Molecular testing and treatment patterns for patients with advanced non-small cell lung cancer: PIvOTAL observational study.

BACKGROUND: The goals of this multinational retrospective study were to describe treatment patterns and survival outcomes by receipt of molecular testing and molecular status of patients with advanced non-small cell lung cancer (NSCLC). METHODS: This chart review study, conducted in Italy, Spain, Germany, Australia, Japan, Korea, Taiwan, and Brazil, included 1440 patients with newly diagnosed advanced (stage IIIB/IV) NSCLC initiating systemic therapy from January 2011 through June 2013, with follow-up until July 2016. We evaluated treatment patterns and survival by histology, line of therapy, molecular testing, and test results for epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase (ALK) rearrangement. Country-specific data were analyzed descriptively and presented as ranges (lowest to highest country). Overall survival (OS) was estimated using Kaplan-Meier method. RESULTS: Patients with ≥1 molecular test varied from 43% (Brazil) to 85% (Taiwan). Numerically greater proportions of patients who were female, Asian, or never/former-smokers, and those with nonsquamous histology or stage-IV NSCLC, received a test. Testing was common for nonsquamous NSCLC (54%, Brazil, to 91%, Taiwan), with positive EGFR and ALK tests from 17% (Brazil and Spain) to 67% (Taiwan) and from 0% (Brazil) to 60% (Taiwan), respectively. First-line treatment regimens for nonsquamous NSCLC with positive EGFR/ALK tests included targeted therapy for 30% (Germany) to 89% (Japan); with negative/inconclusive test results, platinum-based combinations for 88% (Japan) to 98% (Brazil); and if not tested, platinum-based combinations for 80% (Australia) to 95% (Japan), except in Taiwan, where 44% received single agents. Median OS from first-line therapy initiation was 10.0 (Japan) to 26.7 (Taiwan) months for those tested and 7.6 (Australia/Brazil) to 19.3 (Taiwan) months for those not tested. CONCLUSIONS: We observed substantial variation among countries in testing percentages, treatment patterns, and survival outcomes. Efforts to optimize molecular testing rates should be implemented in the context of each country's health care scenario.

Impact of a Dynamic Microbiological Environment on the Clinical Efficacy of Ertapenem and Piperacillin/Tazobactam in the Treatment of Complicated Community-Acquired Intra-Abdominal Infection in Spain: A Cost-Consequence Analysis.

BACKGROUND AND OBJECTIVE: The microbial susceptibility of many antibiotics has been affected by prescribing patterns and their extensive use. The purpose of this evaluation was to assess how these changes could affect the initial efficacy of ertapenem and piperacillin/tazobactam in the treatment of complicated intra-abdominal infections (IAIs) acquired in the community and the potential consequences this may have in healthcare costs in Spain. METHODS: The Initial efficacy of ertapenem and piperacillin/tazobactam for patients with APACHE (Acute Physiology and Chronic Health Evaluation) II scores <10 was extracted from a multicenter randomized study and were combined with the current microbial susceptibilities obtained from the SMART study, a multinational surveillance program. Country-specific pathogens distribution was extracted from a national study in patients with community-acquired IAI. The estimated effectiveness was used in a decision-analytic model to compare total costs between ertapenem and piperacillin/tazobactam in the treatment of complicated IAI. The model performs extensive one-way and probabilistic sensitivity analyses. RESULTS: The model suggested a savings of €209 (year 2012 values) per patient when complicated IAIs acquired in the community (APACHE II <10) were treated with ertapenem instead of piperacillin/tazobactam. One-way sensitivity analyses showed length of stay as the key driver parameter. Further analysis of this parameter and probabilistic sensitivity analysis confirmed the robustness of our evaluation, with a 58% likelihood of ertapenem being dominant. CONCLUSIONS: Ertapenem appears to be a cost-saving strategy over piperacillin/tazobactam for the treatment of patients with complicated IAIs acquired in the community in Spain.

Antibiotic expected effectiveness and cost under real life microbiology: evaluation of ertapenem and ceftriaxone in the treatment of community-acquired pneumonia for elderly patients in Spain.

BACKGROUND: Clinical efficacy of antibiotics may be affected by changes in the susceptibility of microorganisms to antimicrobial agents. The purpose of this study is to assess how these changes could affect the initial efficacy of ertapenem and ceftriaxone in the treatment of community-acquired pneumonia (CAP) in elderly patients and the potential consequences this may have in health care costs. METHODS: Initial efficacy in elderly was obtained from a combined analysis of two multicenter, randomized studies. An alternative scenario was carried out using initial efficacy data according to the pneumonia severity index (PSI). Country-specific pathogens distribution was obtained from a national epidemiological study, and microbiological susceptibilities to first- and second-line therapies were obtained from Spanish or European surveillance studies. A decision analytic model was used to compare ertapenem versus ceftriaxone for CAP inpatient treatment. Inputs of the model were the expected effectiveness previously estimated and resource use considering a Spanish national health system perspective. Outcomes include difference in proportion of successfully treated patients and difference in total costs between ertapenem and ceftriaxone. The model performed one-way and probabilistic sensitivity analyses. RESULTS: First-line treatment of CAP with ertapenem led to a higher proportion of successfully treated patients compared with ceftriaxone in Spain. One-way sensitivity analysis showed that length of stay was the key parameter of the model. Probabilistic sensitivity analysis showed that ertapenem can be a cost-saving strategy compared with ceftriaxone, with a 59% probability of being dominant (lower costs with additional health benefits) for both, elderly patients (>65 years) and patients with PSI >3. CONCLUSION: The incorporation of the current antimicrobial susceptibility into the initial clinical efficacy has a significant impact in outcomes and costs in CAP treatment. The treatment with ertapenem compared with ceftriaxone resulted in better clinical outcomes and lower treatment costs for two segments of the Spanish population: elderly patients and patients with severe pneumonia (PSI >3).

Healthcare costs associated with change in body mass index in patients with type 2 diabetes mellitus in Spain: the ECOBIM study.

BACKGROUND: Weight management is considered a key therapeutic strategy in type 2 diabetes mellitus. However, little is known about the impact of weight loss or body mass index (BMI) reduction on type 2 diabetes-related healthcare costs. OBJECTIVE: The aim of this study was to estimate the economic impact of change in BMI among patients with type 2 diabetes mellitus from the Spanish healthcare system perspective. METHODS: The ECOBIM study is an observational, non-interventional study in which data on BMI change and costs incurred by patients with type 2 diabetes were collected cross-sectionally and retrospectively for a 12-month period. Generalized linear mixed models were applied to estimate the effects of (i) BMI change in general (one-slope model); (ii) BMI gain and no BMI gain (two-slope model); and (iii) BMI gain and no BMI gain among obese and non-obese patients (four-slope model). RESULTS: We studied 738 patients with a mean (SD) age of 66 (11) years and BMI of 30.6 (5.2) kg/m2. During the 12-month study period, 41.2% of patients gained BMI (BMI gainers) and 58.8% experienced either loss (52.2%) or no change (6.6%) in BMI (non-BMI gainers). One-unit gain (or loss) in BMI was significantly (p < 0.001) associated with a 2.4% cost increase (or decrease) [one-slope model]. Every unit gain in BMI was associated with a 20.0% increase in costs among BMI gainers while losing one unit was associated with an 8.0% decrease in costs among non-BMI gainers (two-slope model, p < 0.01). The economic benefit associated with reducing one BMI unit was 9.4% cost decrease in obese and 2.7% in non-obese patients (4-slope model). CONCLUSION: An increase in BMI among patients with type 2 diabetes was associated with increased 1-year direct healthcare costs. A reduction in BMI was associated with appreciable short-term economic benefits, especially in obese patients.

Early response and remission as predictors of a good outcome of a major depressive episode at 12-month follow-up: a prospective, longitudinal, observational study.

OBJECTIVE: The goal of treating major depressive disorder (MDD) should be not only achieving remission in a particular episode but also avoiding relapses and attaining long-term recovery. The current study was designed to evaluate whether response and remission achieved within the first 6 weeks of antidepressant treatment are associated with a 12-month good outcome (achieving remission by 6 months and remaining in remission until the end of follow-up). METHOD: This prospective, longitudinal, multicenter study included adult outpatients who had a DSM-IV diagnosis of MDD, baseline scores ≥ 15 on the 17-item Hamilton Depression Rating Scale (HDRS(17)), Clinical Global Impressions-Severity of Illness scores ≥ 4, and a minimum remission period of 12 weeks between the index episode and the immediately prior episode (or who were in their first MDD episode). The primary efficacy measure was early response (a 50% decrease from baseline in HDRS(17) score by week 6). The secondary efficacy measure was early remission (HDRS(17) score ≤ 7 by week 6). RESULTS: Among the total of 930 patients included from December 2006 to June 2007, 38.2% showed early response, and 20.5% showed early remission. Of the early responders, 76.1% had a 12-month good outcome as compared to 81.1% of early remitters. Logistic regression showed that factors associated with a good outcome included early response (odds ratio [OR] = 4.14), being employed, and the absence of physical comorbidities. Early remission was also strongly associated with a good outcome (OR = 4.72). CONCLUSIONS: Either response or remission achieved by week 6 is the strongest prognostic factor for the 12-month good outcome of an episode of MDD.

Relapse and therapeutic interventions in a 1-year observational cohort study of nonadherent outpatients with schizophrenia.

OBJECTIVES: To evaluate the incidence rate of relapse, the clinical profiles, and the therapeutic interventions employed for patients with schizophrenia deemed as likely nonadherers to oral antipsychotic drugs. METHODS: A cohort of 597 outpatients whose therapy was modified because of a psychiatrist-perceived risk of nonadherence was followed for 12 months in an observational study. Baseline correlates of subsequent relapse were analyzed with Cox regression. RESULTS: At baseline, patients' mean (SD) age and time since diagnosis were 40.1 (11.1) and 15.2 (10.0) years, respectively; 63.7% were males. The Clinical Global Impression scale-Severity (CGI-S) score was ≥ 4 in 87.3% of the patients. Antipsychotic drugs were modified in 506 patients (84.8%); nonpharmacologic therapies were modified in 190 patients (31.8%). In both cases, the primary reason for the modifications was insufficient efficacy of current therapeutic regimen. The proportion of patients in oral antipsychotic monopharmacy decreased from 83.8% to 57.6%; 15.4% started long-acting (depot) formulations. Over the 12-month observation period, 90 patients (15.1%) relapsed. The hazard rate of relapse was higher in patients with substance use disorder or familial psychiatric antecedents and lower in patients who underwent modifications of nonpharmacological therapies or with negative attitude toward antipsychotic medication at baseline. CONCLUSIONS: Effective interventions to prevent relapse in patients with long-standing schizophrenia involving therapeutic challenges related to nonadherence are feasible. Rationale for the baseline correlates, and cues for clinical prevention of relapse in these patients are provided.

Validation of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room.

BACKGROUND: Despite the wide use of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a clinical setting to assess agitated patients, a validation study to evaluate its psychometric properties was missing. METHODS: Data from the observational NATURA study were used. This research describes trends in the use of treatments in patients with acute psychotic episodes and agitation seen in emergency departments. Exploratory principal component factor analysis was performed. Spearman's correlation and regression analyses (linear regression model) as well as equipercentile linking of Clinical Global Impression of Severity (CGI-S), Agitation and Calmness Evaluation Scale (ACES) and PANSS-EC items were conducted to examine the scale's diagnostic validity. Furthermore, reliability (Cronbach's alpha) and responsiveness were evaluated. RESULTS: Factor analysis resulted in one factor being retained according to eigenvalue ≥1. At admission, the PANSS-EC and CGI-S were found to be linearly related, with an average increase of 3.4 points (p < 0.001) on the PANSS-EC for each additional CGI-S point. The PANSS-EC and ACES were found to be linearly and inversely related, with an average decrease of 5.5 points (p < 0.001) on the PANSS-EC for each additional point. The equipercentile method shows the poor sensitivity of the ACES scale. Cronbach's alpha was 0.86 and effect size was 1.44. CONCLUSIONS: The factorial analyses confirm the unifactorial structure of the PANSS-EC subscale. The PANSS-EC showed a strong linear correlation with rating scales such as CGI-S and ACES. PANSS-EC has also shown an excellent capacity to detect real changes in agitated patients.

Health economics: the start of clinical freedom.

BACKGROUND: Since Professor Hampton announced the death of clinical freedom in 1983, the increasing influence of Evidence-based Medicine and Health Technology Assessment has contributed to augment the feeling that clinicians have a secondary role in the therapeutic decision-making process. DISCUSSION: This article constitutes a reflection on how clinicians may use the results of economic evaluations in their daily clinical practice, making decisions about cost-effectiveness on a case by case basis, and addressing both the patient's and society's needs. To that end, some illustrating examples are taken from the literature to show there are factors with great impact on cost-effectiveness results that can be easily identified and modified by clinicians. SUMMARY: The evolution of the discipline and the trend towards a tailored therapy suggest that health economics is not the end of clinical freedom but the start of it.

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population.

BACKGROUND: The objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting. METHODS: A Markov model was designed consisting of stable, responsive, progressive disease and death states. Patients could also experience adverse events as long as they received chemotherapy. Clinical inputs were based on an analysis of a phase III clinical trial that identified a statistically significant improvement in overall survival for non-squamous patients treated with pemetrexed compared with docetaxel. Costs were collected from the Spanish healthcare perspective. RESULTS: Outcomes of the model included total costs, total quality-adjusted life years (QALYs), total life years gained (LYG) and total progression-free survival (PFS). Mean survival was 1.03 years for the pemetrexed arm and 0.89 years in the docetaxel arm; QALYs were 0.52 compared to 0.42. Per-patient lifetime costs were 34677 euros and 32343 euros, respectively. Incremental cost-effectiveness ratios were 23967 euros per QALY gained and 17225 euros per LYG. CONCLUSIONS: Pemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the 30000 euros /QALY threshold commonly accepted in Spain.

P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli.

p38 alpha mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38 alpha knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38 alpha are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38 alpha-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38 alpha also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38 alpha. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38 alpha-/- cells. Thus, p38 alpha seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

Long-term treatment with insulin induces apoptosis in brown adipocytes: role of oxidative stress.

Trying to define the precise role played by insulin regulating the survival of brown adipocytes, we have used rat fetal brown adipocytes maintained in primary culture. The effect of insulin on apoptosis and the mechanisms involved were assessed. Different from the known effects of insulin as a survival factor, we have found that long-term treatment (72 h) with insulin induces apoptosis in rat fetal brown adipocytes. This process is dependent on the phosphatidylinositol 3-kinase/mammalian target of rapamycin/p70 S6 kinase pathway. Short-term treatment with the conditioned medium from brown adipocytes treated with insulin for 72 h mimicked the apoptotic effect of insulin. During the process, caspase 8 activation, Bid cleavage, cytochrome c release, and activation of caspases 9 and 3 are sequentially produced. Treatment with the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (Z-VAD), prevents activation of this apoptotic cascade. The antioxidants, ascorbic acid and superoxide dismutase, also impair this process of apoptosis. Moreover, generation of reactive oxygen species (ROS), probably through reduced nicotinamide adenine dinucleotide phosphate oxidases, and a late decrease in reduced glutathione content are produced. According to this, antioxidants prevent caspase 8 activation and Bid cleavage, suggesting that ROS production is an important event mediating this process of apoptosis. However, the participation of uncoupling protein-1, -2, and -3 regulating ROS is unclear because their levels remain unchanged upon insulin treatment for 72 h. Our data suggest that the prolonged hyperinsulinemia might cause insulin resistance through the loss of brown adipose tissue.

Differential role of PPAR gamma in the regulation of UCP-1 and adipogenesis by TNF-alpha in brown adipocytes.

Extracellular regulated kinases (ERKs) mediate the inhibitory effect of tumor necrosis factor alpha (TNF-alpha) on uncoupling protein-1 (UCP-1), but not on lipid accumulation. TNF-alpha-induced ERK-dependent peroxisome proliferator activator receptor gamma (PPAR gamma) phosphorylation could be responsible for UCP-1 downregulation. Thus, the negative effect of TNF-alpha on UCP-1 mRNA expression at 4-5 h, under basal conditions or in cells treated with the PPAR gamma agonist, rosiglitazone, was reversed by the MEK1 inhibitor PD98059. In contrast, fatty acid synthase and malic enzyme mRNA downregulation was not prevented. Moreover, rosiglitazone has no positive effect on adipogenic gene expression or lipid accumulation. Therefore, there is a differential regulation of thermogenic and adipogenic differentiation by PPAR gamma, which might account for the differences in the TNF-alpha regulation through ERKs.