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Objective: We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS)., Methods: We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS., Results: We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies., Conclusion: Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to "real world" settings where the MS population commonly has comorbid conditions., (© 2016 American Academy of Neurology.)

Objective: To reach consensus about the most relevant comorbidities to study in multiple sclerosis (MS) with respect to incidence, prevalence, and effect on outcomes; review datasets that may support studies of comorbidity in MS; and identify MS outcomes that should be prioritized in such studies., Methods: We held an international workshop to meet these objectives, informed by a systematic review of the incidence and prevalence of comorbidity in MS, and an international survey regarding research priorities for comorbidity., Results: We recommend establishing age- and sex-specific incidence and prevalence estimates for 5 comorbidities (depression, anxiety, hypertension, hyperlipidemia, and diabetes); evaluating the effect of 7 comorbidities (depression, anxiety, hypertension, diabetes, hyperlipidemia, chronic lung disease, and autoimmune diseases) on disability, quality of life, brain atrophy and other imaging parameters, health care utilization, employment, and mortality, including age, sex, race/ethnicity, socioeconomic status, and disease duration as potential confounders; harmonizing study designs across jurisdictions; and conducting such studies worldwide. Ultimately, clinical trials of treating comorbidity in MS are needed., Conclusion: Our recommendations will help address knowledge gaps regarding the incidence, prevalence, and effect of comorbidity on outcomes in MS., (© 2016 American Academy of Neurology.)

Background: The quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS., Materials and Methods: We reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC) between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed., Results: Among the 272 studies identified, 117 were analyzed and 35 (18,140 patients) were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57--0.15; P = 0.02). Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046) but not between FLDMDs (-0.33%/y) and placebo (P = 0.11) or between FLDMDs and SLDMDs (P = 0.49). Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001) and FLDMDs (-0.46%/y, P<0.005), but no difference was detected between FLDMDs and placebo (P = 0.12)., Conclusions: SLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS.

Background: The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys., Subjects and Methods: A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 ±2.48 DS)., Results: The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p<0.01)., Conclusions: Both time to rise from the floor and baseline 6MWT were relevant for predicting 6MWT changes in the group above the age of 7 years, with no interaction between the two measures, as the impact of time to rise from the floor on 6MWT change was similar in the patients below and above 350 m. Our results suggest that, time to rise from the floor can be considered an additional important prognostic factor of 12 month changes on the 6MWT and, more generally, of disease progression.

Background: In recent years the impact of disease-modifying drugs on long-term progression in multiple sclerosis (MS) was assessed both in observational studies and in extension of randomized controlled trial (RCT). Aim of this work was to quantitatively summarize by a meta-analysis the long-term impact of immunomodulatory drugs (Interferon-Beta (IFN-β) or Glatiramer Acetate (GA)) in relapsing-remitting (RR) MS patients., Methods: We collected all published observational studies reporting the long-term efficacy of IFN-β or GA in RRMS patients. The primary outcome was the treatment effect on progression to a sustained EDSS score of 6 or to the Secondary Progressive (SP) phase. A non-parametric approach was adopted to test the overall treatment effect significance, while a random effect model was used to obtain a pooled quantitative estimate of the treatment benefit, in terms of hazard-ratios (HR) or Relative Risks, with their 95% confidence interval (CI)., Results: Fourteen studies, on a total of 13,238 RRMS patients, were included in the meta-analysis. All studies but two reported a consistent effect of immunomodulatory treatment on long-term disease progression; the pooled effect on progression to EDSS 6 or SP was significant (p<0.01) when tested by the non-parametric test. The quantitative estimate of the treatment effect in reducing progression to EDSS 6 in the subset of studies reporting this outcome was HRpooled=0.49 (95% CI: 0.34-0.69), p<0.001., Conclusions: Treatment with immunomodulators seems to reduce long-term probability of disability progression. Additional well-designed observational studies could help to confirm these findings., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS)., Methods: A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome [CIS] or relapsing-remitting MS) and were also compared to two other population- and clinic-based PPMS cohorts., Results: Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6-5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow-up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow-up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS., Interpretation: Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age-dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum., (© 2015 American Neurological Association.)

The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between -14 and +9 (mean -0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between -2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess whether it is feasible to establish specific cut-off values able to discriminate 'physiological' or 'pathological' brain volume rates in patients with multiple sclerosis (MS)., Methods: The study was based on the analysis of longitudinal MRI data sets of patients with MS (n=206, 87% relapsing-remitting, 7% secondary progressive and 6% primary progressive) and healthy controls (HC; n=35). Brain atrophy rates were computed over a mean follow-up of 7.5 years (range 1-12) for patients with MS and 6.3 years (range 1-12.5) for HC with the SIENA software and expressed as annualised per cent brain volume change (PBVC/y). A weighted (on the follow-up length) receiver operating characteristic analysis and the area under the curve (AUC) were used for statistics., Results: The weighted PBVC/y was -0.51±0.27% in patients with MS and -0.27±0.15% in HC (p<0.0001). There was a significant age-related difference in PBVC/y between HC older and younger than 35 years of age (p=0.02), but not in patients with MS (p=0.8). The cut-off of PBVC/y, as measured by SIENA that could maximise the accuracy in discriminating patients with MS from HC, was -0.37%, with 67% sensitivity and 80% specificity. According to the observed distribution, values of PBVC/y as measured by SIENA that could define a pathological range were above -0.52% with 95% specificity, above -0.46% with 90% specificity and above -0.40% with 80% specificity., Conclusions: Our evidence-based criteria provide values able to discriminate the presence or absence of 'pathological' brain volume loss in MS with high specificity. Such results could be of great value in a clinical setting, particularly in assessing treatment efficacy in MS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

To describe a new test to quantitatively evaluate hand function in patients affected by Charcot-Marie-Tooth neuropathy (CMT). The sensor-engineered glove test (SEGT) was applied to CMT patients (N: 26) and compared with a cohort of healthy controls (HC, N: 26). CMT patients were further divided into subjects with clinically normal (group 1) or impaired hand (group 2) function. The SEGT parameters evaluated were touch duration, inter-tapping interval, and movement rate parameters of two different sequences: finger tapping (FT) and index-medium-ring-little (IMRL) performed at self-paced mode (SPM) and maximum velocity (MV). Hand function and strength were assessed by the 9-hole peg test (9HPT) and dynamometry. Disability of patients was measured by the CMT neuropathy score. CMT patients had significantly worst performances at SEGT than controls regarding the rate of execution of both FT (at MV) and IMRL sequences (at SPM and MV). The rate parameter at MV in IMRL sequence showed a significant trend of decreasing in its average between HC (n: 26, rate = 3.08 ± 0.52 Hz), group 1 (n: 9, rate = 2.64 ± 0.66 Hz) and group 2 (n: 17, rate = 2.19 ± 0.45 Hz) (p for trend <0.001). No correlations were found with either 9HPT, dynamometry, electrophysiology, and the CMT neuropathy score. The SEGT test is sensitive to show hand dysfunction in CMT patients, with and without clinically impaired hands., (© 2015 Peripheral Nerve Society.)

Importance: The patents for the first approved treatments for relapsing-remitting multiple sclerosis are expiring, creating the opportunity to develop generic alternatives., Objective: To evaluate in the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study whether generic glatiramer acetate (hereafter generic drug) is equivalent to the originator brand glatiramer acetate (hereafter brand drug) product, as measured by imaging and clinical end points, safety, and tolerability., Design, Setting, and Participants: Randomized, multicenter, double-blind, active and placebo-controlled phase 3 trial. The setting included academic medical centers and clinical practices. Participants were patients with relapsing-remitting multiple sclerosis 18 to 55 years old with at least 1 relapse in the prior year and 1 to 15 gadolinium-enhancing brain magnetic resonance imaging lesions. They were randomized between December 7, 2011, and March 21, 2013. The last participant completed follow-up December 2, 2013., Interventions: Participants were randomized 4.3:4.3:1 to receive generic glatiramer acetate (20 mg), brand glatiramer acetate (20 mg), or placebo by daily subcutaneous injection for 9 months., Main Outcomes and Measures: The primary end point was the total number of gadolinium-enhancing lesions during months 7, 8, and 9. Additional end points included other magnetic resonance imaging parameters, annualized relapse rate, and Expanded Disability Status Scale score. Safety and tolerability were assessed by monitoring adverse events, injection site reactions, and laboratory test results., Results: In total, 794 participants were randomized and treated with generic drug (n  = 353), brand drug (n = 357), or placebo (n = 84). The estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo (ratio, 0.488; 95% CI, 0.365-0.651; P < 001), confirming study sensitivity. For gadolinium-enhancing lesions, the estimated ratio of generic drug to brand drug was 1.095 (95% CI, 0.883-1.360), which was within the predefined equivalence margin of 0.727 to 1.375. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups., Conclusions and Relevance: As treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability., Trial Registration: clinicaltrials.gov Identifier: NCT01489254.

Intra-arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first-in-human, exploratory, non-randomized open-label phase I-IIa clinical trial of intra-arterial HLA-matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor-derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2-month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Two months after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor-derived dystrophin in 1. Intra-arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.

Multiple Sclerosis (MS) is a chronic inflammatory/demyelinating and neurodegenerative disease of the central nervous system (CNS). Most patients experience a relapsing-remitting (RR) course, while about 15-20% of patients experience a primary progressive (PP) course. Cognitive impairment affects approximately 40-70% of all MS patients and differences in cognitive impairment between RR-MS and PP-MS have been found. We aimed to compare RR-MS and PP-MS patients in terms of cognitive performance, and to investigate the MRI correlates of cognitive impairment in the two groups using measures of brain volumes and cortical thickness. Fifty-seven patients (42 RR-MS, 15 PP-MS) and thirty-eight matched controls underwent neuropsychological (NP) testing and MRI. PP-MS patients scored lower than RR-MS patients on most of the NP tests in absence of any specific pattern. PP-MS patients showed significantly lower caudate volume. There was no significant difference in MRI correlates of cognitive impairment between the two groups except for a prevalent association with MRI measures of cortical GM injury in RR-MS patients and with MRI measures of subcortical GM injury in PP-MS patients. This suggests that although cognitive impairment results from several factors, cortical and subcortical GM injury may play a different role depending on the disease course.

Background: Autologous hematopoietic stem cell transplantation (AHSCT) has been successfully used to treat aggressive forms of multiple sclerosis (MS) that are unresponsive to approved therapies. In the last years, in view of the risk of mortality related to the procedure, the utilization of low-intensity conditioning regimens has been considered., Objective: To report magnetic resonance imaging (MRI) and clinical data in a small cohort of patients treated with a low-intensity lympho-ablative regimen, followed by AHSCT., Methods: Seven patients affected by relapsing-remitting MS (RRMS) underwent AHSCT, with cyclophosphamide 120 mg/kg in 2 days as the conditioning regimen; and were then followed with serial MRI evaluations until 36 months, with clinical evaluations until 60 months., Results: The mean number of gadolinium (Gd)-enhancing lesions significantly decreased after treatment, but a complete suppression of inflammatory activity was not obtained. No deaths occurred, but every patient developed adverse events, although not severe. After 5 years of follow-up, two patients remained stable, one patient markedly improved and four patients had a mild progression of the disease. Only one patient experienced a relapse after treatment., Conclusion: A low-intensity conditioning regimen with AHSCT has a profound effect on MRI inflammation and relapses, but is not able to completely abrogate MRI activity and disease progression of aggressive RRMS., (© The Author(s), 2015.)

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Therapies that target the underlying pathology of multiple sclerosis (MS), including focal and diffuse damage, may improve long-term disease control. Focal damage (inflammatory lesions) manifests clinically mainly as relapses, whereas diffuse damage (neurodegeneration and brain volume loss) has been more closely associated with disability progression and cognitive decline. Given that first-line therapies such as beta-interferon and glatiramer acetate, which are primarily directed against inflammation, might fail to adequately control disease activity in some patients, it has been recommended to switch these patients early to a therapy of higher efficacy, possibly targeting both components of MS pathology more rigorously. This review provides an overview of the efficacy of EU-approved disease-modifying therapies on conventional MS outcome measures (relapses, disability progression and paraclinical magnetic resonance imaging endpoints) in addition to brain volume loss, a measure of diffuse damage in the brain. In addition, the evidence supporting early treatment optimization in patients with high disease activity despite first-line therapy will be reviewed and an algorithm for optimal disease control will be presented., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To compare ultrasound (US) and magnetic resonance imaging (MRI) in the diagnosis of Morton's neuroma., Methods: Studies that assessed the diagnostic accuracy of US and MRI for Morton's neuroma were retrieved from major medical libraries independently by two reviewers up to 1 April 2014. Predefined inclusion and exclusion criteria were adopted., Results: 277 studies were initially found, and the meta-analysis was conducted on 14 studies. US sensitivity was studied in five studies, MRI sensitivity in three studies, and bothin six studies. All studies used surgery as the reference standard. A high sensitivity (SE) of diagnostic testing was observed for both US (SE (95 % CI) = 0.91 (0.83-0.96)) and MRI (SE (95 % CI) = 0.90 (0.82-0.96)) with no significant differences between the two modalities in diagnosis (Q test p = 0.88). For MRI, specificity of test was 1.00 with a pooled estimation of 1.00 (0.73-1.00), while the pooled specificity was 0.854 (95 % CI: 0.41-1.00) for US. No differences were observed between US and MRI in study design (p = 0.76)., Conclusion: This meta-analysis shows that the SE of US (0.91) is equal to (p = 0.88) that of MRI (0.90) for identification of Morton's neuroma., Key Points: • For Morton's neuroma, US sensitivity is equal to MRI. • US is as accurate as MRI in diagnosing Morton's neuroma. • US may be the most cost-effective imaging method for Morton's neuroma.

Background: To assess the test-retest reproducibility of cortical mapping of T2 * relaxation rates at 7 Tesla (T) MRI. T2 * maps have been used for studying cortical myelo-architecture patterns in vivo and for characterizing conditions associated with changes in iron and/or myelin concentration., Methods: T2 * maps were calculated from 7T multi-echo T2 *-weighted images acquired during separate scanning sessions on 8 healthy subjects. The reproducibility of surface-based cortical T2 * mapping was assessed at different depths of the cortex; from pial surface (0% depth) towards gray/white matter boundary (100% depth), across cortical regions and hemispheres, using coefficients of variation (COVs = SD/mean) between each couple (scan-rescan) of average T2 * measurements., Results: Average cortical T2 * was significantly different among 25%, 50%, and 75% depths (analysis of variance, P < 0.001). Coefficient of variations were very low within cortical regions, and whole cortex (average COV = 0.83-1.79%), indicating a high degree of reproducibility in T2 * measures., Conclusion: Surface-based mapping of T2 * relaxation rates as a function of cortical depth is reproducible and could prove useful for studying the laminar architecture of the cerebral cortex in vivo, and for investigating physiological and pathological states associated with changes in iron and/or myelin concentration., (© 2014 Wiley Periodicals, Inc.)

Background: Brain volume loss occurs in patients with relapsing-remitting MS. Fingolimod reduced brain volume loss in three phase 3 studies., Objective: To evaluate whether the effect of fingolimod on disability progression was mediated by its effects on MRI lesions, relapses or brain volume loss, and the extent of this effect., Methods: Patients (992/1272; 78%) from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study were analyzed. Month-24 percentage brain volume change, month-12 MRI-active lesions and relapse were assessed. The Prentice criteria were used to test surrogate marker validity. The proportion of treatment effect on disability progression explained by each marker was calculated., Results: Two-year disability progression was associated with active T2 lesions (OR = 1.24; p = 0.001) and more relapses during year 1 (OR = 2.90; p < 0.001) and lower percentage brain volume change over two years (OR = 0.78; p < 0.001). Treatment effect on active T2 lesions, relapses and percentage brain volume change explained 46%, 60% and 23% of the fingolimod effect on disability. Multivariate analysis showed the number of relapses during year 1 (OR = 2.62; p < 0.001) and yearly percentage brain volume change over two years (OR = 0.85; p = 0.009) were independent predictors of disability progression, together explaining 73% of fingolimod effect on disability., Conclusions: The treatment effect on relapses and, to a lesser extent, brain volume loss were both predictors of treatment effect on disability; combining these predictors better explained the effect on disability than either factor alone., (© The Author(s), 2015.)

Background and Purpose: The Rio score (RS) and the modified Rio score (MRS) are two scoring systems that can identify the early predictive factors of disability progression in relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-β (IFN-β). The objective of the study was to validate the usefulness of the RS and MRS in a large cohort of multiple sclerosis patients treated with IFN-β in daily clinical practice., Methods: The analysis included a cohort of RRMS patients treated with different formulations of IFN-β for at least 1 year. The RS and MRS were used to classify the patients after 1 year of treatment. Multivariate analysis was performed to identify predictive variables of suboptimal response at 5 years, defined as Expanded Disability Status Scale confirmed progression or switching to a second-line therapy., Results: Sixty-nine of 416 included patients were considered as suboptimal responders at 5-year evaluation. The possible score range was 0-3. A higher risk of suboptimal response was found for RS and MRS in the presence of ≥2 scores (hazard ratio 3.0, P = 0.002, and hazard ratio 5.0, P < 0.0001, respectively)., Conclusions: Our study confirmed, in a daily clinical setting, that MRS had a better specificity and accuracy than RS in identifying the patients who will have a poor response to long-term IFN-β treatment., (© 2015 EAN.)

Background and Purpose: No subgroups of patients with higher treatment effects have been clearly detected in multiple sclerosis (MS). The aim of the present work was to evaluate whether there are subgroups of relapsing-remitting MS (RRMS) patients who are more responsive to treatments., Methods: All published randomized clinical trials in RRMS reporting a subgroup analysis of treatment effect were collected. Two main outcomes, the annualized relapse rate (ARR) and the disability progression, were studied. The treatment effect in each subgroup was reported as a relative effect (RE), defined as the treatment effect in the subgroup relative to the overall effect. A meta-analysis was run to compare the RE between subgroups., Results: Six trials (6693 RRMS patients) were included. Treatment effects on ARR were significantly higher in younger than in older subjects (RE = 0.83 vs. RE = 1.30, P < 0.001), in patients with than those without gadolinium activity (RE = 0.86 vs. RE = 1.15, P = 0.005) and in patients with lower than in those with higher Expanded Disability Status Scale (RE = 0.96 vs. RE = 1.23, P = 0.02), and on disability progression in younger than in older subjects (RE = 0.82 vs. RE = 1.28, P = 0.017)., Conclusions: This study formally shows that in RRMS higher treatment effects are associated with characteristics of earlier (lower age and Expanded Disability Status Scale) and more active (higher gadolinium activity) disease., (© 2015 EAN.)

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end., (© 2015 American Academy of Neurology.)

Objective: To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 integrin antibody natalizumab in patients with multiple sclerosis (MS)., Methods: We evaluated CD45(low)CD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10)., Results: Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and nonmobilizer subgroups. Nonmobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile., Conclusions: The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab., (© 2015 American Academy of Neurology.)

The increasing practice of hormonal infertility treatments (HITs) raised concerns about their effects on breast cancer (BC) risk. Available evidence reported conflicting results. The aim of this study was to assess the potential association between HITs and BC risk. The literature was searched through November 2014. Eligible studies included cohort studies reporting BC incidence in women undergone HITs. Data were analyzed with standard meta-analytic techniques. Subgroup analyses were performed by type of intervention (IVF vs. NO IVF), follow-up duration (<10 vs. >10 years), and type of control (population vs. infertile). 20 eligible studies (207.914 women, 2347 BC) were retrieved: no increased risk was detected (SRR = 1.05, 95 % CI 0.96-1.14), with a significant heterogeneity (I (2) = 59 %, p = 0.001) among studies. In the seven studies with the in vitro fertilization (IVF) procedure, no increase in BC risk was observed (SRR = 0.96, 95 % CI 0.80-1.14); in the three NO IVF studies, an increased BC risk was identified (SRR = 1.26, 95 %CI 1.06-1.50). A borderline interaction between type of intervention (IVF vs. NO IVF) and BC risk was observed (p = 0.06). An increased risk with longer follow-up (≥10 vs. <10 years) was detected (SRR = 1.13, 95 % CI 1.02-1.26 vs. SRR = 0.95, 95 % CI 0.85-1.06). Overall, HITs are not associated with an increased BC risk. In particular, no increased risk was observed in women undergoing IVF. Conversely, an increased in BC risk cannot be ruled out with older treatment protocols based on clomiphene. The long-term administration of clomiphene outside the current indications should be discouraged because of a possible increase in BC risk.

Objective: To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI., Methods: We conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans., Results: AHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability., Conclusion: Intense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24., (© 2015 American Academy of Neurology.)

The gold standard for measuring treatment effects is the randomized controlled trial. In patients with multiple sclerosis (MS), trial durations are typically 2-3 years, and the long-term effects of drugs for MS can only be assessed through trial extensions or observational studies that take advantage of data from registries or large single-centre databases. The main limitation of observational studies is an unavoidable selection bias that is introduced through nonrandom assignment of the intervention. Propensity score methods can mitigate this bias by balancing the groups with respect to baseline covariates, but this approach cannot correct for unmeasurable confounding factors. Extensions of clinical trials are free from selection biases because of the initial randomization, but they can only provide an assessment of early versus delayed treatment effects. Here, we discuss these methodological issues and analyse how they have been managed in studies of the long-term effects of IFN-β in patients with MS.

Objectives: To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS)., Methods: In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient's disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis., Results: Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0-175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%)., Conclusions: The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To assess the role of pathologic complete response (pCR) after neoadjuvant therapy as surrogate end point of disease-free survival (DFS) and overall survival (OS) in patients with breast cancer, we performed a trial-based meta-regression of randomized studies comparing different neoadjuvant systemic treatments., Methods: The systematic literature search included electronic databases and proceedings of oncologic meetings. Endocrine therapy trials were excluded. Treatment effects on DFS and OS were expressed as hazard ratios (HRs), and treatment effects on pCR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome., Results: Twenty-nine trials, 59 arms, and 30 comparisons, for a total of 14,641 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for DFS or the log(HR) for OS on the log(OR) for pCR demonstrated only weak associations (R(2) = 0.08; 95% CI, 0 to 0.47; and R(2) = 0.09; 95% CI, 0.01 to 0.41, respectively). Better associations were found in an exploratory analysis assessing a subset of trials comparing intensified/dose-dense chemotherapy versus standard-dose regimens (DFS: R(2) = 0.79; 95% CI, 0.26 to 0.95; P = .003; and OS: R(2) = 0.57; 95% CI, 0.19 to 0.93; P = .03)., Conclusion: This meta-regression analysis of 29 heterogeneous neoadjuvant trials does not support the use of pCR as a surrogate end point for DFS and OS in patients with breast cancer. However, pCR may potentially meet the criteria of surrogacy with specific systemic therapies., (© 2014 by American Society of Clinical Oncology.)

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of -15.8 (SD 77.3) m at 12 months, of -58.9 (SD 125.7) m at 24 months and -104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

Umbilical cord blood transplant recipients are exposed to an increased risk of graft failure, a complication leading to a higher rate of transplant-related mortality. The decision and timing to offer a second transplant after graft failure is challenging. With the aim of addressing this issue, we analyzed engraftment kinetics and outcomes of 1268 patients (73% children) with acute leukemia (64% acute lymphoblastic leukemia, 36% acute myeloid leukemia) in remission who underwent single-unit umbilical cord blood transplantation after a myeloablative conditioning regimen. The median follow-up was 31 months. The overall survival rate at 3 years was 47%; the 100-day cumulative incidence of transplant-related mortality was 16%. Longer time to engraftment was associated with increased transplant-related mortality and shorter overall survival. The cumulative incidence of neutrophil engraftment at day 60 was 86%, while the median time to achieve engraftment was 24 days. Probability density analysis showed that the likelihood of engraftment after umbilical cord blood transplantation increased after day 10, peaked on day 21 and slowly decreased to 21% by day 31. Beyond day 31, the probability of engraftment dropped rapidly, and the residual probability of engrafting after day 42 was 5%. Graft failure was reported in 166 patients, and 66 of them received a second graft (allogeneic, n=45). Rescue actions, such as the search for another graft, should be considered starting after day 21. A diagnosis of graft failure can be established in patients who have not achieved neutrophil recovery by day 42. Moreover, subsequent transplants should not be postponed after day 42., (Copyright© Ferrata Storti Foundation.)

Objective: To investigate the plasma levels of lopinavir by enzyme-linked immunosorbent assay (ELISA) in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV)., Methods: Plasma levels of lopinavir (Cmin) were determined by ELISA test in patients treated with lopinavir/ritonavir-based combined antiretroviral therapy who had achieved virological response after 4 wk of therapy. Reference lopinavir concentrations were Cmin 1-8 μg/mL. Correlation between lopinavir plasma concentration and continuous variables was evaluated by mean of Pearson correlation coefficient. Differences in lopinavir (LPV) concentration for binary categorical variables were assessed by Mann-Whitney test, while for variables with more than two categories Kruskal-Wallis test was used., Results: Thirty-four patients were enrolled; median age was 133 mo (15-265). The median lopinavir dose tested was 383.5 mg/kg (IQR: 266.6-400 mg/kg), with a median plasma concentration of 8.8 μg/mL (IQR: 5-14 μg/mL). Lopinavir Cmin was <1 μg/mL in only one sample (2.9 %), while 14 samples had Cmin between 1 and 8 μg/mL (41.2 %) and 19 (55.9 %) > 8 μg/mL. No significant correlations were found between plasma concentrations of lopinavir and the continuous variables considered in the study. A negative but, not completely significant, correlation was found between plasma drug concentration and body mass index (r = -0.29; p = 0.09)., Conclusions: The use of a simple and relatively cost-effective methodology might render therapeutic drug monitoring (TDM) appeal in the daily clinical practice.

Importance: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS)., Objective: To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS., Design, Setting, and Participants: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab., Interventions: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod., Main Outcomes and Measures: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year., Results: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery., Conclusions and Relevance: This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug., Trial Registration: Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined., (© 2014 American Academy of Neurology.)

Purpose: To compare MRI sequences for breast density measurements on a 3T MRI system using IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) as possible physiology-like reference., Materials and Methods: MRI examination was performed in 48 consecutive patients (mean age 41, years; range, 35-67 years) on a 3.0T scanner and 46 were included. All (fertile) women, were examined between days 5 and 15 of their menstrual cycle. MRI protocol included: T1-turbo spin-echo (T1-tSE), T2-turbo spin-echo (T2-tSE), VIBRANT (Volume Imaging for Breast Assessment) before and after injection of contrast media and IDEAL. Breast density was calculated with semi-automated software. Statistical analysis was performed with non-parametric tests., Results: Mean percentage of breast density calculated in each sequence was: T1-tSE = 56%; T2-tSE  = 52%; IDEAL FatOnly  = 55%; IDEAL WaterOnly  = 53%, VIBRANT = 55%. Significant differences were observed between T2-tSE and both T1-tSE (p<0.001), VIBRANT sequences (p = 0.009), T1-tSE and both IDEAL WaterOnly (p = 0.007) and IDEAL FatOnly (p = 0.047). Breast density percentage showed a positive linear correlation among different sequences: r ≥ 0.93., Conclusions: Differences exist between MRI sequences used to assess breast density percentage. T1-weighted sequences values were similar to IDEAL sequences.

Background: Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized., Methods: Longitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called "Better EDSS Trend (BET)", was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated., Results: Previous EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03)., Conclusion: Subjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.

Background: To assess the risk of subclinical neck nodal involvement of levels IB, IV and V for early T-stage, node positive, human papilloma virus (HPV)-related oropharyngeal carcinoma., Material and Methods: We retrospectively identified the patients with clinically positive and un-violated neck that underwent upfront ipsilateral neck dissection for HPV-related oropharyngeal cancer between 1998 and 2010. From the pathology report we extracted the prevalence rate of involvement of each selected level and then estimated the risk that a level that does not contain any node larger than 10 mm at computed tomography (CT) harbors subclinical disease. Predictors of involvement were investigated as well., Results: Ninety-one patients were analyzed. The risk of subclinical disease in both levels IB and V is < 5%, while it is 6.5% (95% CI 3.1-9.9%) for level IV. Level IB subclinical involvement slightly exceeds 5% when 2 + ipsilateral levels besides IB are involved. The risk of occult disease in level IV tends to be < 5% when level III is not involved., Conclusion: These data support the exclusion from the elective nodal volume of level V and level IB but when 2 + other levels are involved. Level IV might also be spared when level III is negative. Clinical implementation within a prospective study is justified.

Background: Multiple sclerosis (MS) is a heterogeneous disorder with a progressive course that is difficult to predict on a case-by-case basis. Natural history studies of MS have demonstrated that age influences clinical progression independent of disease duration., Objective: To determine whether age would be associated with greater CNS injury as detected by magnetization transfer MRI., Materials and Methods: Forty MS patients were recruited from out-patient clinics into two groups stratified by age but with similar clinical disease duration as well as thirteen controls age-matched to the older MS group. Images were segmented by automated programs and blinded readers into normal appearing white matter (NAWM), normal appearing gray matter (NAGM), and white matter lesions (WMLs) and gray matter lesions (GMLs) in the MS groups. WML and GML were delineated on T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) and T1 weighted MRI volumes. Mean magnetization transfer ratio (MTR), region volume, as well as MTR histogram skew and kurtosis were calculated for each region., Results: All MTR measures in NAGM and MTR histogram metrics in NAWM differed between MS subjects and controls, as expected and previously reported by several studies, but not between MS groups. However, MTR measures in the WML did significantly differ between the MS groups, in spite of no significant differences in lesion counts and volumes., Conclusions: Despite matching for clinical disease duration and recording no significant WML volume difference, we demonstrated strong MTR differences in WMLs between younger and older MS patients. These data suggest that aging-related processes modify the tissue response to inflammatory injury and its clinical outcome correlates in MS.

Objective: To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria., Methods: Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model., Results: Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11-74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01-21.1 y). Clinical events were identified in 34% (standard error=3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96-0.99); p=0.03], sex (male) [HR: 1.93 (1.24-2.99); p=0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06-4.62); p=<0.001] were identified as significant predictors for the development of a first clinical event., Interpretation: These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

Background: The accrual of brain focal pathology is considered a good substrate of disability in relapsing-remitting multiple sclerosis (RRMS). However, knowledge on long-term lesion evolution and its relationship with disability progression is poor., Objective: The objective of this paper is to evaluate in RRMS the long-term clinical relevance of brain lesion evolution., Methods: In 58 RRMS patients we acquired, using the same scanner and protocol, brain magnetic resonance imaging (MRI) at baseline and 10±0.5 years later. MRI data were correlated with disability changes as measured by the Expanded Disability Status Scale (EDSS)., Results: The annualized 10-year lesion volume (LV) growth was +0.25±0.5 cm(3) (+6.7±8.7%) for T2-weighted (T2-W) lesions and +0.20±0.31 cm(3) (+11.5±12.3%) for T1-weighted (T1-W) lesions. The univariate analysis showed moderate correlations between baseline MRI measures and EDSS at 10 years (p < 0.001). Also, 10-year EDSS worsening correlated with LV growth and the number of new/enlarging lesions measured over the same period (p < 0.005). In the stepwise multiple regression analysis, EDSS worsening over 10 years was best correlated with the combination of baseline T1-W lesion count and increasing T1-W LV (R = 0.61, p < 0.001)., Conclusion: In RRMS patients, long-term brain lesion accrual is associated with worsening in clinical disability. This is particularly true for hypointense, destructive lesions.