Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials

This is an open-access paper.-- et al.Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatmentrelated side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12- 2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomibthalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.Peer Reviewe

Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach

Under a Creative Commons license.-- et al.Melphalan 200 mg/m2 (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m2 (MEL140) versus MEL200 mg/m2 as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m2 in a 1:2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCT conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT. (Clinicaltrials.gov identifier: NCT00560053 and NCT00804947.).This study was supported in part by research funding from grants “Red Temática de Investigación Cooperativa en Cancer”RD06/0020/0031 and RD06/0020/0005 and “Red de Biobancos Hospitalarios”RD09/0076/00021, research project PS09/01882 from the “Instituto de Salud Carlos III”, research grant CA08/00141, CM10/00321 and CM09/00038 from the “Instituto de Salud Carlos III”, and “Ministerio de Ciencia e Innovación” grant BES2008-008053.Peer Reviewe

Conditioning of hiPSC-derived cardiomyocytes using surface topography obtained with high throughput technology

Surface functionalization of polymers aims to introduce novel properties that favor bioactive responses. We have investigated the possibility of surface functionalization of polyethylene terephthalate (PET) sheets by the combination of laser ablation with hot embossing and the application of such techniques in the field of stem cell research. We investigated the response of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to topography in the low micrometer range. HiPSC-CMs are expected to offer new therapeutic tools for myocardial replacement or regeneration after an infarct or other causes of cardiac tissue loss. However, hiPSC-CMs are phenotypically immature compared to myocytes in the adult myocardium, hampering their clinical application. We aimed to develop and test a high-throughput technique for surface structuring that would improve hiPSC-CMs structural maturation. We used laser ablation with a ps-laser source in combination with nanoimprint lithography to fabricate large areas of homogeneous micron- to submicron line-like pattern with a spatial period of 3 µm on the PET surface. We evaluated cell morphology, alignment, sarcomeric myofibrils assembly, and calcium transients to evaluate phenotypic changes associated with culturing hiPSC-CMs on functionalized PET. Surface functionalization through hot embossing was able to generate, at low cost, low micrometer features on the PET surface that influenced the hiPSC-CMs phenotype, suggesting improved structural and functional maturation. This technique may be relevant for high-throughput technologies that require conditioning of hiPSC-CMs and may be useful for the production of these cells for drug screening and disease modeling applications with lower costs.Fil: Cortella, Lucas R. X.. Universidade de Sao Paulo; BrasilFil: Cestari, Idágene A.. Universidade de Sao Paulo; BrasilFil: Lahuerta, Ricardo D.. Universidade de Sao Paulo; BrasilFil: Arana, Matheus C.. Universidade de Sao Paulo; BrasilFil: Soldera, Marcos Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. Universidad Nacional del Comahue. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; ArgentinaFil: Rank, Andreas. Technische Universität Dresden; AlemaniaFil: Lasagni, Andrés F.. Technische Universität Dresden; AlemaniaFil: Cestari, Ismar N.. Universidade de Sao Paulo; Brasi

Trailing edge subcomponent testing for wind turbine blades–Part A: Comparison of concepts

As a complement to the mandatory structural full‐scale test for wind turbine blades, the method of subcomponent testing has recently been proposed by international standards and guidelines for the experimental investigation of design‐critical full‐scale parts. This work investigated different subcomponent test (SCT) concepts for a trailing edge of an outboard segment from a 34‐m blade. Detailed analytical models to design the SCT concepts with regard to the boundary conditions were derived. Finite element analyses of the SCT's linear response were benchmarked against each other and against the full blade model in terms of displacements, rotations, in‐plane strains, and energy consumption. All SCT concepts were in good agreement with the full‐scale test with respect to the longitudinal strain response but showed deviations in the transverse and shear strain, as well as in the rotational and displacement response

Muscle thickness and echogenicity measured by ultrasound could detect local sarcopenia and malnutrition in older patients hospitalized for hip fracture

Background: The aim of this work was to assess whether the muscle thickness and echogenicity were associated with dysphagia, malnutrition, sarcopenia, and functional capacity in acute hospital admission for a hip fracture. Methods: Observational study that assessed nutritional status by Global Leadership Initiative on Malnutrition, risk of dysphagia and sarcopenia by European Working Group on Sarcopenia in Older People and Barthel functional index. We measured muscle thickness and echogenicity of masseter, bicipital, and quadriceps rectus femoris (RF) and vastus intermedius (VI) by ultrasound. Results: One hundred and one patients were included in the study (29.7% sarcopenia and 43.8% malnutrition). Logistic regression models adjusted for age, sex, and body mass index showed an inverse association of the masseter thickness with both sarcopenia (OR: 0.56) and malnutrition (OR: 0.38) and quadriceps with sarcopenia (OR: 0.74). In addition, patients at high risk of dysphagia had lower masseter thickness (p: 0.0001) while patients able to self-feeding had thicker biceps (p: 0.002) and individuals with mobility on level surfaces higher thickness of biceps (p: 0.008) and quadriceps (p: 0.04). Conclusion: Thickness of the masseter was associated with risk of dysphagia, biceps with the ability to self-feed, and that of the quadriceps RF-VI with mobility

Intravenous Busulfan and Melphalan as a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Matched Comparison to a Melphalan-Only Approach

AbstractMelphalan 200 mg/m2 (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m2 (MEL140) versus MEL200 mg/m2 as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m2 in a 1:2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCT conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT. (Clinicaltrials.gov identifier: NCT00560053 and NCT00804947.

A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control

GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group: et al.Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ∼60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.Peer Reviewe

Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

This is an open-access paper.-- et al.A multistep model has been proposed of disease progression starting in monoclonal gammopathy of undetermined significance continuing through multiple myeloma, sometimes with an intermediate entity called smoldering myeloma, and ending in extramedullary disease. To gain further insights into the role of the transcriptome deregulation in the transition from a normal plasma cell to a clonal plasma cell, and from an indolent clonal plasma cell to a malignant plasma cell, we performed gene expression profiling in 20 patients with monoclonal gammopathy of undetermined significance, 33 with high-risk smoldering myeloma and 41 with multiple myeloma. The analysis showed that 126 genes were differentially expressed in monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma as compared to normal plasma cell. Interestingly, 17 and 9 out of the 126 significant differentially expressed genes were small nucleolar RNA molecules and zinc finger proteins. Several proapoptotic genes (AKT1 and AKT2) were down-regulated and antiapoptotic genes (APAF1 and BCL2L1) were up-regulated in multiple myeloma, both symptomatic and asymptomatic, compared to monoclonal gammopathy of undetermined significance. When we looked for those genes progressively modulated through the evolving stages of monoclonal gammopathies, eight snoRNA showed a progressive increase while APAF1, VCAN and MEGF9 exhibited a progressive downregulation. In conclusion, our data show that although monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma are not clearly distinguishable groups according to their gene expression profiling, several signaling pathways and genes were significantly deregulated at different steps of the transformation process.This study was partially supported by Spanish FIS (PI080568, PS09/01450 and PS0901897), “Gerencia Regional de Salud, Junta de Castilla y León” (GRS 702/A/11) grant, and the Spanish Myeloma Network Program (RD06/0020/0006, RD12/0036/0058 and RD12/0036/0046).Peer Reviewe

The prognostic value of multiparameter flow cytometry minimal residual disease assessment in relapsed multiple myeloma

Letter to the editor.-- et al.This study was supported by the Cooperative Research Thematic Network grants RD12/0036/0058 of the Red de Cancer (Cancer Network of Excellence); Instituto de Salud Carlos III, Spain, Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01897/01370; G03/136; Sara Borrell: CD13/00340); and Asociación Española Contra el Cáncer (GCB120981SAN), Spain. The study was also supported internationally by the International Myeloma Foundation Junior Grant Proposal and the Multiple Myeloma Research Foundation research fellow award.Peer Reviewe