Longitudinal myelin content measures of slowly expanding lesions using 7T MRI in multiple sclerosis.

BACKGROUND AND PURPOSE: Slowly expanding lesions (SELs) are thought to represent a subset of chronic active lesions and have been associated with clinical disability, severity, and disease progression. The purpose of this study was to characterize SELs using advanced magnetic resonance imaging (MRI) measures related to myelin and neurite density on 7 Tesla (T) MRI. METHODS: The study design was retrospective, longitudinal, observational cohort with multiple sclerosis (n = 15). Magnetom 7T scanner was used to acquire magnetization-prepared 2 rapid acquisition gradient echo and advanced MRI including visualization of short transverse relaxation time component (ViSTa) for myelin, quantitative magnetization transfer (qMT) for myelin, and neurite orientation dispersion density imaging (NODDI). SELs were defined as lesions showing ≥12% of growth over 12 months on serial MRI. Comparisons of quantitative measures in SELs and non-SELs were performed at baseline and over time. Statistical analyses included two-sample t-test, analysis of variance, and mixed-effects linear model for MRI metrics between lesion types. RESULTS: A total of 1075 lesions were evaluated. Two hundred twenty-four lesions (21%) were SELs, and 216 (96%) of the SELs were black holes. At baseline, compared to non-SELs, SELs showed significantly lower ViSTa (1.38 vs. 1.53, p < .001) and qMT (2.47 vs. 2.97, p < .001) but not in NODDI measures (p > .27). Longitudinally, only ViSTa showed a greater loss when comparing SEL and non-SEL (p = .03). CONCLUSIONS: SELs have a lower myelin content relative to non-SELs without a difference in neurite measures. SELs showed a longitudinal decrease in apparent myelin water fraction reflecting greater tissue injury.

The relationship between cognition, education, and employment in multiple sclerosis patients.

Background: Processing speed decline is a common manifestation of multiple sclerosis (MS). The processing speed test (PST) is a validated electronic cognitive assessment based on the Symbol-Digit Modalities Test, which is routinely administered as part of the multi-institutional Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) initiative. The longitudinal relationship between education, processing speed, and employment is unclear. Objectives: Determine the longitudinal impact of educational attainment on processing speed and employment. Methods: MS PATHS data through March 2020 were analyzed. Repeat PST assessments at 1, 2, and 3 years were classified as improved, worsened, or stable. Linear regression was used to evaluate the relationship between education and baseline PST performance and logistic regression was used to determine the odds of PST worsening by educational attainment. Employment outcomes were analyzed by PST status and educational level. Results: There were 13,732 patients analyzed. Education impacted baseline PST scores, but had a limited effect on PST performance over time. Education was protective with respect to employment in the setting of both PST worsening and improvement. Conclusion: Greater education results in better baseline processing speed and is protective with respect to employment status. Its impact on processing speed over time is marginal.

Symptomatic and restorative therapies in neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune inflammatory conditions that primarily target the optic nerves, spinal cord, brainstem, and occasionally the cerebrum. NMOSD is characterized by recurrent attacks of visual, motor, and/or sensory dysfunction that often result in severe neurological deficits. In recent years, there has been a significant progress in relapse treatment and prevention but the residual disability per attack remains high. Although symptomatic and restorative research has been limited in NMOSD, some therapeutic approaches can be inferred from published case series and evidence from multiple sclerosis literature. In this review, we will discuss established and emerging therapeutic options for symptomatic treatment and restoration of function in NMOSD. We highlight NMOSD-specific considerations and identify potential areas for future research. The review covers pharmacologic, non-pharmacologic, and neuromodulatory approaches to neuropathic pain, tonic spasms, muscle tone abnormalities, sphincter dysfunction, motor and visual impairment, fatigue, sleep disorders, and neuropsychological symptoms. In addition, we briefly discuss remyelinating agents and mesenchymal stem cell transplantation in NMOSD.

Clinical features and outcomes of COVID-19 despite SARS-CoV-2 vaccination in people with multiple sclerosis.

BACKGROUND: Several studies have demonstrated reduced serological response to vaccines in patients treated with anti-CD20 agents. However, limited data exist surrounding the clinical effect of disease modifying therapy (DMT) use on vaccine efficacy. OBJECTIVES: To investigate breakthrough coronavirus disease 2019 (COVID-19) in vaccinated people with multiple sclerosis (PwMS) on DMT. METHODS: PwMS on DMT diagnosed with COVID-19 after full vaccination were identified from an existing Cleveland Clinic COVID-19 registry, supplemented by provider-identified cases. Demographics, disease history, DMTs, comorbidities, exposures, vaccination status, and COVID-19 outcomes were confirmed by review of the electronic medical record. RESULTS: Thirteen (3.8%) of 344 fully vaccinated people with multiple sclerosis on disease modifying therapy were diagnosed with COVID-19 after vaccination. Ten patients (76.9%) were on an anti-CD20 therapy, the remaining 3 (23.1%) on fingolimod. Only 2 patients (15.4%), both on anti-CD20 therapy, required hospitalization and steroid treatment. Neither required Intensive Care Unit admission. CONCLUSION: Patients treated with anti-CD20 agents and sphingosine 1-phosphate receptor modulators may still be at risk for COVID-19 despite vaccination. While still at risk for hospitalization, intubation and death from COVID-19 appear rare. Larger studies analyzing how this may differ in the setting of emerging variants are needed.

Measures of Thalamic Integrity are Associated with Cognitive Functioning in Fingolimod-treated Multiple Sclerosis Patients.

BACKGROUND: Cognitive impairment is common in relapsing-remitting multiple sclerosis (RRMS) and multiple domains are affected, including information processing speed, episodic memory, and executive function. Damage to the thalamus appears to be related to cognitive functioning in MS. Fingolimod is a disease-modifying therapy for RRMS, which has been shown to have a protective effect on thalamic volume. OBJECTIVE: To determine the relationship between cognitive measures and the thalamus in fingolimod-treated RRMS patients and healthy controls using ultra high-field magnetic resonance imaging (MRI). METHODS: Fingolimod-treated RRMS and healthy participants were recruited from a single center to undergo neuropsychological testing and 7 tesla MRI. These assessments were performed at baseline, 6 months, and 12 months. The neuropsychological testing included the Brief Visuospatial Memory Test-Revised (BVMTR), the Symbol Digit Modalities Test (SDMT), the Selective Reminding Test (SRT), and the Delis-Kaplan Executive Function System (DKEFS). MRI metrics included thalamic volume, thalamic myelin density, thalamic axon density, T2 lesion volume, brain parenchymal fraction, and cortical thickness. Mixed-effects linear regression was used to determine the relationship between MRI parameters and neuropsychological test performance over time. Rates of change in patients and controls were compared using two-sample t-tests. RESULTS: We enrolled 15 RRMS patients and 5 healthy controls. Controls performed better than patients at baseline, but this difference was only significant for the letter fluency subtest of the DKEFS and for long-term storage as assessed by the SRT. Thalamic volume and thalamic myelin density were significantly associated with visuospatial (BVMTR) and verbal memory (SRT). Thalamic volume alone was also associated with inhibitory control (Color word interference subtest of the DKEFS) and cognitive flexibility (Number letter switching subtest of the DKEFS), whereas thalamic myelin density alone was associated with semantic knowledge (Verbal fluency subtest of the DKEFS). There were no significant changes in the rates of change in neurometric test performance or MRI metrics between patients and controls from baseline to 6 months and baseline to 12 months. CONCLUSIONS: Thalamic injury is associated with cognitive performance in several domains. Fingolimod-treated RRMS patients evolved similarly to healthy controls over one year with regards to neuropsychological test performance and changes on MRI.

Assessing Access to Five Types of Insurance by People with Multiple Sclerosis Using a Cross-sectional Online Survey.

BACKGROUND: Many individuals with multiple sclerosis (MS) depart the workforce prematurely. In the United States, access to insurance, including health, disability income, long-term care, and life insurance, is largely employment-based or purchased from earnings. Many individuals we see in the clinic experience financial hardship because of a lack of insurance, even if working. We sought to determine the proportion of workers who are financially protected through insurance coverage and the sources of this coverage in a large sample. METHODS: We developed an online survey and opened it to individuals aged 18 to 65 years registered with the North American Research Committee on Multiple Sclerosis, iConquerMS, or the National Multiple Sclerosis Society Minority Advisory Council. Data collected included demographic and disease characteristics, current information about each insurance type (coverage vs no coverage), and when the current insurance policies were obtained relative to MS diagnosis. RESULTS: Of 2507 survey respondents, 82.9% were female, 3.8% Hispanic/Latino, and 91.2% White. The mean ± SD age was 53.5 ± 8.5 years and disease duration was 16.4 ± 8.5 years after diagnosis. The most frequently held insurance types were health (96.3%) and life (58.8%). Only 9.7% of respondents had long-term care insurance. Except for life insurance, most current policies were obtained after MS diagnosis. CONCLUSIONS: Individuals with MS might not prioritize the possible short- and long-term benefits of these types of insurance. Health care providers can direct patients to nonprofit agencies that educate about of these insurance types and emphasize that others with MS have obtained these insurance types after their diagnosis.

Obtaining Patient Priorities in a Multiple Sclerosis Comprehensive Care Center: Beyond Patient-Reported Outcomes.

BACKGROUND: In order to provide patient center care, our multiple sclerosis (MS) clinic assesses patient concerns before clinical encounters, first by asking the optional qualitative question "What is the most important thing you what your health-care provider to know today" (most important concern of the patient [MIPC]) and then completing quantitative patient-reported outcome measures (PROMs) including Quality of Life in Neurological Disorders (Neuro-QoL). Both sets of questions are designed to facilitate encounters that address patients' values and preferences. OBJECTIVE: Determine whether the qualitative MIPC responses provided unique information not included in PROMs or clinical assessments. METHODS: We randomly selected 400 first-time MIPC responders and 400 first-time MIPC nonresponders from 2788 participants in our database. We categorized MIPC responses by content and number of unique concerns and appended them to the Neuro-QoL framework. Nonresponders were compared to those who provided 1 and 2 or more responses. RESULTS: Several MIPCs MS symptoms categories were added to the Neuro-QoL Physical domain. Most important concern of the patients work and cost-of-care categories were added to the Social Domain. Domains regarding treatment satisfaction and disease management were added. Two hundred thirty (58%) MIPC respondents reported 1 concern, 140 (35%) expressed 2 to 6 concerns, and 30 (7%) reported MS-unrelated concerns and not analyzed. Physical symptoms were the most common MIPC (69.9%). Respondents with more concerns were more likely African American, lacked private insurance, and worse disability. CONCLUSIONS: Importantly, MIPC responders described idiosyncratic symptoms, disease management, and social concerns not included in the PROMS, suggesting the MIPC question offered patients a unique opportunity to share specific concerns with their providers.

Does obesity exacerbate brain lesion volume and atrophy in patients with multiple sclerosis?

BACKGROUND: Obesity is common among patients with multiple sclerosis (pwMS) and has been shown to exacerbate central inflammation, a key factor in disease progression. The purpose of this cross-sectional study is to examine the possible relationships between obesity, as measured by body mass index (BMI), and MS-related brain changes in atrophy and lesion volume, as measured from MRI, in a large, representative sample of pwMS. METHODS: BMI and MRI data, along with demographic and disease variables, were acquired from the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) registry. Unadjusted and adjusted partial correlations, controlling for gender, race, age, education level, MS phenotype, disability and disease duration, examined the associations between BMI and MRI outcomes, which included brain parenchymal fraction, white matter fraction, gray matter fraction, thalamic volume, and T2 lesion volume. RESULTS: The sample consisted of 3,046 pwMS. Unadjusted and adjusted BMI-MRI correlations accounted for between 0.4% and 2.0% of shared variance (R2). When considering the relationship between MRI outcomes and BMI category (normal weight, overweight, obese), multiple regression analyses continued to show minimal association, with BMI category accounting for no more than 1.5% of shared variance. CONCLUSIONS: No clinically meaningful associations were found between BMI and MRI outcomes in this large, representative sample of MS patients, regardless of demographics and disease variables. These unexpected negative results will require replication with a longitudinal design using more precise measures of obesity.

Achieving effective patient and public involvement in international clinical trials in neurology.

There is a growing need for patient and public involvement (PPI) to inform the way that research is developed and performed. International randomized controlled trials are particularly likely to benefit from PPI, but guidance is lacking on how or when it should be incorporated. In this article, we describe the PPI process that occurred during the design and initiation of an international treatment clinical trial in MS. PPI was incorporated using a structured approach, aiming to minimize bias and achieve equivalence in study design, implementation, and interpretation. Methods included PPI representation within the study research team, and the use of focus groups, analyzed using thematic framework analysis. We report the outcomes of PPI and make recommendations on its use in other neurology clinical trials. By sharing our model for PPI, we aim to maximize effectiveness of future public involvement and to allow its effect to be better evaluated.

Is Obesity Related to Processing Speed Impairment in Patients with Multiple Sclerosis: Results of a Large-Scale, Multicenter Study.

BACKGROUND: Obesity is linked to greater physical disability and increased comorbidities among patients with multiple sclerosis (MS). Its contribution to cognition in this group is unclear. This observational study examines the link between obesity and processing speed in a large sample of patients with MS (PwMS). METHODS: As part of routine clinical care at our center, PwMS completed the Processing Speed Test (PST), an electronic implementation of the Symbol Digit Modalities Test (SDMT). Height and weight were used to calculate body mass index (BMI). Bivariate correlations were conducted to examine the association between PST and BMI in the group overall and in subgroups based on demographic and clinical variables. A one-way ANOVA examined differences in PST by BMI categories (normal weight, overweight, obese). RESULTS: The sample included 8,713 patients. No association between PST and BMI was found in the entire sample (r = .01), nor within subgroups based on demographic and disease variables. No difference in PST score was found between BMI categories. CONCLUSIONS: No association between BMI and processing speed was found among PwMS regardless of demographic or disease-specific patient characteristics.

Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol.

Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access.

Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation.

BACKGROUND: Serum neurofilament light chain concentration is a proposed biomarker of axonal injury in multiple sclerosis. Mesenchymal stem cells have anti-inflammatory and repair-promoting activities, making them of interest for potential multiple sclerosis treatment. OBJECTIVES: The purpose of this study was to assess correlation of serum neurofilament light chain concentration and measures of multiple sclerosis disease activity/severity, longitudinal stability of serum neurofilament light chain concentration, and treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration. METHODS: Twenty-four multiple sclerosis patients underwent intravenous infusion of autologous mesenchymal stem cells. Clinical assessments, serum collection, and brain magnetic resonance imaging were performed at months -1, 0 (transplant), 1, 3, and 6. Matched control serum was collected once (n = 10). Serum neurofilament light chain concentration was measured by single-molecule array. Serum neurofilament light chain concentration correlations with disease measures were analyzed by Spearman correlations and linear mixed effect models. Pre-post transplant serum neurofilament light chain concentration was compared by Wilcoxon signed rank testing. RESULTS: There were significant (p<0.01) correlations between serum neurofilament light chain concentration and gadolinium-enhancing lesion number (rho = 0.55) and volume (rho = 0.65), and new/enlarging T2 lesions (rho = 0.65). Patients without disease activity had lower fluctuation in serum neurofilament light chain concentration (p = 0.01). Mean pre- versus post-treatment serum neurofilament light chain concentration values were not significantly different. CONCLUSIONS: Serum neurofilament light chain concentration correlated with magnetic resonance imaging measures of disease activity cross sectionally and longitudinally, and was stable in patients without disease activity. There was no clear treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.

Tuberculosis screening in multiple sclerosis: effect of disease-modifying therapies and lymphopenia on the prevalence of indeterminate TB screening results in the clinical setting.

BACKGROUND: Tuberculosis screening is recommended in multiple sclerosis patients starting certain disease-modifying therapies. Disease-modifying therapies may affect interferon-gamma release assay results. OBJECTIVE: To determine the effects of multiple sclerosis disease-modifying therapies on interferon-gamma release assay results. METHODS: Indeterminate interferon-gamma release assay results among multiple sclerosis patients were compared across disease-modifying therapies by Fisher's exact test. Logistic regression evaluated the effects of lymphopenia on interferon-gamma release assay results. RESULTS: A total of 1058 patients underwent interferon-gamma release assay: 2.0% (21) positive, 6.1% (65) indeterminate, with 59.4% (628) on disease-modifying therapies. Results were significantly different across disease-modifying therapies (P = 0.002). Absolute lymphocyte count less than 0.5 k/µL had 9.39 times (95% confidence interval 5.2-17.0) increased odds of indeterminate interferon-gamma release assay results. CONCLUSIONS: Disease-modifying therapies affecting lymphocytes had a higher risk of indeterminate interferon-gamma release assay results.

Early highly effective versus escalation treatment approaches in relapsing multiple sclerosis.

Treatment decisions in multiple sclerosis are complex given the large number of disease-modifying therapies with diverse safety and efficacy profiles. The importance of early treatment has been recognised but how intensively to treat at onset is not known. Substantial variability exists in treatment selection with weak clinical trial evidence to guide initial treatment choices. Decision-making is made more complicated by variable tolerance for risk of side-effects and inability to accurately predict treatment response. Whether to use moderately effective and safe medications with escalation as needed, or to use higher efficacy medications from the outset, is a key question in clinical practice. Clinical trials in patients with relapsing multiple sclerosis have focused on pairwise comparisons but the effectiveness of different treatment approaches has not been tested. Future pragmatic randomised clinical trials and observational studies will help to inform more rational selection of initial therapies and improve the quality of life of patients with relapsing multiple sclerosis.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Exploratory MRI measures after intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

BACKGROUND: Mesenchymal stem cells (MSC) have immunomodulatory and neuro-protective properties and are being studied for treatment of multiple sclerosis (MS). Tractography-based diffusion tensor imaging (DTI), cortical thickness (Cth) and T2 lesion volume (T2LV) can provide insight into treatment effects. OBJECTIVE: The objective of this study was to analyse the effects of MSC transplantation in MS on exploratory MRI measures. METHODS: MRIs were obtained from 24 MS patients from a phase 1 open-label study of autologous MSC transplantation. DTI metrics were obtained in lesions and normal-appearing white matter motor tracts (NAWM). T2LV and Cth were derived. Longitudinal evolution of MRI outcomes were modelled using linear mixed effects. Pearson's correlation was calculated between MRI and clinical measures. RESULTS: Lesional radial diffusivity (RD) and axial diffusivity (AD) decreased pre-transplant and showed no changes post-transplant. There were mixed trends in NAWM RD and AD pre/post-transplant. Transplantation stabilized T2LV growth. NAWM RD and AD correlated with Cth, T2LV and with leg and arm function but not with cognition. Lesional DTI demonstrated similar but less robust correlations. CONCLUSIONS: Microstructural tissue integrity is altered in MS. DTI changes pre-transplant may be influenced by concomitant lesion accrual. Contributor to DTI stabilization post-transplant is multifactorial. DTI of major motor tracts correlated well with clinical measures, highlighting its sensitivity to clinically meaningful changes.

Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. OBJECTIVE: To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. METHODS: In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 106 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. RESULTS: One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. CONCLUSION: Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

BACKGROUND: Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. OBJECTIVE: To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. METHODS: Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 106 MSCs/kg were thawed and administered IV. RESULTS: In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 106 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. CONCLUSION: Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.

Modulators of Redox Metabolism in Head and Neck Cancer.

SIGNIFICANCE: Head and neck squamous cell cancer (HNSCC) is a complex disease characterized by high genetic and metabolic heterogeneity. Radiation therapy (RT) alone or combined with systemic chemotherapy is widely used for treatment of HNSCC as definitive treatment or as adjuvant treatment after surgery. Antibodies against epidermal growth factor receptor are used in definitive or palliative treatment. Recent Advances: Emerging targeted therapies against other proteins of interest as well as programmed cell death protein 1 and programmed death-ligand 1 immunotherapies are being explored in clinical trials. CRITICAL ISSUES: The disease heterogeneity, invasiveness, and resistance to standard of care RT or chemoradiation therapy continue to constitute significant roadblocks for treatment and patients' quality of life (QOL) despite improvements in treatment modality and the emergence of new therapies over the past two decades. FUTURE DIRECTIONS: As reviewed here, alterations in redox metabolism occur at all stages of HNSCC management, providing opportunities for improved prevention, early detection, response to therapies, and QOL. Bioinformatics and computational systems biology approaches are key to integrate redox effects with multiomics data from cells and clinical specimens and to identify redox modifiers or modifiable target proteins to achieve improved clinical outcomes. Antioxid. Redox Signal.

CNS disease diminishes the therapeutic functionality of bone marrow mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have emerged as a potentially powerful cellular therapy for autoimmune diseases including multiple sclerosis (MS). Based on their success in treating animal models of MS like experimental autoimmune encephalomyelitis (EAE), MSCs have moved rapidly into clinical trials for MS. The majority of these trials use autologous MSCs derived from MS patients, although it remains unclear how CNS disease may affect these cells. Here, we report that bone marrow MSCs derived from EAE mice lack therapeutic efficacy compared to naïve MSCs in their ability to ameliorate EAE. Treatment with conditioned medium from EAE-MSCs also fails to modulate EAE, and EAE-MSCs secrete higher levels of many pro-inflammatory cytokines compared to naïve MSCs. Similarly, MSCs derived from MS patients have less therapeutic efficacy than naïve MSCs in treating EAE and secrete higher levels of some of the same pro-inflammatory cytokines. Thus diseases like EAE and MS diminish the therapeutic functionality of bone marrow MSCs, prompting reevaluation about the ongoing use of autologous MSCs as a treatment for MS.