Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma

PURPOSE: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS: In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1, 100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10-6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial. RESULTS: Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%. CONCLUSION: The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM

Global Metabolomic Profiling of Acute Myocarditis Caused by Trypanosoma cruzi Infection

© 2014 Gironès et al. Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients.This work was supported by ‘‘Ministerio de Ciencia e Innovación’’ (SAF2010-17833); ‘‘Fondo de Investigaciones Sanitarias’’ (PS09/00538 and PI12/00289); ‘‘Red de Investigación de Centros de Enfermedades Tropicales’’ (RICET RD12/0018/0004); European Union (HEALTH-FE-2008-22303, ChagasEpiNet);‘‘Universidad Autónoma de Madrid’’ and ‘‘Comunidad de Madrid’’ (CC08-UAM/SAL-4440/08); AECID Cooperation with Argentine (A/025417/09 and A/031735/10), Comunidad de Madrid (S-2010/BMD-2332) and ‘‘Fundación Ramón Areces’Peer Reviewe

Atrio-Esophageal Fistula: A Rare Entity Complicating a Common Procedure

A 66-year-old female with a history of radiofrequency ablation for atrial fibrillation presented with hematemesis and fever. A CT chest revealed an atrio-esophageal fistula (AEF) and a CT head showed bilateral septic emboli. Blood cultures were positive for Streptococcus sanguinis. She underwent primary repair of the atrial defect on cardiopulmonary bypass where a large atrial vegetation was retrieved, followed by a right thoracotomy with the closure of the esophageal defect the next day. She was discharged to a rehabilitation facility after 18 days of hospital stay with a 6 weeks antibiotics plan. The incidence of AEF following ablation procedures has been estimated at 0.01 to 0.04%, and the pathogenesis is linked to direct tissue and vagus nerve injury. The most common clinical findings are fever and neurologic deficits. CT chest is the best diagnostic modality. CT head might demonstrate embolic phenomena and TTE can show vegetation. Early surgical intervention, even in an unstable patient, is paramount for survival

Reference values to assess hemodilution and warn of potential false-negative minimal residual disease results in myeloma

Although the majority of patients with myeloma who achieve undetectable minimal residual disease show prolonged survival, some of them relapse shortly afterwards. False-negative results due to hemodiluted bone marrow samples could explain this inconsistency, but there is no guidance on how to evaluate them. We analyzed three cell populations normally absent in peripheral blood in 1404 aspirates obtained in numerous disease settings and in 85 healthy adults. Pairwise comparisons according to age and treatment showed significant variability, thus suggesting that hemodilution should be preferably evaluated with references obtained after receiving identical regimens. Leveraging the minimal residual disease results from 118 patients, we showed that a comparison with age-matched healthy adults could also inform on potential hemodilution. Our study supports the routine assessment of bone marrow cellularity to evaluate hemodilution, using as reference values either treatment-specific or from healthy adults if the former are unavailable