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In addition cheap 160 mg malegra dxt plus with mastercard, more tered to 10 allogeneic HSCT recipients buy malegra dxt plus 160 mg without prescription, with a response rate of 80% 160 mg malegra dxt plus amex, recent strategies have attempted to move away from the use of live including one patient with a biopsy-proven EBV lymphoma and 3 patients with double viral reactivations order genuine malegra dxt plus. In the first trial to use the multimer approach, 9 kines in a short ex vivo culture are under way. Third-party cells These small numbers expanded by several logs in vivo and 8 of 9 With current manufacturing methodologies, it is difficult to patients cleared the viremia, including one patient with drug- manufacture CTLs from virus-naive donors, although preclinical resistant disease. HLA A2-restricted T cells specific for epitopes in 2 EBV The first study to evaluate this approach was reported by Haque antigens were selected and infused, resulting in a clinical et al, who used banked polyclonal EBV CTL lines to treat EBV response. CMV has been the major target of approaches refractory viral infections and reported an overall cumulative using IFN- capture. Feuchtinger et al used pp65 protein as a source incidence of first CR/PR by day 42 postinfusion of 73. Clinical trials using third-party virus-specific CTLs Viruses targeted N Type of CTL Results Trial EBV 33 Closely matched allogeneic EBV-specific CR or PR rate was 64% at 5 wk and Haque et al37 CTLs 52% at 6 mo EBV 5 Closely matched allogeneic EBV-specific 4 attained CR: 1 had progressive Doubrovina et al4 CTLs disease EBV 1 Haploidentical GLC-peptide–separated 1 attained CR; recurrence 9 mo later Uhlin et al32 CTLs responded to second infusion CMV 2 Gamma-capture–selected CMV pp65 cells 1 CR; 1 failed to respond Feuchtinger et al18 Adenovirus 1 Gamma-capture–selected adenovirus 1 CR Qasim et al38 specific T cells from haploidentical donor EBV, CMV, and adenovirus 50 Closely matched allogeneic trivirus-specific First CR/PR by day 42 postinfusion Leen et al5 CTLs 73. The more donor-derived CTLs, there is significant activity. Apart from one widespread testing of this strategy has been limited by the report of bystander-induced liver GVHD after third-party adeno- complexity of some of the CTL-manufacturing methodologies virus CTLs,38 there does not seem to be an increased risk of and the lengthy production time. It is not yet clear what the optimal criteria are for groups have developed more rapid CTL generation protocols that selecting a matched line and what factors are associated with appear to have equivalent activity, allowing definitive testing in failure to respond. Possible reasons for failure include the late-phase trials. It will be important to design such studies with presence of HLA antibodies reactive with the infused line or appropriate end points, standard criteria for instituting and insufficient activity against the infecting virus through shared stopping antiviral drugs, and including comparative effective- alleles. Use of viral CTLs after solid organ transplantation Disclosures Adoptive immunotherapy with virus-specific CTLs has also been Conflict-of-interest disclosures: H. Off-label drug use: IND ated from peripheral blood of the recipient, with responses reported cell therapy products. Infusion of Correspondence third-party CTLs derived from a bank of EBV-seropositive donors Dr Helen Heslop, Center for Cell and Gene Therapy, 1102 Bates St, resulted in a 52% response rate at 6 months in patients who had Suite 1640, Houston, TX 77030; Phone: 832-824-4662; Fax: received solid organ transplantation or HSCT. Of the 14 References patients who achieved an initial complete response, only 1 subse- 1. Nat CTLs after solid organ transplantation is that infused CTLs may also Rev Clin Oncol. Cellular immunotherapy for viral infec- In summary, these clinical studies show that both donor-derived tion after HSC transplantation. Adoptive efficacy in the post-HSCT setting and can reconstitute immunity immunotherapy with unselected or EBV-specific T cells for and clear viral reactivations and disease. The incidence of GVHD biopsy-proven EBV lymphomas after allogeneic hematopoi- did not appear to be increased over that which would be expected etic cell transplantation. Multicenter donor-derived virus-specific CTLs to treat viral reactivation or study of banked third party virus-specific T-cells to treat severe disease have ranged from 70% to 100%, whereas response rates viral infections after hematopoietic stem cell transplantation. Functionally active important to infuse a product with broad reactivity and to ensure virus-specific T cells that target CMV, adenovirus, and EBV that the infused line contains antiviral activity restricted by HLA can be expanded from naive T-cell populations in cord blood Hematology 2013 345 and will target a range of viral epitopes. Infusion of cytomegalovi- responses to viral infection in humans: lessons from Epstein- rus (CMV)-specific T cells for the treatment of CMV infection Barr virus. Adoptive cellular T lymphocytes for therapeutic applications. Transferring functional tion after allogeneic stem cell transplantation. Use of gene-modified use in cellular therapy show specificity to multiple antigens and virus-specific T lymphocytes to control Epstein-Barr-virus- polyfunctional cytokine responses. Clinical-grade varicella EBV-specific T-cell infusions to prevent or treat EBV-related zoster virus-specific T cells produced for adoptive immuno- lymphoproliferative disease in transplant recipients. Rapidly generated deletion mutant associated with fatal lymphoproliferative dis- multivirus-specific cytotoxic T lymphocytes for the prophylaxis ease unresponsive to therapy with virus-specific CTLs. Simultaneous lymphocytes specific for multiple viruses expand and produce isolation of CD8( ) and CD4( ) T cells specific for clinically relevant effects in immunocompromised individuals. Generation of and Epstein-Barr virus infections after haploidentical and CMV-specific T lymphocytes using protein-spanning pools of matched unrelated stem cell transplantation. Adoptive transfer of specific T cells reduce the requirement for CMV-directed cytomegalovirus-specific CTL to stem cell transplant patients pharmacotherapy after allogeneic stem cell transplantation. Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus- adoptive CTL therapy as a treatment for EBV-associated specific CD8 T cells leads to virus clearance in patients after lymphoma after stem cell transplantation. Cancer Immunol allogeneic peripheral blood stem cell transplantation. Effective and cytomegalovirus-reactive donor T cells confer rapid and safe long-term control of EBV PTLD after transfer of peptide- systemic reconstitution of virus-specific immunity following selected T cells. Effective treatment of of pp65-specific T cells for the treatment of chemorefractory refractory CMV reactivation after allogeneic stem cell transplan- cytomegalovirus disease or reactivation after haploidentical and tation with in vitro-generated CMV pp65-specific CD8 T-cell matched unrelated stem cell transplantation. Safe epstein-barr virus (EBV) nuclear antigen 1-specific t cells as adoptive transfer of virus-specific T-cell immunity for the treatment for EBV reactivation and lymphoproliferative disor- treatment of systemic adenovirus infection after allogeneic ders after allogeneic stem-cell transplantation. Safety and clinical therapy in hematopoietic transplantation. T-cell therapy for EBV-positive posttransplantation lymphopro- 22. Reconstitution of liferative disease: results of a phase 2 multicenter clinical trial. Allogeneic specific T cells eradicate adenoviraemia but trigger bystander T-cell therapy for Epstein-Barr virus-positive posttransplant graft-versus-host disease. Rapid salvage treatment specific cytotoxic T lymphocytes (CTLs). Update on the treatment of HIV-associated hematologic malignancies Richard F. Little1 and Kieron Dunleavy1 1National Cancer Institute, National Institutes of Health, Bethesda, MD HIV is associated with an excess cancer risk, particularly of lymphoid malignancies. Modern therapeutics has changed the landscape of HIV disease and typical opportunistic complications of AIDS are now largely avoided. Although the risk of lymphoma has decreased, it still remains high. Nevertheless, treatment outcomes have improved due both to improvements in HIV medicine and in cancer therapeutics for the common lymphomas occurring in those with HIV infection. Other hematologic malignancies are rarely seen in HIV-infected patients, but the standardized risk ratio for many of these cancers is higher than in the background population. Principles of cancer care and appreciation for HIV infection as a comorbid condition can guide physicians in setting realistic goals and treatment for this patient population. In many cases, expected outcomes are very similar to the HIV-unrelated patients and therapeutic planning should be based on this understanding. Treatment tolerance can be predicted based on the status of the HIV disease and the cancer therapy being administered. For those hematologic cancers in which transplantation is part of standard care, this modality should be considered an option in those with HIV infection. Of huge importance is the Excess cancer and infection risk in the late 1970s and early 1980s relationship between the degree of CD4 cell depletion and heralded a new immunodeficiency syndrome now known as the type of lymphoma that develops. The advent of modern HIV therapeutics has revealed a spectrum of lymphomas that occur in patients with higher CD4 second act for HIV-related cancer and infection epidemiology. Indeed, this immunologic shift commonly occurring hematologic malignancies in HIV have consequent to widespread cART use most likely explains the improved. This article focuses on the role that combination survival improvement of HIV-related lymphomas in the cART antiretroviral therapy (cART) has played in this emerging era. The to the various hematological malignancies should be in the standardized incidence ratio (SIR) is 70 (145 if CD4 is 100; context of advanced HIV therapeutics. For example, The principal hematologic malignancies occurring with increased cHL occurs with relatively high frequency during the first few frequency in association with HIV infection are lymphoid months after initiation of cART as the CD4 cell counts are neoplasms, principally lymphomas (Table 1). Therefore, all patients increasing and the HIV viral loads are decreasing, suggesting that cHL may be driven by immune recovery rather than by CD4 cell presenting with classical Hodgkin lymphoma (cHL), Burkitt lym- count depletion.

EXCEL trial 1397 Age > 18 years with asthma for a minimum FP/SM (500/100) DPI of 6 months buy malegra dxt plus 160 mg on-line, not controlled on 1000-2000 24 weeks BDP or equivalent buy 160mg malegra dxt plus with mastercard, moderate to severe generic malegra dxt plus 160 mg online, excluded smokers with ≥ 10 pack-year history Multicenter 98 Kuna et al discount 160 mg malegra dxt plus with mastercard. AND Multicenter, outpatients FP/SM (500/100) pMDI 100b Kuna 2010 Controller medications for asthma 66 of 369 Final Update 1 Report Drug Effectiveness Review Project Table 12. Characteristics of head-to-head studies comparing ICS+LABA with ICS+LABA Study design Country Comparison Equipotent N Population (total daily ex-mouthpiece dose in steroid Quality Study Duration Setting mcg) component rating 101 Ringdal et al. Controller medications for asthma 67 of 369 Final Update 1 Report Drug Effectiveness Review Project 2. ICS/LABA for both maintenance and as-needed relief (ICS/LABA MART) vs. ICS/LABA for maintenance with a Short-Acting Beta-Agonist (SABA) for relief Summary of findings We found four fair or good quality RCTs (making five relevant comparisons) meeting our 98-100, 103-106 inclusion/exclusion criteria (Table 13). All compared the combination of budesonide (BUD) plus formoterol (FM) in a single inhaler for maintenance and as-needed relief with a fixed dose ICS/LABA combination plus a Short-Acting Beta-Agonist (SABA) for as-needed relief. BUD/FM is not approved for use as a relief medication in the United States, but it has been approved for maintenance and reliever therapy in Canada when administered via a DPI. Delivery of BUD/FM via pMDI is not indicated for MART. Two trials compared BUD/FM for 98-100, 103, 105 maintenance and relief to BUD/FM for maintenance with a SABA for relief; three trials compared BUD/FM for maintenance and relief to the combination of fluticasone and 98, 100, 104, 106 salmeterol (FP/SM) for maintenance with a SABA for relief. Several of the trials included in this section significantly reduced the total ICS doses for many of the subjects upon randomization (some studies averaged a 75% dose reduction). Overall, results from large trials up to twelve months in duration found statistically significantly lower odds of exacerbations requiring medical intervention for those treated with BUD/FM for maintenance and relief than for those treated with ICS/LABA for maintenance and a SABA for relief (moderate strength of evidence, Appendix H, Table H-6). A separate meta-analysis of exacerbations resulting in emergency department visits or hospital admissions revealed similar findings; the odds ratio for MART was 0. MART was also associated with fewer nocturnal awakenings, compared with 2 ICS/LABA + SABA (SMD = -0. I values for each of those meta-analyses were < 25%, indicating low heterogeneity, and sensitivity analysis results did not change our conclusions in either case. None of the individual trials found a significant difference in symptoms. Our meta-analyses found no statistically significant differences in symptom-free days (SMD = 0. Sensitivity analyses for each of these comparisons did not reveal anything that would change our conclusions. Detailed Assessment Description of Studies Of the four RCTs we included (Table 13), two compared BUD/FM MART to BUD/FM for 98-100, 103, 105 maintenance and SABA for relief, and three compared BUD/FM MART to FP/SM for maintenance and SABA for relief. All trials administered the ICS/LABA combinations in a 98, 100, 104 103, 105, 106 single inhaler. Controller medications for asthma 68 of 369 Final Update 1 Report Drug Effectiveness Review Project Total daily maintenance ICS components of the BUD/FM MART groups varied. One study compared low starting and mean ex-mouthpiece doses of BUD (in the MART arm) with 103, 105 low fixed-dose BUD (fixed-dose BUD/FM arm), one compared low mean daily dose of 98-100 BUD (MART arm) with medium and high doses of non-adjustable combinations, one 106 compared medium dose with medium dose, and one compared medium dose BUD (MART 104 arm) with high fixed-dose FP (FP/SM + SABA arm). In two studies, the mean total daily dose of ICS administered ex-mouthpiece in the BUD/FM MART group was less than the total daily 98-100, 104 dose in the ICS/LABA with a SABA for relief group. Several of the trials significantly reduced the total ICS doses for many of the subjects upon randomization. Some studies reduced the starting ICS doses to levels that could be considered inadequate compared to the subjects’ previous dose requirements. In three studies all medications were delivered via DPIs; one study 98-100 compared BUD/FM DPI with FP/SM pMDI. Study Populations The four head-to-head RCTs included a total of 10,547 subjects. Three studies were conducted in 105 adolescent and/or adult populations. One study included children and adults, and one 103 publication further described the subset of children four to 11 years of age from that study. All enrolled subjects that were not adequately controlled on 103-105 current therapy. Two were conducted in subjects with mild to moderate persistent asthma 98-100, 106 and two did not report asthma severity classification. Two trials did not report smoking 98-100, 104 rates and two allowed some smokers. Trials enrolling smokers reported that 4% to 7% of subjects in each group were current smokers. Sponsorship Of the four head-to-head trials, all four (100%) were funded by pharmaceutical companies. BUD/FM MART compared with ICS/LABA for maintenance and SABA for relief The results of the four RCTs contributing five comparisons (one study compared BUD/FM MART with BUD/FM maintenance and SABA relief and with FP/SM maintenance and SABA relief) are described below under the appropriate drug comparisons. Overall, all five comparisons reported statistically significantly lower rates of exacerbations for those treated with BUD/FM MART, but no differences in symptoms. We conducted meta-analyses for seven outcomes that were reported with sufficient data in multiple trials (Appendix I). These included symptom-free days, symptom scores, nocturnal awakenings, exacerbations requiring medical intervention, exacerbations resulting in emergency visit or hospital admission, rescue-free days, and rescue medicine use (puffs/day). Our meta-analysis for exacerbations requiring medical intervention shows an odds ratio of 0. A separate meta-analysis of exacerbations resulting in emergency department visits or hospital admissions revealed similar findings; the odds ratio for MART was 0. MART was also associated with fewer nocturnal awakenings, compared with ICS/LABA + SABA (SMD = - 2 0. We found no statistically significant differences in symptom-free days (SMD = 0. Of note, the comparisons that administered scheduled maintenance ICS doses that were lower in the BUD/FM MART group all found statistically significantly lower exacerbation rates 98-100, 104 for those treated with BUD/FM MART. In addition, the BUD/FM MART group had a lower mean daily steroid dose (maintenance plus relief) than the ICS/LABA for maintenance 98-100, 104, 106 with SABA relief in three of the five trials. Thus, it does not appear that delivering a higher total ICS dose explains the better exacerbations outcomes in the BUD/FM MART group. BUD/FM MART compared with BUD/FM for maintenance and SABA for relief 98-100 103, 105 We found one good- and one fair-quality RCT for this comparison. Both trials reported asthma symptoms, nocturnal awakenings, exacerbations, and rescue medicine use 98-100 (Table 13). One trial also reported missed work, hospitalizations, and emergency visits (Evidence Tables A and B). The results are mixed but show a trend favoring the BUD/FM MART for several outcomes. Both reported statistically significant differences in exacerbations favoring BUD/FM MART, but reported no difference in symptoms. One trial reported fewer 103, 105 nocturnal awakenings in both children and adults treated with BUD/FM MART. The single study reporting hospitalizations and emergency visits found no difference between groups in the 98, 99 full population analysis but a small but significant decrease in hospitalizations / emergency 100 visits favoring BUD/FM MART among those age 16 and older. The trial reporting missed work found a numerical difference favoring BUD/FM MART, but the statistical significance was 98-100 not reported. None of the trials reported any outcomes favoring the BUD/FM for maintenance and SABA for relief. BUD/FM MART compared with FP/SM for maintenance and SABA for relief 98-100, 104 106 We found two good- and one fair-quality RCTs comparing these treatments. All three trials reported asthma symptoms, exacerbations, and rescue medicine use (Evidence Tables A 98-100, and B). Two trials reported nocturnal awakenings and hospitalizations or emergency visits. The results are mixed but show a trend favoring BUD/FM MART for some outcomes.

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Placebo-controlled trials Metoprolol succinate reduced total mortality buy genuine malegra dxt plus, sudden in mild-moderate heart death discount malegra dxt plus 160mg without a prescription, and death due to progressive heart failure and failure: Good improved quality of life (MERIT-HF) order malegra dxt plus 160 mg free shipping. Carvedilol reduced total mortality buy malegra dxt plus 160mg mastercard, sudden death, and death due to pump failure (MOCHA). Nebivolol significantly reduced the composite outcome of all-cause mortality or cardiovascular hospital admission, but had nonsignificant effects each component as individual secondary outcomes. Bisoprolol reduced total mortality and sudden death. No studies of carvedilol phosphate (extended-release carvedilol) in patients with mild to moderate heart failure were identified. Placebo-controlled trials Carvedilol reduced mortality and the combined in severe heart failure: endpoint of mortality and hospitalizations in a Fair for carvedilol and prospective trial. Fair for metoprolol A post-hoc subgroup analysis of MERIT-HF suggests succinate that metoprolol succinate is similarly effective in comparable patients. No studies of carvedilol phosphate (extended-release carvedilol) in patients with severe heart failure were identified. Atrial arrhythmia Overall grade: Fair Bisoprolol equivalent to carvedilol in preventing relapse of atrial fibrillation in a head-to-head trial. Metoprolol succinate reduced incidence of atrial arrhythmia/fibrillation in a placebo-controlled trial. Carvedilol reduced 24-hour ventricular rate in patients with atrial fibrillation and heart failure in 1 placebo- controlled trial. These placebo-controlled trials did not offer Beta blockers Page 57 of 122 Final Report Update 4 Drug Effectiveness Review Project a Strength of evidence Conclusion comparative data. Migraine Overall grade: Fair Atenolol, slow release metoprolol, immediate release metoprolol, and timolol were all similar to propranolol in their effects on pain outcomes and acute medication use in 5 head-to-head trials. No significant differences were found between nebivolol and metoprolol on frequency of migraine attacks and severity. Bleeding esophageal varices Overall grade: Poor Results of 1 head-to-head trial of atenolol and propranolol, 1 placebo-controlled trial of nadolol, and 6 placebo-controlled trials of immediate release and 2 formulations of extended release propranolol, all fair quality, didn’t clearly differentiate one beta blocker from another. Adverse effects Hypertension, stable angina, Overall grade: Fair A few differences in specific adverse event rates were heart failure, atrial arrhythmia, noted across longer-term trials directly comparing one migraine, bleeding esophageal beta blocker to another. Demographics (age, gender, Overall grade: Fair Evidence showed that age, gender, and race did not race) impact the effectiveness of carvedilol, immediate and controlled release metoprolol, and propranolol. There was insufficient evidence on the effect of beta blockers on perinatal mortality or preterm birth based on 1 systematic review. High risk populations Overall grade: Fair Heart failure. Subgroup analyses of placebo-controlled trials showed that a history of myocardial infarction may reduce the protective effect of bisoprolol on mortality (CIBIS). No risk factor was found to confound the protective effect of carvedilol (COPERNICUS) or controlled release metoprolol (MERIT-HF) on mortality. The MIAMI trial found that metoprolol had the greatest protective effect on mortality in patients with numerous risk factors. The BHAT trial found no variation in propranolol’s protective effect on total mortality based on history of heart failure. Subgroup analysis of the SHEP trial found that the addition of atenolol to chlorthalidone did not significantly affect mortality relative to placebo. Metoprolol use reduced all-cause mortality and hospitalizations relative to placebo in a subgroup analysis of the MERIT-HF trial. Abbreviations: NYHA, New York Heart Association classification. Beta blockers Page 58 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 18. Sum m ary ofcom parative efficacy A ftercoronary B leeding artery bypass H eart A trial esoph ageal M yocardial Drug H ypertension A ngina graft failure arrh yth m ias M igraine varices infarction E ffectivein Acebutolol reducing all- causem ortality E quivalentto bisoprololinpatients E quivalentto E quivalentto with com orbidchronic E quivalentto propranolol carvedilolintim e obstructivepulm onary propranololinforreducing toserious diseaseinreducing Atenolol decreasing all-cause cardiovascular attackfrequency; m igraine m ortalityand eventpost- E quivalenttolabetalol days deathsdueto m yocardial inreducing nitrateuse rebleeding infarction whenboth com bined with chlorthalidone E quivalentto propranolol; E quivalentto m etoprololtartratein Betax olol chestpainepisodes; E quivalentto m etoprololtartratein5 of 6quality-of-life dim ensions E quivalenttoatenolol E quivalentto inpatientswith M oreeffectivethanplacebo carvedilolin Bisoprolol com orbidchronic inall-causem ortalityand preventing obstructivepulm onary suddendeath relapseof atrial disease fibrillation Carteolol Beta blockers Page 59 of 122 Final Report Update 4 Drug Effectiveness Review Project A ftercoronary B leeding artery bypass H eart A trial esoph ageal M yocardial Drug H ypertension A ngina graft failure arrh yth m ias M igraine varices infarction M oreeffectivethan m etoprololtartrateinall- E ffectivein causem ortality, reducing all- cardiovascularevents, causem ortalityin unstableanginainm ild- patientswith left m oderateHF (CO M E T); ventricular E quivalenttom etoprolol E quivalentto dysfunctionpost- tartrateinim proving bisoprololin m yocardial sym ptom sandex ercise preventing infarction; param eters; relapseof atrial E quivalentto E quivalentto Im provem entsinN YHA fibrillation; atenololintim e m etoprololin functionclassandon M oreeffective toserious Carvedilol increasing ex ercise walking distance(6-m inute thanplaceboin cardiovascular tolerance walktest)weresim ilarly reducing 24-hour eventpost- slightforboth carvediloland ventricularratein m yocardial nebivolol; patientswith infarction; M oreeffectivethanplacebo atrialfibrillation E quivalentto intotalm ortality,sudden andheartfailure m etoprolol death,death duetopum p tartrateinall- failure(M O CHA); causem ortality, M oreeffectivethanplacebo cardiovascular inall-causem ortalityin death,nonfatal patientswith severe heart reinfarction failure(CO PE R N ICU S) Carvedilol phosphate E quivalenttoatenolol inreducing nitrateuse L abetalol whenboth com bined with chlorthalidone E quivalentto L esseffectivethancarvedilol E quivalentto E ffectivein carvedilolinincreasing inreducing totalm ortality, propranololin reducing total ex ercisetolerance; E quivalentto cardiovascularevents, all m ortality,sudden M etoprololtartrate E quivalenttobetax ololplacebofor unstableangina(CO M E T); param eters death,and inchestpainepisodes;m ortality E quivalenttocarvedilolin m easured; reinfarction; E quivalenttobetax olol im proving sym ptom s/ E quivalentto E quivalentto in5of 6quality-of-life ex erciseparam eters nebivololin carvedilolinall- Beta blockers Page 60 of 122 Final Report Update 4 Drug Effectiveness Review Project A ftercoronary B leeding artery bypass H eart A trial esoph ageal M yocardial Drug H ypertension A ngina graft failure arrh yth m ias M igraine varices infarction dim ensions all causem ortality, param eters cardiovascular m easured death,nonfatal reinfarction M oreeffectivethanplacebo inreducing totalm ortality, L esseffective suddendeath,death dueto CR /X L thannebivolol progressiveheartfailureand form ulationm ore inqualityof im provedqualityof lifein effectivethan M etoprolol sleep; m ild-m oderateheartfailure placeboin succinate L esseffective (M E R IT-HF ); lowering atrial thannebivolol M oreeffectivethanplacebo fibrillation/flutter inerectile inreducing m ortalityin relapserates function severeheartfailure(post- hoc,subgroup analysisof M E R IT-HF ) M ore effectivethan placeboin N adolol effecton rebleeding rates Penbutolol E quivalentto propranololin E quivalentto Pindolol increasing ex ercise placeboinall- tolerance,decreasing causem ortality attackfrequency E quivalentto E quivalentto E quivalentto atenolol, atenololfor placeboin E ffectivein m etoprolol reducing all- m ortality, E quivalenttobetax olol reducing total Propranolol tartrate, cause cardiovascularandpindolol m ortalityand m etoprolol m ortalityand events,quality suddendeath succinate, deathsdueto of life andtim olol rebleeding Beta blockers Page 61 of 122 Final Report Update 4 Drug Effectiveness Review Project A ftercoronary B leeding artery bypass H eart A trial esoph ageal M yocardial Drug H ypertension A ngina graft failure arrh yth m ias M igraine varices infarction E ffectivein reducing total E quivalentto Tim olol m ortality,sudden propranolol death,and reinfarction E quivalenttoplaceboinall- causem ortalityand cardiovascularhospital adm issionasindividual M oreeffective secondaryoutcom es; than M oreeffectivethanplacebo m etoprolol ascom positeoutcom e; succinatein E quivalenttoplaceboin E quivalentto qualityof sleep N YHA,tim etofirst m etoprololin N ebivolol M oreeffective hospitaliz ation,qualityof life, all than survivalrate; param eters m etoprolol E quivalenttoplaceboin m easured succinatein ex ercisetest; erectile Im provem entsinN YHA function functionclassandon walking distance(6-m inute walktest)weresim ilarly slightforboth carvediloland nebivolol Abbreviations:N YHA,N ew YorkHeartAssociationclassification. Beta blockers Page 62 of 122 Final Report Update 4 Drug Effectiveness Review Project REFERENCES 1. Current methods of the US Preventive Services Task Force: a review of the process. Blood pressure and mood responses in hypertensive patients on antihypertensive medications. Journal of the American Academy of Nurse Practitioners. The effects of replacing beta-blockers with an angiotensin converting enzyme inhibitor on the quality of life of hypertensive patients. Walle PO, Westergren G, Dimenas E, Olofsson B, Albrektsen T. Effects of 100 mg of controlled-release metoprolol and 100 mg of atenolol on blood pressure, central nervous system-related symptoms, and general well being. Modest antihypertensive effect of epanolol, a beta 1-selective receptor blocker with beta 1 agonist activity: an acute and long-term hemodynamic study at rest and during exercise and double crossover comparison with atenolol on ambulatory blood pressure. The effects of antihypertensive agents on the quality of life in Indian hypertensives. Steiner SS, Friedhoff AJ, Wilson BL, Wecker JR, Santo JP. Antihypertensive therapy and quality of life: a comparison of atenolol, captopril, enalapril and propranolol. Foerster EC, Greminger P, Siegenthaler W, Vetter H, Vetter W. Atenolol versus pindolol: side-effects in hypertension. Fogari R, Zoppi A, Corradi L, Preti P, Mugellini A, Lusardi P. Beta-blocker effects on plasma lipids during prolonged treatment of hypertensive patients with hypercholesterolemia. Efficacy and safety of bisoprolol and atenolol in patients with mild to moderate hypertension: a double-blind, parallel group international multicentre study. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC trial of treatment of mild hypertension: principal results. Wikstrand J, Warnold I, Olsson G, Tuomilehto J, Elmfeldt D, Berglund G. Primary prevention with metoprolol in patients with hypertension. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? Beta blockers Page 63 of 122 Final Report Update 4 Drug Effectiveness Review Project 16. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Yilmaz MB, Erdem A, Yalta K, Turgut OO, Yilmaz A, Tandogan I. Impact of beta- blockers on sleep in patients with mild hypertension: a randomized trial between nebivolol and metoprolol. Short-term behavioral effects of beta- adrenergic medications in men with mild hypertension. Double-blind comparison of the cardioselective beta-blockers bisoprolol and atenolol in hypertension: the Bisoprolol International Multicenter Study (BIMS). No difference in general well-being during antihypertensive treatment with atenolol or metoprolol CR. Brixius K, Middeke M, Lichtenthal A, Jahn E, Schwinger RHG. Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men. Oberman A, Wassertheil-Smoller S, Langford HG, et al.

Femoral neck: No change from baseline in placebo group malegra dxt plus 160 mg otc. Trend for increased BMD in E2 or E2 + MPA groups buy malegra dxt plus overnight, but not significant All 3 progestin treatments were similar to placebo Hormone therapy Page 44 of 110 Final Report Update 3 Drug Effectiveness Review Project Study Design; Study/year Number; Population (quality) Duration characteristics Interventions Main outcomes/results Warming 160mg malegra dxt plus visa, Double-blind; Postmenopausal; E2 1 mg + 1mg Difference between HRT and placebo after 2 years: 2004 N=240; 0/240 drospirenone cheap 160mg malegra dxt plus otc, Spine: 7% (p<0. At 36 months, combination therapy had a significantly greater increase in total hip BMD than those on either ALN or HRT alone (p<. Conjugated synthetic estrogen combination Lindsay, Double-blind Postmenopausal Conjugated estrogens % of patients who did not lose >2% of spine BMD at 2005 Multicenter; Mean age 51. Placebo: 30%; 27% who did not lose >2% in 12 months lost >2% at 24 months. Transdermal estrogens Estradiol patch Ettinger, 2004 Double-blind Postmenopausal; estradiol patch releasing Lumbar spine BMD: Increased 2. N=417; Mean 67 ±5 years; (replaced once/week) Between group difference at 2 years: 2. Hormone therapy Page 45 of 110 Final Report Update 3 Drug Effectiveness Review Project Study Design; Study/year Number; Population (quality) Duration characteristics Interventions Main outcomes/results Estradiol patch/levonorgestrel Warming, Double-blind Postmenopausal, 45 micrograms estradiol Difference in BMD, HRT vs. One trial did not report treatment and placebo group differences, but stated that forearm bone density in the treatment group was statistically 125 significantly increased from baseline while the placebo group showed no change. Another trial reported a trend in E2 groups towards increased bone density, however statistical 126 significance was not reached for between group comparisons. All 15 trials of transdermal E2 reported statistically significant improvements in bone 127-139 density compared to placebo. Only three trials did not use concomitant 129, 134, 138, 140, 141 progestin/progesterone. Five trials of E2V with concomitant progestin/progesterone reported bone density 111, 142-145 outcomes. Four of the five trials noted improvement in treatment groups compared to 111, 142-144 145 placebo, and one did not. All trials reported significant within-group changes in bone density at multiple sites for various doses with higher doses showing greater changes. In a good-quality trial comparing combination treatment with CEE (with or without medroxyprogesterone) plus alendronate to either treatment alone, patients on combination therapy had a significantly greater increase in total hip BMD than those 170, 171 151 on either ALN or HRT alone after 3 years (p<. A more recent substudy of the Women’s HOPE trial found that most women on lower doses of CE with or without medroxyprogesterone (0. Similar improvements were found in the lumbar spine. In subjects with 6-year follow-up BMD data (n=443), the percentage increase in lumbar spine BMD was 7. The CEE-only study of the WHI produced modest but consistent positive effects on bone 173 mineral density. Hormone therapy Page 46 of 110 Final Report Update 3 Drug Effectiveness Review Project 174 One study of esterified estrogen examined dosages of 0. Effect of discontinuation of estrogen on bone density Two studies reported the effect on bone density after discontinuing the use of estrogen to determine if bone density gains were sustained after discontinuation, or if there was evidence that bone loss was accelerated in women who had used estrogen therapy when compared with 175, 176 those who had not used it. Both studies found the rate of bone loss after stopping estrogen was similar to that of women who did not receive estrogen treatment, as described below. Further bone density gains were not observed in women after discontinuation of estrogen therapy, but there was also no evidence of accelerated bone loss when compared with those who had taken placebo. The second study reported the effect on bone mineral density of discontinuation of estrogen therapy for one year after 5 years of treatment in women enrolled in a randomized placebo-controlled trial of raloxifene and estrogen for 176 prevention of postmenopausal bone loss. This study also found that changes in bone density after one year of discontinuation were not significantly different in women using CEE compared with women randomized to placebo. Comparison with other meta-analyses A Cochrane review and meta-analysis published in 2002 on estrogen and bone density 7 and fractures was reviewed for this report. Fifteen of the trials included in the Cochrane review did not meet inclusion criteria for this review because they used ineligible estrogen 177-191 preparations. Results of the Cochrane meta-analysis included: • The pooled percent change in bone density was statistically significantly increased with estrogen compared to placebo at all measurement sites when combining results for all prevention and treatment trials and for both opposed and unopposed regimens. Hormone therapy Page 47 of 110 Final Report Update 3 Drug Effectiveness Review Project o For high-dose estrogen (equivalent to 0. For the lumbar spine, the differences between estrogen and placebo groups were: o 5. This study was restricted to placebo-controlled trials of at least 2 year’s duration and enrollment of at least 60 subjects. Although the study did not report a systematic assessment of the quality of the trials selected for review, the number of dropouts in each trial and use of intention-to-treat results were assessed. The 2-year mean changes in lumbar spine BMD (weighted for the ratio of sample size/dropouts) are summarized as follows: o 7. Fractures Head-to-head comparisons No head-to-head trials were found. Placebo comparisons We identified 11 studies of estrogen that included outcome data on fractures (Evidence 128, 135, 144, 155, 156, 168, 193 7 Table 6). Seven were included in a recent Cochrane meta-analysis, and 4, 117, 149, 194 the remainder were more recently published. Only one study of oral E2 evaluated fracture outcomes and found a statistically significant risk reduction for forearm fractures (RR=0. Both studies of transdermal E2 indicated no 128, 135 128 significant improvement in vertebral and non-vertebral fractures. One trial of E2V in early postmenopausal women reported a significant decrease in nonvertebral (RR=0. Although some of these studies showed a trend toward reduction of fractures at various sites in the treatment groups, only 4 the WHI showed a significant result. When compared with the placebo group, total fractures for 4 women on CEE were significantly reduced (HR=0. Risks were also reduced for site-specific fractures of the hip and vertebra, although confidence intervals adjusted for multiple comparisons included 1. This effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, bone density, or summary fracture risk score. Hip fractures and clinical vertebral fractures were also decreased, although 95% confidence intervals adjusted for multiple comparisons overlapped a HR of 1. Additional data on fractures recorded 173 through the study termination (average 7. These positive effects occurred largely irrespective of baseline risk factors for osteoporosis or fracture. The global index of overall health risks and benefits was balanced, however, with no evidence of overall benefit or risk noted even for women in the highest tertile of risk for fracture. Comparison with Cochrane meta-analysis 128, 135, 144, 155, 156, 168, 193 Seven studies reporting fracture outcomes were included in a 7 Cochrane review published in 2002. Two trials indicating significant fracture risk reduction, including the WHI, were not included because they were published after the Cochrane 117 analysis. Findings included: • Four of five studies measuring vertebral fracture outcomes indicated non-statistically 131, 151 ,164, significant reductions in estrogen groups (RR=0. What is the comparative safety of different hormone therapy preparations for short-term use (<5 years)? Summary points - Breast tenderness and vaginal bleeding increase with all estrogen preparations. Hormone therapy Page 49 of 110 Final Report Update 3 Drug Effectiveness Review Project - All of the trials of symptoms and most of the trials of bone density and fractures were less than 5 years in duration and few enrolled more than 200 participants. Head-to-head trials Adverse events reported in short-term head-to-head trials of different estrogen preparations are shown in Evidence Tables 7 (trials with symptom outcomes) and 8 (trials with bone outcomes). Head-to-head comparison trials provided insufficient evidence to determine the relative adverse effects of different estrogens. One trial of CEE and oral E2 reported that the incidence of possible drug-related adverse experiences ranged from 20% in placebo, E2 1 mg/day, and CEE 0. Most head-to-head trials reported similar rates of specific adverse events and withdrawals due to adverse events between treatment groups, with a few exceptions. In one trial, a significantly greater incidence of breast tenderness was found in women randomized to oral E2 2 mg plus NETA versus CE 5 mg plus MPA, and more women in the E2/NETA group withdrew 19 from the trial during the first 3 months (17. A trial of a vaginal ring releasing E2 compared with an E2 vaginal tablet found more withdrawals in the vaginal ring group, mainly occurring during the first 3 months of treatment and due to abdominal discomfort, 25 lower back pain, and slippage of the ring. In a head-to-head trial of an intravaginal ring delivering E2 compared with oral E2 for treatment of vasomotor symptoms, there were no 24 significant differences between groups in the frequency of the most common adverse events. Placebo-controlled trials Withdrawals due to adverse effects and withdrawals due to specific adverse effects in placebo controlled trials are summarized in Evidence Table 9 for trials of hot flashes and Evidence Table 10 for trials of bone density and fractures.

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Fair evidence showed no difference ® ® between glatiramer and interferon beta-1a SC (Rebif ) or interferon beta-1b (Betaseron ) buy malegra dxt plus 160 mg cheap. The strength of the evidence in other populations was low discount malegra dxt plus 160mg overnight delivery. There was no direct evidence in patients with primary and secondary progressive multiple sclerosis discount malegra dxt plus 160 mg free shipping, and no evidence in patients with progressive relapsing multiple sclerosis cheap malegra dxt plus 160mg online. There is moderate evidence that the beta interferons are similar in harms. The strength of the evidence for the presence and clinical effect of neutralizing antibodies was low, with no head-to-head trials. Observational studies were limited by lack of control for confounding factors and insufficient duration to make conclusions. The strength of the evidence for comparative effectiveness in patients with a clinically isolated syndrome was low, with no head-to-head trials. Evidence of efficacy compared with ® ® placebo was available for glatiramer (Copaxone ), interferon beta-1a IM (Avonex ), interferon ® ® beta-1a SC (Rebif ), and interferon beta-1b (Betaseron ). There was no evidence for ® ® mitoxantrone (Novantrone ) or natalizumab (Tysabri ) in this population. We identified no trials in progress that would meet inclusion criteria for this review and potentially change conclusions. Disease-modifying drugs for multiple sclerosis Page 81 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 38. Summary of the evidence Quality of the Key Question evidence Conclusion Key Question 1. Fair Relapsing remitting multiple sclerosis What is the • Direct evidence from 4 fair-quality head-to-head trials comparative showed little difference in relapse outcomes between ® effectiveness of interferon β-1a SC (Rebif ) and interferon β-1b ® ® disease-modifying (Betaseron ), while interferon β-1a IM (Avonex ) was ® treatments for less effective than interferon β-1a SC (Rebif ) and ® multiple sclerosis, interferon β-1b (Betaseron ) on this measure. Glatiramer was more effective than placebo in relapse rate based on 3 small fair-quality trials but no difference on the percentage relapse free. The evidence on the effect of glatiramer on disease progression is inconclusive based on data from 1 trial. Natalizumab and mitoxantrone were more effective than placebo for relapse-related and disease progression outcomes in placebo-controlled trials. Evidence was based on a small number of trials (2 for natalizumab and 1 for mitoxantrone). Secondary progressive multiple sclerosis • There is no direct evidence. Evidence from placebo- controlled trials showed that the all of β interferons were similarly effective at reducing relapse rates. A positive effect on disease progression was observed with ® interferon β-1b (Betaseron ) although similar effects were not consistently observed with the interferon β-1a products. Primary progressive multiple sclerosis • The only evidence available (from 1 small, good quality ® trial comparing interferon β-1a IM (Avonex ) to placebo) is insufficient to make any judgments regarding effectiveness in PPMS patients. PRMS: • No studies of DMD use in PRMS patients were identified through literature searches. Fair Evidence for interferon β-1b SC (Betaseron ) and interferon β-1a ® Do disease- SC (Rebif ) indicates that consistent positive neutralizing modifying antibody status with high titer adversely affects the impact of treatments for these drugs on relapse rates, by one-half to two-thirds, during multiple sclerosis longer periods of follow-up. Fair Interferon β-1a IM (Avonex ) appears to have the lowest What is the immunogenicity, with rates of development of neutralizing evidence that antibodies of 2-8. Fair to poor No direct evidence comparing 1 DMD to another in patients with What is the a clinically isolated syndrome was available. Placebo-controlled ® ® effectiveness of trials of glatiramer (Copaxone ), interferon β-1a IM (Avonex ), ® ® disease-modifying interferon β-1a SC (Rebif ) and interferon β-1b (Betaseron ) treatments for found them all more effective than placebo at reducing the patients with a probability of converting to clinically definite MS. The drugs had clinically isolated higher rates of adverse events relative to placebo. Fair Withdrawals due to adverse events Do disease- No difference in withdrawal rates among β interferons in head-to- modifying head trials, although adverse events in generally were poorly treatments for reported in these trials. Withdrawal rates ranged from 3% ® multiple sclerosis (glatiramer acetate) to 9% (Interferon β-1b SC [Betaseron ]) in differ in harms? Serious adverse events NAbs: The clinical impact of the presence of neutralizing antibodies is unclear although limited data suggests they may negatively impact relapse rate after 3-4 years of treatment. Liver function: ALT elevations are common with all β interferon products, with little difference in rates of occurrence. Thyroid function: Limited data from 2 observational studies found similar rates of clinical and subclinical thyroid autoimmunity with ® Interferon β-1a IM (Avonex ) and Interferon β-1b SC ® (Betaseron ) Depression: There was a lower rate of depression in patients ® taking interferon β-1a (Rebif ) compared with the other interferons based on limited trial data. One small observational study comparing β interferons and glatiramer also found no differences in depression rates, although our own analysis of the all published trials reporting rates of depression indicates an increase in risk for all interferon β1 products. Cancer: Data from 1 cohort study found a potentially increased risk of cancer development in women with either β interferon or glatiramer acetate use; these results are inconclusive. Therapy- related acute leukemia was reported in 2/1620 patients taking mitoxantrone. Cardiotoxicity: Two cases of congestive heart failure were Disease-modifying drugs for multiple sclerosis Page 83 of 120 Final Report Update 1 Drug Effectiveness Review Project Quality of the Key Question evidence Conclusion potentially linked to mitoxantrone use in 1 meta-analysis of 3 (2 unpublished) studies (incidence 0. Tolerability ® Flu-like syndrome: Interferon β-1a IM (Avonex ) was associated with the highest rates of flu-like syndrome compared with the other β interferons (~62% compared with 28%). Systemic reactions: Post-injection systemic reactions were observed in patients receiving glatiramer acetate, although these were usually limited to a single episode. There were no events reported of this outcome in trials of β interferons, natalizumab or mitoxantrone. Long-term safety in observational studies Long-term safety data from comparative and non-comparative, non-randomized studies was consistent with that reported in trials. Significant concerns include progressive multifocal leukoencephalopathy in patients receiving natalizumab >12 months, lipoatrophy with prolonged use of glatiramer and permanent amenorrhea in older women receiving higher total dose of mitoxantrone. Key Question 6: Poor Observational studies did not show increased risk of adverse Are there pregnancy outcomes associated with exposure to beta subgroups of interferons or glatiramer, but studies were too small to make patients based on strong conclusions about the safety of MS drugs in pregnancy. Abbreviations: ALT, alanine aminotransferase; EDSS, Expanded Disability Status Scale; IM, intramuscular; DMD; disease-modifying drug; MS, multiple sclerosis; NAb, neutralizing antibody; PRMS, progressive relapsing multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; SC, subcutaneous. Disease-modifying drugs for multiple sclerosis Page 84 of 120 Final Report Update 1 Drug Effectiveness Review Project REFERENCES 1. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Prevalence Estimates for MS in the United States and Evidence of an Increasing Trend for Women. Costs and Quality of Life in Multiple Sclerosis: A Cross Sectional Study in the United States. Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the "McDonald Criteria". Rating Neurological Impairment in Multiple Sclerosis: An Expanded Disability Status Scale (EDSS). Clinical Outcome Measures and Rating Scales in Multiple Sclerosis Trials. Multiple Sclerosis- The Plaque and its Pathogenesis. Copaxone (Glatiramer Acetate Injection) [Product Information] Kansas City MO, Teva Neuroscience Inc. Avonex (Interferon beta-1a) IM injection [Product Information]Cambridge, MA: Biogen Idec Inc. Rebif (Interferon Beta-1a) [Product Information]Rockland MA: Serono, Inc,. Betaseron (Interferon Beta-1b) [Product Information]Montville, NJ: Berlex Laboratories. Novantrone (mitoxantrone for injection concentrate) [Product Information] Rockland MA: Serono, Inc,. Extavia (Interferon beta 1-b) [product information]. Tysabri (natalizumab) [Product Information] Cambridge, MA: Biogen Idec Inc.

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Chromo- This work was supported by the Intramural Research Program of the somal abnormalities clustering in multiple myeloma reveals National Cancer Institute of the National Institutes of Health buy malegra dxt plus 160 mg. International Myeloma Disclosures Working Group molecular classification of multiple myeloma: Conflict-of-interest disclosure: The author declares no competing spotlight review buy online malegra dxt plus. Timing of clinical trials (lenalidomide buy generic malegra dxt plus 160 mg, carfilzomib) malegra dxt plus 160mg without prescription. Genetics and cytogenet- Dr Ola Landgren, Multiple Myeloma Section, Metabolism Branch, ics of multiple myeloma: a workshop report. Center for Cancer Research, National Cancer Institute, National 2004;64(4):1546-1558. Institutes of Health, 9000 Rockville Pike, Bldg 10/Room 13N240, 18. Rasmussen T, Kuehl M, Lodahl M, Johnsen HE, Dahl IM. Bethesda, MD 20892; Phone: 301-496-0670; Fax: 301-496-9956; Possible roles for activating RAS mutations in the MGUS to e-mail: landgreo@mail. MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors. Clinical and thy of undetermined significance (MGUS) and smoldering biological significance of RAS mutations in multiple myeloma. MYD88 L265P somatic mutation in IgM conditional mouse model of post-germinal center malignancies. Monoclonal gammopathy of undetermined signifi- signature of benign monoclonal gammopathy evident in mul- cance. Criteria for the classification of monoclonal gammopathies, smouldering myeloma to myeloma: sequential analysis of a multiple myeloma and related disorders: a report of the single case. Initial genome thy of undetermined significance (MGUS) and smoldering sequencing and analysis of multiple myeloma. Clinical course gammopathies, from MGUS to myeloma status. Monoclonal gammopa- clonal architecture and propagating cells in leukaemia. Covalent histone modifications– IgH translocations are highly associated with nonhyperdiploid miswritten, misinterpreted and mis-erased in human cancers. Linking DNA methylation and histone abnormalities clustering and its implications for pathogenesis modification: patterns and paradigms. Aberrant global Hematology 2013 485 methylation patterns affect the molecular pathogenesis and 48. Diagnosis of smoldering prognosis of multiple myeloma. Challenges and opportunities of oncogenes and tumor suppressors. Molecular pathogenesis of multiple mendations for standard investigative workup: report of the myeloma and its premalignant precursor. The radiological marrow microenvironment in myelomagenesis: its potential demonstration of osseous metastases: experimental observa- role in early diagnosis. Serum free light patterns similar to multiple myeloma: a large (n 544) clinical chain ratio is an independent risk factor for progression in study using whole-body MRI [abstract]. Blood (ASH Annual monoclonal gammopathy of undetermined significance. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rodjer S, Westin J. Initial versus deferred melphalan-prednisone therapy sion of smoldering (asymptomatic) multiple myeloma. Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, 1993;50(2):95-102. Antitumor activity of high-risk smoldering multiple myeloma. Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC. Haematological cancer: treatment of previously untreated indolent or smoldering multiple myeloma. New criteria to progression with thalidomide for smoldering myeloma: partial identify risk of progression in monoclonal gammopathy of response identifies subset requiring earlier salvage therapy for uncertain significance and smoldering multiple myeloma based symptomatic disease. Prevalence and son with its use as later salvage therapy in relapsed or refractory risk of progression of light-chain monoclonal gammopathy of multiple myeloma. Published online ahead of dexamethasone for relapsed or refractory multiple myeloma. Lenalidomide uninvolved immunoglobulins defined by heavy/light chain pair plus high-dose dexamethasone versus lenalidomide plus low- suppression is a risk factor for progression of MGUS. Leuke- dose dexamethasone as initial therapy for newly diagnosed mia. Mechanism of action of cance on early diagnosis and prevention of myeloma-related lenalidomide in hematological malignancies. Safety and cance of focal lesions in whole-body magnetic resonance efficacy of single-agent lenalidomide in patients with relapsed imaging in patients with asymptomatic multiple myeloma. Lenalidomide 486 American Society of Hematology plus dexamethasone for high-risk smoldering multiple my- 75. Lenalidomide or observation in treating patients with asymptom- assessment of their skeletons is important. Clin Lymphoma atic high-risk smoldering multiple myeloma. Criteria for diagnosis, staging, risk smoldering myeloma&rank 6. A phase II trial of IPH2101 (anti-KIR) in smoldering multiple Leukemia. Celecoxib in preventing multiple myeloma in results? Available disease state in patients with smoldering or indolent multiple from: http://clinicaltrials. Golombick T, Diamond TH, Badmaev V, Manoharan A, disease progression in early stage chronic lymphocytic leuke- Ramakrishna R. The potential role of curcumin in patients with mia (ES-CLL), monoclonal gammopathy of undetermined monoclonal gammopathy of undefined significance–its effect significance (MGUS) and smoldering multiple myeloma (SMM). Smoldering OR Indolent&cond Multiple Myeloma&rank 7. Curcumin (diferuloylmeth- Accessed September 21, 2009. Green tea extract in treating patients ylation in human multiple myeloma cells. Accessed September 21, multiple myeloma cells, leading to suppression of proliferation 2009. Curcumin in combination randomized trial of thalidomide plus zoledronic acid versus with bortezomib synergistically induced apoptosis in human zoledronic acid alone in patients with asymptomatic multiple multiple myeloma U266 cells. Waxman AJ, Kuehl WM, Balakumaran A, Weiss B, Landgren randomized clinical trial comparing zoledronic acid versus O. Smoldering (asymptomatic) multiple myeloma: revisiting observation in patients with asymptomatic myeloma. San Miguel3 1Hospital Universitario de Salamanca and 2Instituto de Investigacio´ n Biome´ dica de Salamanca, Instituto de Biología Molecular y Celular del Ca´ ncer (Universidad de Salamanca-Consejo Superior de Investigaciones Científicas), Salamanca, Spain; and 3Clinica Universidad de Navarra, Pamplona, Spain Multiple myeloma (MM) is the second most frequent hematological disease. Two-thirds of newly diagnosed MM patients are more than 65 years of age. Elsewhere in this issue, McCarthy et al discuss the treatment of transplantation candidates; this chapter focuses on the data available concerning therapy for non-transplantation-eligible MM patients. Treatment goals for these non-transplantation-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life.

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Results of meta-analyses for mean change in HbA1c and weight for sitagliptin 100 mg compared with placebo Pooled analysis Heterogeneity 2 Outcome N Measure Units Estimate 95% CI P value I a HbA1c 7 WMD % −0 purchase cheap malegra dxt plus on line. Three trials assessed the effects of sitagliptin compared to placebo in 36 buy malegra dxt plus 160mg online, 47 cheap malegra dxt plus 160mg line, 50 patients who were considered to have “failed” therapy with metformin purchase malegra dxt plus 160mg line, 2 studies assessed sitagliptin compared to placebo in patients who were considered to have “failed” therapy with 48, 49 pioglitazone or glimepiride, and 1 study assessed sitagliptin compared to placebo in patients 51 who were inadequately controlled on metformin and insulin >15 units daily. Approximately 60% of patients were on more than 1 oral hypoglycemic agent, while 30% were on more than 2 oral agents (Table 13). Patients were considered to have “failed” therapy with metformin, pioglitazone, or glimepiride at screening or after 10-19 weeks of dose stabilization and if HbA1c was between 7% and 10% or 7. Patients also entered 2-week single-blind, placebo run-in periods prior to randomization. The addition of sitagliptin to metformin, pioglitazone, or glimepiride appears to show larger reductions in HbA1c and compared with the addition of placebo over 18 to 30 weeks (Table 16). Subjects who received placebo plus glimepiride showed worsening glycemic control, while subjects on placebo plus metformin or placebo plus pioglitazone had slight improvements or no change in HbA1c from baseline. Weight gain was generally seen in patients taking sitagliptin in combination with pioglitazone or glimepiride to a similar extent of those taking pioglitazone alone, however no weight gain was seen in those taking glimepiride alone. Patients randomized to add sitagliptin or placebo to metformin lost weight by 0. Pooled analysis was not conducted due to small number of studies and significant heterogeneity. Unlike the other studies , this trial evaluated the effects of sitagliptin in patients with worse glycemic control (baseline HbA1c between 8% and 11%). These patients were on metformin and diet and exercise for 6 weeks, had baseline HbA1c between 8% and 11%, and had ≥85% adherence to their regimens during a 2-week, placebo run- in period. No patients were naïve to oral hypoglycemic agents and approximately 50% were already taking metformin monotherapy or combination oral therapy at baseline. The addition of sitagliptin to ongoing metformin therapy was more effective than placebo plus metformin at lowering HbA1c (placebo-corrected difference: −1. One study was unique in that it included patients who were inadequately controlled on 51 insulin and/or metformin therapy. Patients were randomized to sitagliptin 100 mg or placebo in addition to their pre-study doses insulin and metformin (if they were taking). Approximately 70% of patients in both groups were taking metformin at baseline. Doses of insulin and metformin were not increased, however insulin could be decreased if hypoglycemia occurred. Similar results were seen in this study as others, with greater HbA1c lowering seen in patients randomized to sitagliptin than placebo (difference in LS mean change −0. Authors reported no difference in HbA1c lowering in patients on metformin or not on metformin (p=0. No difference was noted in weight change from baseline between the two groups, P value NR (Table 16). Efficacy outcomes of sitagliptin or placebo added to one oral hypoglycemic agent Change in HbA1c from baseline at a Author, year (%) Change in weight from baseline at (kg) 24 weeks 24 weeks S/Pio P/Pio S/Pio P/Pio 48 b Rosenstock, 2006 −0. Results of sitagliptin or placebo added to glimepiride alone have already been reviewed. In patients already on glimepiride plus metformin, the addition of sitagliptin improved HbA1c over 24 weeks of treatment whereas the addition of placebo showed worsening glycemic control (difference in LS mean change -0. Efficacy outcomes of sitagliptin or placebo added to 2 oral hypoglycemic agents Author, year Change in HbA1c from baseline (%) Change in weight from baseline (kg) 24 weeks 24 weeks S/G/M P/G/M S/G/M P/G/M a 49 b Hermansen, 2006 −0. Summary of Findings for Saxagliptin Evidence in children • We found no studies including children and adolescents ≤ 18 years Evidence in adults • All studies focused on intermediate outcomes with none focusing on health outcomes as primary outcomes. Some studies reported some health outcomes such as all-cause mortality or cardiac death among secondary outcomes or adverse events. Overall evidence was insufficient to determine how saxagliptin compares with other treatments for their impact on health outcomes. Detailed Assessment for Saxagliptin Randomized controlled trials We found 5 fair-quality randomized placebo-controlled trials meeting our inclusion/exclusion criteria. This section is organized by how saxagliptin was used (monotherapy or add-on therapy). There were no active control studies identified that met inclusion criteria. Characteristics of included studies are shown in Table 18. Characteristics of saxagliptin placebo-controlled trials in adults with type 2 diabetes Sample a size (N) Age (years) (SD) Baseline a Author, year Follow- % Female HbA1c (%) a a Country up % White (SD) Intervention a a b Quality (weeks) % Hispanic Weight (kg) Dosages Monotherapy 7. Monotherapy: Saxagliptin compared with placebo In 2 fair-quality randomized controlled trials carried out over 12-24 weeks, a wide variety of 53, 54 doses were compared to placebo. Data abstracted was for approved doses in the United States, Saxagliptin 2. All patients included in the trials were treatment naïve and mean baseline HbA1c for participants ranged from 7. Overall, reduction in HbA1c was greater with saxagliptin compared to placebo and slightly greater with saxagliptin 5 mg compared to 2. There was a 53 numerically greater HbA1c reduction with saxagliptin in the 12 week trial compared to the 24 54 week trial, however the placebo corrected change was similar between the two trials. Patients were similar between the 2 trials except patients in the 24 week trial had diabetes for longer than those in the 12 week trial (mean duration 2. Weight loss was seen across all groups, however more weight loss was seen in the placebo group than in either saxagliptin 2. Patients randomized to saxagliptin 5 mg had less weight loss than those randomized to saxagliptin 2. Efficacy outcomes for saxagliptin monotherapy compared with placebo Author, year Change in HbA1c from baseline (%) Change in weight from baseline (kg) 12 Weeks 12 weeks S2. Add-on therapy: Saxagliptin or placebo added to one oral hypoglycemic agent Three fair-quality trials were identified that compared saxagliptin to placebo as add-on therapy in patients not achieving adequate glycemic control on either metformin, a thiazolidinedione, or 55-57 glyburide. Patients were deemed to have inadequate glycemic control if their HbA1c was ≥7% to ≤10% or ≥7% to ≤10. In general, the addition of saxagliptin to metformin, a thiazolidinedione, or glyburide appears to show larger reductions in HbA1c compared with the addition of placebo over 24 weeks (Table 20). Results were not stratified by which thiazolidinedione patients were taking. Varying results were seen in regards to change in weight. The addition of placebo to glyburide or a thiazolidinedione resulted in less weight gain than the addition of saxagliptin to glyburide or a thiazolidinedione. Slightly more weight loss was seen with the addition of saxagliptin 2. No statistical testing was done to determine the statistical significance of these differences. One study randomized patients who had inadequate glycemic control on submaximal 57 doses of sulfonylurea therapy. Patients were switched from their current sulfonylurea to open label glyburide 7. After a 4 week single blind run-in period, patients continued their open label glyburide and were randomized to either saxagliptin 2. Therefore patients randomized to placebo had a total daily dose of glyburide 10 mg daily as compared with glyburide 7. Efficacy outcomes for saxagliptin or placebo added to one oral hypoglycemic agent Author, year Change in HbA1c from baseline (%) Change in weight from baseline (kg) 24 Weeks 24 Weeks S2. Summary of Findings for GLP-1 Agonists Efficacy and effectiveness Exenatide compared with liraglutide • In the one included head-to-head trial (N=464), liraglutide 1. Evidence in adults • Except for one study reporting quality of life, no included studies examined the impact of treatment with exenatide on health outcomes (such as MI, death, stroke, or renal failure) (insufficient strength of evidence). The longest duration of an included study was 52 weeks. In one of the trials, the substitution of exenatide for insulin did not improve HbA1c compared to continuing insulin.

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