Faculty Bibliography

Members of a disintegrin and metalloproteinases with thrombospondin motif (ADAMTS) family have been implicated in various vascular diseases. However, their functional roles in early embryonic vascular development are unknown. In this study, we showed that Adamts18 is highly expressed at E11.5-E14.5 in cells surrounding the embryonic aortic arch (AOAR) and the common carotid artery (CCA) during branchial arch artery development in mice. Adamts18 deficiency was found to cause abnormal development of AOAR, CCA, and the third and fourth branchial arch appendages, leading to hypoplastic carotid body, thymus, and variation of middle cerebral artery. Adamts18 was shown to affect the accumulation of extracellular matrix (ECM) components, in particular fibronectin (Fn), around AOAR and CCA. As a result of increased Fn accumulation, the Notch3 signaling pathway was activated to promote the differentiation of cranial neural crest cells (CNCCs) to vascular smooth muscle cells. These data indicate that Adamts18-mediated ECM homeostasis is crucial for the differentiation of CNCCs.

OBJECTIVE:We reviewed the literature on cerebrospinal fluid (CSF) testing in patients with altered olfactory/gustatory function due to COVID-19 for evidence of viral neuroinvasion. METHODS:We performed a systematic review of Medline and Embase to identify publications that described at least one patient with COVID-19 who had altered olfactory/gustatory function and had CSF testing performed. The search ranged from December 1, 2019 to November 18, 2020. RESULTS:We identified 51 publications that described 70 patients who met inclusion criteria. Of 51 patients who had CSF SARS-CoV-2 PCR testing, 3 (6%) patients had positive results and 1 (2%) patient had indeterminate results. Cycle threshold (Ct; the number of amplification cycles required for the target gene to exceed the threshold, which is inversely related to viral load) was not provided for the patients with a positive PCR. The patient with indeterminate results had a Ct of 37 initially, then no evidence of SARS-CoV-2 RNA on repeat testing. Of 6 patients who had CSF SARS-CoV-2 antibody testing, 3 (50%) were positive. Testing to distinguish intrathecal antibody synthesis from transudation of antibodies to the CSF via breakdown of the blood-brain barrier was performed in 1/3 (33%) patients; this demonstrated antibody transmission to the CSF via transudation. CONCLUSION/CONCLUSIONS:Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare in patients with altered olfactory/gustatory function. While pathology studies are needed, our review suggests it is unlikely that these symptoms are related to viral neuroinvasion.

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.

Background and aims: The Work Productivity and Activity Impairment (WPAI) questionnaire is a patientreported outcome assessing percentage of work time missed, impairment while working, overall work impairment and activity impairment over seven days prior. We report 2-year changes in WPAI, and associations with the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and SymptoMScreen (self-reported symptom burden) among patients with relapsing-remitting MS (RRMS) in the Phase IIIb CASTING trial (NCT02861014). Method(s): Patients (n=680; Expanded Disability Status Scale score <=4.0) with a suboptimal response to one or two prior disease-modifying therapies (DMTs) received intravenous ocrelizumab 600mg every 24 weeks for 96 weeks. WPAI, MSIS-29 and SymptoMScreen were completed at baseline, Week 24, Year 1 and Year 2. Spearman correlations were assessed between change in WPAI subscores from baseline to Year 2, MSIS-29 subscores, and SymptoMScreen total score. Result(s): WPAI improved from baseline to Year 2, with significant reduction in overall work impairment (-3.08, p=0.020) and activity impairment (-5.69, p<0.001), and consistent trends in work time missed (-2.54, p=0.102) and impairment while working (-1.66, p=0.129). Improvement in SymptoMScreen score correlated with reduction in all WPAI measures: work time missed (rs=0.196), impairment while working (rs=0.387), overall work impairment (rs=0.362) and activity impairment (rs=0.421) over two years (all p<0.01). MSIS-29 improvements correlated with WPAI improvements over two years (Table 1). Table 1 Conclusion(s): Patients with a suboptimal response to one or two prior DMTs who switched to ocrelizumab showed improvement in work productivity (WPAI), which correlated with improvement in physical/psychological impacts of MS (MSIS-29) and decrease in symptom burden (SymptoMScreen) over two years

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3 to 6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n=13)mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n=13), mean hemoglobin increased 1.4 g/dL (from 11.9 to 13.4 g/dL, n=12), mean platelet count increased by 87% (from 67.6 to 122.6 x 10⁹ /L, n=12), median chitotriosidase decreased by 82% (from 13,394 to 2312 nmol/hr/ml, n=11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 μg/mL, n=11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/mL, n=10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n=9). Together, these outcomes regardless of time on eliglustat showed comparable improvements in Gaucher manifestations and disease biomarkers. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment. This article is protected by copyright. All rights reserved.

OBJECTIVE:To determine a suitable outcome measure for assessing muscle strength in neurofibromatosis type 1 (NF1) and type 2 (NF2) clinical trials, we evaluated the intra-observer reliability of hand-held dynamometry (HHD) and developed consensus recommendations for its use in neurofibromatosis clinical trials. METHODS:Patients ≥5 years with weakness in at least 1 muscle group by manual muscle testing (MMT) were eligible. Maximal isometric muscle strength of a weak muscle group and the biceps of the dominant arm were measured by HHD. An average of 3 repetitions per session was used as an observation, and 3 sessions with rest period between each were performed on the same day by a single observer. Intra- and inter-session intraclass correlation (ICC) and coefficient of variation (CV) were calculated to assess reliability and measurement error. RESULTS:Twenty NF1 and 13 NF2 patients enrolled; median age was 12 years (interquartile range (IQR) 9-17) and 29 years (IQR 22-38) respectively. By MMT, weak muscle strength ranged from 2-/5 to 4+/5. Biceps strength was 5/5 in all patients. Inter-session ICC for the weak muscles were 0.98 and 0.99 in the NF1 and NF2 cohorts respectively and for biceps were 0.97 and 0.97 respectively. The median CV for average session strength were 5.4% (IQR 2.6%-7.3%) and 2.9% (IQR 2.0%-6.2%) for weak muscles and biceps respectively. CONCLUSION/CONCLUSIONS:HHD performed by a trained examiner with a well-defined protocol is a reliable technique to measure muscle strength in NF1 and NF2. Recommendations for strength testing in NF1 and NF2 trials are provided.