INTRODUCTIONAlthough mean physical activity in COPD patients declines by 400-500steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to identify ...distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants. METHODSWe pooled data from two cohorts (usual care arm of Urban Training NCT01897298 and PROactive initial validation NCT01388218 studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns. RESULTSIn 291 COPD patients (mean±SD 68±8 years, 81% male, FEV1 59±19%pred) we identified three distinct physical activity progression patterns: Inactive (n=173 59%, baseline: 4621±1757 steps/day, 12-month change (Δ): -487±1201 steps/day), ActiveImprovers (n=49 17%, baseline: 7727±3275 steps/day, Δ:+3378±2203 steps/day) and ActiveDecliners (n=69 24%, baseline: 11 267±3009 steps/day, Δ: -2217±2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR 95% CI 0.94 0.90-0.98 per 10m, P=.001) and a higher mMRC dyspnea score (1.71 1.12-2.60 per 1 point, P=.012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver. CONCLUSIONSThe natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline.
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Introduction
MRI is the imaging gold standard method for the detection of bone marrow involvement in multiple myeloma (MM) (Dimopoulos. J Clin Oncol.2015). MRI of the spine and pelvis can detect ...approximately 90% of focal lesions in MM and is the procedure of choice to evaluate a painful lesion in myeloma patients, mainly in the axial skeleton. It has also been reported that in patients treated with frontline autologous stem cell transplantation (ASCT) the number of MRI focal lesions and the presence of diffuse pattern correlate with inferior survival (Walker et al. J Clin Oncol.2007). MRI might also help in the better definition of complete response (CR). However, the high number of false positive results suggests that another imaging method, such as Positron Emission Tomography combined with computed tomography using fluoro-deoxy-glucose (PET-CT), might be of more value in this setting (Zamagni. Clin Cancer Res.2015). The goal of our study was to compare prospectively MRI and PET-CT at 3 different time-points, at diagnosis, after 3 cycles of triplet induction therapy and prior to maintenance therapy in a group of patients enrolled into IFM-DFCI 2009 trial comparing frontline or delayed ASCT.
Patients and methods
700 patients with de novo symptomatic MM eligible for high-dose therapy (HDT) have been prospectively randomized in France and Belgium to receive either 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by 1-year maintenance with lenalidomide, or 3 cycles of VRD followed by HDT and ASCT plus 2 cycles of VRD consolidation and 1-year lenalidomide maintenance. 134/700 patients were also included in the IMAJEM trial (NCT01309334) aimed at comparing in both arms of the IFM-DFCI 2009 study spine and pelvis MRI and whole-body PET-CT at diagnosis (number of lesions, primary end-point), after 3 cycles of VRD, and prior to maintenance (prognosis impact of imaging normalization, secondary end-point). MRI and PET-CT data were analyzed locally in each of the 15 participating centers, and systematically reviewed blindly by an independent committee consisting of 2 radiologists and 2 nuclear medicine physicians with extensive experience in MM field.
Results
At diagnosis, MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, respectively (McNemar test = 0.94, p = 0.33).
Following 3 cycles of VRD, MRI remained positive in 93%, and PET-CT in 55% of the patients, respectively. Normalization of MRI after 3 months of induction therapy was not predictive neither for progression-free survival (PFS) (p = 0.99) nor for overall survival (OS) (p = 0.99). Normalization of PET-CT after 3 months of induction therapy was associated with a significant improvement in PFS (30-month PFS rate: 60% in patients PET-CT positive vs 79% in patients PET-CT negative, p = 0.04), but not OS (30-month OS rate: 82 % in patients PET-CT positive vs 93 % in patients PET-CT negative, p = 0.15).
Prior to maintenance therapy, MRI remained positive in 83%, and PET-CT in 21% of the patients, respectively. Normalization of MRI before maintenance was not predictive neither for PFS (p = 0.31) not for OS (p = 0.98). Normalization of PET-CT before maintenance was associated with a significant improvement in both PFS (30-month PFS rate: 54.4% in patients PET-CT positive vs 75.9% in patients PET-CT negative, p = 0.0004, figure 1) and OS (30-month OS rate: 69.9% in patients PET-CT positive vs 94.6% in patients PET-CT negative, p = 0.01, figure 2).
Conclusion
MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement at diagnosis. Few patients achieved normal MRI after 3 cycles of VRD and before maintenance. Normalization of MRI following 3 cycles of VRD and before maintenance has no prognostic value for both PFS and OS. 45% of the patients achieved normal PET-CT following 3 cycles of VRD and 79% of the patients achieved normal PET-CT before maintenance. Normalization of PET-CT following 3 cycles of VRD and before maintenance was associated with a significant improvement for PFS. Normalization of PET-CT before maintenance was a predictor for an improved OS. PET-CT should be incorporated in the follow-up of young patients receiving novel-agent based therapy to predict outcome.
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Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Honoraria. Karlin:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Stoppa:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Laribi:Hospira SAS: Research Funding. Hulin:Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene Corporation: Honoraria. Richardson:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Celgene: Consultancy; Gilead: Consultancy; BMS: Consultancy; Millennium: Consultancy; Acetylon: Equity Ownership; Oncopep: Equity Ownership.
Introduction
Magnetic resonance imaging (MRI) of the spine and the pelvis is an important tool to evaluate bone disease in patients with symptomatic multiple myeloma (MM) at the time of diagnosis. In ...the context of high-dose therapy and autologous stem cell transplantation (ASCT), it has also been reported that the number of MRI focal lesions (> 7) and the presence of diffuse pattern correlate with inferior survival (Walker et al. J Clin Oncol; 25:1121-1128 2007). MRI might help in the better definition of complete response (CR). However, the high number of false positive results suggests that another imaging method, such as Positron emission tomography combined with computed tomography using fluoro-deoxy-glucose (PET-CT), might be of more value in this setting. Moreover, imaging techniques have rarely been compared to minimal residual disease (MRD) evaluated by flow cytometry from bone marrow aspiration in the context of frontline therapy including novel agents and ASCT. The goal of our study was to compare prospectively MRI and PET-CT at 3 different time-points, at diagnosis, after 3 cycles of triplet induction therapy and prior to maintenance therapy in a group of patients enrolled into IFM-DFCI 2009 trial comparing frontline or delayed ASCT.
Patients and methods
In the prospective IFM-DFCI 2009 trial, 700 patients with de novo symptomatic MM eligible for high-dose therapy have been randomized in France and Belgium to receive either 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by 1-year maintenance with lenalidomide, or 3 cycles of VRD followed by high-dose therapy and ASCT plus 2 cycles of VRD consolidation and 1-year lenalidomide maintenance. 134 / 700 patients were also included in the IMAJEM trial (NCT01309334, also supported by STIC program granted by the French NCI) aimed at comparing in both arms of the IFM-DFCI 2009 study spine and pelvis MRI and whole-body PET-CT at diagnosis (number of lesions, primary end-point), after 3 cycles of VRD, and prior to maintenance (prognosis impact of imaging negativity, secondary end-point). PET-CT and MRI results before maintenance were also compared with MRD assessed by 8-color flow cytometry. MRI and PET-CT data were analyzed locally in each of the 15 participating centers, and systematically reviewed blindly by an independent committee consisting of 2 radiologists and 2 nuclear medicine physicians with extensive experience in MM field.
Results
At diagnosis, MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, respectively (McNemar test = 0.94, p-value = 0.33). MRI patterns of marrow involvement were the following: (1) normal in 7 cases (5%); (2) focal lesions (FL) in 46 cases (34%); (3) homogeneous diffuse infiltration in 41 cases (31%); (4) combined diffuse infiltration and FL in 35 cases (26%); and (5) variegated or "salt-and-pepper" pattern with inhomogeneous bone marrow with interposition of fat islands in 5 cases (4%). PET-CT patterns were the following: (1) normal in 12 cases (9%); (2) FL in 44 cases (33%); (3) diffuse infiltration in 12 cases (9%); (4) combined diffuse infiltration and FL in 66 cases (49%); (5) extramedullary disease in 10 cases (7.5%). The median number of FL assessed by PET-CT was 3.
Conclusion
MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis. The prognosis relevance of both MRI and PET-CT, and the comparison with MRD assessed by flow cytometry will be presented at the meeting.
Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Janssen: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hulin:Celgene Corporation: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.
Purpose: To examine overall diet quality in relation to advanced age-related macular degeneration (AMD).
Methods: This case-control study identified 437 advanced AMD patients and 259 unrelated ...controls using stereoscopic color fundus photographs. Participants were predominantly non-Hispanic White men and women from North Carolina and Tennessee. A 97-item Block food frequency questionnaire was used to gather diet information, and overall diet quality was measured using the Healthy Eating Index (HEI) and Alternate Healthy Eating Index (AHEI).
Results: Participants in the highest quartile of diet quality had significantly reduced odds of AMD according to the AHEI score (0.54, 95% confidence interval 0.30-0.99) and non-significantly reduced odds of AMD according to the HEI (0.75, 0.41-1.38). Odds of AMD were also 51% lower in the highest quartile of fish intake compared to the lowest quartile (odds ratio = 0.49, 0.26-0.90).
Conclusions: We found that advanced AMD was significantly related to overall diet quality. The AHEI score may be a useful instrument for assessing AMD risk due to diet, and it could potentially be improved by incorporating more specific information regarding micronutrient intake.
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Background
Induction therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with symptomatic multiple myeloma less than 66 years old. The quality of ...response to the induction treatment is an important prognostic factor and is predictive of progression free survival (PFS) following ASCT. The triplet combinations bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) have demonstrated high response rates in prospective phase 2 and phase 3 clinical trials, they are 2 of the most commonly used induction regimens prior to ASCT, and are both recommended in the International guidelines. To date, no comparative data from prospective randomized trials of the safety and efficacy of VTD vs VCD are available. This provided the rationale for the phase 3 investigation of VTD vs VCD prior to ASCT in patients with de novo MM in this randomized multicenter study (NCT01564537).
Methods
Patients with de novo symptomatic MM less than 66 years old were prospectively randomized to receive either 4 cycles of VTD (arm A) or 4 cycles of VCD (arm B) followed by ASCT. The VTD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, subcutaneously (SC) D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Thalidomide 100 mg/d, PO D1 to D21. The VCD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, SC D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15. Patients were stratified according to ISS (1-2 versus 3) and cytogenetics (high-risk defined by 17p deletion and t(4;14) versus other).The primary endpoint was very good partial response (VGPR) rate following 4 cycles. Response was assessed in a central lab according to the IMWG criteria. Assuming a VGPR rate of 60% in the VTD arm versus 45% in the VCD arm (15% difference), the possibility to detect a statistically significant difference required the enrolment of 340 patients overall (170 per arm). Adverse events were graded using the NCI CTCAE catalogue, version 4.0.
Results
From 11/2013 to 02/2015, 358 patients were enrolled into the study. 18 were screening failures, and 170 were randomized each to arm A (VTD) and arm B (VCD). The median age was 60 years (range, 26-65), 62% of the patients were male, and overall, the patient characteristics were well-balanced across the 2 arms of the study. The median number of induction cycles administered in both arms was 4 (1-4). On an intent-to-treat basis, the overall response rate (> partial response PR) was 92.3% in arm A, including a 10.7% complete response (CR) rate and a VGPR rate of 66.7%, while in arm B the overall response rate was 84%, with a 9.5% CR and a 56.2% VGPR rate. VGPR and PR rates were significantly higher in the VTD arm with p-values of 0.04 and 0.02, respectively. Seven patients died during induction therapy (2%), 3 in arm A from infections (2) and pulmonary embolism (1), and 4 in arm B from progression to extramedullary myeloma (2) and infections (2). Grades 3 / 4 peripheral neuropathy occurred in 4% and 2.2% in Arm A and B, respectively. Grade 3/4 neutropenia was seen in 11.9% vs 22.5% in Arm A and B, respectively.
Conclusion
This trial is the first prospective randomized comparison of 4 cycles of VTD versus 4 cycles of VCD administered as induction therapy prior to ASCT. VTD was shown to be significantly superior to VCD in terms of VGPR and PR rates. Neuropathy rates low in both arms, while neutropenia was more frequent with VCD.
Moreau:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Stoppa:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Laribi:Hospira SAS: Research Funding. Avet-Loiseau:jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees.
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Although mean physical activity in COPD patients declines by 400•500steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to ...identify distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants.
We pooled data from two cohorts (usual care arm of Urban Training NCT01897298 and PROactive initial validation NCT01388218 studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns.
In 291 COPD patients (mean±SD 68±8 years, 81% male, FEV1 59±19%pred) we identified three distinct physical activity progression patterns: Inactive (n=173 59%, baseline: 4621±1757 steps/day, 12-month change (): ∧487±1201 steps/day), ActiveImprovers (n=49 17%, baseline: 7727±3275 steps/day, :+3378±2203 steps/day) and ActiveDecliners (n=69 24%, baseline: 11 267±3009 steps/day, : ∧2217±2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR 95% CI 0.94 0.90•0.98 per 10m, P=.001) and a higher mMRC dyspnea score (1.71 1.12•2.60 per 1 point, P=.012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver.
The natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline.
Aunque la actividad física en pacientes con EPOC declina una media anual de 400-500 pasos/día, se desconoce si esta progresión es igual en todos los pacientes. Este estudio pretendió identificar los patrones de progresión de la actividad física mediante mèc)todos libres de hipótesis y evaluar sus determinantes.
Se estudiaron 291 pacientes con EPOC estable (media±DE: 68±8años, 81% hombres, VEMS 59±19%pred) de dos cohortes europeas con actividad física basal y a 12meses (acelerómetro Dynaport MoveMonitor). Se identificaron conglomerados (patrones) de progresión de actividad física basados en los niveles y cambios de pasos/día usando k-means, y se compararon entre patrones las características sociodemográficas, interpersonales, ambientales, clínicas y psicosociales basales.
Se identificaron tres patrones: inactivo (n=173 59%, basal: 4.621±1.757 pasos/día, cambio en 12meses (): ∧487±1.201 pasos/día), activo que aumenta (n=49 17%, basal: 7.727±3.275 pasos/día, : +3.378±2.203 pasos/día) y activo que reduce (n=69 24%, basal: 11.267±3.009 pasos/día, : ∧2.217±2.085 pasos/día). La distancia en la prueba de la marcha de 6minutos (6MWD) y la disnea se asociaron independientemente con ser inactivo: RRR IC95% 0,94 0,90-0,98 por cada 10m de 6MWD (p=0,001) y 1,71 1,12-2,60 por cada punto en la escala mMRC (p=0,012), respectivamente, en comparación con el patrón activo que reduce. No se encontraron variables basales independientemente asociadas con ser activo que aumenta.
La progresión natural de la actividad física en pacientes con EPOC es heterogèc)nea. Mientras que el patrón de pacientes inactivo se relaciona con peores características clínicas de EPOC, no se pudo predecir la evolución de los activos a aumentar o reducir.
Autosomal recessive Duchenne-like muscular dystrophy (DLMD) is a severe dystrophic myopathy. The incidence is unknown because of its clinical similarity to Duchenne muscular dystrophy (DMD). Three ...highly inbred DLMD families from Tunisia were analysed for chromosomal linkage using 135 polymorphic microsatellite markers. A significant lod score of z = 9.15 at theta = 0.03 was found with the 13q12 locus D13S115. Two additional 13q12 markers, D13S143 and D13S120, also gave significant lod scores. Therefore, the primary DLMD defect gene lies in the pericentrometric region of chromosome 13q.
The interaction between two regulatory proteins plays a crucial role in the control of several biological events, including gene transcription. In this report, we demonstrate that the interaction ...between the cellular sequence-specific single-stranded DNA binding protein Purα and the HIV type 1 (HIV-1) Tat protein is mediated by specific ribonucleic acids. The region of Tat that is important for its interaction with Purα includes the region demonstrated to bind Tat's viral RNA target, TAR. A 10-nucleotide GC-rich consensus sequence identified in RNAs associated with Purα derived from human U-87MG cells plays an important role in the Purα . Tat interaction as examined by an in vitro reconstitution assay. Furthermore, expression of the Purα - associated RNA in these cells enhances transcriptional activation of the HIV-1 promoter by Tat and Purα .
Autosomal recessive Charcot–Marie–Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has ...previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.
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