Summary Background The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in ...patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial. Methods We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1–21, plus dexamethasone 20 mg per day on days–1–4 and days 12–15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1–21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00480363. Findings Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67–85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached 95% CI 47 months–not reached vs 23 months 16–31; hazard ratio HR 0·24 95% CI 0·14–0·41; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months–not reached vs 53 months–not reached; HR 0·43 95% CI 0·21–0·92, p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 95% CI 0·54–3·30; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four 6%), asthenia (four 6%), neutropenia (three 5%), and skin rash (two 3%); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six 10% of 62 patients vs one 2% of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070). Interpretation This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. Funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).
Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene ( LPA ) on vascular diseases with different atherosclerotic and thrombotic components. ...Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST Trial of Org 10172 in Acute Stroke Treatment subtypes) (effective sample size ne = 9,396); peripheral arterial disease ( ne = 5,215); abdominal aortic aneurysm ( ne = 4,572); venous thromboembolism ( ne = 4,607); intracranial aneurysm ( ne = 1,328); CAD ( ne = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio OR: 1.27; p = 6.7 × 10–4 ), peripheral artery disease (OR: 1.47; p = 2.9 × 10–14 ), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10–5 ), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10–12 ). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (–1.58 years/allele; p = 8.2 × 10–8 ) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.
Background Obesity hypoventilation syndrome (OHS) is associated with a high burden of cardiovascular morbidity (CVM) and mortality. The majority of patients with OHS have concomitant OSA, but there ...is a paucity of data on the association between CVM and OSA severity in patients with OHS. The objective of our study was to assess the association between CVM and OSA severity in a large cohort of patients with OHS. Methods In a cross-sectional analysis, we examined the association between OSA severity based on tertiles of oxygen desaturation index (ODI) and CVM in 302 patients with OHS. Logistic regression models were constructed to quantify the independent association between OSA severity and prevalent CVM after adjusting for various important confounders. Results The prevalence of CVM decreased significantly with increasing severity of OSA based on ODI as a continuous variable or ODI tertiles. This inverse relationship between OSA severity and prevalence of CVM was seen in the highest ODI tertile and it persisted despite adjustment for multiple confounders. Chronic heart failure had the strongest negative association with the highest ODI tertile. No significant CVM risk change was observed between the first and second ODI tertiles. Patients in the highest ODI tertile were younger, predominantly male, more obese, more hypersomnolent, had worse nocturnal and daytime gas exchange, lower prevalence of hypertension, better exercise tolerance, and fewer days hospitalized than patients in the lowest ODI tertile. Conclusions In patients with OHS, the highest OSA severity phenotype was associated with reduced risk of CVM. This finding should guide the design of future clinical trials assessing the impact of interventions aimed at decreasing cardiovascular morbidity and mortality in patients with OHS. Trial Registry Clinicaltrial.gov; No.: NCT01405976 ; URL: www.clinicaltrials.gov
Vaginoplasty aims to create a functional feminine vagina, sensate clitoris, and labia minora and majora with acceptable cosmesis. The upward trend in the number of transfemale vaginoplasties has ...impacted the number of published articles on this topic. Herein, we conducted an updated systematic review on complications and patient-reported outcomes.
A update on our previous systematic review was conducted. Several databases including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were assessed. Random effects meta-analysis and subgroup analyses were performed.
After compiling the results of the update with the previous systematic review, a total of 57 studies pooling 4680 cases were included in the systematic review, and 52 studies were used in the meta-analysis. Overall pooled data including any surgical technique showed rates of 1% 95% confidence interval (CI) <0.1%-2% of fistula, 11% (95% CI 8%-14%) of stenosis and/or strictures, 4% (95% CI 1%-9%) of tissue necrosis, and 3% (95% CI 1%-4%) of prolapse. Overall satisfaction was 91% (81%-98%). Regret rate was 2% (95% CI <1%-3%). Average neovaginal depth was 9.4 cm (7.9-10.9 cm) for the penile skin inversion and 15.3 cm (13.8-16.7 cm) for the intestinal vaginoplasty.
Transfemale vaginoplasty is a key component of the comprehensive surgical treatment of transfemale patients with gender dysphoria. Over time, we will see an increased demand for these procedures, so adequate surgical training, clinical/surgical experience, and research outcomes are required, as we continue to strive to provide the best care possible for a population in need.
Study objective We seek to examine the efficacy and safety of prereperfusion emergency medical services (EMS)–administered intravenous metoprolol in anterior ST-segment elevation myocardial ...infarction patients undergoing eventual primary angioplasty. Methods This is a prespecified subgroup analysis of the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction trial population, who all eventually received oral metoprolol within 12 to 24 hours. We studied patients receiving intravenous metoprolol by EMS and compared them with others treated by EMS but not receiving intravenous metoprolol. Outcomes included infarct size and left ventricular ejection fraction on cardiac magnetic resonance imaging at 1 week, and safety by measuring the incidence of the predefined combined endpoint (composite of death, malignant ventricular arrhythmias, advanced atrioventricular block, cardiogenic shock, or reinfarction) within the first 24 hours. Results From the total population of the trial (N=270), 147 patients (54%) were recruited during out-of-hospital assistance and transferred to the primary angioplasty center (74 intravenous metoprolol and 73 controls). Infarct size was smaller in patients receiving intravenous metoprolol compared with controls (23.4 SD 15.0 versus 34.0 SD 23.7 g; adjusted difference –11.4; 95% confidence interval CI –18.6 to –4.3). Left ventricular ejection fraction was higher in the intravenous metoprolol group (48.1% SD 8.4% versus 43.1% SD 10.2%; adjusted difference 5.0; 95% CI 1.6 to 8.4). Metoprolol administration did not increase the incidence of the prespecified safety combined endpoint: 6.8% versus 17.8% in controls (risk difference –11.1; 95% CI –21.5 to –0.6). Conclusion Out-of-hospital administration of intravenous metoprolol by EMS within 4.5 hours of symptom onset in our subjects reduced infarct size and improved left ventricular ejection fraction with no excess of adverse events during the first 24 hours.
Background Infarct size predicts post-infarction mortality. Oral β-blockade within 24 hours of a ST-segment elevation acute myocardial infarction (STEMI) is a class-IA indication, however early ...intravenous (IV) β-blockers initiation is not encouraged. In recent magnetic resonance imaging (MRI)–based experimental studies, the β1 -blocker metoprolol has been shown to reduce infarct size only when administered before coronary reperfusion. To date, there is not a single trial comparing the pre- vs. post-reperfusion β-blocker initiation in STEMI. Objective The METOCARD-CNIC trial is testing whether the early initiation of IV metoprolol before primary percutaneous coronary intervention (pPCI) could reduce infarct size and improve outcomes when compared to oral post-pPCI metoprolol initiation. Design The METOCARD-CNIC trial is a randomized parallel-group single-blind (to outcome evaluators) clinical effectiveness trial conducted in 5 Counties across Spain that will enroll 220 participants. Eligible are 18- to 80-year-old patients with anterior STEMI revascularized by pPCI ≤6 hours from symptom onset. Exclusion criteria are Killip-class ≥III, atrioventricular block or active treatment with β-blockers/bronchodilators. Primary end point is infarct size evaluated by MRI 5 to 7 days post-STEMI. Prespecified major secondary end points are salvage-index, left ventricular ejection fraction recovery (day 5-7 to 6 months), the composite of (death/malignant ventricular arrhythmias/reinfarction/admission due to heart failure), and myocardial perfusion. Conclusions The METOCARD-CNIC trial is testing the hypothesis that the early initiation of IV metoprolol pre-reperfusion reduces infarct size in comparison to initiation of oral metoprolol post-reperfusion. Given the implications of infarct size reduction in STEMI, if positive, this trial might evidence that a refined use of an approved inexpensive drug can improve outcomes of patients with STEMI.
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