Summary Melphalan–prednisone (MP) has been the gold standard treatment for more than 30 years in elderly multiple myeloma (MM) patients. In order to assess whether the combination of dexamethasone with melphalan (MD) could improve on the efficacy of MP, we have carried out a randomized trial comparing both treatment approaches. A total of 201 patients ≥70 years old were included in the study. The overall response rate was similar after six cycles (MP: 67·9%versus MD: 64·5%) and after 12 cycles (MP: 49·4%versus MD: 46·1%). However, the proportion of complete responses (CR) was higher in the MD arm, particularly after 12 cycles (MD: 22·4%versus MP: 9·1%; P < 0·05). There was no significant difference in event‐free survival (MP: 15·9 months versus MD: 23·3 months). The median overall survival in both arms was almost identical (MP: 29·4 months versus MD: 27·2 months; P = 0·63). No significant differences in haematological toxicity were observed, but non‐haematological toxicity was significantly higher in the MD arm. According to these results MP remains as the gold standard for treatment of MM and should be the reference for comparison of new therapeutic approaches involving novel agents.
IMPORTANCETruncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.OBJECTIVE To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTSThis cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURESThe primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTSIn total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (Ն500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF Յ35%) LVSD (HR, 1.29 [95% CI,]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI,]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). CONCLUSIONS AND RELEVANCEThe high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.
Splenic marginal zone lymphoma (SMZL), characterized in the WHO classification of lymphoid tumors, is a rare disorder comprising less than 1% of lymphoid neoplasms; only a few series concerning this entity have been published. Although this type of lymphoma is well defined histologically, its histogenesis remains obscure. Moreover, specific biological markers are still lacking and immunophenotype profile is not specific. These and other reasons, such as the existence of cytogenetic subtypes, have led to some authors to suspect that SMZL constitutes a heterogeneous entity. We have analyzed a series of sixteen SMZL cases from four hospitals in our community, from a clinical, biological and pathological point of view. When compared with those reported in the literature, our findings show three main differences: our patients less frequently showed an intrasinusoidal bone marrow infiltration pattern; the presence of a serum monoclonal component was rarely seen; and CD5-positive SMZL cases appear to be more common than previously thought.
Background Truncating variants in Filamin C (FLNCtv) are associated with arrhythmogenic (AC) and dilated cardiomyopathies (DCM). Affected patients are reported to demonstrate a high incidence of arrhythmic and heart-failure related cardiovascular events. The aim of this study was to determine factors that predict adverse events in mutation carriers. Methods The study cohort comprised 168 FLNCtv carriers followed at 19 European centres. Baseline and longitudinal follow-up clinical data were collected. The primary endpoint was a composite of sudden cardiac death (SCD), aborted SCD, appropriate implantable cardioverter-defibrillator (ICD) shock, cardiac transplantation (HTx) and mortality from end-stage heart failure (ESHF). Results 47 different pathogenic or likely-pathogenic FLNCtv were identified in 60 unrelated probands. In those with baseline and longitudinal data (160 patients; 57 probands), 114 (71.3%) patients exhibited evidence of cardiac disease at initial evaluation. Gene penetrance was 85% by the age of 40 years. During a median follow-up of 1.5 years (IQR 4.1), 24 individuals (15%) reached the primary endpoint – 16 arrhythmic (SCD/aborted SCD/ICD shock) and 8 heart failure (ESHF/HTx) related-events. Univariable predictors at baseline evaluation of the composite primary endpoint included proband status (HR 4.0, 95% CI: 1.5–10.9, p=0.01), symptoms of dyspnoea (HR 2.8, 95% CI: 1.2–6.4, p=0.02), LV systolic dysfunction (LVSD) (HR 12.4, 95% CI: 2.9–53.2, p=0.001), frequent ventricular ectopy (VE>500) on 24-hour Holter (HR 9.3, 95% CI: 1.2–74.7, p=0.04) and the presence of late gadolinium enhancement on CMR (HR 8.9, 95% CI: 1.2–68.5, p=0.04). Multivariable analysis identified LVSD (LVEF <50%) at baseline as an independent predictor of the primary endpoint with a hazard ratio of 8.6 (95% CI: 1.8–41.5, p=0.007). ROC analysis using LV systolic dysfunction to predict the primary endpoint demonstrated an area under the curve of 0.84 (95% CI: 0.76–0.91, p<0.001) and identified an optimal LVEF “cut-off” of 47% for predicting adverse events with a Youden's index of 0.61 (sensitivity 0.91; specificity 0.70). Kaplan-Meier plot to demonstrate freedom Conclusions LVSD is associated with an over 8-fold increase in the hazard of a primary endpoint event in FLNCtv gene carriers indicating that these patients should be considered for implantable cardioverter-defibrillator (ICD) implantation, optimal heart failure medical therapy and close clinical follow-up. Acknowledgement/Funding NIHR Biomedical Research Centre; Instituto de Salud Carlos III; DETECTIN-HF project; Wellcome Trust;CIBERCV; EU Regional Development Fund; FEDER.
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