Asthma diagnosis and treatment - 1012. The efficacy of budesonide in the treatmetn of acute asthma in children: a double-blind, randomized, controlled trial.

Background Current evidence suggests that inhaled glucocorticoids (IGC) have a more profound topical none genomic effect on bronchial airways as compared to systemic glucocorticoids. The value of adding IGC to current therapy of acute asthma is not well established. Methods We conducted a double-blind, randomized, two-arm, parallel groups, controlled clinical trial to compare the addition of budesonide 1500 mcg or placebo (normal saline) to standard acute asthma treatment (albuterol and ipratropium bromide) administered in 3 divided mixed doses within 1 hour in the emergency department (ED). Children 2-12 years of age with moderate or severe acute asthma, scoring 8-15/15 on a well-validated scoring system were included. Both groups received a single dose of prednisone 2 mg/kg/day (max. 60 mg) at the beginning of therapy. The primary outcome was admission rate within 2-4 hours from starting therapy. Results A total of 723 children were enrolled in the study over 17 months duration, of whom 139 were allowed to re-enroll and be randomized to constitute 906 randomization assignments (458 on the treatment group and 448 on the control group); with baseline mean + SD asthma score of 10.63 + 1.73; age 5.52 + 2.76 years; 35% girls; 30.8% (16.5%) with baseline severe asthma score of ≥12 (≥ 13). Statistical Analysis plan allowed for the potential dependency in response due to reenrollments of a subset of children, using Generalized Linear Mixed Modeling (GLMM) techniques. Baseline demographic and clinical characteristics were not significantly different between the two randomized groups. Seventy-five out of 458 (16.4%) of the treatment group vs. 82/448 (18.3%) of the control group were admitted, (OR 0.85, CI: 0.59-1.23, p-value=0.39). Among the severe asthmatics with baseline score ≥13, treatment vs. placebo group, GLMM adjusted admission rate was 30% vs. 47%, indicating a 17% difference in admission rate in favor of the treatment group (adjusted OR of 0.49, CI: 0.25-0.95; p-value= 0.035) that indicated a 51% reduction in the risk of admission for the treatment vs. control group. Conclusions Children with baseline severe asthma score ≥13 who were treated with budesonide had a significant reduction in their admission rate

Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

PurposeWe hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.Experimental designPatients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.ResultsNinety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m(2). Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥ 6 months (Total SD ≥ 6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in K(trans) although analysis was limited by small sample size (N=12).ConclusionCombination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved

COMPARZ Post Hoc Analysis: Characterizing Pazopanib Responders With Advanced Renal Cell Carcinoma

Background: The phase III COMPARZ study showed noninferior efficacy of pazopanib versus sunitinib in advanced renal cell carcinoma. In this COMPARZ post hoc analysis we characterized pazopanib responders, patient subgroups with better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods: Patients were randomized to pazopanib 800 mg/d (n = 557) or sunitinib 50 mg/d, 4 weeks on/2 weeks off (n = 553). Secondary end points included time to complete response (CR)/partial response (PR); the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results: Median time to response was numerically shorter for patients treated with pazopanib versus sunitinib (11.9 vs. 17.4 weeks). Similar percentages of pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). For patients without versus with adverse event (AE)-related dose reductions, median PFS, median overall survival, and ORR were 7.3 versus 12.5 months, 21.7 versus 36.8 months, and 22% versus 42% (all P <.0001) for pazopanib, and 5.5 versus 13.8 months, 18.1 versus 38.0 months, and 16% versus 34% (all P <.0001) for sunitinib; results were similar for dose interruptions. Conclusion: Dose modifications when required because of AEs were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials

A subset of patients with metastatic renal cell carcinoma treated with sunitinib achieved long-term response (ie, progression-free survival [PFS] > 18 months). Long-term responders had improved objective response rate, PFS, and overall survival versus others. Patient baseline characteristics predictive of long-term response to sunitinib were identified. Background: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months. Patients and Methods: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months (“others”). PFS and overall survival (OS) were summarized using Kaplan–Meier methodology. Results: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P <.0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P =.0018) and greater median maximum on-study tumor shrinkage from baseline (−56.9 vs. −27.1; P <.0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR. Conclusion: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 × 106 U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen

SMARCB1 regulates the hypoxic stress response in sickle cell trait during the pathogenesis of renal medullary carcinoma.

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Prevalence and socio-demographic correlates of physical activity levels among South African adults in Cape Town and Mount Frere communities in 2008-2009

BACKGROUND: Physical activity has been linked to reduced risk of various cardiometabolic disease, cancer, and premature mortality. We investigated the prevalence and socio-demographic correlates of physical activity among adults in urban and rural communities in South Africa. METHODS: This was a cross-sectional survey comprising 1733 adults aged ?35 years from the Cape Town (urban) and Mount Frere (rural) sites of the Prospective Urban Rural Epidemiology study. Physical activity was assessed using the validated International Physical Activity Questionnaire. Multinomial logistic regressions were used to relate physical activity with socio-demographic characteristics. RESULTS: Overall, 74% of participants engaged in moderate-to-vigorous physical activity. In the adjusted regression models, women were 34% less likely to engage in vigorous physical activity (OR =0.66, 95%-CI = 0.47-0.93). Physical activity decreased with age, varied with marital status, education and occupation, always in differential ways between urban and rural participants (all interactions p ? 0.047). For instance, in urban settings, those with secondary education were more likely to engage in moderate physical activity (OR = 2.06, 95%-CI = 1.08-3.92) than those with tertiary education. Single people were more likely to engage in high physical activity (OR = 2.10, 95%-CI = 1.03-4.28) than divorced. Overall, skilled participants were more likely to engage in vigorous physical activity (OR = 2.07, 95%-CI = 1.41-3.05) driven by significant effect in rural area (OR = 2.70, 95%-CI = 1.51-4.83). Urban participants were more likely to engage in moderate physical activity (OR = 1.67, 95%-CI = 1.31-2.13) than rural participants. CONCLUSIONS: To prevent chronic diseases among South Africans, attention should be paid to specific policies and interventions aimed at promoting PA among young adults in rural and urban setting, and across the social-economic diversity

Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma