Effect of atorvastatin on lipogenic, inflammatory and thrombogenic markers in women with the metabolic syndrome.

BACKGROUND AND AIM: Specific drug therapy to target the underlying proinflammatory and prothrombotic state in patients with metabolic syndrome (MS) is lacking. We sought to study the effect of high-intensity atorvastatin on markers of lipogenesis, inflammation and thrombogenesis, in women with MS in the absence of cardiovascular disease or diabetes. METHODS AND RESULTS: This randomized double-blinded controlled trial included 88 women with MS (according to National Cholesterol Education Panel Adult Treatment Panel III criteria) and low atherosclerotic cardiovascular risk. Participants were randomized to receive atorvastatin 80 mg or matching placebo. Thrombogenic, lipogenic and inflammatory markers were collected at the time of enrollment, after a 6-week dietary run-in phase (time of randomization), and at 6- and 12-weeks after randomization. At 6 weeks post-randomization, there was significant reduction in total cholesterol, low density lipoprotein cholesterol, triglycerides, apolipoprotein-B (Apo-B) and Apo-B/Apo-A1 ratio in the atorvastatin arm compared to placebo. This difference persisted at 12-weeks post randomization. There was no significant difference in fasting blood glucose, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, serum leptin, Apo-A1, intercellular adhesion molecule 1 and platelet activity. A significant increase in vascular adhesion molecule 1 at 6 and 12 weeks was seen within the atorvastatin arm. No difference was observed in blood pressure and waist circumference. CONCLUSIONS: In conclusion, high-intensity atorvastatin has an early and significant impact on lipoproteins and apolipoproteins but did not lower inflammatory, thrombogenic or biomarkers of platelet activity and aggregation in women with MS. The use of statins for primary prevention in these patients should be further explored.

Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12†Months of Age: A Randomised Trial.

BACKGROUND: Vitamin C (500 mg·day-1) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported. OBJECTIVE: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age. METHODS: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day-1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance. RESULTS: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec-1 for FEF75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec-1 for FEF50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec-1 for FEF25-75 (95% CI, 9.7 to 100.5; p=0.013). CONCLUSIONS: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway.

Oral Vitamin C (500 mg/d) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP). A Randomized Trial.

Rationale: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. Objectives: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. Methods: A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. Measurements and Main Results: The primary outcome was FEF75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF50 and FEF25-75 obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C (n = 113) had the following FEFs at 3 months of age compared with those randomized to placebo (n = 109) as measured by FEF75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P = 0.10), FEF50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P = 0.02), and FEF25-75 (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34; P = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Conclusions: Although the primary outcome of FEF75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF50 and FEF25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF50 and FEF25-75) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).

The effects of neoadjuvant therapy on morbidity and mortality of esophagectomy for esophageal cancer: American college of surgeons national surgical quality improvement program (ACS-NSQIP) 2005-2012.

OBJECTIVE: This study used a multi-center database to evaluate the impact of neoadjuvant therapy on the 30-day morbidity and mortality following esophagectomy for esophageal cancer. METHODS: The NSQIP database was queried for 2005-2012 for patients, who had esophagectomy for esophageal cancer. Patients were divided into two groups: neoadjuvant therapy and esophagectomy only. RESULTS: The neoadjuvant group had a lower rates of sepsis (8% vs. 13%, unadjusted P = 0.004) and acute renal failure (0.4% vs. 2%, unadjusted P = 0.01), and a higher rate of pulmonary embolism (PE) (3% vs. 1%, unadjusted P = 0.04). The adjusted odds of PE for patients, who received neoadjuvant therapy were 2.8 times the odds of PE for patients in the esophagectomy group, controlling for BMI. The association with renal failure was not significant, when one adjusted for race. There was no difference in the rates of reoperation, readmission, stroke, cardiac arrest, MI, surgical site and deep organ infections, anastomosis failure, blood transfusions, DVT, septic shock, pneumonia, UTI, respiratory failure, and 30-day mortality between the two groups. CONCLUSIONS: We conclude that neoadjuvant therapy followed by esophagectomy for esophageal cancer does not have a negative impact on 30-day mortality. Neoadjuvant therapy is associated with increased odds of PE. J. Surg. Oncol. 2017;115:296-300. © 2016 Wiley Periodicals, Inc.

Assessing patient activation and health literacy in the ED.

BACKGROUND: Low health literacy and patient activation are linked to unmet health needs, excess emergency department (ED) use, and hospital admission. However, most studies have assessed these measures in non-ED populations. OBJECTIVE: The objective of the study is to assess health literacy and patient activation in the ED. METHODS: A cross-sectional study in adults older than 18 years presenting to an ED were selected using systematic sampling. Demographic data and reason for ED visit were collected. Health literacy was assessed using Rapid Estimate of Adult Literacy in Medicine (REALM). Patient activation was assessed using Patient Activation Measure. Kruskal-Wallis tests compared groups. Spearman rank correlations compared numeric variables. RESULTS: A total of 140 patients were approached, and 108 enrolled. Average age was 51 years. Most were unemployed (71%), were unmarried (80%), had a primary physician (62%), were male (60%), were African American (63%), and were on public insurance (58%). Most had an activation level of 3 or 4. The mean REALM score was 52. Patients with higher REALM scores had higher activation levels (rs = 0.30; P = .0017), although, when adjusted for age, this association was no longer significant. Sex, education, insurance status, and race were not significantly associated with REALM or activation levels. Activation levels decreased with increasing age (rs = -0.24; P = .01). Low activation levels and limited health literacy were significantly associated with admission (odds ratio, 4.4; 95% confidence interval, 1.5-12.6; P = .0061). CONCLUSIONS: This is the first study to assess Patient Activation Measure in the ED. Low activation levels and limited REALM scores assessed in the ED population were significantly associated with hospital admission. Assessing activation levels of ED patients could lead to better education and tailored discharge planning by ED clinicians potentially reducing ED revisits.

Impact of Video Discharge Instructions for Pediatric Fever and Closed Head Injury from the Emergency Department.

BACKGROUND: Lack of understanding of diagnosis and disease process remains a major complaint of caregivers who bring their children to the pediatric emergency department (PED). Misunderstanding of diagnosis and discharge instructions can lead to unnecessary return visits and health disparities. OBJECTIVE: We attempted to determine if video discharge instructions when added to standard of care written and verbal instruction improved caregivers' comprehension of their child's diagnosis, disease process, and discharge instructions. METHODS: Caregivers who presented to the PED with a child's chief complaint of fever or closed head injury (CHI) were included and randomized into a control or intervention group. Each group received standard discharge instructions, and the intervention group additionally viewed a video. Participants completed a post-test on knowledge and were followed 2 weeks post-visit to determine follow-up care. RESULTS: Sixty-three caregivers participated in the study. Eleven participants had less than a high school (HS) education and 52 had more than a HS education. Thirty-one children presented with fever and 32 with CHI. The intervention group had significantly higher percentage of correct answers on postintervention tests (median [Mdn] = 88.89) than the control (Mdn = 75.73; p < 0.0001). Participants in the intervention group with less than a HS education (Mdn = 89.47) and more than HS education (Mdn = 88.89) had similar test scores (p = 0.13), whereas those in the control group with less than a HS education (Mdn = 66.67) had significantly lower test scores than those with more than a HS education (Mdn = 77.78; p = 0.03). CONCLUSION: For caregivers with children who presented to the PED with fever and CHI, video discharge instructions improved caregiver comprehension of the child's diagnosis and disease process when added to verbal and written instructions.

Role of thromboelastography and rapid thromboelastography to assess the pharmacodynamic effects of vitamin K antagonists.

Thromboelastography (TEG) measures the effects of antithrombotic agents by assessing global functional clotting status by evaluating the viscoelastic properties of in vitro clot formation. Recently, rapid TEG (r-TEG), which uses tissue factor in addition to standard kaolin to accelerate activation of the clotting cascade, has been proposed to obtain more immediate results. The correlation between results of TEG or r-TEG with international normalized ratio (INR) in patients on vitamin K antagonist (VKA) therapy has not been explored and represents the aim of this study. Patients on chronic therapy with VKAs (n = 100) were included in an observational prospective pharmacodynamic study. The correlation between TEG parameters, in particular markers of thrombus generation [Reaction time (R), maximum rate of thrombus generation (MRTG), and time to maximum rate of thrombus generation (TMRTG)], and INR values as well as the concordance between these parameters and therapeutic INR ranges were evaluated. In addition, in a subgroup of subjects (n = 17), the correlation of r-TEG parameters with TEG parameters and INR values was also assessed. No correlation was found between INR and TEG parameters of thrombus generation, in particular between INR and R (r = 0.189, p = 0.06), MRTG (r = -0.027, p = 0.79), and TMRTG (r = 0.188, p = 0.06). Further, no concordance was found between these parameters and recommended INR ranges. Significant Spearman correlations were found between INR and activated clotting time (rS = 0.546, p < 0.001), r-R (rS = 0.572, p = 0.017), and r-TMRTG (rS = 0.510, p = 0.037), but not r-MRTG (rS = 0.131, p = 0.617). Results were obtained in 24 ± 6 versus 12 ± 4 min with TEG and r-TEG, respectively (p < 0.001). In patients on chronic VKA therapy, TEG is not a useful tool to evaluate VKA anticoagulant effect, compared with standard INR measurements. However, r-TEG parameters of thrombus generation correlate with INR levels, suggesting a possible role of this assay for measuring more expeditiously anticoagulant treatment effects.

Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival.

PURPOSE: To compare gadoteridol and ferumoxytol for measurement of relative cerebral blood volume (rCBV) in patients with glioblastoma multiforme (GBM) who showed progressive disease at conventional magnetic resonance (MR) imaging after chemo- and radiation therapy (hereafter, chemoradiotherapy) and to correlate rCBV with survival. MATERIALS AND METHODS: Informed consent was obtained from all participants before enrollment in one of four institutional review board-approved protocols. Contrast agent leakage maps and rCBV were derived from perfusion MR imaging with gadoteridol and ferumoxytol in 19 patients with apparently progressive GBM on conventional MR images after chemoradiotherapy. Patients were classified as having high rCBV (>1.75), indicating tumor, and low rCBV (≤ 1.75), indicating pseudoprogression, for each contrast agent separately, and with or without contrast agent leakage correction for imaging with gadoteridol. Statistical analysis was performed by using Kaplan-Meier survival plots with the log-rank test and Cox proportional hazards models. RESULTS: With ferumoxytol, rCBV was low in nine (47%) patients, with median overall survival (mOS) of 591 days, and high rCBV in 10 (53%) patients, with mOS of 163 days. A hazard ratio of 0.098 (P = .004) indicated significantly improved survival. With gadoteridol, rCBV was low in 14 (74%) patients, with mOS of 474 days, and high in five (26%), with mOS of 156 days and a nonsignificant hazard ratio of 0.339 (P = .093). Five patients with mismatched high rCBV with ferumoxytol and low rCBV with gadoteridol had an mOS of 171 days. When leakage correction was applied, rCBV with gadoteridol was significantly associated with survival (hazard ratio, 0.12; P = .003). CONCLUSION: Ferumoxytol as a blood pool agent facilitates differentiation between tumor progression and pseudoprogression, appears to be a good prognostic biomarker, and unlike gadoteridol, does not require contrast agent leakage correction.

Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients.

BACKGROUND: Incidental T2 white matter hyperintensities (WMHs) in headache patients on brain magnetic resonance imaging (MRI) may prompt concern for demyelinating disease. OBJECTIVE: We reviewed brain MRI studies in patients with headaches without known demyelinating disease to determine the prevalence meeting imaging criteria for multiple sclerosis (MS) using two different definitions of "juxtacortical" and "periventricular". METHODS: Consecutive patients undergoing pre- and post-contrast MRI for headaches over a 25-month period were retrospectively identified. Exclusions included patients under age 10 and over 55 years or with known demyelinating disorder. Patients were classified as meeting: 1) Barkhof and 2) 2010 McDonald dissemination in space criteria for MS based on: FLAIR/T2 scans for WMH and enhanced T1-weighted images for enhancement. Both groups were further differentiated by defining "periventricular" and "juxtacortical" as WMH contacting ventricle and cortex (Barkhof "touching", McDonald "touching") versus WMH within 3 mm (Barkhof--3 mm, McDonald--3 mm). RESULTS: 326/564 (58%) studies met inclusion criteria. WMH prevalence was 168/326 (51.53%). Barkhof "touching" criteria were met in 4/168 (2.4%) and in 12/168 (7.1%) of the 3 mm group. McDonald criteria were met in 41/168 (24.4%) for "touching" and 58/168 (34.5%) for 3 mm, respectively. CONCLUSION: Barkhof and McDonald criteria were met in 2.4-7.1% and 24.4-34.5%, respectively.

Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model.

Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-α(V) integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.

Correlation of MRI sequences to assess progressive glioblastoma multiforme treated with bevacizumab.

In the context of bevacizumab therapy for the treatment of progressive malignant gliomas, it is currently unclear how different magnetic resonance imaging (MRI) sequences correlate with each other over time. The objective of this study was to determine if a reliable and predictable relationship over time exists between post-gadolinium based contrast agent T1-weighted (T1 + GBCA), T2-weighted, and FLAIR MRI in patients with progressive glioblastoma multiforme (GBM) receiving bevacizumab and chemotherapy. The MRI lesion volumes of 10 patients with progressive GBM that received bevacizumab plus chemotherapy were manually calculated by two independent reviewers. T2 and FLAIR volumes were analyzed by analysis of covariance (ANCOVA) as a function of T1 + GBCA lesion enhancement volume, reviewer, and time interval between MRI acquisitions. Pearson product moment correlation (r) was used to compare pre and post treatment volumes for the group of 10 patients and for each individual patient over their treatment course. ANCOVA demonstrated a significant association between T1 + GBCA and T2-weighted volumes (P = 0.0006) and between T1 + GBCA and FLAIR volumes (P < 0.0001). These associations remained constant over time. The correlation between T1 + GBCA and both T2-weighted and FLAIR volumes improved after bevacizumab treatment. Individual correlations between T1 + GBCA and FLAIR were strong (r ≥ 0.63) with one exception, while correlations between T1 + GBCA and T2 were more variable (r = 0.18-0.99). These findings suggest that FLAIR MRI should be evaluated in addition to T1 + GBCA MRI when evaluating GBM responses.

Sex and Racial Differences in High-Density Lipoprotein Levels in Acute Coronary Syndromes.

BACKGROUND: This study aimed to assess sex and racial differences related to high-density lipoprotein cholesterol (HDL-C) levels in those presenting with acute coronary syndromes (ACS). METHODS: Records from patients with ACS presenting to the Emergency Department of University of Florida Hospital Jacksonville from 2009 to 2012, were reviewed. Detailed medical history was obtained. HDL-C levels were measured within 72 h of presentation. Pearson chi-square and Wilcoxon rank sum tests were used to compare groups in univariate analysis. Analysis of variance was performed to determine independent predictors of higher HDL-C levels using variable selection. RESULTS: Of 2400 patients screened, 614 (382 men and 232 women) met inclusion criteria. Hypertension, chronic kidney disease or prior CAD history was similar between sexes and races. Women were more likely to be older (62.4 vs 58.4 years), diabetic (56.5 vs 36.5%) and have higher body mass index (31.2 vs 30.1 kg/m2). Blacks were more likely to be diabetic (50.3 vs 41.3%). After adjusting for all clinical markers, women and blacks along with absence of CAD or diabetes, were significantly associated with higher HDL-C levels. CONCLUSIONS: High HDL-C levels (> 40 mg/dL), considered cardio-protective, were seen in women and blacks with ACS more often than in men and whites. Significant differences in HDL-C levels between sexes were seen in whites but not in blacks. Relevance and quality of HDL-C levels in racial groups need further study as this may have important implications in the interpretation of current guidelines.

Effect of drug sample removal on prescribing in a family practice clinic.

PURPOSE: Little is known about the impact of recent restrictions on pharmaceutical industry detailing and sampling on prescribing behavior, particularly within smaller, independent practices. The objective of this study was to evaluate the effect of a policy prohibiting prescription drug samples and pharmaceutical industry interaction on prescribing patterns in a rural family practice clinic in central Oregon. METHODS: Segmented linear regression models were used to evaluate trends in prescribing using locally obtained pharmacy claims. Oregon Medicaid pharmacy claims were used to control for secular prescribing changes. Total and class-specific monthly trends in branded, promoted, and average prescription drug costs were analyzed 18 months before and after policy implementation. RESULTS: Aggregate trends of brand name drug use did not change significantly after policy implementation. In aggregate, use of promoted agents decreased by 1.43% while nonpromoted branded agents increased by 3.04%. Branded drugs prescribed for respiratory disease declined significantly by 11.34% compared with a control group of prescribers. Relative to the control group, prescriptions of promoted cholesterol-lowering drugs and antidepressants were reduced by approximately 9.98% and 11.34%, respectively. The trend in average cost per prescription for lipid-lowering drugs was significantly reduced by $0.70 per prescription per month. Overall, average prescription drug costs increased by $5.18 immediately after policy implementation. CONCLUSIONS: Restriction of pharmaceutical industry representatives and samples from a rural family practice clinic produced modest reductions in branded drug use that varied by class. Although aggregate average costs increased, prescriptions for branded and promoted lipid-lowering agents and antidepressants were reduced.

Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators.

AIMS: To determine the effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish on the incidence of recurrent ventricular arrhythmia in implantable cardioverter defibrillator (ICD) patients by combining results from published trials. METHODS AND RESULTS: We searched in the Medline, EMBASE, and Cochrane databases and performed a meta-analysis on all three available trials on fish oil and ventricular arrhythmia. Furthermore, we pooled individual data of two of these randomized, double-blind, placebo-controlled trials (Raitt et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-2891 and Brouwer et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006;295:2613-2619). The main outcome was time to first confirmed ventricular fibrillation (VF) or ventricular tachycardia (VT) combined with death for the meta-analysis, and time to first spontaneous confirmed VF or VT for the pooled analysis. The meta-analysis (n = 1148) showed no convincing protective effect of fish oil (RR 0.90; 95% CI 0.67-1.22). The hazard ratio for the subgroup of patients with coronary artery disease at baseline (0.79; 0.60-1.06) tended towards a protective effect. The pooled analysis (n = 722) showed that time to appropriate ICD intervention was similar for fish oil and placebo treatment (log-rank P = 0.79). CONCLUSION: These findings do not support a protective effect of omega-3 PUFAs from fish oil on cardiac arrhythmia in all patients with an ICD. Current data neither prove nor disprove a beneficial or a detrimental effect for subgroups of patients with specific underlying pathologies.

Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model.

To evaluate efficacy and MRI findings after intravenous bevacizumab and/or carboplatin in a human glioma animal model, we randomized male nude rats with intracerebral UW28 human glioma xenografts to four groups: (1) controls (n = 9), (2) bevacizumab 10 mg/kg (n = 6), (3) carboplatin 200 mg/m(2) (n = 6), and (4) bevacizumab + carboplatin (n = 6). MRI was performed on the day of treatment (day 7-10) and 1 week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab with or without carboplatin before and 24 h after treatment. Median overall survival (OS) was as follows: group 1, 16 days; group 2, 23 days; group 3, 22 days; group 4, 36 days. OS was significantly longer in group 4 than in group 1 (p = 0.0011), group 2 (p = 0.0014), and group 3 (p = 0.0015), and rats had significantly larger tumors. No objective tumor responses were observed on MR images at 1 week after treatment; however, after bevacizumab, dynamic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability. Carboplatin + bevacizumab is effective and superior over bevacizumab or carboplatin monotherapy in this animal model. Increased survival concomitant with increased asymptomatic tumor volume is suggestive that vascular targeting with reduced peritumoral edema and mass effect contributes to the efficacy of bevacizumab. The promising survival data warrant future clinical trials using bevacizumab + carboplatin.

Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma.

To determine the efficacy of methotrexate and/or rituximab in a CNS lymphoma model and to evaluate MRI modalities for monitoring efficacy, we inoculated female athymic nude rats (rnu/rnu) intracerebrally with human MC116 B-lymphoma cells. Between days 16 and 26, rats were randomized to receive intravenous (IV) treatment with (1) saline (controls, n = 15), (2) methotrexate 1,000 mg/m(2) (n = 6), (3) rituximab 375 mg/m(2) (n = 6), or (4) rituximab plus methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and 1 week after treatment. IV rituximab gave an objective tumor response in four of six animals (>50% reduction in tumor volume comparing pre- and posttreatment T2/FLAIR MRI) and resulted in stable disease (50%-125% of baseline) in another animal. The percent change in tumor volume on T2/FLAIR images was significantly different in the control versus rituximab group (p = 0.0051). IV methotrexate slowed tumor growth, compared to controls, but only one of six animals had an objective response. In untreated controls, tumor histological volumes correlated well with T2/FLAIR or contrast-enhanced T1 images (r = 0.877). In the treatment groups, T2/FLAIR correlation was good, but the gadolinium-enhanced T1 MRI was not significantly correlated with histology (r = 0.19). The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly effective, but methotrexate was only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy.

Ifosfamide or trofosfamide in patients with intraocular lymphoma.

We evaluated response, progression-free survival (PFS), overall survival (OS), relapse patterns and long-term toxicity of intraocular lymphoma (IOL) patients treated with ifosfamide (IFO) or trofosfamide (TRO). In a prospective single center study, IFO or TRO were given to 10 patients with IOL. The median patient age was 73 (range 46-83) years. Six patients were pretreated with up to four treatment regimens for ocular or cerebral lymphoma, and four were therapy-naive. All patients responded, including nine complete remissions and one partial remission, with a median PFS of 18 (7-36) months. Seven patients relapsed: five in the eye and two in the brain. Median OS was 32 (7-37+) months. No long-term toxicity was observed in patients treated with IFO or TRO alone. IFO or TRO were active and well tolerated in this study. Thus, they may represent suitable combination partners for other cytostatics used for PCNSL and IOL treatment.

A Simulated Approach to Fostering Competency in End-of-Life Care Among Pharmacy Students.

Objective. To determine if pharmacy students participating in simulation-based scenarios reported fewer learning needs about the transition from acute to end-of-life (EOL) care compared to students participating in solely case-based scenario delivery. Methods. Four end-of-life cases were developed for both paper-based case study and simulation delivery. Pharmacy students on three distant campuses were exposed to the case study approach while four teams of nine to ten pharmacy students were exposed to simulated versions of the same cases. A validated questionnaire was administered before and after exposure to assess end-of-life care learning needs. Results were analyzed following a Bonferroni-adjustment for multiple testing. Results. The case study groups produced similar pre/post changes on the questionnaire. After results were pooled and compared to the simulation only group, significantly higher changes in pre/post scores were found for the simulation group. Conclusion. Pharmacy students exposed to simulated EOL scenarios experienced significantly reduced learning needs following the scenarios, unlike their classroom-based counterparts.

Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models.

Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50-1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 +/- 8.2 and 123.3 +/- 8.2, respectively) or CR (2.3 +/- 0.38 and 1.77 +/- 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 +/- 6.8, CR 0.47 +/- 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are affected by the dose and route of administration.

Immunomodulator and Biologic Agent Effects on Sleep Quality in Patients With Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) can disrupt normal sleep physiology and amplify a negative perception about quality of life. Evidence suggests increased circulation of inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1, may play a role. METHODS: A total of 56 patients completed the Pittsburgh Sleep Quality Index (PSQI) to measure 7 sleep domains: sleep quality, sleep latency, sleep duration, sleep efficacy, sleep disturbance, sleep medications, and daytime dysfunction. Domain scores were summed to determine the presence or absence of sleep impairment. We compared patients taking immunomodulators or biologic agents to patients not on immunomodulator or biologic agent therapy. Demographics and IBD-related clinical information were collected to adjust for potential confounders that may secondarily affect sleep, such as body mass index, depression/anxiety, and sleep-affecting medications. RESULTS: The majority of patients with IBD (46 [82%]) reported poor sleep quality; 22 (79%) of the patients taking immunomodulators or biologic agents and 24 (86%) of the patients not on these therapies had a global PSQI score ≥5, suggestive of poor sleep quality. However, we found no significant difference between the 2 groups. When we analyzed the 7 PSQI sleep domains individually, we found improved sleep duration in the group taking immunomodulators or biologic agents compared to the group not on therapy, although the difference was not statistically significant. CONCLUSION: The majority of patients with IBD experience some degree of sleep impairment, and treatment with immunomodulators and biologic agents does not appear to improve sleep quality. A multicenter study with a larger sample size is warranted to better assess the diverse population of patients with IBD and the factors that impact their sleep. Routine assessment of sleep quality during IBD clinical encounters is recommended.