Objectives This study sought to evaluate the efficacy of enalapril and carvedilol to prevent chemotherapy-induced left ventricular systolic dysfunction (LVSD) in patients with hematological ...malignancies. Background Current chemotherapy may induce LVSD. Angiotensin-converting enzyme inhibitors and beta-blockers prevent LVSD in animal models of anthracycline-induced cardiomyopathy. Methods In this randomized, controlled study, 90 patients with recently diagnosed acute leukemia (n = 36) or patients with malignant hemopathies undergoing autologous hematopoietic stem cell transplantation (HSCT) (n = 54) and without LVSD were randomly assigned to a group receiving enalapril and carvedilol (n = 45) or to a control group (n = 45). Echocardiographic and cardiac magnetic resonance (CMR) imaging studies were performed before and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in LV ejection fraction (LVEF). Results The mean age of patients was 50 ± 13 years old, and 43% were women. At 6 months, LVEF did not change in the intervention group but significantly decreased in controls, resulting in a −3.1% absolute difference by echocardiography (p = 0.035) and −3.4% (p = 0.09) in the 59 patients who underwent CMR. The corresponding absolute difference (95% confidence interval CI) in LVEF was −6.38% (95% CI: −11.9 to −0.9) in patients with acute leukemia and −1.0% (95% CI: −4.5 to 2.5) in patients undergoing autologous HSCT (p = 0.08 for interaction between treatment effect and disease category). Compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02). Conclusions Combined treatment with enalapril and carvedilol may prevent LVSD in patients with malignant hemopathies treated with intensive chemotherapy. The clinical relevance of this strategy should be confirmed in larger studies. (Prevention of Left Ventricular Dysfunction During Chemotherapy OVERCOME; NCT01110824 )
The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel ...disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls. Variant- and gene-level computational methods, as well as immunologic hypotheses, can help narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on 3 key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and selection criteria for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing–based approaches in order not to assign a condition to an irrelevant variant. Finding the needle in the haystack takes patience, prudence, and discernment.
Predicting sudden cardiac death risk in the first months after ST-segment elevation myocardial infarction (STEMI) remains challenging.
The purpose of this study was to investigate the ability of late ...gadolinium enhancement cardiac magnetic resonance (LGE-CMR) to identify the potentially arrhythmogenic substrate and its temporal evolution after STEMI.
One hundred consecutive patients with a first STEMI were included. Three-dimensional high-resolution LGE-CMR was obtained at 3 T on days 7 and 180. Left ventricular wall was segmented and characterized by pixel signal intensity algorithm in 5 layers from endocardium to epicardium. A 3-dimensional color-coded shell map was obtained for each layer, depicting scar core and border zone (BZ) distribution. Presence and characteristics of BZ channels were registered for each layer.
At 180 days, left ventricular ejection fraction had improved significantly (from 46.7% ± 10% to 51.5% ± 10%; P <.001) and scar mass was reduced (from 22.6 ± 20 g to 13.8 ± 12 g; P <.001). Most BZ channels (89%) were identified in the same myocardial layer and American Heart Association (AHA) segment, with the same orientation and morphology in both studies. Early LGE-CMR had 96% sensitivity and 90% specificity for predicting presence of BZ channels at 180 days. Greater presence was observed in patients with no-reflow phenomenon at baseline (P = .01).
Most BZ channels can be identified by LGE-CMR at day 7 post-STEMI and, despite scar mass reduction, remain unaltered at 6 months, suggesting that the potentially arrhythmogenic substrate is established within the first week post-STEMI.
Abstract Introduction Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) are characterized by a wide range of etiologies, symptoms, and outcomes, but have a common etiopathogenic ...pathway leading to organ damage: an excessive inflammatory response. Biological therapies have been proposed as a therapeutic option for refractory HLH, but have also been related to the development of HLH in severe immunosuppressed patients. Objectives and methods The purpose of this study was to analyze the clinical characteristics and outcomes of adult patients who developed HLH after receiving biological therapies. Results We identified 30 patients (29 from the PubMed search and one unpublished case), including 19 women and 11 men, with a mean age of 46.5 years. Underlying diseases consisted of rheumatologic/autoimmune diseases in 24 patients and hematological neoplasia in the remaining 6. Biological agents received before the development of HLH were mainly anti-TNF agents ( n = 19). Search for microorganisms confirmed systemic infection in 20 (67%) patients, including Mycobacterium tuberculosis ( n = 5), cytomegalovirus (CMV) ( n = 4), Epstein–Barr virus (EBV) ( n = 3), Histoplasma capsulatum ( n = 3), Escherichia coli ( n = 2), Staphylococcus aureus , Leishmania amastigotes and Brucella melitensis ( n = 1, respectively); viral infections were mainly reported in inflammatory bowel disease (IBD) patients. Patients with infections had more frequently received previous immunosuppressive therapies ( p = 0.036) and had lower leukocyte counts ( p = 0.020) in comparison with patients without associated infections. The outcome was described in 29 patients. After a mean follow-up of 6.3 months, 8 patients died (28%) and 6 had received anti-TNF agents. There was a high mortality rate in patients aged >65 years and those with tuberculosis (62% and 60%, respectively). Conclusions In patients receiving biological therapies who develop HLH, searching for a concomitant infectious process is mandatory, and specific surveillance for EBV/CMV infections (in patients with IBD) and for bacteria, including mycobacteria (in elderly patients receiving anti-TNF therapy), is recommended.
The patient did not carry the JAK2 V617F mutation typical of primary myelofibrosis and karyotype was normal. Because of refractory pancytopenia with transfusion dependence and due to the patient's ...wish for definitive cure, HSCT with peripheral blood stem cells from a 10/10 matched unrelated donor (MUD) was performed following conditioning with ATG 10 mg/kg, treosulfan 14 g/m2, and Fludarabine 150 mg/m2. ...the long-term risks and benefits of plerixafor treatment in WHIM syndrome are unknown, especially in the context of myelofibrosis. ...WHIM syndrome carries a substantial risk of potentially fatal infection and of development of lymphoma and cancerous skin/genital lesions.
Abstract Background Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 ...years in high-risk individuals. However, there are limited data in lower-risk populations. The H eart O utcomes P revention E valuation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels. Methods A total of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/d or placebo and to candesartan/hydrochlorothiazide 16/12.5 mg/d or placebo (2 × 2 factorial design) and will be followed for a mean of 5.8 years. The coprimary study outcomes are the composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke and the composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and arterial revascularization. Results Participants were recruited from 21 countries in North America, South America, Europe, Asia, and Australia. Mean age at randomization was 66 years and 46% were women. Conclusions The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate-risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.gov NCT00468923 ).
IgG4-related disease (IgG4-RD) is a systemic disease characterized by the infiltration of IgG4-bearing plasma cells and, more importantly, distinctive histopathological features: storiform fibrosis, ...obliterative phlebitis, a lymphoplasmacytic infiltrate, and mild-to-moderate tissue eosinophilia. The diagnostic approach is complex and relies on the coexistence of various clinical, laboratory, and histopathological findings, none of which is pathognomonic in and of itself. IgG4-related disease should be suspected in patients presenting with unexplained enlargement or swelling of 1 or more organs or tissue organs. Four laboratory abnormalities often provide initial clues to the diagnosis of IgG4-RD: peripheral eosinophilia, hypergammaglobulinemia, elevated serum IgE levels, and hypocomplementemia. Elevated serum IgG4 levels provided critical information in identifying the first cases of IgG4-RD, but recent studies have reported substantial limitations to the measurement of serum IgG4 concentrations, precluding reliance on serum IgG4 concentrations for diagnostic purposes. In contrast, new studies have suggested a promising role of flow cytometry studies in the diagnosis and longitudinal management of IgG4-RD. Demonstration of the classic histopathological features of IgG4-RD remains crucial to diagnosis in most cases, and biopsy proof is preferred strongly by most disease experts before the initiation of treatment. Of note, the multiorgan nature of IgG4-RD was first established in 2003. This review intends to provide most recent knowledge about the clinical, laboratory, radiological, and pathological characteristics of IgG4-RD that may guide the physician to establish an early diagnosis. We searched PubMed and MEDLINE for relevant articles published between January 1, 2000, and November 1, 2014, using the search terms IgG4 and IgG4-related.
Abstract Aims ST-segment elevation myocardial infarction (STEMI) triggers remote extracellular matrix expansion. Myocardial extracellular volume fraction (ECV), determined by cardiovascular magnetic ...resonance, permits quantification of interstitial space expansion. Our aim was to determine the relationship between early serum fibrosis biomarkers and 180-day post-infarct remote myocardium remodeling using ECV. Methods and results In 26 patients with STEMI, functional imaging, T1-mapping, and late-gadolinium-enhancement were performed on a 3-T CMR scanner at baseline (days 3 to 5) and 180 days. Biomarkers were measured at days 1, 3, and 7 after STEMI. The mean initial and follow-up left ventricular ejection fraction (LVEF) were 48.3 ± 18.1% and 52.6 ± 12.3%, respectively. Initial infarct size was 11.6 ± 16.8% of LV mass. ECV in the remote myocardium at 180 days correlated with indexed end-systolic volume (r = 0.4, p = 0.045). A significant correlation was observed between galectin-3 at day 7 and ECV at 6 months (r = 0.428, p = 0.037). A trend towards a direct correlation was found for BNP (r = 0.380, p = 0.059). Multivariate analysis revealed that BNP and galectin-3 were independent predictors of long-term changes in ECV and explained nearly 30% of the variance in this parameter (r2 = 0.34; p = 0.01). A galectin-3 cutoff value of 10.15 ng/mL was the most powerful predictor of high ECV values (≥ 28.5%) at follow-up. Galectin-3 at day 7 was an independent predictor of high ECV values at follow-up (OR = 22.51; CI
95%: 2.1–240.72; p = 0.01) with 0.76 AUC (CI: 0.574–0.964; p = 0.03). Conclusions Galectin-3 measured acutely after STEMI is an independent predictor of increased ECV at 6-month follow-up that might be useful for long-term risk stratification.
Low IL-6 production upon stimulation by TLR/IL-1R ligands is associated with increased susceptibility to bacterial skin infections and to invasive infections with P. aeruginosa and/or with a ...IRAK-4/MyD88/NEMO defect.
Abstract Monoclonal antibodies have emerged as a new class of agents causing drug-related pulmonary involvement in patients with systemic rheumatologic autoimmune diseases. The most frequently ...associated noninfectious pulmonary diseases are interstitial pneumonia (118 cases reported by August 2010), sarcoid-like disease and vasculitis (40 cases), and 97% of cases are associated with agents blocking tumor necrosis factor (TNF), a cytokine implicated in pulmonary fibrosis, granuloma formation, and maintenance. Drug-induced interstitial pneumonia has a poor prognosis, with an overall mortality rate of around one-third, rising to two-thirds in patients with pre-existing interstitial disease. Sarcoid-like disease has a better prognosis, with resolution or improvement in 90% of cases. Although the evidence comes overwhelmingly from case reports and case series, suggested recommendations for patient management include a detailed pre-therapeutic evaluation, early identification of symptoms suggestive of pulmonary disease, and tailored therapy. Mycobacterial infection should be exhaustively investigated, especially after anti-TNF administration. Large, prospective, postmarketing studies including nonbiological agents as controls may help elucidate the real risk of pulmonary disease in patients with rheumatologic autoimmune diseases receiving monoclonal antibodies.
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