Jones, David

PURPOSE Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer-predisposing signals. METHODS To address this gap, we interrogated 189 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts. RESULTS Analysis across all cases with cancer revealed enrichment of TP53 PV. Cancer-specific analyses confirmed known associations including germline TP53 PV in adrenocortical carcinoma, high-grade glioma (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in neuroblastoma. In addition, four novel associations were uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5 in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the SMARCAL1 :OS association was significant in the discovery (6/230, 2.6%, false discovery rate [FDR] logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; P Fisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, P Fisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, P Fisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data. CONCLUSION Our study confirms the relevance DDR genetic variation in pediatric cancer risk and establishes SMARCAL1 as a novel OS predisposing gene, providing insights into tumor biology and creating opportunities to optimize care for patients with this challenging tumor.

Dysarthric speech poses significant challenges for clinical assessment and diagnosis due to wide variability in the nature and severity of speech impairments associated with it. To address this, this study investigates the phonetic variations in different types of dysarthric speech using the deep learning model Phonet. Recordings of the word “Catastrophe” from 54 patients diagnosed with dysarthria were analyzed to extract posterior probabilities of consonants and vowels. The analysis revealed distinct posterior probability patterns for consonants and vowels across three types of dysarthria, indicating disorder-specific articulatory-based speech characteristics. Moreover, within each dysarthric group, variations in posterior probabilities aligned with the severity of rated articulation difficulty, reflecting nuanced intra-disease phonetic differences. These findings demonstrate Phonet’s ability to capture subtle speech variations and link them to both dysarthria type and severity. By quantifying these phonetic alterations, this study offers a novel and robust framework for objectively evaluating articulation difficulties in dysarthric speech. The results emphasize the clinical potential of Phonet as an advanced tool for improving the diagnosis and monitoring of dysarthria, paving the way for innovative applications in speech-based clinical assessments.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait deterioration, cognitive disturbances, and urinary incontinence. Gait deficits pose safety hazards due to frequent falls, yet objective investigations of gait improvement following ventriculoperitoneal shunt (VPS) placement are limited. Therefore, the aim of this study was to assess objective improvement in gait parameters for patients with iNPH after VPS placement. METHODS All patients treated with a VPS for iNPH by the senior author at a single tertiary care center from December 2017 to January 2023 were retrospectively reviewed. Patients who underwent detailed motion analysis testing before surgery with > 1 follow-up assessment were included. Analyzed parameters included gait velocity, gait cadence, stride length, stride width, gait stability ratio, total support, and single support. Time-dependent linear mixed-effects models and generalized additive mixed-effects models (GAMMs) were used to model short-term and longitudinal gait parameter changes, respectively. RESULTS A total of 212 patients (137 male, median age was 75.2 years) who underwent VPS placement for iNPH were included, with a total of 747 gait analyses performed at a median last-gait analysis follow-up duration of 12.0 months. Statistically significant changes in all gait parameter values were seen between the preoperative time point and first postoperative follow-up (within 3 months) time point (paired Wilcoxon p < 0.001), with a statistically significant majority of patients experiencing improvement (binominal p < 0.0001). Longitudinal analyses using a GAMM showed increased gait velocity, single support, and stride length, with decreased stability ratio, step width, and total support at early time points, while a plateau was achieved around 6 months. CONCLUSIONS A detailed gait analysis demonstrated significant improvements in objective ambulation metrics, particularly in the gait velocity, stride length, and gait stability ratio, following VPS placement in patients with iNPH. Most patients maintained marked improvement from baseline to the last follow-up assessment, although a plateau of the benefit was experienced over longer follow-up.

Abstract Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) results in significant morbidity in the elderly with symptoms of dementia, gait instability, and urinary incontinence. In well-selected patients, ventriculoperitoneal shunt (VPS) placement often results in clinical improvement. Most postshunt assessments of patients rely on subjective scales. The goal of this study was to assess the utility of remote activity monitoring to provide objective evidence of gait improvement following VPS placement for iNPH. METHODS Patients with iNPH were prospectively enrolled and fitted with 5 activity monitors (on the hip and bilateral thighs and ankles) that they wore for 4 days preoperatively within 30 days of surgery and for 4 days within 30 days postoperatively. Monitors collected continuous data for number of steps, cadence, body position (upright, prone, supine, and lateral decubitus), gait entropy, and the proportion of each day spent active or static. Data were retrieved from the devices and a comparison of pre- and postoperative movement assessment was performed. The gait data were also correlated with formal clinical gait assessments before and after lumbar puncture and with motion analysis laboratory testing at baseline and 1 month and 1 year after VPS placement. RESULTS Twenty patients fulfilled the inclusion and exclusion criteria (median age 76 years). The baseline median number of daily steps was 1929, the median percentage of the day spent inactive was 70%, the median percentage of the day with a static posture was 95%, the median gait velocity was 0.49 m/sec, and the median number of steps required to turn was 8. There was objective improvement in median entropy from pre- to postoperatively, increasing from 0.6 to 0.8 (p = 0.002). There were no statistically significant differences for any of the remaining variables measured by the activity monitors when comparing the preoperative to the 1-month postoperative time point. All variables from motion analysis testing showed statistically significant differences or a trend toward significance at 1 year after VPS placement. Among the significantly correlated variables at baseline, cadence was inversely correlated with percentage of gait cycle spent in the support phase (contact with ground vs swing phase). CONCLUSIONS This pilot study suggests that activity monitoring provides an early objective measure of improvement in gait entropy after VPS placement among patients with iNPH, although a more significant improvement was noted on the detailed clinical gait assessments. Further long-term studies are needed to determine the utility of remote monitoring for assessing gait improvement following VPS placement.