What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Results of the California Healthy Homes Indoor Air Quality Study of 2011-2013: impact of natural gas appliances on air pollutant concentrations.

This study was conducted to assess the current impact of natural gas appliances on air quality in California homes. Data were collected via telephone interviews and measurements inside and outside of 352 homes. Passive samplers measured time-resolved CO and time-integrated NOX , NO2 , formaldehyde, and acetaldehyde over ~6-day periods in November 2011 - April 2012 and October 2012 - March 2013. The fraction of indoor NOX and NO2 attributable to indoor sources was estimated. NOX , NO2 , and highest 1-h CO were higher in homes that cooked with gas and increased with amount of gas cooking. NOX and NO2 were higher in homes with cooktop pilot burners, relative to gas cooking without pilots. Homes with a pilot burner on a floor or wall furnace had higher kitchen and bedroom NOX and NO2 compared to homes without a furnace pilot. When scaled to account for varying home size and mixing volume, indoor-attributed bedroom and kitchen NOX and kitchen NO2 were not higher in homes with wall or floor furnace pilot burners, although bedroom NO2 was higher. In homes that cooked 4 h or more with gas, self-reported use of kitchen exhaust was associated with lower NOX , NO2 , and highest 1-h CO. Gas appliances were not associated with higher concentrations of formaldehyde or acetaldehyde.

Morphologic and cytogenetic variables affect the flow cytometric recovery of plasma cell myeloma cells in bone marrow aspirates.

INTRODUCTION: It is widely recognized that plasma cells (PCs) are under-represented in flow cytometry (FC) studies, but the causes of this phenomenon are poorly understood. We sought to study potential variables that affect PC recovery by flow cytometry (FC) in the analysis of plasma cell myeloma (PCM). METHODS: We retrospectively performed PC differential counts and morphologic assessment on PCM peripheral blood (PB) smears, bone marrow (BM) aspirate smears and posterythrocyte lysis cytospins. PCs were enumerated by FC, excluding erythroid events/debris, and were defined as CD38(bright+), CD45(dim to negative) events. PC recovery was calculated as follows: cytospin/aspirate, FC/aspirate, and FC/cytospin. RESULTS: Sixty-four BM analyses from 42 patients showed a mean aspirate PC% of 32.9 ± 23.2%. The mean PC% decreased in both the cytospin (10.9%) and by FC (8.2%). The difference between PC% in the cytospin and by FC was statistically significant (P < 0.03). Mature PC morphology and lower aspirate PC% had poorer recovery (P < 0.05) but higher-risk cytogenetics (deletions of 13q and TP53) was associated with increased PC recovery. Immunophenotype, heavy chain type, and treatment did not affect PC recovery. PB specimens had superior recovery compared with BM samples. CONCLUSIONS: Similar to prior reports, the greatest loss of PC in BM evaluation occurs between the aspirate and postlysis specimens; however, a small amount occurs from further processing. Additional morphologic and cytogenetic factors also appear to influence recovery in addition to overall PC%.

Arachidonic acid metabolites and enzyme transcripts in asthma are altered by cigarette smoking.

BACKGROUND: Arachidonic acid metabolites are implicated in the pathogenesis of asthma although only limited information is available on the impact of current smoking history on these metabolites. The aim of the study was to examine the effect of smoking status on urinary, sputum, and plasma eicosanoid concentrations and relevant enzyme transcripts in asthma. METHODS: In 108 smokers and never smokers with asthma and 45 healthy controls [smokers and never smokers], we measured urinary tetranor prostaglandin (PG)D2 (PGDM) and leukotriene (LT)E4 , induced sputum fluid LTB4 , LTE4 , PGD2 , and PGE2 , plasma secretory phospholipase A2 (sPLA2 ), and 11ß prostaglandin F2α (11ßPGF2α ), and, in a subgroup with severe asthma, airway leukocyte and epithelial cell mRNA expression levels of arachidonic acid metabolic enzymes. RESULTS: Smokers with asthma had higher urinary LTE4 ; 83 (59, 130) vs 59 (40, 90) pg/mg creatinine, P = 0.008, and PGDM; 60 (35, 100) vs 41 (28, 59) ng/mg creatinine, P = 0.012 concentrations, respectively, and lower sputum PGE2 concentrations 80 (46, 157) vs 192 (91, 301) pg/ml, P = 0.001 than never smokers with asthma. Sputum LTB4 (P = 0.013), and plasma 11ßPGF2α (P = 0.032), concentrations, respectively, were increased in smokers with asthma compared with healthy smokers. Asthma-specific and smoking-related increases (>1.5-fold expression) in arachidonate 15-lipoxygenase and gamma-glutamyltransferase transcripts were demonstrated. CONCLUSIONS: Several arachidonic acid metabolites and enzyme transcripts involving both lipoxygenase and cyclooxygenase pathways are increased in smokers with asthma and differ from never smokers with asthma. Possibly targeting specific lipoxygenase and cyclooxygenase pathways that are activated by asthma and cigarette smoking may optimize therapeutic responses.

The immunophenotypic stability of plasma cell myeloma by flow cytometry.

INTRODUCTION: Flow cytometry (FC) has become increasingly utilized in the diagnosis and monitoring of plasma cell myeloma (PCM), though few studies have evaluated the longitudinal stability of antigen expression. METHODS: We studied 45 PCM patients by four-color FC for shifts in CD19, CD20, CD38, CD45, CD56, and cytoplasmic light chain expression, between diagnostic/first encounter and positive follow-up analyses. An immunophenotypic (IP) change was defined as gain, loss, or ½ log shift of antigen expression. RESULTS: An IP change was observed in 14/45 (31%) patients, with single IP changes in 9/14, two changes in 2/14, and three changes in 3/14. 3/14 reverted from an aberrant to a normal plasma cell IP, while remaining light chain-restricted. Changes in expression of CD45 occurred in 9/45 (20%), CD19 in 5/45 (11.1%), CD20 in 2/45 (4.4%), and CD56 in 5/45 (11.1%). CONCLUSION: Approximately 1/3 of PCM cases show IP changes over time, with CD45 the least stable antigen. Recognition of this relative instability is important to avoid narrow targeting of follow-up FC analyses, especially for minimal residual disease monitoring.

Peripheral blood dendritic cell subtypes are significantly elevated in subjects with asthma.

BACKGROUND: Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non-smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. OBJECTIVE: Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. METHODS: Forty-three asthmatics (17 smokers, nine ex-smokers and 17 never-smokers) and 16 healthy volunteers (nine smokers and seven never-smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA-2, CD303), type 1 conventional (cDC) (BDCA-1, CD1c), and type 2 cDC (BDCA-3, CD141)]. RESULTS: Subjects with asthma displayed increases in all DC subtypes compared with normal never-smokers: [type 1 cDCs - asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never-smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs - asthma: 0.04% (0.02, 0.06), normal never-smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs - asthma: 0.32% (0.27, 0.46), normal never-smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never-smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non-asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical trials.gov identifier: NCT00411320)

In situ quantification of HER2-protein tyrosine kinase 6 (PTK6) protein-protein complexes in paraffin sections from breast cancer tissues.

BACKGROUND: Protein tyrosine kinase 6 (PTK6; breast tumour kinase) is overexpressed in up to 86% of the invasive breast cancers, and its association with the oncoprotein human epidermal growth factor receptor 2 (HER2) was shown in vitro by co-precipitation. Furthermore, expression of PTK6 in tumours is linked with the expression of HER2. METHOD AND RESULTS: In this study, we used the proximity ligation assay (PLA) technique on formalin-fixed paraffin sections from eighty invasive breast carcinoma tissue specimens to locate PTK6-HER2 protein-protein complexes. Proximity ligation assay signals from protein complexes were assessed quantitatively, and expression levels showed a statistically significant association with tumour size (P=0.015) and course of the cancer disease (P=0.012). CONCLUSION: Protein tyrosine kinase 6 forms protein complexes with HER2 in primary breast cancer tissues, which can be visualised by use of the PLA technique. Human epidermal growth factor receptor 2-PTK6 complexes are of prognostic relevance.

Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma.

Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 microg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV(1)) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75)) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-gamma agonists in steroid-resistant airway disease are indicated.

Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study.

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.

Role of symptoms and lung function in determining asthma control in smokers with asthma.

BACKGROUND: Cigarette smoking in asthma increases the severity and accelerates the decline in lung function. The relative role of symptoms and lung function in determining asthma control in smokers with asthma is not known. AIM OF THE STUDY: The aim of this study was to compare asthma control in smokers vs never-smokers with asthma, using the validated Juniper asthma control questionnaire (ACQ), and assess if any difference was because of a particular symptom or the forced expiratory volume in one second (FEV(1)) value. METHODS: This was a cross-sectional study of 134 asthmatics (74 never-smokers and 60 smokers) with >or=15% reversibility in FEV(1) after salbutamol. All subjects completed the ACQ, recording FEV(1) and asthma symptoms (night awakening, morning symptoms, dyspnoea, wheeze, activity limitation and use of reliever inhaler). RESULTS: Compared with the never-smokers, smokers with asthma had significantly worse median (IQR) total asthma control score [1.6 (1.1-2.3) vs 2.8 (1.7-3.4); (P < 0.0001)] and in each of the six individual symptom question scores (P < 0.001), but no difference in FEV(1) levels (P = 0.908). CONCLUSION: Asthma control is significantly worse in asthmatics who smoke compared with never-smokers, with all symptoms related to asthma control uniformly worse in smokers, independent of FEV(1).

Type I receptor tyrosine kinases as predictive or prognostic markers in early breast cancer.

The type I receptor tyrosine kinase (RTK) family of proteins play an essential role in the progression of early breast cancer. Our understanding of the role of these proteins has increased over the last 20 years, however, as yet, there are still a number of unanswered questions regarding their position in endocrine resistance, chemotherapy resistance and in the biology of breast cancer. There have been, and are currently, a number of clinical trials that have examined the use of anticancer therapy such as cytotoxic drugs, and treatments that target the RTKs and signaling pathways that have been identified. There is clear evidence that molecular subtypes of cancer respond differently to different therapeutic options, which challenges the 'one size fits all' approach to chemotherapy. Here we review the human epidermal growth factor receptor family of proteins and their potential predictive or prognostic role in early breast cancer.

Graduate education in food service systems management: clarifying the focus.

Administrators of dietetic services and educators in food service systems management identified levels of education and degree of experience needed to develop competencies in food service systems management. Master's level competencies that emerged from the analysis provide a framework for design and evaluation of graduate programs. Also, the differentiation of bachelor's and master's level competencies should assist in clarifying appropriate program focuses. The data on experience levels indicate performance areas for which the educational institution is primarily responsible and those for which responsibility should be shared by educators and employers.