By G. Mojok. Granite State College.

FISH is not always readily available and is has only been documented in a minority of cases 50mg viagra mastercard erectile dysfunction drugs sublingual. Cases with a MYC rearrangement double-hit score (DHS) 2 group cheap 100 mg viagra mastercard erectile dysfunction foods that help, those with overexpression of MYC were more likely to be associated with a high IPI score and a tumor and BCL2 by IHC and comprising 29% of patients, there was a of GCB origin compared with cases without a rearrangement. In addition, when the investiga- 2-year OS for MYC-rearranged patients was significantly inferior, tors compared patients who were DHL by FISH with FISH-negative with 35% alive compared with 61% in the FISH-negative group. In patients in the DHS 2 group, outcomes were similarly poor. What another study, the British Columbia Cancer Agency (BCCA) was interesting in this analysis was that, whereas almost all patients reported 135 cases of DLBCL treated with R-CHOP and identified with DHL by FISH (91%) had tumors of GCB origin, the opposite 9% of cases with a MYC rearrangement; 25% (3/12) had a was true in the FISH-negative DHS 2 group: the majority (73%) of concurrent BCL2 translocation. The DHS maintained its prognos- rearranged cases was just 33% compared with 72% for those tic significance in both the GCB and non-GCB group. MYC rearrangement was associated with did a similar analysis in a group of homogeneously treated higher tumor proliferation and a higher likelihood of central nervous (R-CHOP) patients with de novo DLBCL and identified 21% with system relapse. The BCCA recently reported on 167 R-CHOP concurrent high expression of MYC and BCL2 by IHC. This was associated with a poor OS of pared with cases not doubly overexpressing the proteins, even after just 27% at 5 years and most patients had tumors of GCB origin. Interestingly, as with the Danish 14- versus 21-day cycles of R-CHOP in patients 60 years of age study, whereas most cytogenetically defined DHL cases were of found that a MYC rearrangement was not negatively prognostic GCB origin, most cytogenetically negative double-expressor cases when adjusted for other clinical factors. Others have 108 American Society of Hematology Table 2. Impact of double expression of MYC and BCL2 on outcome in DLBCL Study N Type of study High MYC/BCL2 % Treatment Outcome Green et al11 193 Retrospective cohort study 29% R-CHOP 3-y PFS of 39% vs 75% (P. Perry et al24 106 Retrospective cohort study 44% R-CHOP or CHOP-like High MYC/BCL2 expression, independent predictor of EFS (P. High MYC/BCL2 coexpression rubicin, and dexamethasone). However, the median OS was just was associated with an aggressive clinical course and inferior 18. One recently reported large, multicenter, retrospective analysis across 15 centers looked at the impact of So should double-expressor cases be approached differently and induction regimen and consolidative stem cell transplantation in strategies other than R-CHOP used? In robust and highly reproducible, IHC techniques and scoring have an early report of the analysis, 106 patients were included and the been reported to be quite variable and optimal cutoff points have majority of these (89%) had MYC and BCL2 rearrangements. At the same time, several Primary refractory disease was the primary predictor of OS. There methotrexate, ifosfamide, etoposide, cytarabine), and DA- appear to be distinct mechanisms of MYC and BCL2 activation EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclo- within subtypes of DLBCL and these should be elucidated further to phosphamide, doxorubicin and rituximab) were used. DA- guide the development of effective novel agents and strategies. EPOCH-R resulted in a higher rate of complete responses compared Management of DHLs: beyond R-CHOP with R-CHOP (P. In Although several studies demonstrate poor efficacy of R-CHOP in addition, primary refractory disease occurred less frequently in DHLs, with short OS, other strategies have not been well studied patients treated with DA-EPOCH-R compared with R-CHOP and there are no prospective data due to the rarity of these tumors. Overall, patients achieving a Considering that these lymphomas harbor a MYC rearrangement, complete response did not appear to benefit from consolidative stem testing approaches that are effective in Burkitt lymphoma make cell transplantation, but the numbers were low. However, one big challenge in that regard is the median age group also recently presented their experience with DHL over 15 of this group of patients. They did not identify an optimal regimen lymphoma are poorly tolerated and not typically feasible in this age retrospectively and the survival of patients undergoing frontline group. In both of these series, there were a Hematology 2014 109 Table 3. Treatment and outcome of double-hit lymphoma Type of Study DHL (N) study Treatment Comments Outcome Johnson et al8 54 Retrospective CHOP R; (63%); HD 52% were 60 y of age; Median OS 1. BCL2 cases As with DHL cases, outcomes after standard approaches for Although these studies highlight the poor prognosis of DHL double-expressor cases are poor and optimal management ap- histology, they do not provide any definitive guidance about how to proaches remain to be defined. Although a small proportion of these manage these patients. However, it is interesting that higher cases represent cytogenetically defined DHL histology and are complete response rates and lower rates of primary refractory associated with the GCB subtype, the majority do not have a MYC disease were associated with more intensive regimens than R- or BCL2 rearrangement and appear to be of non-GCB derivation CHOP.

Internal validity of controlled clinical trials Study or Author Score Year (good/ fair/ poor) Shah H buy cheap viagra 75 mg diabetes and erectile dysfunction causes, 2007 Poor Verri V cheap 100 mg viagra otc erectile dysfunction medicine ranbaxy, 2004 Fair-Poor Mallon P, 2006 Fair-Poor Statins Page 343 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Author, year Setting Study design Duration Eligibility criteria Bonnet F, et al 2007 Not reported Randomized, placebo-controlled, 3 months Adults with positive anti-HIV antibodies; had double-blind trial been receiving stable antiretroviral therapy including at least one PI for ≥3 months; had a plasma HIV RNA level of <50 copies/mL for ≥3 months before randomization; a TC ≥5. Calza L, et al 2008 Single-center, university Open-label, randomized, 12 months Adults on stable PI-based antiretroviral hospital; outpatient prospective, single-center therapy since at least 12 months, with HIV setting viral load <50 copies/mL for at least 6 months and presenting hypercholesterolemia ± hypertriglyceridemia and lipodystrophy of at least 3 months and unresponsive to diet/exercise Statins Page 344 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Bonnet F, et al 2007 Had current AIDS event or infectious disease; Pravastatin 40 mg QHS 31 1 tumoral, inflammatory, or muscle diseases; Placebo 21 1 kidney or hepatic failure; psychiatric conditions; 20 20 biological elevated muscular enzymes; chronic alcohol consumption; or if pregnant or displayed no evidence of use of effective contraception. Statins Page 345 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Age Gender Other population characteristics Author, year Ethnicity (diagnosis, etc) How adverse events assessed Bonnet F, et al 2007 42 yrs All patients using at least 1 protease inhibitor Specific adverse events were graded in severity 1-4 78-92% Male HIV stage C: 67-71% and lab measurements were taken. NR CD4 count: 465-484 cells/mm3 IVDU: 58-37% Baseline lipids (median) TC 239 mg/dL LDL 154 mg/dL HDL 39 mg/dL Calza L, et al 2008 37 yrs AIDS: 3% Specifics on how adverse events were assessed were 56-74% Males Mean CD4 count: 383 cells/mm3 not reported, however, authors did report that adverse NR All patients were using PI, ~88% were using events were carefully checked on monthly outpatient regimens that included ritonavir visits in addition to lab measurements. Baseline lipid panel (mean) TC 282 mg/dL TG 274 mg/dL LDL 177 mg/dL HDL 51 mg/dL Statins Page 346 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Author, year Adverse events reported Comments Funding source Bonnet F, et al 2007 There were a total of 12 adverse events Center Hospital of Prava: 7 Bordeaux; Roche labs Placebo: 5 Grade 2 myalgias: Prava, 3 (1 patient had a 2x increase of CPK); Placebo, 1 Digestive symptoms: Prava, 4; Placebo, 3 Depressive symptoms: Prava, 1; Placebo, 0 Headache: Prava, 1; Placebo, 0 2-fold increase in CPK at week 4: Prava, 2; Placebo, 1 (CPK levels were normal at week 8) Others: Prava, 3; Placebo, 1 1 patient in the Prava group prematurely discontinued the study because of seizure and hospitalization not related to study treatment and another patient in the Prava group temporarily stopped treatment because of diarrhea between week 4-12. There was no significant change of AST, ALT, Bili, glucose, CPK, and myoglobin in both groups. Calza L, et al 2008 No reports of myalgia or myositis across all groups Not reported No significant increases in CPK (>250) or ALT (>200) across all groups For Rosuva, Prava, Atorva Nausea: 7. Studies on harms Author, year Setting Study design Duration Eligibility criteria Franceschini G, 2007 University hospital in Italy Randomized, double-blind trial, 8 weeks Italian and French patients with low HDL-C parallel (<40 mg/dl) and moderate elevations of both LDL-C (<160 mg/dl) and triglycerides (150–500 mg/dl) Mallon P, et al 2006 Single-center, university Randomized, placebo-controlled, 3 months HIV-infected men on stable PI therapy (min 12 hospital (Sydney, double-blind trial weeks before screening and minimal changes Australia); outpatient to ART regimen during the study) setting Statins Page 348 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Franceschini G, 2007 NR Fenofibrate 160 mg/day NR/NR/52 NR/NR/52 Simvastatin 40 mg/day Mallon P, et al 2006 HTN, congestive cardiac failure, malabsorption or Pravastatin 40 mg QHS 34 2 other serious illness, active AIDS illness, serum Placebo 33 0 lactate >2. Statins Page 349 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Age Gender Other population characteristics Author, year Ethnicity (diagnosis, etc) How adverse events assessed Franceschini G, 2007 Mean age Fenofibrate vs Simvastatin Laboratory tests and self report Fenofibrate: 56 years; Height (cm): 171. Studies on harms Author, year Adverse events reported Comments Funding source Franceschini G, 2007 NR Fournier Pharma Spa Mallon P, et al 2006 There were no significant changes in Scr, Bili, ALT, AST in either treatment group. Partial funding provided Safety data were not shown in the publication. Studies on harms Author, year Setting Study design Duration Eligibility criteria Milazzol L, et al 2007 Outpatient setting Retrospective chart review Not reported Adults with HIV/HCV co-infection using statins (exploratory) at least 6 months after diagnosis of hepatitis C special group-co- and patients who were HIV-positive but infection group HCV/Hep B negative using statins Rahman A, 2008 Single-center, VA North Retrospective chart review Minimum 6 Adults with HIV infection who received Texas Health Care months efavirenz-based HAART and simvastatin 20 System mg/day. Patients had to be receiving stable HAART regimen (no changes to NRTI backbone or any other concurrent antiretroviral) for a minimum of 4 weeks before and after starting simvastatin. Lipid profiles w/in a 6 month period before simvastatin were required. Adults without HIV infection who received 20 mg/day were randomly selected as controls. These patients had to have been simvastatin naive for 6 months before starting treatment. Statins Page 352 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Milazzol L, et al 2007 Alcohol abuse; concomitant hepatotoxic Statins in HCV+ versus Statins in NR NA (exploratory) medications other than antiretrovirals and HCV/Hep B-negative patients NR NA special group-co- patients on anti-HCV treatment 80 80 infection group Most frequently prescribed statins: Atorvastatin 64% Pravastatin 29% Rosuvastatin 5% Simvastatin 2. NR NA agents while receiving simvastatin; had simvastatin 20 mg/day 32 32 significant changes in DM control; new diagnosis of thyroid disorder; uncontrolled thyroid disorder; had additions or dosage modifications of progestins, glucosteroids, isotretinoin, estrogens, azole antifungals, anabolic steroids, sevelamer, red yeast rice, and TZDs; any evidence of significant changes in dietary/exercise patterns. Statins Page 353 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Age Gender Other population characteristics Author, year Ethnicity (diagnosis, etc) How adverse events assessed Milazzol L, et al 2007 45. Studies on harms Author, year Adverse events reported Comments Funding source Milazzol L, et al 2007 There was no significant difference in the fold change of LFTs in both groups. There were statistically significant differences Not reported (exploratory) between treatment groups in baseline age, sex, special group-co- There was no significant difference in the percentage of patients with increased AST, and LFTs.

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