Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Effects of Myopia on Rates of Change in Optical Coherence Tomography Measured Retinal Layer Thicknesses in People with Multiple Sclerosis and Healthy Controls.

PURPOSE: To quantify the associations of myopia with longitudinal changes in retinal layer thicknesses in people with multiple sclerosis (PwMS) and healthy controls (HC). METHODS: A cohort of PwMS and HC with recorded refractive error (RE) prospectively scanned on Cirrus HD-OCT at the Johns Hopkins MS Center was assessed for inclusion. Exclusion criteria included OCT follow-up < 6 months, ocular comorbidities, incidental OCT pathologies, and inadequate scan quality. Eyes were classified as having high myopia (HM) (RE≤ -6 diopters), low myopia (LM) (RE> -6 and ≤ -3 diopters), or no myopia (NM) (RE> -3 and ≤ +2.75). Linear mixed-effects regression models were used in analyses. RESULTS: A total of 213 PwMS (eyes: 67 HM, 98 LM, 207 NM) and 80 HC (eyes: 26 HM, 37 LM, 93 NM) were included. Baseline average ganglion cell/inner plexiform (GCIPL) and peri-papillary retinal nerve fiber layer (pRNFL) thicknesses were lower in MS HM compared with MS NM (diff: -3.2 µm, 95% CI: -5.5 to -0.8, p = 0.008 and -5.3 µm, 95% CI: -9.0 to -1.7, p = 0.004, respectively), and similarly in HC HM, as compared with HC NM. Baseline superior, inferior, and nasal pRNFL thicknesses were lower in HM compared with NM, while temporal pRNFL thickness was higher, both in MS and HC (MS: 7.1 µm, 95% CI: 2.7-11.6, p = 0.002; HC: 4.7 µm, 95% CI: -0.3 to 9.7, p = 0.07). No longitudinal differences in rates of GCIPL change were noted between HM and LM vs. NM, either in MS or HC. CONCLUSION: Cross-sectional differences in average GCIPL and pRNFL thicknesses are commonly seen in people with HM as compared to reference normative values from people with NM and can lead to false attribution of pathology if RE is not taken into account. However, our study suggests that longitudinal changes in average GCIPL thickness in PwMS with myopia are similar in magnitude to PwMS with NM, and therefore are appropriate for monitoring disease-related pathology.

Characterization of tumor-associated macrophages in prostate cancer transgenic mouse models.

BACKGROUND: Tumor-associated macrophages (TAMs) are critical components of the tumor microenvironment (TME) in prostate cancer. Commonly used orthotopic models do not accurately reflect the complete TME of a human patient or the natural initiation and progression of a tumor. Therefore, genetically engineered mouse models are essential for studying the TME as well as advancing TAM-targeted therapies. Two common transgenic (TG) models of prostate cancer are Hi-Myc and transgenic adenocarcinoma of the mouse prostate (TRAMP), but the TME and TAM characteristics of these models have not been well characterized. METHODS: To advance the Hi-Myc and TRAMP models as tools for TAM studies, macrophage infiltration and characteristics were assessed using histopathologic, flow cytometric, and expression analyses in these models at various timepoints during tumor development and progression. RESULTS: In both Hi-Myc and TRAMP models, macrophages adopt a more pro-tumor phenotype in higher histological grade tumors and in older prostate tissue. However, the Hi-Myc and TRAMP prostates differ in their macrophage density, with Hi-Myc tumors exhibiting increased macrophage density and TRAMP tumors exhibiting decreased macrophage density compared to age-matched wild type mice. CONCLUSIONS: The macrophage density and the adenocarcinoma cancer subtype of Hi-Myc appear to better mirror patient tumors, suggesting that the Hi-Myc model is the more appropriate in vivo TG model for studying TAMs and TME-targeted therapies.

Evaluation of Patient and Family Engagement Strategies to Improve Medication Safety.

BACKGROUND: Patient and family engagement (PFE) is critical for patient safety. We systematically reviewed types of PFE strategies implemented and their impact on medication safety. METHODS: We searched MEDLINE, EMBASE, reference lists and websites to August 2016. Two investigators independently reviewed all abstracts and articles, and articles were additionally reviewed by two senior investigators for selection. One investigator abstracted data and two investigators reviewed the data for accuracy. Study quality was determined by consensus. Investigators developed a framework for defining the level of patient engagement: informing patients about medications (Level 1), informing about engagement with health care providers (Level 2), empowering patients with communication tools and skills (Level 3), partnering with patients in their care (Level 4), and integrating patients as full care team members (Level 5). RESULTS: We included 19 studies that mostly targeted older adults taking multiple medications. The median level of engagement was 2, ranging from 2-4. We identified no level 5 studies. Key themes for patient engagement strategies impacting medication safety were patient education and medication reconciliation, with a subtheme of patient portals. Most studies (84%) reported implementation outcomes. The most commonly reported medication safety outcomes were medication errors, including near misses and discrepancies (47%), and medication safety knowledge (37%). Most studies (63%) were of medium to low quality, and risk of bias was generally moderate. Among the 11 studies with control groups, 55% (n = 6) reported statistically significant improvement on at least one medication safety outcome. Further synthesis of medication safety measures was limited due to intervention and outcome heterogeneity. CONCLUSIONS: Key strategies for engaging patients in medication safety are education and medication reconciliation. Patient engagement levels were generally low, as defined by a novel framework for determining levels of patient engagement. As more patient engagement studies are conducted, this framework should be evaluated for associations with patient outcomes.