Taiwo, Rukayat

ABSTRACT Leptomeningeal disease (LMD) is a rapidly fatal complication of systemic cancer for which sensitive diagnostic tools and informative biomarkers remain limited. Here, we introduce CSF-Seq, a method for whole-transcriptome sequencing of cell-free RNA (cfRNA) from human cerebrospinal fluid (CSF), designed to enable molecular profiling of LMD and other central nervous system (CNS) conditions. Using a prospectively collected CSF biobank, we analyzed 125 samples spanning multiple pathologies, including breast and lung LMD, glioblastoma, traumatic brain injury, and non-cancer neurological controls. Through optimized RNA extraction, library preparation, and deep sequencing, CSF-Seq generated robust and reproducible transcriptome-wide profiles despite the low abundance and fragmentation of cfRNA in CSF. CSF transcriptomes exhibited disease-specific expression, separating LMD from non-cancer controls and from non-LMD cancers, independent of CSF collection modality. Tumor-associated epithelial transcripts, including CEACAM6 and MUC1, were consistently enriched in LMD samples, whereas immune and CNS-associated transcripts were broadly detected across disease states, consistent with contributions from both tumor and non-tumor sources. Cross-site processing of matched samples demonstrated high concordance, indicating preservation of sample-specific transcriptional signatures across independent workflows. Importantly, we identified a collection method– independent LMD gene expression signature that was significantly associated with overall survival, supporting its potential prognostic relevance. Together, these findings establish CSF-Seq as a technically robust and clinically informative platform for transcriptomic biomarker discovery in CNS metastatic disease, offering a minimally invasive approach for disease characterization, risk stratification, and longitudinal monitoring in patients with LMD.

OBJECTIVEScoliosis is frequently a presenting sign of Chiari malformation type I (CM-I) with syrinx. The authors’ goal was to define scoliosis in this population and describe how radiological characteristics of CM-I and syrinx relate to the presence and severity of scoliosis.METHODSA large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°).RESULTSBased on available imaging of patients with CM-I and syrinx, 260 of 825 patients (31%) had a clear diagnosis of scoliosis based on radiographs or coronal MRI. Forty-nine patients (5.9%) did not have scoliosis, and in 516 (63%) patients, a clear determination of the presence or absence of scoliosis could not be made. Comparison of patients with and those without a definite scoliosis diagnosis indicated that scoliosis was associated with wider syrinxes (8.7 vs 6.3 mm, OR 1.25, p < 0.001), longer syrinxes (10.3 vs 6.2 levels, OR 1.18, p < 0.001), syrinxes with their rostral extent located in the cervical spine (94% vs 80%, OR 3.91, p = 0.001), and holocord syrinxes (50% vs 16%, OR 5.61, p < 0.001). Multivariable regression analysis revealed syrinx length and the presence of holocord syrinx to be independent predictors of scoliosis in this patient cohort. Scoliosis was not associated with sex, age at CM-I diagnosis, tonsil position, pB–C2 distance (measured perpendicular distance from the ventral dura to a line drawn from the basion to the posterior-inferior aspect of C2), clivoaxial angle, or frontal-occipital horn ratio. Average curve magnitude was 29.9°, and 37.7% of patients had a left thoracic curve. Older age at CM-I or syrinx diagnosis (p < 0.0001) was associated with greater curve magnitude whereas there was no association between syrinx dimensions and curve magnitude.CONCLUSIONSSyrinx characteristics, but not tonsil position, were related to the presence of scoliosis in patients with CM-I, and there was an independent association of syrinx length and holocord syrinx with scoliosis. Further study is needed to evaluate the nature of the relationship between syrinx and scoliosis in patients with CM-I.