Broderick, Daniel F.

Abstract IntroductionRadiotherapy is considered standard of care for adjuvant peri-operative treatment of many spinal tumors, including those with instrumented fusion. Unfortunately, radiation treatment has been linked to increased risk of pseudoarthrosis. Newerfocused radiotherapy strategies with enhanced conformalitycould offer improved fusion rates for these patients, but this has not been confirmed.MethodsWe performed a retrospective analysis of patients at three tertiary care academic institutions withprimary and secondary spinal malignancies that underwent resection, instrumented fusion, and peri-operative radiotherapy. Two board certified neuro-radiologists used theLenke fusion score to grade fusion status at6 and 12-months after surgery. Secondary outcomes includedclinical pseudoarthrosis, wound complications, and the effect of radiation timing, radiobiological dose delivered, the use of photons versus protons, tumor type, tumor location,and use of autograft on fusion outcomes.ResultsAfter reviewof 1252 spinal tumor patients, there were 60 patients with at least 6 months follow-up that were included in our analyses. Twenty-five of these patients received focused radiotherapy,20 patients received conventional radiotherapy, and 15 patients were treated with protons. There was no significant difference between the groups for covariates such assmoking status,obesity, diabetes, intraoperative use of autograft, and use of peri-operative chemotherapy. There was a significantly higher rate of fusion for patients treated with focused radiotherapy compared to those treated with conventional radiotherapy at 6-months (64.0% versus 30.0%, Odds ratio: 4.15, p=0.036) and 12-months (80.0% versus 42.1%, OR: 5.50, p=0.022). There was a significantly higher rate of clinical pseudoarthrosis in the conventional radiotherapy cohortcompared to patients in the focused radiotherapy cohort (19.1% versus 0%,p=0.037). There was no difference in fusion outcomes for any of the secondary outcomes except for use of autograft. The use ofintra-operative autograft was associated with an improved fusion at 12-months (66.7% versus 37.5%, OR: 3.33, p=0.043). ConclusionFocused radiotherapy may be associated withan improved rate of fusion and clinical pseudoarthrosis when compared to conventional radiation delivery strategiesin patients with spinal tumors.Use of autograft at the time of surgery may be associated with improved 12-month fusion rates.Further large-scale prospective and randomized controlled studies are needed to better stratify the effects of radiation delivery modality in these patients.

AbstractBackgroundColony‐stimulating factor‐1 receptor (CSF1R)‐related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease‐modifying treatment.ObjectiveThe objective of this study was to determine the effect of HSCT on disease progression.MethodsWe collected all available clinical data from a cohort of 7 patients with CSF1R‐related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board‐certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI).ResultsOur patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow‐up time (median, 11; range, 2–27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden.ConclusionsThis is the largest series of patients with CSF1R‐related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease‐modifying therapy for CSF1R‐related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease‐specific therapies. © 2021 International Parkinson and Movement Disorder Society

Background. The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. Methods. A newly characterized and suspected pathogenic variant in ABCD1 was analyzed using our protein informatics platform (PIP). Personalized protein-level molecular studies were completed on genetic testing data, complementing the analysis and clinical study. Results. A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 variant are presented. The unique ABCD1 protein is discussed, and the proband’s case is compared to existing reports of AMN. Conclusions. Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient’s disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity.