Objective: The purpose of this study was to assess the nature of TCP in patients receiving CRRT. Methods: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria. Results: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32–3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU. Conclusion: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care.

The hypothalamic-pituitary-adrenal (HPA) axis is a critical hormonal system involved in stress response. A number of studies have investigated the HPA axis response of drug-dependent individuals to stressors. Stress-induced vulnerabilities in the HPA axis may differ in response to chronic use of different substances, possibly leading to different target therapies. There has not been a direct comparison of HPA axis and subjective response between individuals with different types of substance use disorders following a laboratory stress intervention.The primary goal of the current study was to compare subjective and neuroendocrine response to the Trier Social Stress Task (TSST) across multiple primary types of substance use disorders and investigate differential response between males and females.Four hundred participants were drawn from seven studies completed at the Medical University of South Carolina between 2011 and 2021. The TSST was utilized across studies and subjective and neuroendocrine responses measured following completion. Generalized linear mixed effects models and area under the response curve analysis were used to compare both substance type and sex differences.The study groups involving individuals with cocaine use disorder had blunted stress, craving and cortisol response following the TSST as compared to other substance use groups. Females in the cocaine groups reported higher subjective stress but lower cortisol than males.The study results indicate that there may be differential effects of substances on the HPA axis, with cocaine using individuals exhibiting more blunting of the HPA axis response as compared to users of other substances.

BACKGROUND: Peripheral sensory stimulation augments post-stroke upper extremity rehabilitation outcomes. Most sensory stimulations interfere with natural hand tasks and the stimulation duration is limited. We developed TheraBracelet, low-level random-frequency vibration applied via a wristwatch, to enable stimulation during hand tasks and potentially extend stimulation durations. OBJECTIVE: To determine safety of prolonged exposure to TheraBracelet. METHODS: Single-site double-blind cross-over randomized controlled trial. Chronic stroke survivors were instructed to wear a device on the affected wrist for ≥8hr/day everyday for 2 months while coming to the laboratory weekly for evaluations, with a 2-week break between each month. The device applied vibration at 60% and 1% of the sensory threshold for the real and sham month, respectively. The order of the real and sham months was randomized/balanced. Adverse events (AEs) were assessed weekly, including worsening of hand sensation, dexterity, grip strength, pain, or spasticity and occurrence of skin irritation or swelling. Device-related AE rates were compared between the real and sham month. RESULTS: Twenty-five participants completed the study. Six participants (24%) experienced mild AEs involving worsened sensory scores that may be related to the intervention with reasonable possibility. Two experienced them in the real stimulation month only, 3 in the sham month only, and 1 in both months. Therefore, less participants experienced device-related AEs in the real than sham month. CONCLUSION: Daily stimulation using the device for a month is safe for chronic stroke survivors. Future studies examining the efficacy of pairing TheraBracelet with therapy for increasing neurorehabilitation outcomes is a logical next step.

Background Peripheral sensory stimulation has been used in conjunction with upper extremity movement therapy to increase therapy-induced motor gains in patients with stroke. The limitation is that existing sensory stimulation methods typically interfere with natural hand tasks and thus are administered prior to therapy, requiring patients’ time commitment. To address this limitation, we developed TheraBracelet. This novel stimulation method provides subthreshold (ie, imperceptible) vibratory stimulation to the wrist and can be used during hand tasks/therapy without interfering with natural hand tasks. Objective The objective was to determine the feasibility of using TheraBracelet during therapy to augment motor recovery after stroke. Design The design was a triple-blinded pilot randomized controlled trial. Methods Twelve chronic stroke survivors were assigned to the treatment or control group. All participants completed 2-hour task practice therapy sessions thrice weekly for 2 weeks. Both groups wore a small vibrator on the paretic wrist, which was turned on to provide TheraBracelet stimulation for the treatment group and turned off for the control group to provide sham stimulation. Outcome measures (Box and Block Test [BBT] and Wolf Motor Function Test [WMFT]) were obtained at baseline, 6 days after therapy, and at follow-up 19 days after therapy. Results The intervention was feasible with no adverse events. The treatment group significantly improved their BBT scores after therapy and at follow-up compared with baseline, whereas the control group did not. For WMFT, the group × time interaction was short of achieving significance. Large effect sizes were obtained (BBT d = 1.43, WMFT d = 0.87). No indication of desensitization to TheraBracelet stimulation was observed. Limitations The limitation was a small sample size. Conclusions TheraBracelet could be a promising therapy adjuvant for upper extremity recovery after stroke.

Despite advances in prevention and treatment, cigarette smoking remains a leading cause of preventable death in the United States. Although men and women are equally likely to attempt to quit smoking cigarettes, women are far less likely to achieve abstinence both during and following cessation treatment. Recent evidence suggests that ovarian hormone levels may play a role in successful abstinence attempts in women smokers. The primary goal of this exploratory prospective observational study was to estimate the association between within-participant levels of progesterone and estradiol with associated cigarettes smoked per day in adult women smokers (n = 104). The primary study outcome was self-reported cigarettes smoked per day (CPD) during a 2-week observational period collected using a daily smoking diary. Additionally, participants collected saliva daily, from which hormone levels (progesterone and estradiol) were derived. Higher within-participant progesterone levels were associated with a significant decrease in CPD (p = .008) whereas within-participant estradiol levels were unrelated to CPD (p = .25). Regression models indicated a single change in the trajectory of smoking behavior for both within-participant progesterone and estradiol. When progesterone values were below the change point, there was a significant inverse relationship between within-participant progesterone levels and smoking behavior (p = .025) whereas the relationship was attenuated for higher within-participant progesterone levels (p = .59). The effect of estradiol on smoking behavior was not significant when it was either below (p = .92) or above (p = .16) the change point. Higher within-participant levels of progesterone but not estradiol are associated with reduced CPD in nontreatment seeking women smokers.

Patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) continue to have an unacceptably high mortality rate despite the progress achieved with pulmonary arterial vasodilator therapies.We sought to determine whether SSc-PAH is a clinically distinct pulmonary vascular disease phenotype when compared with idiopathic pulmonary arterial hypertension (IPAH) on the basis of progression of echocardiographic right ventricular (RV) dysfunction.Retrospective analysis of echocardiographic data in 13 patients with SSc-PAH and 11 patients with IPAH was used to delineate the progression of RV dysfunction during single or combination pulmonary arterial vasodilator therapy. All patients had right heart catheterization-confirmed pulmonary arterial hypertension as well as complete baseline (at the time of diagnosis) and follow-up (most recent) echocardiograms. We excluded patients with significant scleroderma-associated interstitial lung disease. Adjusting for time of follow-up and disease duration, we performed mixed model regression analyses comparing the changes between the two groups for different echocardiographic variables: tricuspid annular plane systolic excursion, tricuspid regurgitation jet velocity, right atrial area, and RV diameter.The mean ages for the SSc-PAH and IPAH groups were 60.8 and 48.2 years, respectively. The mean follow-up periods for the two groups were 3.8 and 1.95 years, respectively. Tricuspid annular plane systolic excursion did not improve in patients with SSc-PAH, whereas it increased in the patients with IPAH (-0.38 mm, P = 0.87; vs. +5.6 mm, P = 0.02). The other echocardiographic variables showed a trend toward worsening in the SSc-PAH group and improvement in the IPAH group.Our results indicate that, in patients with SSc-PAH, echocardiographic RV function does not improve over time compared with that of patients with IPAH, despite institution of pulmonary artery vasodilator therapies.

RATIONALE: Female cigarette smokers tend to show greater cessation failure compared to males. Variables that contribute to the maintenance of smoking, including stress and craving, may differentially impact male and female smokers. Novel pharmacotherapies, such as oxytocin, may attenuate stress reactivity and craving in smokers, but work in this area is limited. OBJECTIVES: This study assessed the influence of gender and oxytocin on stress reactivity, craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm. METHODS: Male and female adult cigarette smokers (ages 18–45) were enrolled (women oversampled 2:1) and completed a laboratory session, in which intranasal oxytocin or placebo was administered followed by a laboratory social stress task. The role of gender and oxytocin were assessed on measures of stress reactivity, cigarette craving, latency to smoke in a resistance task, subjective responses to smoking, and ad-libitum smoking. RESULTS: Participants (N=144) had a mean age of 31, were 63% female and 56% White. Following stress induction, female smokers evidenced greater subjective stress than males, though males demonstrated greater neuroendocrine reactivity and smoking intensity than females. No gender differences were demonstrated for craving. Oxytocin did not attenuate any aspect of stress reactivity, craving, smoking, or subjective responses to smoking compared to placebo. CONCLUSIONS: Gender differences in stress reactivity were shown in the hypothesized direction, but oxytocin appeared to exert little impact on subjective or behavioral metrics. Results highlight the complex relationship between gender, stress, and smoking, as well as the implications for oxytocin as a potential pharmacotherapy for smoking cessation.

OBJECTIVE: We sought to examine the impact of the Affordable Care Act on preventable hospitalizations and associated charges for patients living with systemic lupus erythematosus (SLE), before and after Medicaid expansion. METHODS: A retrospective, quasi-experimental study, using an Interrupted Time Series (ITS) research design, was used to analyze data from the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) for eight states. Lupus hospitalizations with a principal diagnosis of pre-determined ambulatory care sensitive (ACS) conditions were the unit of primary analysis. The primary outcome variable was access to care measured by preventable hospitalizations caused by an ACS condition. RESULTS: There were 204,150 lupus hospitalizations in the final analysis with the majority (53.5%) of lupus hospitalizations in states that did not expand Medicaid. In unadjusted analysis, Medicaid expansion states had significantly lower odds of having preventable lupus hospitalizations (OR 0.958); however, after adjusting for several covariates, Medicaid expansion states had increased odds of having preventable lupus hospitalizations (OR 1.302). Adjusted analysis showed that those with increased age, public insurance (Medicare or Medicaid), no health insurance, rural residence, or low income had significantly higher odds of having a preventable lupus hospitalization. States that expanded Medicaid had $523 significantly more charges than states that did not expand Medicaid. Older age and rural residence were associated with significantly higher charges. CONCLUSION: Our findings suggest that while Medicaid expansion increased health insurance coverage, it did not address other issues related to access to care that could reduce the number of preventable hospitalizations.

Background Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that is associated with increased morbidity, mortality, healthcare costs and decreased quality of life. African Americans in the USA have three to four times greater prevalence of SLE, risk of developing SLE at an earlier age, and SLE-related disease activity, damage, and mortality compared with Caucasians, with the highest rates experienced by African American women. There is strong evidence that patient-level factors are associated with outcomes, which justifies targeting them with intervention. While evidence-based self-management interventions that incorporate both social support and health education have reduced pain, improved function, and delayed disability among patients with SLE, African Americans and women are still disproportionately impacted by SLE. Peer mentoring interventions are effective in other chronic conditions that disproportionately affect minorities, such as diabetes mellitus, HIV, and kidney disease, but there is currently no empirically tested peer mentoring intervention developed for patients with SLE. Preliminary data from our group suggest that peer mentoring improves self-management, reduces disease activity, and improves health-related quality of life (HRQOL) in African American women with SLE. Methods This study will test an innovative, manualized peer mentorship program designed to provide modeling and reinforcement by peers (mentors) to other African American women with SLE (mentees) to encourage them to engage in activities that promote disease self-management. Through a randomized, “mentored” or “support group” controlled design, we will assess the efficacy and mechanism(s) of this intervention in self-management, disease activity, and HRQOL. Discussion This is the first study to test peer mentorship as an alternative strategy to improve outcomes in African American women with SLE. This could result in a model for other programs that aim to improve disease self-management, disease activity, and HRQOL in African American women suffering from chronic illness. The peer mentoring approach is uniquely fitted to African Americans, and this intervention has the potential to lead to health improvements for African American women with SLE that have not been attainable with other interventions. This would significantly reduce disparities and have considerable public health impact. Trial registration ClinicalTrials.gov, NCT03734055. Registered on 27 November 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3580-4) contains supplementary material, which is available to authorized users.

Peripheral sensory stimulation has been used as a method to stimulate the sensorimotor cortex, with applications in neurorehabilitation. To improve delivery modality and usability, a new stimulation method has been developed in which imperceptible random-frequency vibration is applied to the wrist concurrently during hand activity. The objective of this study was to investigate effects of this new sensory stimulation on the sensorimotor cortex. Healthy adults were studied. In a transcranial magnetic stimulation (TMS) study, resting motor threshold, short-interval intracortical inhibition, and intracortical facilitation for the abductor pollicis brevis muscle were compared between vibration on vs. off, while subjects were at rest. In an electroencephalogram (EEG) study, alpha and beta power during rest and event-related desynchronization (ERD) for hand grip were compared between vibration on vs. off. Results showed that vibration decreased EEG power and decreased TMS short-interval intracortical inhibition (i.e., disinhibition) compared with no vibration at rest. Grip-related ERD was also greater during vibration, compared to no vibration. In conclusion, subthreshold random-frequency wrist vibration affected the release of intracortical inhibition and both resting and grip-related sensorimotor cortical activity. Such effects may have implications in rehabilitation.

Current clinical classifications of chronic rhinosinusitis (CRS) have weak prognostic utility regarding treatment outcomes. Simplified discriminant analysis based on unsupervised clustering has identified novel phenotypic subgroups of CRS, but prognostic utility is unknown.We sought to determine whether discriminant analysis allows prognostication in patients choosing surgery versus continued medical management.A multi-institutional prospective study of patients with CRS in whom initial medical therapy failed who then self-selected continued medical management or surgical treatment was used to separate patients into 5 clusters based on a previously described discriminant analysis using total Sino-Nasal Outcome Test-22 (SNOT-22) score, age, and missed productivity. Patients completed the SNOT-22 at baseline and for 18 months of follow-up. Baseline demographic and objective measures included olfactory testing, computed tomography, and endoscopy scoring. SNOT-22 outcomes for surgical versus continued medical treatment were compared across clusters.Data were available on 690 patients. Baseline differences in demographics, comorbidities, objective disease measures, and patient-reported outcomes were similar to previous clustering reports. Three of 5 clusters identified by means of discriminant analysis had improved SNOT-22 outcomes with surgical intervention when compared with continued medical management (surgery was a mean of 21.2 points better across these 3 clusters at 6 months, P.05). These differences were sustained at 18 months of follow-up. Two of 5 clusters had similar outcomes when comparing surgery with continued medical management.A simplified discriminant analysis based on 3 common clinical variables is able to cluster patients and provide prognostic information regarding surgical treatment versus continued medical management in patients with CRS.

Grip relaxation is a voluntary action that requires an increase in short-interval intracortical inhibition (SICI) in healthy young adults, rather than a simple termination of excitatory drive. The way aging affects this voluntary inhibitory action and timing of grip relaxation is currently unknown. The objective of this study was to examine aging-related delays in grip relaxation and SICI modulation for the flexor digitorum superficialis (FDS) muscle during grip relaxation. The main finding was that young adults increased SICI to relax their grips, whereas older adults did not increase SICI with a prolonged grip relaxation time (p

Introduction Some evidence suggests that female smokers may show more context-dependent smoking and that males may show more stereotyped smoking (regardless of stress or cue exposure). The goal of this study was to characterize sex differences in response to stressful and smoking cues ecologically presented in daily life and variability in day-to-day smoking behavior. Methods Adult smokers (N = 177) provided ratings of mood and cigarette craving before and after stress and smoking cues were presented four times daily for 14 days via a mobile device. Linear mixed models tested whether (1) female smokers exhibited greater reactivity to stressful cues than male smokers; (2) pre-cue negative affect increased reactivity to smoking cues more in female smokers than male smokers; (3) across both sexes, greater reactivity to stressful and smoking cues correlated with greater quantity of smoking within a day; and (4) female smokers exhibited greater variability in cigarettes per day (CPD) relative to males. Results Relative to male smokers, female smokers reported greater negative affect, stress, and craving in response to stressful cues, but not smoking cues, after accounting for time since last cigarette and pre-cue responding. No sex differences in CPD or variability in CPD were detected. Days with higher subjective reactivity to cues were not associated with increased smoking, in either males or females. Conclusions Sex differences were observed in response to stress but not smoking cues in the natural environment of regular cigarette smokers. Further research is necessary to evaluate whether stress reactivity in female smokers is associated with reduced latency to smoke following stress exposure in daily life. Implications This study provides naturalistic evidence that female smokers may not be more reactive to smoking cues than males, but experience heightened stress and craving following stress exposure. There was no evidence to support the hypothesis that amount smoked per day varied more for females, relative to males, as a result of more context-driven smoking for females.

Objective To evaluate the Specific Test of Early Infant Motor Performance (STEP), a rapid screening test of preterm infants at risk for developmental delay. Study Design We prospectively studied 23 preterm infants’ performance on the STEP and the Test of Infant Motor Performance (TIMP) at term and 3 months, and on the Bayley-III at 12 months. We investigated the psychometric qualities of the STEP and determined STEP cutoff scores for low and high-performing infants. Results STEP scores at term and 3 months strongly correlate with 12-month Bayley-III gross motor and cognitive scaled scores, while TIMP scores did not. The STEP showed excellent reliability and required 6–10 min to administer. Conclusion STEP is a short, easy to administer, early developmental assessment with unique scoring that emphasizes qualitative and quantitative aspects of muscle tone in movements and predicts 12-month Bayley gross motor and cognitive scaled scores.

Objective: Evaluate brain metabolites, which reflect neuroinflammation, and relate to neurodevelopmental outcomes in healthy term neonates exposed to chorioamnionitis. Study Design: Thirty-one healthy term neonates with documented fetal inflammatory response after maternal chorioamnionitis underwent magnetic resonance spectroscopy (MRS), with voxels placed in basal ganglia (BG) and frontal white matter. Bayley III examinations were performed at 12 months of age. Result: Infants with below average outcomes did not show the same increase in NAA/Cho ratios postnatally as the group with normal outcomes. Decreased NAA/Cho and increased Lac/Cr in BG correlated with lower motor and cognitive composite scores, respectively, controlling for postnatal age. In males, increased lactate/NAA in BG were associated with lower motor scores. Funisitis severity was associated with decreased NAA/Cho and increased mI/NAA in males. Conclusion: In healthy term newborns with chorioamnionitis, MRS ratios shortly after birth may provide evidence of occult neuroinflammation, which may be associated with worse performance on 1-year neurodevelopmental tests.

OBJECTIVE: To identify the vitamin D status to optimize calcium and bone health in preterm infants. STUDY DESIGN: Very low birth weight infants had measurement of 25-hydroxyvitamin D status and markers of calcium and bone health from birth to term age. Piecewise linear regression modeling was performed to identify a 25-hydroxyvitamin D threshold associated with stable parathyroid hormone concentration and bone mineralization. RESULTS: In a cohort of 89 infants at term age, femur BMC and density increased linearly with 25-hydroxyvitamin D status until reaching a threshold of 48 ng/mL and 46 ng/mL, respectively. Parathyroid hormone status decreased as vitamin D status increased until reaching a plateau at 25-hydroxyvitamin D of 42 ng/mL. CONCLUSION: Preterm infant vitamin D status was significantly associated with PTH status and femur mineralization with suggestion that achieving a specific 25-hydroxyvitamin concentration is associated with optimal calcium homeostasis and femur bone mineralization.

Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m2 for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies. Clin Cancer Res; 20(22); 5652–62. ©2014 AACR.

PURPOSE: To determine specific motor skills in premature infants, match those that correlate with standards tests of motor performance, and MRS measures of abnormal brain biochemistry. METHODS: Prospective cohort study of preterm infants (n = 22). Infant motor assessments were completed at term and 12 weeks corrected gestational age (CGA) using the Test of Infant Motor Performance (TIMP) and Bayley Scales of Infant and Toddler Development-III at 12 months CGA. Infants (n = 12) received MRS scans at term CGA. Rasch analysis and MRS findings investigated TIMP items well targeted to high and low risk infants. RESULTS: A 10 item subset of motor skill items correlated strongly with full 42-item TIMP at term and 12 week testing ( r> 0.90, p< 0.001 for both), and with Bayley gross motor scores. MRS metabolites in basal ganglia correlated significantly with both TIMP and 10 item motor tests at term, while frontal white matter metabolites correlated with TIMP and 10 item tests at 12 weeks and Bayley motor scores. CONCLUSION: A short motor skill assessment may be representative of a longer standardized test and relate to brain metabolic function in key areas for motor movement and development. Validation of a shortened assessment may improve early identification of high-risk preterm infants.

Purpose Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. Experimental design Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. Results Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m2 and dacarbazine 580 mg/m2 are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. Conclusions Bortezomib 1.6 mg/m2 and dacarbazine 580 mg/m2 administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

OBJECTIVE To evaluate outcomes of robot-assisted sacrocolpopexy (RSCP) and sacrocervicopexy (RCSP). METHODS We conducted a prospective study of women undergoing RSCP or RCSP between June 2008 and January 2010. RESULTS A total of 85 cases (48 RSCP and 37 supracervical hysterectomy with concomitant RCSP) were performed: 33% (28/85) for stage II, 54% (46/85) for stage III, and 13% (11/85) for stage IV pelvic organ prolapse (POP). Six weeks postoperatively, 96% (80/83) had stage 0, 2.4% (2/83) had stage I, and 1.2% (1/83) had stage II POP (P < 0.001). Six months postoperatively, 77% (24/31) had stage 0, 6.5% (2/31) had stage I, and 16% (5/31) had stage II POP (P < 0.001). Mean surgical time, estimated blood loss, and length of hospital stay was 194 ± 54 minutes, 49 ± 48 cm, and 1.6 ± 0.72 days, respectively. There were 2 cases of mesh erosion (2.3%), both in the RSCP group. CONCLUSIONS RSCP and RCSP are effective, efficient, and safe procedures.

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non–Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively. Clin Cancer Res; 17(10); 3388–97. ©2011 AACR.

Context. Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and persistent consequence of numerous classes of antineoplastic agents, affecting up to 30%e40% of patients. To date, there is no effective prevention or therapy. An evolving hypothesis for reducing CIPN pain involves direct nerve stimulation to reduce the pain impulse. Objectives. To evaluate the impact on CIPN associated with the MC5-A Calmare therapy device (Competitive Technologies, Inc. Fairfield, CT). Methods. The MC5-A Calmare therapy device is designed to generate a patient-specific cutaneous electrostimulation to reduce the abnormal pain intensity. Sixteen patients from one center received one-hour interventions daily over 10 working days. Results. Of 18 patients, 16 were evaluable. The mean age of the patients was 58.6 yearsdfour men and 14 womendand the duration of CIPN was three months to eight years. The most common drugs were taxanes, platinums, and bortezomib (Velcade, Millenium Pharmaceuticals, Cambridge MA). At the end of the study (Day 10), a 20% reduction in numeric pain scores was achieved in 15 of 16 patients. The pain score fell 59% from 5.81 � 1.11 before treatment to 2.38 � 1.82 at the end of 10 days (P < 0.0001 by paired t-test). A daily treatment benefit was seen with a strong statistically significant difference between the preand post-daily pain scores (P < 0.001). Four patients had their CIPN reduced to zero. A repeated-measures analysis using the scores from all 10 days confirmed these results. No toxicity was seen. Some responses have been durable without maintenance. Conclusions. Patient-specific cutaneous electrostimulation with the MC5-A Calmare device appears to dramatically reduce pain in refractory CIPN patients with no toxicity. Further studies are underway to define the benefit, mechanisms of action, and optimal schedule. J Pain Symptom Manage 2010;-:-e-. 2010 Published by Elsevier Inc on behalf of U.S. Cancer Pain Relief Committee.

Purpose Many seriously ill patients with cancer do not discuss prognosis or advance directives (ADs), which may lead to inappropriate and/or unwanted aggressive care at the end of life. Ten years ago, patients with cancer said they would not like to discuss ADs with their oncologist but would be willing to discuss them with an admitting physician. We assessed whether this point of view still held. Patients and Methods Semi-structured interviews were conducted with 75 consecutively admitted patients with cancer in the cancer inpatient service. Results Of those enrolled, 41% (31 of 75) had an AD. Nearly all (87%, 65 of 75) thought it acceptable to discuss ADs with the admitting physician with whom they had no prior relationship, and 95% (62 of 65) thought that discussing AD issues was very or somewhat important. Only 7% (5 of 75) had discussed ADs with their oncologist, and only 23% (16 of 70) would like to discuss ADs with their oncologist. When specifically asked which physician they would choose, 48% (36 of 75) of patients would prefer their oncologist, and 35% (26 of 75) would prefer their primary care physician. Conclusion Fewer than half of seriously ill patients with cancer admitted to an oncology service have an AD. Only 23% (16 of 70) would like to discuss their ADs with their oncologist but nearly all supported a policy of discussing ADs with their admitting physician. However, fully 48% (36 of 75) actually preferred to discuss advance directives with their oncologist if AD discussion was necessary. We must educate patients on why communicating their ADs is beneficial and train primary care physicians, house staff, hospitalists, and oncologists to initiate these difficult discussions.

We report results of a randomized, double-blind, placebo-controlled, within-subject study (n = 8) to determine the ability of cocaethylene to modulate acute responses to cocaine and identify significant pharmacokinetic interactions between cocaine and cocaethylene. Stable plasma cocaethylene concentrations (0, 50, or 200 ng/ml) were maintained for 840 minutes. Cocaine (0, 0.25, or 0.5 mg/kg) was injected over 1 minute after 240 minutes of cocaethylene. Blood samples, subjective, and physiological measures were collected. No differences over baseline responses were observed following 240 minutes of a steady state cocaethylene infusion for cardiovascular or subjective responses. "Rush" duration following a cocaine challenge (0.5 mg/kg) declined when administered during the course of a 200 ng/mL cocaethylene infusion. (p = 0.01). No pharmacokinetic interaction occurred when cocaine was administered in conjunction with cocaethylene. Findings indicate that continuous 8-hour exposure to cocaethylene is safe, produces acute tolerance to itself, and reduces some behavioral effects of coadministered cocaine. Agonist substitution therapy may have potential as an alternative treatment for cocaine dependence.

Overdispersion is a common problem in count data. It can occur due to extra population-heterogeneity, omission of key predictors, and outliers. Unless properly handled, this can lead to invalid inference. Our goal is to assess the differential performance of methods for dealing with overdispersion from several sources. We considered six different approaches: unadjusted Poisson regression (Poisson), deviance-scale-adjusted Poisson regression (DS-Poisson), Pearson-scale-adjusted Poisson regression (PS-Poisson), negative-binomial regression (NB), and two generalized linear mixed models (GLMM) with random intercept, log-link and Poisson (Poisson-GLMM) and negative-binomial (NB-GLMM) distributions. To rank order the preference of the models, we used Akaike's information criteria/Bayesian information criteria values, standard error, and 95% confidence-interval coverage of the parameter values. To compare these methods, we used simulated count data with overdispersion of different magnitude from three different sources. Mean of the count response was associated with three predictors. Data from two real-case studies are also analyzed. The simulation results showed that NB and NB-GLMM were preferred for dealing with overdispersion resulting from any of the sources we considered. Poisson and DS-Poisson often produced smaller standard-error estimates than expected, while PS-Poisson conversely produced larger standard-error estimates. Thus, it is good practice to compare several model options to determine the best method of modeling count data.

Introduction Preclinical and human laboratory research suggests that (a) progesterone may decrease drug reward, craving, and smoking behavior, and (b) estradiol may enhance drug reward and smoking behavior. A modest majority of treatment research examining the relationship between menstrual cycle phase and outcomes suggests that the luteal menstrual phase, with its uniquely higher progesterone levels, is associated with better cessation outcomes. However, no studies to date have examined the effects of naturally occurring variation in progesterone and estradiol levels on medication-assisted smoking cessation. The present study sought to fill this notable gap in the treatment literature. Methods Weekly plasma progesterone and estradiol levels were obtained from nicotine-dependent female smokers enrolled in a 4-week cessation trial. Participants (N = 108) were randomized to receive a 4-week course of either varenicline (VAR) tablets and placebo patches or placebo tablets and nicotine patches. Plasma samples were obtained 1 week before their cessation attempt and weekly during medication administration. Abstinence was assessed weekly. Results Weekly hormone data replicated commonly observed menstrual cycle patterns of progesterone and estradiol levels. Importantly, increases in progesterone level were associated with a 23% increase in the odds for being abstinent within each week of treatment. This effect was driven primarily by nicotine patch-treated versus VAR-treated females. Conclusions This study was the first to identify an association between progesterone level (increasing) and abstinence outcomes in free-cycling women smokers who participated in a medication-based treatment. Furthermore, the potential benefits of progesterone may vary across different pharmacotherapies. Implications of these findings for smoking cessation intervention are discussed.

Objective The purpose of this study was to determine the rate of new bowel symptoms and anal sphincter defects in primiparous women with and without recognized anal sphincter (AS) injury. Study design One hundred seventeen primiparous women classified with increasing degrees of perineal trauma and 21 controls delivered by cesarean section were enrolled immediately postpartum and demographic and delivery data were collected. At 6 weeks' postpartum, subjects completed a bowel function questionnaire and endoanal ultrasonography was performed. Logistic regression, chi-square, and 2-sample t tests were used for statistical analysis. Results A significant difference in new bowel symptoms was reported in women with (39%) and without (11%) recognized AS injury (P = .002). AS defects were present in 0%, 15%, 23%, 37%, and 67% of women with C/S, first-, second-, third-, and fourth-degree lacerations, respectively. Combined defects of the internal and external AS were associated with the greatest risk of new bowel symptoms (OR 32.1 [95% CI 9.6-107], P Conclusion In women with and without recognized AS trauma, new bowel symptoms were strongly correlated with the presence of anatomic AS defects postpartum.

OBJECTIVE To compare the prevalence of anal incontinence and anal sphincter injury in women with pelvic floor disorders (cases) with those in a group of normal control subjects and to evaluate the relationship between sphincter injury and anal incontinence in each group. METHODS We previously reported the results of a cross-sectional study of 100 women with pelvic floor disorders (> or = stage II pelvic organ prolapse and/or urinary incontinence). In this study, we compared those cases with 90 controls (stage 0 or I pelvic organ prolapse and no urinary incontinence) who completed the Rockwood-Thompson fecal incontinence severity index, in which scoring (0-61) is based on the frequency and type of anal incontinence. All women underwent endoanal ultrasonography, and the internal and external anal sphincters were reported as intact versus disrupted. Chi-square test, Student t test, and logistic regression were used for statistical analysis. RESULTS Women with pelvic floor disorders were significantly more likely to report anal incontinence (54% versus 17.8%, odds ratio [OR] 5.4, 95% confidence interval [CI] 2.8-10.6, P < .001) and had higher mean fecal incontinence severity index scores (22.3 +/- 13 versus 12.7 +/- 6.3, P = .006) than controls. Cases demonstrated higher rates of anal sphincter defects on ultrasound examination than did controls (52% versus 30%, P = .007). Anal incontinence was significantly associated with anal sphincter injury in women with pelvic floor disorders (OR 36.4, 95% CI 12-114, P < .001) and in controls (OR 5.9, 95% CI 3-11, P = .002). CONCLUSION Anal incontinence was more common in women with pelvic floor disorders than normal controls and may be due to higher rates of anatomic anal sphincter disruption in this group.

Current clinical classifications of chronic rhinosinusitis (CRS) have been largely defined based upon preconceived notions of factors thought to be important, such as polyp or eosinophil status. Unfortunately, these classification systems have little correlation with symptom severity or treatment outcomes. Unsupervised clustering can be used to identify phenotypic subgroups of CRS patients, describe clinical differences in these clusters and define simple algorithms for classification.A multi-institutional, prospective study of 382 patients with CRS who had failed initial medical therapy completed the Sino-Nasal Outcome Test (SNOT-22), Rhinosinusitis Disability Index (RSDI), Medical Outcomes Study Short Form-12 (SF-12), Pittsburgh Sleep Quality Index (PSQI), and Patient Health Questionnaire (PHQ-2). Objective measures of CRS severity included Brief Smell Identification Test (B-SIT), CT, and endoscopy scoring. All variables were reduced and unsupervised hierarchical clustering was performed. After clusters were defined, variations in medication usage were analyzed. Discriminant analysis was performed to develop a simplified, clinically useful algorithm for clustering.Clustering was largely determined by age, severity of patient reported outcome measures, depression, and fibromyalgia. CT and endoscopy varied somewhat among clusters. Traditional clinical measures, including polyp/atopic status, prior surgery, B-SIT and asthma, did not vary among clusters. A simplified algorithm based upon productivity loss, SNOT-22 score, and age predicted clustering with 89% accuracy. Medication usage among clusters did vary significantly.A simplified algorithm based upon hierarchical clustering is able to classify CRS patients and predict medication usage. Further studies are warranted to determine if such clustering predicts treatment outcomes.

Background Although new interventions treating neonatal brain injury show great promise, our current ability to predict clinical functional outcomes is poor. Quantitative biomarkers of long-term neurodevelopmental outcome are critically needed to gauge treatment efficacy. Kinematic measures derived from commonly used developmental tasks may serve as early objective markers of future motor outcomes. Aim To develop reliable kinematic markers of head control at 12 week corrected gestational age (CGA) from two motor tasks: head lifting in prone and pull-to-sit. Study design and subjects Prospective observational study of 22 preterm infants born between 24 and 34 weeks of gestation. Outcome measures Bayley Scales of Infant Development III (Bayley) motor scores. Results Intrarater and interrater reliability of prone head lift angles and pull-to-sit head angles were excellent. Prone head lift angles at 12 week CGA correlated with white matter NAA/Cho, concurrent Test of Infant Motor Performance (TIMP) scores, and 12-month Bayley motor scores. Head angles during pull-to-sit at 12-week CGA correlated with TIMP scores. Conclusions Poor ability to lift the head in prone and an inability to align the head with the trunk during the pull-to-sit task were associated with poorer future motor outcome scores. Kinematic measurements of head control in early infancy may serve as reliable objective quantitative markers of future motor impairment and neurodevelopmental outcome.

Stress and drug-paired cues increase drug craving and noradrenergic activity in cocaine-dependent individuals. Thus, medications that attenuate noradrenergic activity may be effective therapeutic treatment options for cocaine-dependent individuals.To examine the impact of acute administration of the α2 adrenergic receptor agonist guanfacine on responses to multiple risk factors for relapse in cocaine-dependent individuals.In a double-blind, placebo-controlled study, cocaine-dependent individuals (n = 84), were randomized to receive either 2 mg guanfacine (n = 50) or placebo (n = 34). Within each treatment arm, subjects were randomized to either a stress (guanfacine n = 26; placebo n = 15) or a no-stress (guanfacine n = 24; placebo n = 19) group. Participants in the stress group performed the Trier Social Stress Test. Subjects in each group were exposed to a neutral cue and then to cocaine-related cues. Plasma cortisol and subjective responses were compared between the four groups.The no-stress guanfacine group reported greater craving in response to cocaine cues as compared to the neutral cue (p 0.001). The guanfacine stress group reported greater subjective stress at the neutral cue than at baseline (p = 0.032). The cocaine cue increased subjective stress in the guanfacine (p 0.001) no-stress group. There were no effects of guanfacine on cortisol levels in either the stress or no stress groups (all p 0.70).This study found no effects of a single 2 mg dose of guanfacine on reactivity to stress and cues alone or on the interaction of stress and drug cues. In cocaine-dependent individuals an acute 2 mg dose of guanfacine may not be an effective therapeutic treatment strategy.

Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.Yohimbine increased ratings of anxiety both before (p 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p 0.001).Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.

Objectives To estimate the prevalence and severity of asthma in an adolescent population by sex and race. Methods Cross-sectional, population-based survey of school children. Setting Midwestern city experiencing damage from the 1993 Mississippi River flood. Participants: 2,693 children attending grades 7 to 12. Measurements Questions from the International Study of Asthma and Allergies in Childhood (ISAAC). Results Two thousand six hundred ninety-three children were surveyed, for a response rate of 90%. In this population, 16.4% reported having ever been diagnosed with asthma; 25% reported wheezing in the last 12 months; 32% reported symptoms of rhinitis in the last 12 months; and 22% reported ever having hay fever. The prevalence rate for current asthma was 12.6%. Female students had significantly greater prevalence rates for current asthma (16.4% vs 9.0%, OR=1.85); ever-diagnosed asthma (18.5% vs 14.3%, OR=1.36); wheezing ≥ 4 times in the last 12 months (12.0% vs 5.6%, OR=1.95); current rhinitis (38.7% vs 25.4%, OR=1.73); and hay fever (26.4% vs 18.4%, OR=1.57). All associations with sex remained significant, except ever-diagnosed asthma, after controlling for other known risk factors in logistic regression. African-Americans had higher prevalence rates than other races with differences reaching statistical significance for ever-diagnosed asthma and current asthma; however, these relationships did not remain significant after controlling for other known risk factors in logistic regression. Conclusions Our prevalence rates were similar to those reported by other studies that used the ISAAC questionnaire. Female students reported significantly more asthma, wheezing, rhinitis, and hay fever than male students. Female students also reported more severe symptoms and a greater number of emergency room and hospital admissions.

Background Asthma mortality rates in Chicago are among the highest in the United States, with substantially greater rates in poor and minority populations. How much of the differential can be attributed to differences in prevalence versus severity or access to care has not been determined. Objective To examine rates of asthma prevalence, severity, and symptoms and to explore the relationships of these rates to race and socioeconomic status in a random sample of Chicago school children. Methods Self-administered survey. Results Overall, rates of asthma were higher than previously reported, with 16% of students in the stratified cluster random sample of 3,670 children in the 7th and 8th grades having had asthma. Prevalence rates were significantly higher in schools with >98% African Americans than in other schools, with the highest prevalence rates seen in African American schools in low income neighborhoods. Rates were associated with the percent of African American children in the school and with median income of the school's census tract. Relationships were most consistent with indices of more severe disease. Conclusions Asthma prevalence is higher than previously noted, with rates greatest in minority and low income populations. Differences are more striking for measures of severity than for symptoms of wheezing, but are far less than previously reported differences in mortality, suggesting that additional factors, such as differential access to continuous health care, may be affecting high death rates from asthma in Chicago.

In this paper, a method with which to identify a national cohort of elderly twins is proposed. Record linkage algorithms were developed and applied to the > 30 million records contained in the Medicare beneficiary file. The matching algorithm for male/male pairs used race (black or white), last name, date of birth, and state of issuance of the Social Security number. Female/female and male/female pairs were selected with matching on race, date of birth, and the first seven digits of the Social Security number to compensate for the absence of maiden names. A stratified random sample of same-sex and opposite-sex white and black pairs (six groups) were selected and surveyed for determination of the actual prevalence of twins. On the basis of these results, the authors conclude that this method could identify an estimated 18,308 male/male, 7,544 female/female, and 204 male/female pairs of twins aged 65 years or more. This would be the largest sample of older twins ever assembled in the United States and represents a significant new resource for epidemiologic studies of the aging population.

Background Advanced heterogeneous emphysema with hyperinflation impacts exercise tolerance in COPD. Bronchoscopic lung volume reduction using Zephyr endobronchial valves (EBVs) has been shown to improve lung function in patients with heterogeneous emphysema. It is unclear whether the target lobe perfusion of patients receiving EBV therapy impacts exercise tolerance as measured by the 6-min walk test distance (6MWTD). Methods We performed a retrospective analysis on the treatment group of the Endobronchial Valve for Emphysema Palliation Trial (VENT) to evaluate the impact of perfusion, measured by 99m Tc-MAA-perfusion scintigraphy, on the 6-month improvement in 6MWTD. A mixed-model analysis was performed for the treatment outcome, adjusting for other variables such as age, target lobe position, fissure integrity, BMI, sex, destruction score, and lobar exclusion. Results Dichotomized at the median, of the 169 patients who received EBV therapy, 88 had a low target lobe regional perfusion and 81 had high target lobe regional perfusion at baseline. Patients with a low target lobe regional perfusion had a significant improvement in 6MWTD when compared with those with a high baseline target lobe regional perfusion (30.24 m vs 3.72 m, P = .03). Shifts in perfusion after EBV therapy occurred only in patients with high baseline perfusion and did not correlate with improved 6MWTD. Conclusions Patients having heterogeneous emphysema with a low baseline target lobe regional perfusion benefit from EBV therapy, independent of the degree of target lobe destruction. This effect is attenuated if the EBV therapy is not occlusive. Characterization of baseline perfusion may enhance clinical results of patients with emphysema undergoing EBV therapy. Trial registry ClinicalTrials.gov; No.: NCT00000606; URL: www.clincialtrials.gov

Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-minute loading infusion) followed by 20 mg/m2 (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. Clin Cancer Res; 19(7); 1873–83. ©2013 AACR.

Abnormalities in taste and smell are commonly reported in patients receiving chemotherapy and may hinder appetite, dietary intake, nutritional well-being, and quality of life. Oral zinc has been used to treat taste and smell abnormalities in several altered physiologic states, including renal failure, liver disease, head trauma, and pregnancy, with varying results. The authors conducted a double-blinded, placebo-controlled randomized clinic trial over 3 months. Eligible patients were those taking chemotherapy that had alterations in taste and/or smell. The measurement of the primary end point, improvement in altered taste and smell, was made using a 0–100 scale (100 describing no loss or distortion in taste and smell, and 0 describing the worst distortion or loss of taste and smell). Twenty-nine subjects were enrolled in each treatment group, of whom 31 were white, 26 African American, and 1 Native American. Forty-one patients were female. A wide range of cancer types was represented, with breast the most common (21 patients). The zinc dose was 220 mg orally twice daily (equivalent of 50 mg elemental zinc twice daily). There was no statistically significant improvement in loss or distortion of taste or smell with the addition of zinc. There was a trend toward improvement over time in all groups, except in the zinc group where there was a nonsignificant worsening in loss of smell over time. Zinc at standard doses did not provide significant benefit to taste or smell in patients receiving chemotherapy.

The clinical significance of tumor-infiltrating immune cells has been reported in a variety of human carcinomas including breast cancer. However, molecular signature of tumor-infiltrating immune cells and their prognostic value in breast cancer patients remain elusive. We hypothesized that a distinct network of immune function genes at the tumor site can predict a low risk versus high risk of distant relapse in breast cancer patients regardless of the status of ER, PR, or HER-2/neu in their tumors. We conducted retrospective studies in a diverse cohort of breast cancer patients with a 1–5 year tumor relapse versus those with up to 7 years relapse-free survival. The RNAs were extracted from the frozen tumor specimens at the time of diagnosis and subjected to microarray analysis and real-time RT-PCR. Paraffin-embedded tissues were also subjected to immunohistochemistry staining. We determined that a network of immune function genes involved in B cell development, interferon signaling associated with allograft rejection and autoimmune reaction, antigen presentation pathway, and cross talk between adaptive and innate immune responses were exclusively upregulated in patients with relapse-free survival. Among the 299 genes, five genes which included B cell response genes were found to predict with >85% accuracy relapse-free survival. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes.

The discipline of palliative care is growing rapidly in the United States but, as in many other areas of medical care, multiple barriers exist to providing such care to low-income patients with end-stage cancer and other diseases. Reports vary with regard to definition and scope of these and other barriers. This article briefly reports a pilot study of perceived barriers to palliative care and related issues in an urban cancer clinic, reviews the current literature, and suggest ways to identify and overcome such barriers in low-income patients with cancer.

We sought to determine the differential rates and complications of hysterectomy type in the year prior to and following the introduction of robotic technology.This was a retrospective chart review of 461 hysterectomies performed from July 2007 through June 2008 (period 1) and July 2008 through June 2009 (period 2) at Virginia Commonwealth University Medical Center.In all, 199 vs 262 hysterectomies were performed in periods 1 and 2: open, 52.3% vs 43.1%; laparoscopic, 18.1% vs 8.0%; robotic, 2.5% vs 24.8%; and vaginal, 27.4% vs 24.1%, respectively. The increase in robotic hysterectomies in period 2 was associated only with a decline in laparoscopic hysterectomy (P.0001). Major morbidity by route was 23.04% open, 11/1% vaginal, 7.02% laparoscopic, and 4.29% robotic (P.0001).Route of hysterectomy changed significantly after the introduction of robotic technology primarily due to a change in management of pelvic organ prolapse. Open hysterectomy was associated with significantly higher complication rates.

We prospectively compared the clinical course of 119 patients treated for status epilepticus (SE) in private practice community hospitals and 344 SE patients treated in the VCU university hospitals in Richmond, Virginia USA over a 2-year period to test the hypothesis that SE presents with the same mortality and clinical patterns in both clinical settings. Of the patients reviewed, the major etiologies for SE were cerebrovascular disease, decreased anti-epileptic drug levels in epileptic patients, anoxia–hypoxia, and remote symptomatic. The other etiologies included were alcohol related, trauma, central nervous system infections, tumors, systemic infection, metabolic disorders, idiopathic, and hemorrhage. These observations provide the first direct prospective comparison of SE present in university and private practice community hospital settings in the same geographic area. Mortality was the highest in the elderly population while the pediatric population had low mortality in both clinical settings. Etiology risk factors for outcome were similar for both the populations. The data also suggest that the higher degree of illness severity in university hospitals may be associated with a higher incidence of SE, but not with mortality or a different clinical presentation of the condition. The results of this study demonstrate that SE has the same mortality and is present in an essentially identical manner in university and private practice community hospitals and underscores the fact that mortality in SE is not just associated with tertiary care hospitals and the importance of recognizing the severity of SE in the private practice setting.

Purpose: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies.Experimental Design: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events.Results: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m2/d × 5). The recommended bryostatin 1 phase II dose is 50 μg/m2 for both sequences, bryostatin 1 → fludarabine and fludarabine → bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells.Conclusions: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.

ObjectiveThis study examined the hypothesis that superficial femoral artery (SFA) subintimal angioplasty (SI-PTA) can maintain limb salvage with minimal complications in patients with symptomatic occlusive arterial disease.MethodsFrom March 1, 2004, until April 28, 2006, 78 patients with rest pain (62.2%), gangrene (25.6%), or severe progressive claudication (12.2%) were treated consecutively with 82 SFA SI-PTAs (4 bilateral). The mean age was 59 ± 1.2 years, and 21 (27%) of the patients were female. All patients were treated in the operating room under local anesthesia by using fluoroscopic guidance, and the percentage SFA that was occluded was measured during the diagnostic portion of the procedure. Selective stent placement was performed after successful recanalization of the occluded arterial segments. Patients were treated with chronic aspirin and clopidogrel bisulfate for 3 months and followed up at 30 days and then every 3 months with physical examination and arterial duplex scan.ResultsOf the 82 SFA SI-PTA attempts, 76 (92%) were initially successful, with an increase in the ankle-brachial index from 0.46 ± 0.02 to 0.88 ± 0.01 (P < .001). Five of the six patients with a failed SFA SI-PTA were female, two of the six had had previous bypass attempts, and one of the six had had a previous SFA SI-PTA attempt by another physician. Forty-nine (64%) of the 76 initially successful SFA SI-PTAs required placement of a stent, and 43 (56.5%) of the successful 76 SFA SI-PTAs required additional PTA of 1 or more arterial segments. The group treated with a successful SFA SI-PTA had 42.5% ± 3.5% SFA occlusion, compared with 82% ± 10% (P < .05) in the group with a failed attempt at SFA SI-PTA. Two of the six patients with initial SI-PTA failure underwent leg amputation within 30 days, three were treated with successful leg bypass surgery, and one was lost to follow-up. Of the 76 successful SFA SI-PTAs, 5 (6.5%) failed within 90 days, and the patients were treated successfully with leg bypass surgery. Of the 71 limbs with patent SI-PTAs at 90 days, 68 have remained patent with a mean follow-up 10.4 ± 0.7 months (range, 2-24 months). Three of the 71 SFA SI-PTAs failed between 4 and 7 months (mean, 5 ± 0.7 months): 1 patient was treated with successful bypass surgery, 1 patient is currently considering further intervention, and 1 patient was treated with amputation. Ten (14%) of the 71 successful SFA SI-PTAs required limited PTA for asymptomatic restenosis, as identified by the arterial duplex scan (7.4 ± 1.4 months; range, 2-16 months). There were no perioperative deaths, and three patients have died during follow-up with patent SFA SI-PTAs (9.3 ± 1.4 months).ConclusionsThese data suggest that SFA SI-PTA can be successfully used for limb salvage with minimal morbidity and mortality in a group of patients with severe lower extremity occlusive vascular disease.

Previous studies from our group have demonstrated in vitro that UCN-01 (7-hydroxystaurosporine) and inhibitors of MEK1/2 interact to cause tumor cell death in a wide variety of malignant, but not in nontransformed, cell types. The present studies determined whether UCN-01 and MEK1/2 inhibitors interacted to cause tumor cell death in vivo. In vitro colony formation studies demonstrated that UCN-01 and the MEK1/2 inhibitor PD184352 interacted to synergistically kill human mammary carcinoma cells (MDA-MB-231, MCF7) with similar combination index values. Athymic mice were implanted in the rear flank with either MDA-MB-231 or MCF7 cells and tumors permitted to form to a volume of approximately 100 mm3 prior to a two day exposure of either Vehicle, PD184352 (25 mg/kg), UCN-01 (0.1-0.2 mg/kg) or the drug combination. Tumor volume was measured every other day and tumor growth determined over the following approximately 30 days. Transient exposure of MDA-MB-231 tumors or MCF7 tumors to either PD184352 or UCN-01 did not significantly alter tumor growth rate or the mean tumor volume in vivo approximately 15-30 days after drug administration. In contrast, combined treatment with PD184352 and UCN-01 significantly reduced MDA-MB-231, and largely abolished MCF7 tumor growth. Tumor control values for both cell lines were 0.36. Tumor cells isolated approximately 30 days after combined drug exposure exhibited a significantly greater reduction in plating efficiency using ex vivo colony formation assays than tumor cells that were exposed to either drug individually. Reduced tumor growth correlated with profound tumor cell death within five days of combined drug exposure, which was also evident approximately 30 days after exposure. In addition, tumor cell death correlated with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. Collectively, these findings argue that UCN-01 and MEK1/2 inhibitors have the potential to suppress mammary tumor growth in vivo which is independent of p53 status, estrogen dependency, caspase 3 levels or oncogenic K-RAS expression.

Background Reported family medical history may be the most widely accessible genomics screen currently available. The worth of any population-screening tool may be measured by parameters such as sensitivity and specificity. There is some evidence and theory suggesting that family history of breast cancer may be more frequently communicated about maternal (versus paternal) lines. If true, a discrepancy in reporting family history of breast cancer could mean suboptimal accuracy for this genomics-screening tool. Methods A cross-sectional analysis of reported family history of breast cancer was conducted beginning in early fall 2005 of data collected from April 2003 to March 2005. Study participants were Women’s Health Clinic patients without breast cancer aged at least 40 years. The number of women reporting extended paternal relatives (e.g., aunts, grandmothers) with breast cancer was compared to the number of women reporting maternal relatives. Results More women reported a maternal relative with breast cancer (16%) compared to those reporting paternal relatives (10%) (McNemar odds ratio=1.71, 95% confidence interval=1.26 to 2.34). A discrepancy remained in analyses adjusting for potential covariates (race/ethnicity, awareness of breast cancer, family communication about breast cancer, and perceived risk). Conclusions Self-reported family history of breast cancer may not optimally capture inherited risk from the father’s side of the family. Further research is needed to look for modifiable contributors to this discrepancy to optimize screening for familial breast cancer.

SUMMARY The technology for hybridizing archived tissue specimens and the use of laser-capture microdissection for selecting cell populations for RNA extraction have increased over the past few years. Both these methods contribute to RNA degradation. Therefore, quality assessments of RNA hybridized to microarrays are becoming increasingly more important. Existing methods for estimating the quality of RNA hybridized to a GeneChip, from resulting microarray data, suffer from subjectivity and lack of estimates of variability. In this article, a method for assessing RNA quality for a hybridized array which overcomes these drawbacks is proposed. The effectiveness of the proposed method is demonstrated by the application of the method to two microarray data sets for which external verification of RNA quality is known.

Purpose: Respiratory gating is a commercially available technology for reducing the deleterious effects of motion during imaging and treatment. The efficacy of gating is dependent on the reproducibility within and between respiratory cycles during imaging and treatment. The aim of this study was to determine whether audio-visual biofeedback can improve respiratory reproducibility by decreasing residual motion and therefore increasing the accuracy of gated radiotherapy. Methods and Materials: A total of 331 respiratory traces were collected from 24 lung cancer patients. The protocol consisted of five breathing training sessions spaced about a week apart. Within each session the patients initially breathed without any instruction (free breathing), with audio instructions and with audio-visual biofeedback. Residual motion was quantified by the standard deviation of the respiratory signal within the gating window. Results: Audio-visual biofeedback significantly reduced residual motion compared with free breathing and audio instruction. Displacement-based gating has lower residual motion than phase-based gating. Little reduction in residual motion was found for duty cycles less than 30%; for duty cycles above 50% there was a sharp increase in residual motion. Conclusions: The efficiency and reproducibility of gating can be improved by: incorporating audio-visual biofeedback, using a 30–50% duty cycle, gating during exhalation, and using displacement-based gating.

Objective The purpose of this study was to compare outcomes after third- versus fourth-degree laceration repair. Study design Fifty-six primiparous women who sustained a third- or fourth-degree tear were enrolled at delivery and demographic and obstetric data were collected. At 6 weeks' postpartum, subjects completed a bowel function questionnaire and endoanal ultrasonography was performed. Fisher exact test and chi-square were used for statistical analysis. Results Thirty-nine women with third- and 17 with fourth-degree tears were enrolled. Subjects with fourth- were more likely to report bowel symptoms (59% vs 28%, P = .03), and to demonstrate persistent combined defects of the internal (IAS) and external anal sphincter (EAS) (48% vs 8%, P = .002) than third-degree tears. Combined defects were associated with the highest risk of bowel symptoms (OR 18.7, 95% CI 3-101, P Conclusion Bowel symptoms were more common after fourth- than third-degree repair, and may be secondary to higher rates of combined defects of the IAS and EAS.