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Unsupervised cluster analysis demonstrated response in determining outcome for FL and specifically demon- the relative homogeneity of all grades of FL buy cheap olanzapine 20mg on line. Supervised clustering strated that the number of tumor-associated macrophages and T of cases with low-grade versus high-grade morphology showed cells are prognostically useful generic 5mg olanzapine with visa. Another study used custom-designed distinct GEP signatures for the different grades of the disease. DNA microarrays containing published genes of prognostic value in Genes up-regulated in the aggressive phase of the disease were lymphomas and found that T-cell-related genes and genes involved associated with cell cycle control, DNA synthesis, increased in proliferation could predict outcome in patients with FL. In contrast, tumor cells Specifically, they showed that patients with a poor prognosis from indolent disease highly expressed genes derived from the exhibited increased expression of proliferation genes and/or de- reactive T-cell infiltrate and macrophages. Although T-cell genes creased expression of T-cell-related genes. These findings were confirmed in a ronment in FL tumors and prognosis led to several GEP studies that separate validation cohort. In the difficult or morphologically characterized the immune cells present in the tumor specimens and “ambiguous” case series, 18 of 19 cases were correctly classified the prognostic significance of individual cell populations (Figure into molecular categories of indolent or aggressive disease, which 1). CD8 and CD4 cells, as well as macrophages and other immune cells. The results suggest that these cells affect antitumor immunity In these initial studies, the diagnostic signatures of FL were based and patient outcome in FL. In the case of CD8 T cells, a recently on the germinal center nature of the B cells. Once morphologic published IHC and microscopy study correlated an increased grade and patient outcome were considered, the T cells and amount of intratumoral CD8 T cells with longer overall survival macrophages were identified as the most important factor in and disease-specific survival in FL. The cells population, however, is more complex because there are several within the microenvironment are the primary focus of the following different populations with distinct functions, including regulatory T sections on prognosis and transformation. Prognosis T cells are a small subset of CD4 T cells expressing CD25 reg In a landmark study performed on whole tumor biopsies from 191 regulated by the forkhead/winged helix transcription factor family untreated FL patients, Dave et al defined 2 gene expression member p3 (FOXP3); therefore, FOXP3 is often used as a marker signatures that strongly correlated with patient prognosis. Elevated numbers of Treg cells are frequently and immune response signature 2 (IR2) because they include many observed in FL, resulting in suppressed antitumor immunity. Several GEP and IHC studies investigated whether the number and The IR1 signature is enriched for genes expressed in T cells (CD7, location of T cells alters patient response to therapy in FL. IR1 is associated with genes expressed by non-neoplastic T cells, whereas IR2 is associated with genes expressed by macrophages. Subsequent studies have analyzed specific cell populations within the tumor microenvironment. CCL22 secreted from lymphoma B cells induces the migration of CCR4 Treg cells and may in part account for the increased number of Treg cells in FL. In addition, TAMs overexpress IL-15, which triggers STAT5-dependent FL B-cell activation. TFH cooperate with this IL-15-mediated signal through CD40L- dependent transcriptional induction of STAT5. The transcriptional targets of STAT proteins play roles in cell cycle progression and cell survival. Therefore, TFH and TAMs in the tumor microenvironment are generally associated with poor prognosis in FL. FOXP3 T cells were primarily distributed T-cell population. These cells secrete Another investigation validated the importance of IL4 signaling in cytokines such as IFN- , TGF- , and a variety of interleukins (IL2, FL cells. Until recently, most of the research on TH tumor microenvironment express IL4 at very high levels and cells in FL emphasized the balance between TH1 and TH2 cells. It is suggested that increased IL4 may contribute to FL pathogenesis and generally believed that the TH2 immune response favors tumor represents a novel therapeutic target. Using RT-PCR, Jones et al found that both TH1 and TH2 GEP studies demonstrate that genes expressed by tumor-associated cytokines were expressed at high levels in a cohort of 44 B-cell 23 macrophages (TAMs) correlate with poor prognosis in patients with non-Hodgkin lymphoma patients. These findings have been validated using IHC; unfortunately, with a favorable prognosis had elevated IL4 levels, a cytokine the data are inconsistent. Although several studies showed that predominantly expressed by TH2 cells. However, in another study, increased numbers of CD68 TAMs are associated with adverse high serum levels of IL12, a major cytokine in TH1 immunity, were 24 outcomes in response to chemotherapy,25-27 no correlation was associated with a poor prognosis. Therefore, the data on the role of observed in other investigations. Similarly, the data on T 17 cells rituximab, a monoclonal antibody directed against the B-cell H are limited in FL. TFH cells highly express CXCR5, in the tumor microenvironment can be used to predict patient ICOS (inducible costimulator), CD200, PD-1 (programmed death- prognosis.

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Control group: In a research study cheap olanzapine 5 mg otc, the group of people who do not receive the treatment being tested buy discount olanzapine 7.5 mg line. The control group might receive a placebo, a different treatment for the disease, or no treatment at all. Convenience sample: A group of individuals being studied because they are conveniently accessible in some way. Convenience samples may or may not be representative of a population that would normally be receiving an intervention. Crossover trial: A type of clinical trial comparing two or more interventions in which the participants, upon completion of the course of one treatment, are switched to another. Direct analysis: The practice of using data from head-to-head trials to draw conclusions about the comparative effectiveness of drugs within a class or group. Results of direct analysis are the preferred source of data in Drug Effectiveness Review Project reports. Dosage form: The physical form of a dose of medication, such as a capsule, injection, or liquid. The route of administration is dependent on the dosage form of a given drug. Various dosage Proton pump inhibitors Page 94 of 121 Final Report Update 5 Drug Effectiveness Review Project forms may exist for the same compound, since different medical conditions may warrant different routes of administration. Dose-response relationship: The relationship between the quantity of treatment given and its effect on outcome. In meta-analysis, dose-response relationships can be investigated using meta- regression. Double-blind: The process of preventing those involved in a trial from knowing to which comparison group a particular participant belongs. While double-blind is a frequently used term in trials, its meaning can vary to include blinding of patients, caregivers, investigators, or other study staff. Double-dummy: The use of two placebos in a trial that match the active interventions when they vary in appearance or method of administrations (for example, when an oral agent is compared with an injectable agent). Effectiveness: The extent to which a specific intervention used under ordinary circumstances does what it is intended to do. Effectiveness outcomes: Outcomes that are generally important to patients and caregivers, such as quality of life, responder rates, number and length of hospitalizations, and ability to work. Data on effectiveness outcomes usually comes from longer-term studies of a “real-world” population. Effect size/estimate of effect: The amount of change in a condition or symptom because of a treatment (compared to not receiving the treatment). It is commonly expressed as a risk ratio (relative risk), odds ratio, or difference in risk. Efficacy: The extent to which an intervention produces a beneficial result under ideal conditions in a selected and controlled population. Equivalence level: The amount which an outcome from two treatments can differ but still be considered equivalent, as in an equivalence trial, or the amount which an outcome from treatment A can be worse than that of treatment B but still be considered noninferior, as in a noninferiority trial. Equivalence trial: A trial designed to determine whether the response to two or more treatments differs by an amount that is clinically unimportant. This lack of clinical importance is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence level of clinically acceptable differences. Exclusion criteria: The criteria, or standards, set out before a study or review. Exclusion criteria are used to determine whether a person should participate in a research study or whether an individual study should be excluded in a systematic review. Exclusion criteria may include age, previous treatments, and other medical conditions. External validity: The extent to which results provide a correct basis for generalizations to other circumstances. For instance, a meta‐analysis of trials of elderly patients may not be generalizable to children. Studies are assumed to be measuring the same overall effect. Proton pump inhibitors Page 95 of 121 Final Report Update 5 Drug Effectiveness Review Project Fixed-dose combination product: A formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses. Forest plot: A graphical representation of the individual results of each study included in a meta- analysis and the combined result of the meta-analysis. The plot allows viewers to see the heterogeneity among the results of the studies. The results of individual studies are shown as squares centered on each study’s point estimate.

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Current Medical Research and Opinion 2010;26(2):483-492 purchase 20mg olanzapine mastercard. Effect of ciclesonide and fluticasone on exhaled nitric oxide in patients with mild allergic asthma buy 10mg olanzapine amex. Strength of evidence for the comparative efficacy of inhaled corticosteroids No. Strength of evidence for the comparative efficacy of inhaled corticosteroids No. Strength of evidence for the comparative efficacy of leukotriene modifiers (LMs) Number Overall of studies Result and Other Strength (# of magnitude modifying of the a subjects) Design Quality Consistency Directness of effect factors evidence Overall total: LM compared with LM 1 (40) RCT (12 weeks) Fair NA Direct No difference None Low Montelukast compared with Zafirlukast 1 (40) RCT (12 weeks) Fair NA Direct No difference None Low Montelukast compared with Zileuton We did not identify any systematic reviews or head-to-head trials Zafirlukast compared with Zileuton We did not identify any systematic reviews or head-to-head trials Abbreviations: LM= Leukotriene Modifiers; MA= meta-analysis; RCT= randomized controlled trial; SR= systematic review. Strength of evidence for the comparative efficacy of LABAs Overall Number of Result and Other strength studies (# of magnitude modifying of the a subjects) Design Quality Consistency Directness of effect factors evidence Overall total: LABA compared with LABA No 3 (1107) RCTs Fair Consistent Direct None Moderate difference Eformoterol (eFM) compared with salmeterol (SM) RCTs (8-week No cross-over; 12- difference 2 (625) Fair Consistent Direct None Moderate week open- in health label) outcomes Formoterol (FM) compared with salmeterol (SM) No RCT (open- difference 1 (482) label, 6-month Fair Consistent Direct None Moderate in health trial) outcomes Formoterol (FM) compared with arformoterol (ARF) We did not identify any systematic reviews or head-to-head trials that compared FM to ARF Salmeterol (SM) compared with arformoterol (ARF) We did not identify any systematic reviews or head-to-head trials that compared SM to ARF Abbreviations: ARF= Arformoterol; eFM = Eformoterol; FM = Formoterol; LABAs = Long-Acting Beta-2 Agonists; MA= meta-analysis; RCT= randomized controlled trial; SM= Salmeterol; SR= systematic review. Controller medications for asthma 246 of 369 Final Update 1 Report Drug Effectiveness Review Project Table H-4. Strength of evidence for the comparative efficacy of omalizumab and placebo Omalizumab compared with placebo No. Strength of evidence for the comparative efficacy of BUD/FM and FP/SM No. Strength of evidence for for the comparative efficacy of BUD/FM for maintenance and as-needed relief (BUD/FM MART) and ICS/LABA with a Short- Acting Beta-Agonist (SABA) for relief No. Controller medications for asthma 248 of 369 Final Update 1 Report Drug Effectiveness Review Project Table H-7. Strength of evidence for the comparative efficacy of ICSs and LTRAs Number of Overall studies Other strength (# of Results (magnitude of modifying of subjects) Design Quality Consistency Directness effect) factors evidence Overall total of trials: ICS compared with LTRA 22 RCTs Fair Consistent Direct ICS > LTRA; ICSs had less None High (9,873) rescue medicine use (% rescue free days: SMD - 0. All were statistically significant favoring ICSs (Appendix I). FP compared with ML 9 (3,864) RCTs Fair Consistent Direct FP > ML; had less rescue None High medicine use (% rescue medicine free days: SMD - 0. BDP compared with ML 6 (3,823) RCTs Fair Consistent Direct BDP > ML; had fewer None Moderate exacerbations (SMD -0. Strength of evidence for the comparative efficacy of ICSs and LTRAs Number of Overall studies Other strength (# of Results (magnitude of modifying of subjects) Design Quality Consistency Directness effect) factors evidence symptom score: SMD - 0. Strength of evidence for the comparative efficacy of ICSs and LABAs for monotherapy Number of Overall studies (# Other strength of Results, magnitude of modifying of a subjects) Design Quality Consistency Directness effect factors evidence ICS compared with LABA for monotherapy 13 (4196) RCTs Good (1) Some Direct LABAs had a None High Fair (12) inconsistency significantly higher odds of exacerbations than ICSs (OR = 2. Strength of evidence for the comparative efficacy of leukotriene modifiers and LABAs for monotherapy Number of Overall studies Other strength (# of Results, magnitude modifying of a subjects) Design Quality Consistency Directness of effect factors evidence Montelukast compared with Salmeterol 1 (191) RCT (8 Fair NA Direct Zero compared with None Insufficient weeks) one death in one study (P = NR) Montelukast compared with Eformoterol 1 (58) RCT; Fair, NA Direct Those treated with None Insufficient cross-over unclear eFM had fewer with if one- symptoms (% of unusual week symptom-free days: 23 design; 12 washout compared with 0; P = weeks sufficient 0. Controller medications for asthma 251 of 369 Final Update 1 Report Drug Effectiveness Review Project Table H-10. Strength of evidence for the comparative efficacy of ICS + LABA and same dose ICS alone as first line therapy Number of Overall studies Other strength (# of Result (magnitude modifying of subjects) Design Quality Consistency Directness of effect) factors evidence Overall total: ICS + LABA compared with ICS alone as first line therapy 1 SR 1 SR w/ Good Some Direct No difference in None Moderate a (8050 ) MA inconsistency number of patients with exacerbations 9 RCTs 9 RCTs Fair requiring systemic (3,932) steroids (RR 1. BUD = Budesonide; CI = confidence interval; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=meta-analysis; RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol; SMD = standard mean difference; SR=systematic review Controller medications for asthma 252 of 369 Final Update 1 Report Drug Effectiveness Review Project Table H-11. Strength of evidence for the comparative efficacy of ICS + LABA compared with higher dose ICS Study design Number (Number of studies using 1 Overall (Number inhaler Other strength of for ICS+ Result, modifying of a b c subjects ) LABA ) Quality Consistency Directness magnitude of effect factors evidence Overall total: ICS + LABA compared with higher dose of ICS RCTs d 33 33 RCTs Good Some Direct ICS+LABA had greater None High (18,153) (2) inconsistency improvement in the Fair percentage of symptom- (31) free days (SMD = -0. Strength of evidence for the comparative efficacy of ICS + LABA compared with higher dose ICS Study design Number (Number of studies using 1 Overall (Number inhaler Other strength of for ICS+ Result, modifying of a b c subjects ) LABA ) Quality Consistency Directness magnitude of effect factors evidence (SMD = 0. Some subjects may have received other treatments as several trials had multiple treatment arms. The review looked at two groups of studies, ICS + LABA v same dose ICS and ICS + LABA v higher dose ICS. Controller medications for asthma 254 of 369 Final Update 1 Report Drug Effectiveness Review Project Table H-12. Strength of evidence for the comparative efficacy of addition of LABA to ICS compared with continuing same dose ICS Study design Number (Number of studies using Overall (Number single Other strength of combo Result (magnitude of modifying of a b subjects ) inhaler ) Quality Consistency Directness effect) factors evidence ICS + LABA compared with same dose of ICS 32 RCTs Good Consistent Direct ICS+LABA > ICS for None High (14,737) (2), symptom free days Fair (SMD 0. Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; BUD = Budesonide; CI = confidence interval; eFM = Eformoterol; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; MA=meta-analysis; OCS= oral corticosteroids; RCT= randomized controlled trial; RR = relative risk; SM = Salmeterol; SMD = standard mean difference; SR=systematic review. Some subjects may have received other treatments as several trials had multiple treatment arms. Controller medications for asthma 255 of 369 Final Update 1 Report Drug Effectiveness Review Project c See Appendix I for complete results of meta-analyses. Strength of evidence for the comparative efficacy of ICS + LTRA and ICS Number of studies Overall (Number Other strength of Result, magnitude of modifying of subjects) Design Quality Consistency Directness effect factors* evidence LTRA + ICS compared with ICS same dose 1 (5,871) 1 SR Good Some Direct Exacerbations: non- Few trials Low w/ MA inconsistency statistically significant tested reduction in the risk of licensed exacerbations requiring doses of systemic steroids: RR LTRAs: just 4 0. Strength of evidence for the comparative efficacy of ICS + LTRA and ICS Number of studies Overall (Number Other strength of Result, magnitude of modifying of subjects) Design Quality Consistency Directness effect factors* evidence weeks) One trial reported fewer exacerbations with increased dose BUD Fluticasone (FP)+Montelukast (ML) compared with Fluticasone (FP) increased dose 1 (182) RCT Fair Not Direct No difference in Primary Low (48 applicable hospitalizations due to outcome was weeks, asthma symptoms; 43 a composite triple (FP+ML) vs. Strength of evidence for the comparative efficacy of LABA + ICS and LTRA Number of Overall studies Other strength (# of modifying of subjects) Design Quality Consistency Directness Magnitude of effect factors evidence Overall total: ML compared with FP + SM 5 (2,188) RCTs Good Consistent Direct FP+SM > ML None High (12 to (1) 48 Fair (4) Greater improvement in weeks) symptom-free days (SMD - 0. Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes are similar. Strength of evidence for the comparative efficacy of LTRA + ICS and LABA + ICS Number of Overall studies Other strength (# of modifying of subjects) Design Quality Consistency Directness Magnitude of effect factors evidence Overall total: LTRA plus ICS compared with LABA plus ICS Controller medications for asthma 257 of 369 Final Update 1 Report Drug Effectiveness Review Project 1 (6,030) 1 SR Good Consistent Direct ICS+LABA > ICS+LTRA None High w/ MA Exacerbations requiring 8 (5,459) 8 Good systemic steroids (RR 0. Strength of evidence for the comparative efficacy of ICS + LABA and LTRA + LABA Number of studies Other Overall (# of Result (magnitude of modifying strength of subjects) Design Quality Consistency Directness effect) factors evidence Montelukast plus Salmeterol compared with Beclomethasone plus Salmeterol RCT, ICS+LABA > Composite 1 (192) cross- Fair NA Direct Moderate LTRA+LABA outcome over Abbreviations: ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; RCT= randomized controlled trial.