Citations

Abstract This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich‐club) brain regions on functional outcome post‐stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3‐months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI‐GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas‐defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non‐rich club regions. In spatial specificity analyses, we randomized the split into “rich club” and “non‐rich club” regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex‐specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female‐specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club‐combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long‐term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Abstract Objectives ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. Methods This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. Results Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). Conclusion Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.

Objective The radiologically isolated syndrome (RIS) represents the earliest detectable pre‐clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. Methods We conducted a multi‐center, randomized, double‐blinded, placebo‐controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow‐up period of 96 weeks. An intention‐to‐treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov , NCT02739542 (ARISE). Results Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96‐week study period was highly reduced in the unadjusted Cox proportional‐hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05–0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). Interpretation This is the first randomized clinical trial demonstrating the benefit of a disease‐modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604–614

Abstract Background The minimum clinically important difference (MCID) is intended to detect a change in a patient-reported outcome measure (PROM) large enough for a patient to appreciate. Their growing use in orthopaedic research stems from the necessity to identify a metric, other than the p value, to better assess the effect size of an outcome. Yet, given that MCIDs are population-specific and that there are multiple calculation methods, there is concern about inconsistencies. Given the increasing use of MCIDs in total hip arthroplasty (THA) research, a systematic review of calculated MCID values and their respective ranges, as well as an assessment of their applications, is important to guide and encourage their use as a critical measure of effect size in THA outcomes research. Questions/purposes We systematically reviewed MCID calculations and reporting in current THA research to answer the following: (1) What are the most-reported PROM MCIDs in THA, and what is their range of values? (2) What proportion of studies report anchor-based versus distribution-based MCID values? (3) What are the most common methods by which anchor-based MCID values are derived? (4) What are the most common derivation methods for distribution-based MCID values? (5) How do the reported medians and corresponding ranges compare between calculation methods for each PROM? Methods The EMBASE, MEDLINE, and PubMed databases were systematically reviewed from inception through March 2022 for THA studies reporting an MCID value for any PROMs. Two independent authors reviewed articles for inclusion. All articles calculating new PROM MCID scores after primary THA were included for data extraction and analysis. MCID values for each PROM, MCID calculation method, number of patients, and study demographics were extracted from each article. In total, 30 articles were included. There were 45 unique PROMs for which 242 MCIDs were reported. These studies had a total of 1,000,874 patients with a median age of 64 years and median BMI of 28.7 kg/m 2 . Women made up 55% of patients in the total study population, and the median follow-up period was 12 months (range 0 to 77 months). The overall risk of bias was assessed as moderate using the modified Methodological Index for Nonrandomized Studies criteria for comparative studies (the mean score for comparative papers in this review was 18 of 24, with higher scores representing better study quality) and noncomparative studies (for these, the mean score was 10 of a possible 16 points, with higher scores representing higher study quality). Calculated values were classified as anchor-based, distribution-based, or not reported. MCID values for each PROM, MCID calculation method, number of patients, and study demographics were extracted from each study. Anchor-based and distribution-based MCIDs were compared for each unique PROM using a Wilcoxon rank sum test, given the non-normal distribution of values. Results The Oxford Hip Score (OHS) and the Hip Injury and Osteoarthritis Score (HOOS) Pain and Quality of Life subscore MCIDs were the most frequently reported, comprising 12% (29 of 242), 8% (20 of 242), and 8% (20 of 242), respectively. The EuroQol VAS (EQ-VAS) was the next-most frequently reported (7% [17 of 242]) followed by the EuroQol 5D (EQ-5D) (7% [16 of 242]). The median anchor-based value for the OHS was 9 (IQR 8 to 11), while the median distribution-based value was 6 (IQR 5 to 6). The median anchor-based MCID values for HOOS Pain and Quality of Life were 33 (IQR 28 to 35) and 25 (14 to 27), respectively; the median distribution-based values were 10 (IQR 9 to 10) and 13 (IQR 10 to 14), respectively. Thirty percent (nine of 30) of studies used an anchor-based method to calculate a new MCID, while 40% (12 of 30) used a distribution-based technique. Thirty percent of studies (nine of 30) calculated MCID values using both methods. For studies reporting an anchor-based calculation method, a question assessing pain relief, satisfaction, or quality of life on a five-point Likert scale was the most commonly used anchor (30% [eight of 27]), followed by a receiver operating characteristic curve estimation (22% [six of 27]). For studies using distribution-based calculations, the most common method was one-half the standard deviation of the difference between preoperative and postoperative PROM scores (46% [12 of 26]). Most reported median MCID values (nine of 14) did not differ by calculation method for each unique PROM (p > 0.05). The OHS, HOOS JR, and HOOS Function, Symptoms, and Activities of Daily Living subscores all varied by calculation method, because each anchor-based value was larger than its respective distribution-based value. Conclusion We found that MCIDs do not vary very much by calculation method across most outcome measurement tools. Additionally, there are consistencies in MCID calculation methods, because most authors used an anchor question with a Likert scale for the anchor-based approach or used one-half the standard deviation of preoperative and postoperative PROM score differences for the distribution-based approach. For some of the most frequently reported MCIDs, however, anchor-based values tend to be larger than distribution-based values for their respective PROMs. Clinical Relevance We recommend using a 9-point increase as the MCID for the OHS, consistent with the median reported anchor-based value derived from several high-quality studies with large patient groups that used anchor-based approaches for MCID calculations, which we believe are most appropriate for most applications in clinical research. Likewise, we recommend using the anchor-based 33-point and 25-point MCIDs for the HOOS Pain and Quality of Life subscores, respectively. We encourage using anchor-based MCID values of WOMAC Pain, Function, and Stiffness subscores, which were 29, 26, and 30, respectively.

Abstract BACKGROUND Emavusertib, an oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, targets toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathway in B-cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of NF-κB, causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). In a murine PDX model of primary CNS lymphoma (PCNSL), emavusertib crossed the blood-brain barrier, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vivo anti-cancer synergy in B-cell NHL. METHODS This is an ongoing open-label trial (NCT03328078) in patients with R/R NHL. Currently, we are in the dose escalation portion of combination therapy to evaluate safety and efficacy following treatment of emavusertib at dose levels of 200 or 300mg BID with ibrutinib at full prescribed dose. As of May 6th, 2022, 13 patients have been treated with emavusertib+ibrutinib combination therapy. RESULTS Among the 13 patients, two were diagnosed with R/R PCNSL and had several prior lines of anti-cancer therapy. Emavusertib in combination with ibrutinib (560 mg daily) appeared to be well tolerated in these two subjects. One patient experienced Gr3 treatment-related adverse events (thrombocytopenia, muscle weakness, pain). The preliminary efficacy data demonstrated one CR and one SD. The patient who achieved CR after the combination therapy was originally intolerant to high-dose methotrexate based chemoimmunotherapy and did not achieve complete remission after switching to ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. CONCLUSION In R/R PCNSL, these preliminary data suggest that combination therapy has a tolerable safety profile with promising anti-cancer activity and may overcome ibrutinib resistance.

Abstract While the allure of targeted therapies in oncology has been their high degree of specificity and potency for key tumor drivers, they have been disappointing in glioblastoma (GBM), even for drugs that are blood brain barrier permeable and CNS retained. This point is highlighted by the experience with mitotic spindle inhibitors, drugs which block the G2M transition and induce mitotic catastrophe—a phenotype characterized by cell enlargement and polyploidy that leads to apoptotic cell death. We have shown that one of these, a potent inhibitor of the mitotic kinesin Kif11 (ispinesib), is highly active against GBM tumor initiating cells and prolongs survival in murine models of this disease. However, tumors eventually progress, reflecting the development of drug resistance. Although ispinesib resistant GBM cells develop mitotic catastrophe, they become highly resistant to the apoptosis that typically follows and continue to proliferate. We find that this apoptosis resistance requires phosphorylation of the transcription factor STAT3 at two residues—Y705 and S727. Phosphorylation of Y705, mediated by SRC kinase, translocates STAT3 to the nucleus where it induces transcription of anti-apoptotic proteins. Phosphorylation at S727, mediated by EGFR, translocates STAT3 to the mitochondria where it blocks release of cytochrome c—the penultimate effector in apoptosis. Simultaneously inhibiting both SRC and EGFR with FDA-approved, CNS permeant inhibitors reverses this resistance and significantly prolongs survival in ispinesib-treated GBM-bearing mice. Furthermore, we find that resistance to several other mitotic inhibitors also utilizes this STAT3-driven mechanism and can likewise be reversed with combined EGFR and SRC inhibition. Thus, our work demonstrates how a promising therapeutic approach, which has been disappointing in GBM, can in fact be rendered effective by anticipating and prospectively treating ab initio the mechanism that drives treatment resistance.