Variables Affecting Outcomes After Allogeneic Hematopoietic Stem Cell Transplant for Cerebral Adrenoleukodystrophy

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy (CALD) can stabilize neurologic function and improve survival but has associated risks including transplant related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n=16) with Loes score >9 or neurological function score (NFS) >1 and two early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n=24] and ED2 [Loes >4-9 and NFS ≤1; n=13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) versus AD (41%) cohort (p=0.015) and comparable between ED1 and ED2 cohorts (p=0.991). The stabilization of neurologic function post-transplant was greater in the ED versus AD cohort, with a median change from baseline at 24 months post-allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n=13), 0.5 and 0 in ED2 (n=6), and 2.5 and 3.0 (n=4) in AD cohort. TRM was lower in the ED (7%) compared with AD (22%) cohort, however the difference was not significant (p=0.094). Transplant-related safety outcomes were also impacted by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts versus matched related donors (MRD) (p=0.039), and acute GVHD and graft failure incidences varied by conditioning regimen. The study is registered to https://clinicaltrials.gov as NCT02204904.

INNV-40. REAL WORLD INTEGRATION OF THE NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE IN CLINICAL PRACTICE IN PATIENTS WITH IDH-WT GBM

BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM. METHODS We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference. CONCLUSIONS Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.

Acute Spinal Cord Compression, Spinal Cord Trauma, and Peripheral Neural Injury

Acute spinal cord compression with myelopathy is a neurologic emergency. Recognition of spinal cord compression, timely imaging, and treatment are important to restore and preserve neurologic function. This chapter reviews the causes and clinical approach to spinal cord compression. Traumatic and nontraumatic causes of spinal cord compression are addressed together because of their overlapping symptoms and management. The chapter concludes with a brief discussion of peripheral nerve injury.

Neuropharmacology

Medications used in the treatment of nervous system disorders typically modulate neurotransmitter function or action potential propagation and alter neurologic function. This chapter reviews the principles of pharmacokinetics, the major targets for drug action to provide a basis for understanding how medications exert their action, and disease-specific treatments. An understanding of the pharmacokinetic principles of neurologic medications is important for prescribing and ordering medication. Multiple routes of administration, including intravenous, sublingual, intramuscular, subcutaneous, rectal, oral, and transdermal, are available for delivery of neurologic medications.

Metformin-mediated mitochondrial protection post-cardiac arrest improves EEG activity and confers neuroprotection and survival benefit

Cardiac arrest (CA) produces global ischemia/reperfusion injury resulting in substantial multiorgan damage. There are limited efficacious therapies to save lives despite CA being such a lethal disease process. Surviving patients suffer extensive brain damage with mitochondrial dysfunction implicated as a major source of injury. Metformin, a first-line treatment for diabetes, has also shown promising results in other diseases and is known to interact with mitochondria. In the present study, we evaluated the therapeutic benefits of metformin administration immediately after resuscitation using a 10 min asphxyial-CA rat model. This is the first study to show that metformin treatment post-CA a) improves survival and neurologic function, b) potentiates early normalization of brain electrophysiologic activity, and c) protects mitochondrial function with a reduction in apoptotic brain injury. Overall, as an effective and safe drug, metformin has the potential to be an easily translatable intervention for improving survival and preventing brain damage after CA.

Knockdown of IL-6 Plays a Crucial Role in Protection of Hypoxia-Ischemia in Neonatal Rats via Inhibiting Casp3 and BAX Signaling Pathway

Background: The effect of interleukin-6 (IL-6) knockdown on hypoxia-ischemia (HI) of neonatal rat models was investigated to explore the underlying molecular regulation mechanism. Methods: To establish the HI model, we treated 7days postnatal Sprague-Dawley (SD) rats with the right carotid artery ligation and had them exposed to the environment of 8% oxygen and 92% nitrogen for 2 h, respectively. Then, the neurologic function and morphology changes were assessed. Subsequently, IL-6 siRNA lentivirus was injected into cerebral cortex motor area 2 days before HI; meanwhile, the interference efficiency was detected by quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot. Immunofluorescence staining of Glial fibrillary acidic protein (GFAP), Hexaribonucleotide Binding Protein-3 (NeuN) and IL-6 were used to identify the location and interference effect of IL-6. In order to further research the underlying mechanisms, the expressions of downstream molecular including Bcl-2-associated X protein (BAX) and Casp3 were examined following IL-6 up-regulation by QRT-PCR.Results: It was found that both the growth of cortical neurons and the length of axon were promoted after IL-6 interference, and the cell apoptosis was decreased. In addition, the expression of BAX and Casp3 were closely associated with IL-6. Conclusions: The present findings confirmed that the decreased IL-6 improves the deficiencies in neurologic function and morphology induced by HI, and the potential mechanism may be closely related with the regulation of Casp3 and BAX.