Reliability of patient-reported toxicities during adjuvant chemotherapy.

BACKGROUND: Patient-reported outcomes (PROs) are validated tools to assess the impact of efficacy and toxicities of cancer treatments on patients' health status. Because of the demonstrated little reliability of humans in reporting memories of painful experiences, this work explores the reliability of cancer patients in reporting chemotherapy-related toxicities. AIM: This study aims to evaluate the concordance between toxicities experienced by the patients during chemotherapy and toxicities reported to the doctor at the end of the cycles. METHODS: Questionnaires concerning chemotherapy-related toxicities were administered on days 2, 5, 8, 11, 14, and 17 of each chemo cycle and at the end of the same cycle to patients undergoing adjuvant chemotherapy. The co-primary end-points were Lins's concordance correlation coefficient (CCC) and mean difference between real-time and retrospective toxicity assessments. RESULTS: In total, 7182 toxicity assessments were collected from 1096 questionnaires. Concordance was observed between the retrospective evaluations and the toxicity assessments at early (day 2), peak (maximum toxicity), late (day 14 or 17), and mean real-time evaluations for each chemotherapy cycle (CCC for mean ranging from 0.52 to 0.77). No systematic discrepancy was found between real-time and retrospective evaluations, except for peak, which was systematically underestimated retrospectively. CONCLUSIONS: Toxicities reported by the patients to the doctor at the end of each chemotherapy cycle reflect what they actually experienced without any substantial distortion. This result is very relevant both for the clinical implications in daily patients' management and in the light of the current growing impact on digital monitoring of PROs.

Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series.

OBJECTIVE: To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. METHODS: This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined. RESULTS: The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure. CONCLUSIONS: Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. CLASSIFICATION OF EVIDENCE: This study is rated Class IV because of the uncontrolled, open-label design.

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.

OBJECTIVE: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). METHODS: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. RESULTS: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. INTERPRETATION: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.

Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event.

OBJECTIVE: We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5-year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10-year, multinational, retrospectively identified RIS dataset. METHODS: RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models. RESULTS: Additional follow-up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11-74 years), with a median clinical follow-up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium-enhanced lesions during follow-up was also associated with the risk of a seminal event. The reason for MRI and gadolinium-enhancing lesions at baseline did not influence the risk of a subsequent clinical event. INTERPRETATION: Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407-417.

MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice.

Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions - the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research.

Head-to-head drug comparisons in multiple sclerosis: Urgent action needed.

Disease-modifying drugs are changing the natural history of multiple sclerosis (MS). However, currently available clinical trial data are insufficient to develop accurate personalized treatment algorithms to assign the best possible treatment to each person with MS according to disease features, treatment history, and comorbidities. Such accurate algorithms would require the presence of numerous head-to-head trials of long duration, which is virtually impossible, given the economic costs, required time, and difficulties with attrition. Thus, efforts are being made to compare relative treatment efficacy through observational designs, using large multicenter prospective cohorts or "big MS data," and network meta-analyses. Although such studies can yield useful information, they are liable to biases and their results should be confirmed in other study populations, including smaller, single-center cohorts, where some of these biases can be minimized. In this View article, we analyze the potential benefits and biases of all these strategies alternative to head-to-head trials in MS. Finally, we propose the combination of all these types of studies to obtain reliable head-to-head drug comparisons in the absence of randomized designs.

Laparoscopic Splenectomy Versus Open Splenectomy In Massive and Giant Spleens: Should we Update the 2008 EAES Guidelines?

The objective of this study was to derive some useful parameters to define the feasibility of laparoscopic splenectomy (LS) in massive [spleen longitudinal diameter (SLD)>20 cm] and giant spleens (SLD>25 cm). Between December 1996 and May 2017, 175 patients underwent an elective splenectomy. A laparoscopic approach was used in 133 (76%) patients. Massive spleens were treated in 65 (37.1%) patients, of which 24 were treated laparoscopically. In this subset of massive spleens, the results of laparoscopic splenectomy in massive spleens (LSM) and open splenectomy in massive spleens (OSM) were compared. The clinical outcome of a subgroup of patients with giant spleens was also analyzed. The LSM group resulted in significant longer operative times (143±31 vs. 112±40 min; P=0.001), less blood loss (278±302 vs. 575±583 mL; P=0.007), and shorter hospital stay (6±3 vs. 9±4 d; P=0.004). No conversions were experienced in the LSM group, and the morbidity rate was similar in both the LSM and OSM groups (16.6% vs. 20%; P=0.75). When considering the subset of 9 LSM patients and 26 OSM patients with giant spleens, the same favorable tendency of the laparoscopic group as regards surgical conversion, blood loss, and hospital stay was maintained. The laparoscopic approach can be successfully proposed in the presence of massive splenomegaly also after a careful preoperative evaluation of the expected abdominal "working space." In experienced hands, LS is safe, feasible, and associated with better outcomes than open splenectomy for the treatment of massive and giant spleen, with a maximum SLD limit of 31 cm.

Increased incidence of axonal Guillain-Barré syndrome in La Spezia area of Italy: A 13-year follow-up study.

Guillain-Barré syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy with a worldwide incidence of 0.81-1.89 per 100 000 person-years. In Europe and North America only 5% of patients with GBS have axonal subtypes, which in South America and Asia account for 30%-47% of cases. The aim of our study is to assess the annual incidence and clinical features of GBS in La Spezia area in Italy. A retrospective (from 1 January 2003 to 31 December 2011) followed by a prospective (from 1 January 2012 to 31 December 2015) analysis was carried out on patients admitted to La Spezia hospital who fulfilled the GBS diagnostic criteria. A total of 86 patients (58 men), mean age of 62.7 years (range 21-90), were included. The mean annual incidence rate was 3/100 000 (range: 0.9/100 000-5.37/100 000) significantly higher than the European incidence (P < 0.001). Forty-seven percent were classified as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 35% as acute motor and motor-sensory axonal neuropathy (AMAN-AMSAN), 13% as variant forms, and 5% were not defined. AIDP was most common in "Golfo dei Poeti" (50%) and "Val di Magra" (63.2%), whereas AMAN/AMSAN prevailed in "Val di Vara" (63.6%) and "Riviera Spezzina" (62.5%) (P = 0.024). In La Spezia area GBS incidence (especially the AMAN subtype) is significantly higher than the incidence reported in Europe. AIDP predominates in the eastern area whereas AMAN/AMSAN in the western, with a significantly different incidence rate (P = 0.003). Prospective studies to assess possible predisposing environmental factors are needed.

Innovative quantitative testing of hand function in Charcot-Marie-Tooth neuropathy.

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.

Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis--establishing disease prognosis and monitoring patients.

The role of MRI in the assessment of multiple sclerosis (MS) goes far beyond the diagnostic process. MRI techniques can be used as regular monitoring to help stage patients with MS and measure disease progression. MRI can also be used to measure lesion burden, thus providing useful information for the prediction of long-term disability. With the introduction of a new generation of immunomodulatory and/or immunosuppressive drugs for the treatment of MS, MRI also makes an important contribution to the monitoring of treatment, and can be used to determine baseline tissue damage and detect subsequent repair. This use of MRI can help predict treatment response and assess the efficacy and safety of new therapies. In the second part of the MAGNIMS (Magnetic Resonance Imaging in MS) network's guidelines on the use of MRI in MS, we focus on the implementation of this technique in prognostic and monitoring tasks. We present recommendations on how and when to use MRI for disease monitoring, and discuss some promising MRI approaches that may be introduced into clinical practice in the near future.

Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process.

The clinical use of MRI in patients with multiple sclerosis (MS) has advanced markedly over the past few years. Technical improvements and continuously emerging data from clinical trials and observational studies have contributed to the enhanced performance of this tool for achieving a prompt diagnosis in patients with MS. The aim of this article is to provide guidelines for the implementation of MRI of the brain and spinal cord in the diagnosis of patients who are suspected of having MS. These guidelines are based on an extensive review of the recent literature, as well as on the personal experience of the members of the MAGNIMS (Magnetic Resonance Imaging in MS) network. We address the indications, timing, coverage, reporting and interpretation of MRI studies in patients with suspected MS. Our recommendations are intended to help radiologists and neurologists standardize and optimize the use of MRI in clinical practice for the diagnosis of MS.

Hematopoietic mobilization: Potential biomarker of response to natalizumab in multiple sclerosis.

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.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.

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.

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials.

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI--and patient--resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.

MRI predictors of long-term evolution in amyotrophic lateral sclerosis.

We investigated whether conventional and diffusion tensor (DT) magnetic resonance imaging (MRI) features of the corticospinal tract (CST) contribute to the prediction of the long-term clinical evolution in patients with amyotrophic lateral sclerosis (ALS). Brain conventional and DT MRI were obtained from 18 healthy subjects and 24 patients with sporadic ALS. Mean diffusivity (MD) and fractional anisotropy (FA) of the CST were obtained. Patients were scanned at baseline, then entered a longitudinal clinical follow-up. The ALS Functional Rating scale (ALSFRS) progression rate during follow-up was estimated. Patients were followed up prospectively for a median period of 3.4 years. Two patients were lost at follow-up and eight died during the observation period. The mean ALSFRS progression rate was 0.7/month (range = 0.0­2.0/month). At baseline, ALS patients showed significantly increased MD and decreased FA of the CST compared with controls. CST FA was associated with ALSFRS progression rate. ALSFRS deterioration rate and CST FA were independent predictors of survival in ALS patients. Survival at year 3 was 42% in patients with CST FA ≤ 0.56 compared with 90% in patients with CST FA > 0.56. This study shows that more severe CST DT MRI abnormalities predict a poorer long-term clinical outcome in ALS patients. DT MRI of the brain has the potential to offer in vivo markers of disease severity.

Assessing changes in relapse rates in multiple sclerosis.

Multiple Sclerosis (MS) annualized relapse rates (ARRs) in trials may be declining due to changes in diagnostic criteria, MS etiology, study criteria, and selection biases. This review examines if there is a trend in the ARR for relapsing-remitting MS patients (RRMS) over time and if so, why. A comprehensive literature search was performed using PubMed, Web of Science(®), and the Cochrane Library using electronic searches, screen scraping for abstracts, and hand searching of references for randomized trials conducted between 1960 and 2008. Out of 72 randomized trials, 56 (77.8%) defined relapse. This study uses 32 placebo relapsing-remitting studies out of the 37 (66.1%) with RRMS. The mean ARR for the treatment arms was 0.68 and the one for the placebo groups was 1.002. The year of publication was negatively associated with the ARR (p = 0.0001). The annual reduction amounts to 0.36 relapses over a 10-year period. Age and duration of symptoms were negatively associated with the ARR. Year of publication was significantly negatively associated with ARR after controlling for covariates. ARRs have fallen with relapse definition, entrance criteria remain important, but time exceeds all these variables and reflects two likely sources, selection of patients for trials by clinicians and rescue of patients truncating the number of multiple relapses. The impact of truncating the number of relapses on the falling rates is important, not only on the ARRs, but also on the impact of informative censoring in drop-outs.

Arginase 2 is expressed by human lung cancer, but it neither induces immune suppression, nor affects disease progression.

In human prostate cancer, Arginase 2 (ARG2) and nitric oxide synthase (NOS) are concomitantly expressed by tumor cells, and induce tumor immune escape via peroxynitrite-dependent Tyrosine nitrosylation. Since there were no data regarding this immune suppressive mechanism in other tumor types, and an evaluation of its clinical relevance in human tumors had still to be provided, we have investigated presence and clinical relevance of ARG2 and NOS expression in lung cancer. No evidence of NOS expression was found, no significant NOS enzymatic activity was detected. Instead, ARG2 protein was expressed by tumor cells. In a cohort of 120 patients, the amount of ARG2-positive tumor cells was significantly higher in small cell lung cancers (SCLC) than in non-small cell lung cancers (NSCLC). Large cell undifferentiated carcinomas had twice ARG2 than the other NSCLC subtypes. ARG2 expression was increased in Grade 3 tumors, as compared to Grades 1 and 2. However, no relationship was found with tumor size and stage, and with patient survival. Indeed, the enzyme was active, since the Arginine catabolite Ornithine was produced, but Arginine depletion was not attained. In addition, nitrotyrosine was not found in tumor tissue. Accordingly, when tumor cells isolated from lung cancer were incubated with activated autologous T cells, no inhibition of proliferation was detected. Our results indicate that ARG2 is expressed in lung cancer, but it does not induce tumor immune escape and does not affect disease progression, most probably due to the lack of concomitant NOS expression.

Clinical and conventional MRI predictors of disability and brain atrophy accumulation in RRMS. A large scale, short-term follow-up study.

To assess the value of clinical and MRI variables in predicting short-term brain atrophy accumulation and clinical evolution in a large cohort of patients with RRMS, we studied a cohort of 548 patients, previously enrolled as a placebo arm of a 14-month, double-blind trial of oral glatiramer acetate (GA). A logistic regression model with EDSS progression as the dependent variable was built to assess baseline clinical and MRI variables associated with clinical worsening during follow-up. In 466 patients with complete central brain atrophy assessment, another linear regression model with percentage central brain volume change (PCBVC) as the dependent variable was built to assess baseline clinical and MRI variables associated with atrophy development.A total of 80 patients (15%) had EDSS progression over the follow-up period. Factors independently predicting the probability to have a clinical progression were lower EDSS (OR = 0.78, 95% CI = 0.62-0.97 p = 0.02) and higher T2 LL (OR = 1.022, 95% CI = 1.006-1.038, p = 0.007) at baseline. In the 466 patients with atrophy assessment, PCBVC declined, on average, by -2.0% (SD = 2.8) (p < 0.001) over the follow-up. The multivariate PCBVC analysis revealed that the PCBVC decrease was independently correlated with higher EDSS (p = 0.03) and T2 LL (p = 0.005) at baseline. The squared correlation coefficients of the composite scores made up of EDSS and T2 LL considered together were able to explain only 3 % of the variance in disability progression and only 4 % of the variance of PCBVC.In RRMS patients, clinical and conventional MRI findings at baseline only modestly predict shortterm accumulation of brain atrophy and disability. These data confirm the need to develop clinical and MRI measures more sensitive towards the more disabling aspects of the disease.

A three-year, multi-parametric MRI study in patients at presentation with CIS.

OBJECTIVES: To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS. METHODS: Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM). RESULTS: During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00-2.77) as an independent predictor of evolution to definite MS. CONCLUSIONS: Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.

Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin M.

We evaluated the efficacy and safety of rituximab in an open-label, uncontrolled study of 13 patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (MAG) and correlated the response to therapy with clinical and laboratory features. One year after rituximab therapy, anti-MAG immunoglobulin M (IgM) titers were significantly reduced. At that time, eight patients (62%) had improved in both the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore and the Medical Research Council sumscore for muscle strength and seven of them also in the INCAT disability score. The improvement in the mean INCAT sensory sumscore was significant at 12 months and correlated with lower anti-MAG antibody at entry and at follow-up. This study suggests that rituximab may be efficacious in patients with anti-MAG associated neuropathy and particularly on sensory impairment and in those with moderately elevated antibody titers. These findings suggest that antibody reduction below a critical level may be necessary to achieve clinical improvement.