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Mar Tintoré,1 Maggie Alexander,2 Kathleen Costello,3 Martin Duddy,4 David E Jones,5 Nancy Law,6 Gilmore O’Neill,7 Antonio Uccelli,8 Robert Weissert,9 Sibyl Wray10 1Multiple Sclerosis Centre of Catalonia, Hospital Vall d’Hebron, Barcelona, Spain; 2European Multiple Sclerosis Platform, Brussels, Belgium; 3National Multiple Sclerosis Society, Denver, CO, USA; 4Royal Victoria Infirmary, Newcastle-upon-Tyne, UK; 5Department of Neurology, University of Virginia, Charlottesville, VA, USA; 6Nancy Law Consulting LLC, Parker, CO, USA; 7Biogen, Cambridge, MA, USA; 8Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy; 9Department of Neurology, University of Regensburg, Regensburg, Germany; 10Hope Neurology Multiple Sclerosis Center, Knoxville, TN, USA Background: Managing multiple sclerosis (MS) treatment presents challenges for both patients and health care professionals. Effective communication between patients with MS and their neurologist is important for improving clinical outcomes and quality of life. Methods: A closed-ended online market research survey was used to assess the current state of MS care from the perspective of both patients with MS (≥18 years of age) and neurologists who treat MS from Europe and the US and to gain insight into perceptions of treatment expectations/goals, treatment decisions, treatment challenges, communication, and satisfaction with care, based on current clinical practice. Results: A total of 900 neurologists and 982 patients completed the survey, of whom 46% self-identified as having remitting-relapsing MS, 29% secondary progressive MS, and 11% primary progressive MS. Overall, patients felt satisfied with their disease-modifying therapy (DMT); satisfaction related to comfort in speaking with their neurologist and participation in their DMT decision-making process. Patients who self-identified as having relapsing-remitting MS were more likely to be very satisfied with their treatment. Top challenges identified by patients in managing their DMT were cost, side effects/tolerability of treatment, and uncertainty if treatment was working. Half of the patients reported skipping doses, but only 68% told their health care provider that they did so. Conclusion: Several important differences in perception were identified between patients and neurologists concerning treatment selection, satisfaction, expectations, goals, and comfort discussing symptoms, as well as treatment challenges and skipped doses. The study results emphasize that patient/neurologist communication and patient input into the treatment decision-making process likely influence patient satisfaction with treatment. Keywords: health care provider survey, multiple sclerosis, patient-health care provider relationship, patient survey, treatment expectations, treatment satisfaction

Objective To determine whether glatiramer acetate (GA)-induced lymphoproliferation and IFN-γ and IL-4 modulation correlate with the clinical response in multiple sclerosis (MS). Background GA therapy involves the induction of anti-inflammatory cytokine shifts. However, it is not known whether this response correlates with the clinical outcome. Methods Thirty-six relapsing-remitting (RR) MS patients were treated with GA for at least two years, and classified clinically as GA-responders (GA-R=/22) or hypo/non-responders (GA-HR/NR = 14). Proliferation of peripheral blood mononuclear cells (PBMC) to GA and Tetanus toxoid (TT), as well as IL-4 and IFN-γ ELISPOT, were performed. Findings There was no difference in PBMC proliferation to GA or TT between GA-R and GA-HR/NR before and during treatment (P > 0.05). The mean number of IFN-γ ELISPOTS in unstimulated, TT and anti-CD3/CD28-stimulated PBMC was lower among GA-R (unstimulated: GA-R = 10.1±/6.21 (n = /22) versus GA-HR/NR = 17.8±12.7 (n = 14), P = 0.04; TT-GA-R = 12.2±4.06 (n = 12) versus GA-HR/NR = 26.8±/21.0 (n = 8), P = 0.028; anti-CD-3/CD28 GA-R = 217.3±140.4 (n = 22) versus GA-HR/NR = 368.5±170.1 (n = 14), P = 0.006). In contrast, the number of IL-4 ELISPOTS remained unchanged in the GA-R group, but was progressively reduced in the GA-HR/NR group during GA therapy (GA-HR/NR IL-4: pre-Rx: 59 ± 34 versus 22 ± 11 at 12 months (n = 6), P = 0.0429). The IL-4/IFN-γ ratio in anti-CD3/CD28-stimulated PBMC was significantly higher among GA-R compared to GA-HR/NR (P = 0.0474). Interpretation Lymphoproliferation to GA did not differentiate GA-R from GA-HR/NR. However, reduced IFN-γ expression and stable IL-4 expression in anti-CD3/CD28-stimulated PBMC, and an increased IL-4/IFN-γ ratio was associated with favorable clinical response. More data are needed to validate the prospective use of IL-4/IFN-γ expression in PBMC as a biomarker of clinical response to GA for individual patients. [ABSTRACT FROM AUTHOR]

We conducted an open-label pilot clinical trial to evaluate the safety and efficacy of adding oral azathioprine to the treatment regimen of 15 multiple sclerosis patients breaking through monotherapy with interferon β-1b. There were no serious adverse events. Gastrointestinal side effects and leukopenia were the most common adverse events and limited dose escalation. There was a 65% reduction in the number of gadolinium-enhanced magnetic resonance imaging (MRI) lesions on combination therapy compared to the baseline values (P = 0.003). A total WBC count less than 4800/mm3 was the best predictor of MRI response. [ABSTRACT FROM AUTHOR]

The combined treatment with interferon β(IFNβ) and glatiramer acetate (GA) is of current interest in multiple sclerosis (MS). The therapeutic effect of GA in MS is believed to be mediated by GA-specific Th2 cells. IFNβ has a significant anti-proliferative effect on GA-induced lymphoproliferation in vitro. Therefore, we examined the possibility that IFNβ may interfere with the generation and phenotype of GA T-cell responses in MS patients receiving combined therapy. Sixty-six GA-specific T-cell lines (TCL) were generated ex vivo from five MS patients enrolled in an open-label clinical trial of combined IFNβ/GA treatment. Controls included 83 pretreatment and 131 on-treatment GA-TCL from 11 MS patients treated with GA only, and five GA-TCL generated from four patients receiving IFNβ-1a monotherapy. IFN γ and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by ELISA in GA-TCL supernatants. Th1/Th2 bias was defined by the IFN γ /IL-5 level ratio ( > 2=Th1 bias, < 0.5=Th2 bias, and 0.5– 2=Th0 bias). The frequency with which GA-reactive TCL were generated was 37.0% for the patients in the combination trial compared to 33.3% in the patients receiving GA alone. The mean stimulation index of the GA-TCL was 8.41 (range 2–42) for the combination compared to a mean of 6.29 (range 2–37) for the GA-treated group – a nonsignificant difference. Mean GA-TCL IFNγ production was significantly lower in all treatment groups compared to pretreatment. IL-5 levels were enhanced in all treatment groups compared to pretreatment levels, but the change was not statistically significant. The Th1/Th0/Th2 distribution of GA-TCL was 7%/30%/63% for the GA+IFNβ group, compared to 48%/21%/31% pre-GA treatment. All five GA-TCL from the IFNβ-1a monotherapy patients were Th2-biased. We conclude that IFNβ-1a does not affect the generation of GA-reactive T cells in vivo. Although more Th0 GA-TCL occurred with combination therapy than with GA treatment alone, both groups shared an overall Th2 bias. Therefore, we speculate that combined therapy is unlikely to reduce the efficacy of GA treatment in MS. [ABSTRACT FROM AUTHOR]

Glatiramer acetate (GA) is an approved treatment for multiple sclerosis (MS). The proposed mechanism of action is the induction of GA-specific T cells characterized by protective anti-inflammatory Th2 response. We tested this hypothesis in 11 MS patients treated with GA from 1 – 19 months. Interferon-γ and IL-5 (markers of Th1 and Th2 responses respectively) were assayed by ELISA in GA-specific T-cell lines (TCL) supernatants. Th1/Th2 bias was defined based on the ratio of IFN-γ/IL-5 secretion. Fifty-eight pre-treatment, and 75 on-treatment GA-specific TCL were generated. On-treatment mean IL-5 levels in GA-TCL increased significantly, whereas those for IFN-γ were markedly reduced. Consequently, the ratio of IFN-γ/IL-5 also shifted in favor of a Th2 response. The percentage of GA-TCL classified as Th1 was decreased, whereas those classified as Th2 increased on-treatment as compared to pre-treatment. Some GA-specific TCL, (approximately 25%) generated during treatment secreted predominantly IL-5 in response to MBP and the immunodominant MBP peptide 83 – 99, indicating that these crossreactive antigens can act as partial agonists for GA-reactive TCL. These results strongly suggest that the mechanism of action of GA in MS involves the induction of crossreactive GA-specific T cells with a predominant Th2 cytokine profile. [ABSTRACT FROM AUTHOR]

Abstract Background Human balance during quiet standing is influenced by adding mass to the body with a backpack, with symmetrically-applied loads to the trunk, or with obesity. Adding mass to the body increases both the weight and inertia of the body, which theoretically could provide counteracting effects on body dynamics and balance. Understanding the independent effects of adding weight and inertia on balance may provide additional insight into human balance that could lead to novel advancements in balance training and rehabilitation. Therefore, the purpose of this study was to investigate the independent effects of adding weight and inertia on balance during quiet standing. Methods Sixteen normal-weight young adult participants stood as still as possible on a custom-built backboard apparatus under four experimental conditions: baseline, added inertia only, added weight only, and added inertia and weight. Results Adding inertia by itself had no measurable effect on center of pressure movement or backboard movement. Adding weight by itself increased center of pressure movement (indicated greater effort by the postural control system to stand as still as possible) and backboard movement (indicating a poorer ability of the body to stand as still as possible). Adding inertia and weight at the same time increased center of pressure movement but did not increase backboard movement compared to the baseline condition. Conclusions Adding inertia and adding weight had different effects on balance. Adding inertia by itself had no effect on balance. Adding weight by itself had a negative effect on balance. When adding inertia and weight at the same time, the added inertia appeared to lessen (but did not eliminate) the negative effect of adding weight on balance. These results improve our fundamental understanding of how added mass influences human balance.

Accelerated partial breast irradiation (APBI) and hypofractionated partial breast irradiation (PBI) have emerged as alternative treatments to whole breast irradiation (WBI) for many patients with early breast cancer (BC) based on randomized clinical trials involving > 10,000 patients. As trial data matured, many societies, including the American Society for Radiation Oncology, issued consensus statements regarding suitability of patients for APBI or PBI (A/PBI). However, there are few data regarding utilization of A/PBI in patients with early BC. We examine the National Cancer Database (NCDB) to evaluate the hypothesis that A/PBI use has increased over time but is still used in a minority of patients. Within the NCDB, we identified patients who underwent margin-negative breast conserving surgery and adjuvant radiation therapy in the years 2010-2021 with the following favorable criteria: hormone-receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-); age ≥50 yr; pathologic T1N0; grade 1-2; non-lobular histology; no neoadjuvant systemic therapy use. Patients with missing dosimetry data, those coded as receiving total dose > 66Gy and/or > 36 fractions (Fx), and/or dose groups in which fewer than 250 patients were treated were excluded from analysis. We further classified by type of APBI/PBI technique: external beam (EB-APBI), brachytherapy (Brachy), intraoperative radiation therapy (IORT), or hypofractionated external beam PBI (EB-PBI). We used the following definitions:18Gy/1Fx or 34Gy/10Fx (Brachy); 20Gy in 1Fx or 21Gy/1Fx (IORT); 30Gy/5Fx or 38.5Gy/10Fx (EB-APBI) From 2018-2021, patients that received 40-40.5Gy/15Fx and coded as having received PBI were classified as EB-PBI. All others WBI. Chi-Square test is used to evaluate trends in A/PBI use. Of an initial 3,956,621 patients in the NCDB, 317,437 patients met the eligibility criteria and 242,817 had complete radiation dosimetry data. In this cohort, 25,973(10.7%) received A/PBI, while 216,844(89.3%) underwent WBI. Among patients that underwent A/PBI, 36.7% received EB-APBI, 32% brachy, 20.5% IORT, and 10.7% EB-PBI. The use for A/PBI increased from 8.0% (2010-2017) to 13.7% (2018-2021) (p<0.001). The use of 30Gy/5Fx EB-APBI also increased significantly from 512(1.7%) in 2019 to 2,672(8.8%) in 2021 (p<0.001). In the final year, among the 30,346 patients analyzed, 5444(17.9%) received any form of A/PBI and 3,213(10.6%) were treated with either 30Gy/5Fx EB-APBI or brachy. Over the past decade there has been a significant rise in A/PBI use in patients with low-risk HR+/HER2- BC. Despite the increasing trend, even in the most recent year, less than one in five potentially eligible patients receive A/PBI. Further, among patients treated in 2021, only one in ten patients receive 30Gy/5Fx EB-APBI or brachytherapy, two forms of APBI which possess the combination of similar cancer control outcomes, greater convenience and less toxicity compared to WBI. [ABSTRACT FROM AUTHOR]