Jesús Martín

Sustained Remissions of High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome After Reduced- Intensity Conditioning Allogeneic Hematopoietic Transplantation: Chronic Graft-Versus-Host Disease Is the Strongest Factor Improving Survival

PURPOSE Reduced-intensity conditioning (RIC) for allogeneic stem-cell transplantation (allo-SCT) reduces nonrelapse mortality (NRM). This reduction makes it possible for patients who are ineligible for high-dose myeloablative conditioning allo-SCT to benefit from graft-versus-leukemia reaction. In this multicenter, prospective study of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of RIC allo-SCT from a human leukocyte antigen-identical sibling by using a regimen that uses fludarabine and busulfan. PATIENTS AND METHODS Ninety-three patients with AML (n = 59) and MDS (n = 34) were included, and the median age was of 53 years. Follow-up for survivors was 43 months (range, 3 to 89 months). The conditioning regimen consisted of fludarabine (150 mg/m(2)) and oral busulfan (8 to 10 mg/kg). All except one patient received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine and methotrexate or mycophenolate mofetil. RESULTS The 100-day, 1-year, and 4-year incidences of NRM were 8, 16%, and 21%, respectively. The 1- and 4-year relapse cumulative incidences were 23% and 37%, respectively, and leukemia recurrence was the main cause of death. The 4-year disease-free survival (DFS) and overall survival (OS) rates were 43% and 45%, respectively. The 4-year cumulative incidence of chronic GVHD was 53% (45% extensive), and its development was the major factor associated with lower relapse incidence and improved DFS and OS. CONCLUSION Our results confirm the capacity of this RIC regimen to obtain long-term remissions in patients ineligible for a conventional allo-SCT. The results suggest an important role of the development of chronic GVHD in reducing relapse and improving DFS and OS.

A study of the evolution and characteristics of the invariants of the velocity-gradient tensor in isotropic turbulence

Since the availability of data from direct numerical simulation (DNS) of turbulence, researchers have utilized the joint PDFs of invariants of the velocity gradient tensor to study the geometry of small-scale motions of turbulence. However, the joint PDFs only give an instantaneous static representation of the properties of fluid particles and dynamical Lagrangian information cannot be extracted. The Lagrangian evolution of the invariants of the velocity gradient tensor is studied using conditional mean trajectories (CMT). These CMT are derived using the concept of the conditional mean time rate of change of invariants calculated from a numerical simulation of isotropic turbulence

Axonal loss in the retinal nerve fiber layer in patients with multiple sclerosis

Objective To quantify axonal loss in the retinal nerve fiber layer (RNFL) in patients with multiple sclerosis (MS), with and without a history of optic neuritis, by means of ocular imaging technologies. Methods This cross-sectional study enrolled 50 patients with MS and 25 age- and sex-matched healthy controls. All patients underwent neurologic assessment and a complete ophthalmic examination that included visual acuity, visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (GDx) and visual evoked potentials (VEPs). Visual parameters and RNFL measurements were evaluated in MS eyes with a prior optic neuritis episode (MS-ON), with no prior episode (MS-NON) and control subjects. Results There were significant differences (p < 0.05, analysis of variance) between MS-ON (n = 25 eyes) and healthy eyes (n = 25 eyes) for all RNFL parameters measured by OCT and GDx. Significant differences between MS-NON (n = 75 eyes) and healthy eyes were also found for most of these parameters. RNFL thickness in the temporal quadrant was the parameter with the greatest differences between groups (71.79 μm in healthy eyes, 60.29 μm in MS-NON and 53.92 μm in MS-ON, p < 0.0005). Although there was a highly significant but moderate correlation between RNFL thickness and duration of the disease, no correlation was observed between RNFL thickness and neurologic impairment (Expanded Disability Status Scale). Conclusions Axonal loss was detected not only in MS eyes with a previous acute optic neuritis, but also in MS eyes with no known optic neuritis episode. Structural abnormalities correlate with functional assessments of the optic nerve.

Prognostic Factors of Chronic Graft-versus-Host Disease Following Allogeneic Peripheral Blood Stem Cell Transplantation: The National Institutes Health Scale Plus the Type of Onset Can Predict Survival Rates and the Duration of Immunosuppressive Therapy

Several grading systems have been developed in the bone marrow transplantation setting in attempts to predict survival in patients with chronic graft-versus-host disease (cGVHD). In this study, we evaluated the prognostic value of the National Institutes of Health (NIH) scoring system and investigated for any additional prognostic factors in a series of 171 patients undergoing peripheral blood stem cell transplantation (PBSCT) from matched related donors. The cumulative incidence of cGVHD was 70%; cumulative incidences of mild, moderate, and severe cGVHD were 29%, 42% and 28%, respectively. Overall, 68% of patients were free from immunosuppression 5 years after transplantation. Absence of previous acute GVHD (aGVHD; hazard ratio [HR] = 2; P = .004) and mild cGVHD (HR = 4.2; P = .007) increased the probability of being off immunosuppressive treatment by the last follow-up. Overall survival (OS) at 5 years was 52%. Severe cGVHD, according to the NIH scoring system (HR = 13.27; P = .001) adversely influenced outcome, whereas de novo onset (HR = 0.094; P = .003) had a more favorable impact on survival. The combination of both variables allowed us to identify 4 different subgroups of patients with OS of 82%, 70%, 50%, and 25%. Our findings indicate that the NIH scoring system has some prognostic value in patients undergoing PBSCT and, together with the type of onset, must be considered to predict the possible outcome of patients who develop cGVHD.

Retinal layer segmentation in patients with multiple sclerosis using spectral domain optical coherence tomography.

PURPOSE To evaluate the thickness of the 10 retinal layers in the paramacular area of patients with multiple sclerosis (MS) compared with healthy subjects using the new segmentation technology of spectral domain optical coherence tomography (OCT). To examine which layer has better sensitivity for detecting neurodegeneration in patients with MS. DESIGN Observational, cross-sectional study. PARTICIPANTS Patients with MS (n = 204) and age-matched healthy subjects (n = 138). METHODS The Spectralis OCT system (Heidelberg Engineering, Inc., Heidelberg, Germany) was used to obtain automated segmentation of all retinal layers in a parafoveal scan in 1 randomly selected eye of each participant, using the new segmentation application prototype. MAIN OUTCOME MEASURES The thicknesses of 512 parafoveal points in the 10 retinal layers were obtained in each eye, and the mean thickness of each layer was calculated and compared between patients with MS and healthy subjects. The analysis was repeated, comparing patients with MS with and without previous optic neuritis. Correlation analysis was performed to evaluate the association between each retinal layer mean thickness, duration of disease, and functional disability in patients with MS. A logistic regression analysis was performed to determine which layer provided better sensitivity for detecting neurodegeneration in patients with MS. RESULTS All retinal layers, except the inner limiting membrane, were thinner in patients with MS compared with healthy subjects (P < 0.05). Greater effects were observed in the inner retinal layers (nerve fiber, ganglion cells, inner plexiform, and inner nuclear layers) of eyes with previous optic neuritis (P < 0.05). The retinal nerve fiber layer and ganglion cell layer thicknesses were inversely correlated with the functional disability score in patients with MS. The ganglion cell layer and inner plexiform layer thicknesses could predict axonal damage in patients with MS. CONCLUSIONS Analysis based on the segmentation technology of the Spectralis OCT revealed retinal layer atrophy in patients with MS, especially of the inner layers. Reduction of the ganglion cell and inner plexiform layers predicted greater axonal damage in patients with MS.

Dynamics of the velocity gradient tensor invariants in isotropic turbulence

The evolution of the invariants (R and Q) of the velocity gradient tensor in homogeneous isotropic turbulence is investigated using data from direct numerical simulation (DNS). The concepts of conditional average time rate of change of the invariants and conditional mean trajectories (CMT) in invariant phase space are introduced to study the dynamics of this flow. The resulting dynamical system in the (R,Q) phase space is a clockwise spiral with a stable focus at the origin, illustrating that in the mean, the cyclic sequence of topological evolution following a fluid particle is unstable-node/saddle/saddle (UN/S/S)→stable-node/saddle/saddle (SN/S/S)→stable-focus/stretching (SF/S)→unstable-focus/contracting (UF/C). The mean rates of change of R and Q, i.e., Ṙ, Q, are found to be negligible near the right branch of the null discriminant (D=0) curve, indicating that this curve is an attractor in the (R,Q) space. The effects of both the diffusion term and the anisotropic part of the pressure Hessian term on ...

Progressive changes in the retinal nerve fiber layer in patients with multiple sclerosis.

Purpose To quantify changes in the retinal nerve fiber layer (RNFL) of patients with multiple sclerosis (MS) over a 1-year time period and to compare the ability of noninvasive diagnostic imaging devices and visual evoked potentials (VEP) to detect axonal loss in these patients. Methods Eighty-one patients with MS underwent a complete ophthalmic examination that included assessment of visual acuity and color vision, refractive evaluation, visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (GDx), and measurement of VEP. All the patients were re-evaluated after a period of 12 months in order to quantify any change in the RNFL. Only one randomly chosen eye from each patient was included in the study. Results Statistically significant differences between the 2 examinations were recorded for the overall mean and inferior RNFL thickness and the macular volume, as assessed by OCT, as well as for the temporal-superior-nasal-inferior-temporal average standard deviation provided by GDx. The greatest differences were obtained for the mean RNFL thickness (90.46 μm vs 85.96 μm). Changes in the optic nerve were detected by structural measurements but not by functional assessments. Conclusions Axonal loss in the optic nerve of patients with MS is greater than that expected in healthy subjects, regardless of the presence of a previous optic neuritis.

Fourier-Domain OCT in Multiple Sclerosis Patients: Reproducibility and Ability to Detect Retinal Nerve Fiber Layer Atrophy

PURPOSE To evaluate the ability of Fourier-domain (FD) optical coherence tomography (OCT) to detect retinal nerve fiber layer (RNFL) atrophy in multiple sclerosis (MS) patients. To test the intrasession reproducibility of RNFL thickness measurements in MS and healthy subjects using Cirrus (Carl Zeiss Meditec, Dublin, CA) and Spectralis (Heidelberg Engineering, Heidelberg, Germany) OCT. METHODS Two hundred twenty-two eyes of 111 subjects (50 MS patients and 61 healthy subjects) underwent three 360° circular scans centered on the optic disc by the same experienced examiner using the Cirrus and Spectralis OCT instruments. Differences between healthy and MS eyes were compared. The relationship between average thicknesses with each OCT was evaluated. Repeatability was studied by intraclass correlation coefficients and coefficients of variation (COV). RESULTS RNFL atrophy was detected in the MS eyes for all OCT parameters (P < 0.05). Cirrus and Spectralis showed an RNFL average thickness of 99.4 and 102.5 μm, respectively, in healthy subjects, and 86.0 and 90.4 μm in the MS eyes. RNFL average thickness in the MS eyes determined by both OCTs correlated (r = 0.812; P < 0.001), but were significantly different (P < 0.001). Reproducibility was good. In the MS eyes, Cirrus measurements showed a mean COV of 5.85%, Spectralis 6.80%, and Spectralis with a progression feature 4.16%. Intraclass correlation coefficients were higher than 0.840. RNFL average thickness correlated with disease duration and an optic neuritis antecedent. CONCLUSIONS There are significant differences in RNFL thickness measurements between Cirrus and Spectralis despite a high correlation of measurement between the two instruments. Fourier-domain OCT can be considered a valid device for detecting RNFL atrophy in MS patients.

Sub‐clinical atrophy of the retinal nerve fibre layer in multiple sclerosis

Acta Ophthalmol. 2010: 88: 748–752

Effect of optic neuritis on progressive axonal damage in multiple sclerosis patients

Objective: The objective of this research was to study the effect of optic neuritis (ON) on axonal damage in multiple sclerosis (MS) patients. Specifically, we compared changes over 2 years in the retinal nerve fibre layer (RNFL) between affected and contralateral eyes in MS patients with a prior history of ON. Methods: Thirty-four patients with one unilateral definitive episode of ON were included and underwent a complete ophthalmic examination, optical coherence tomography (OCT), scanning laser polarimetry, visual evoked potentials (VEP) and pattern electroretinogram (pERG). All patients were re-evaluated at 12 and 24 months. Parameters were compared between ON-affected and contralateral eyes in an initial exploration and over the course of the follow-up. Correlations between parameter changes were analysed. Results: RNFL thickness and functional parameters showed more affection in ON eyes (p ≤ 0.05), but changes in measurements during the study were similar between both groups of eyes. Conclusions: Progressive axonal loss can be detected in the optic nerve, but ON is not a risk factor for increased chronic damage in MS patients without ophthalmic relapses. Loss of the RNFL is caused by progressive degeneration associated with the disease.