Brain metastases (BM) constitute a significant cause of oncological mortality. Statistics on the incidence of BM are limited because of the lack of systematic nationwide reporting. We report the incidence of synchronous brain metastases (sBM), defined as BM identified at the time of primary cancer diagnosis from 2015-2019 using NCI’s Surveillance, Epidemiology, and End Results (SEER) Program database. We identified 1,872,057 patients with malignancies between 2015-2019 from the SEER 17 Registries database, including 35,986 (1.9%) patients with sBM. Age-adjusted incidence rates were examined using the NCI Joinpoint software. Kaplan-Meier curves and a multivariate Cox regression model were used to investigate survival. The incidence rate of sBM from 2015 to 2019 was 7.1 persons per 100,000. Lung and bronchus cancers had the highest incidence of sBM (5.18 to 5.64 per 100,000), followed by melanoma (0.30 to 0.34 per 100,000) and breast cancers (0.24 to 0.30 per 100,000). In children, renal tumors had the highest sBM incidence. SBM were associated with poorer survival than extracranial metastases only (HR: 1.40 [95%CI: 1.39 – 1.42], P<0.001). We observed better survival in white patients relative to non-white patients with sBM (HR: 0.91 [95%CI: 0.90 - 0.94], P<0.001). The incidence rate of sBM has remained similar to rates reported over the last 9 years, with the majority associated with primary lung and bronchus cancers. SBM represent a national healthcare burden with tremendous mortality in pediatric and adult populations. This population may benefit from improved screening and treatment strategies.

BACKGROUND: Rapid diagnosis to facilitate urgent intervention is critical for treatment of acute spinal cord injury (SCI). We hypothesized that a multi-analyte blood biomarker would support point-of-care SCI diagnosis, correlate with injury severity, and predict long-term neurologic outcomes. METHODS: Droplet digital PCR (ddPCR) assays were designed to amplify differentially hypomethylated genomic loci in spinal cord tissue. An optimized ddPCR assay was applied to cell-free DNA (cfDNA) from plasma samples collected from prospectively enrolled acute SCI patients. Targeted proteomic profiling was also performed. Spinal cord–derived cfDNA and plasma proteins were tested for their association with SCI and ability to predict conversion in American Spinal Injury Association (ASIA) score at 6 months. RESULTS: A bespoke ddPCR assay detected spinal cord–derived cfDNA in plasma of 50 patients with acute SCI (AUC: 0.89, 95% CI 0.83–0.95, P < 0.0001). Levels of cfDNA were highest in patients with the most severe injury, i.e., ASIA A, compared with those with ASIA B ( P = 0.04), ASIA C ( P = 0.009), and ASIA D injuries ( P < 0.001). Dimensionality reduction identified 4 candidate proteins (FABP3, REST, IL-6, NF-H) that were integrated with spinal cord–derived cfDNA to derive the Spinal Cord Injury Index (SCII), which has high sensitivity and specificity for SCI diagnosis (AUC: 0.91, 95% CI 0.82–0.99, P < 0.0001), correlates with injury severity ( P < 0.0001), and predicts 6-month neurologic improvement (AUC: 0.77, 95% CI 0.61–0.93, P = 0.006). CONCLUSION: The detection of spinal cord–derived cfDNA and plasma protein alterations as part of a multi-analyte blood test can inform SCI diagnosis and prognosis. FUNDING: North American Spine Society Young Investigator Award; Morton Cure Paralysis Fund.

Advanced molecular testing has increasingly become an integral component for accurate diagnosis of central nervous system (CNS) tumors. We sought to establish the current state of molecular testing availability and approaches for the diagnosis of CNS tumors in US hospitals that conduct high volumes of CNS tumor resections. We distributed a 16-item survey inquiring about molecular testing approaches for CNS tumors to 115 neuropathologists at US hospitals with neurosurgery residency programs. Thirty-five neuropathologists (30.4%) responded to the survey, all of whom indicated their institutions perform molecular testing on CNS tumor tissue. The most commonly offered tests were MGMT methylation profiling and next-generation sequencing. Fourteen respondents (40%) indicated that their institution is able to test for and report all of the molecular alterations included in our survey. Nine (25.7%) respondents indicated that molecular testing is performed as standard of care for all patients with resected CNS tumors. Our results suggest that even in academic hospitals with a high volume of CNS tumor resections, molecular testing for these tumors is limited. Continued initiatives are necessary to expand the availability of molecular testing for CNS tumors to ensure diagnostic accuracy and guide targeted therapy.

Background: Brain metastases (BM) portend increased morbidity and mortality in patients with small cell lung cancer (SCLC). We aimed to characterize the prevalence, timing, treatment patterns, and survival outcomes of BM associated with SCLC over the past decade. Methods: Data from 4014 patients with histologically confirmed SCLC were extracted from the TriNetX Oncology database. Clinical and demographic variables were compared between patients with and without BM using Chi-squared and t-tests. Kaplan–Meier and Cox regression analyses were used to evaluate overall survival (OS), after propensity score matching cohorts for age at diagnosis, sex, cancer stage at diagnosis, extracranial metastases, and cancer-directed therapy. Results: Among 4014 patients with SCLC, 35.0% had BM (9.9% synchronous, 21.2% metachronous, 3.9% precocious). Patients who developed BM were younger (P < .001) at SCLC diagnosis, more likely Black/African American (P = .0068), and presented with more advanced cancer stages (P < .001) than patients who did not develop BM. The median BM-free survival from the time of SCLC diagnosis was 27.9 months. Patients with BM received higher rates of cancer-directed therapies than those without BM. Synchronous BM was associated with lower OS than metachronous BM after the diagnosis of SCLC (HR[95% CI] = 1.56[1.32–1.83]), but there was no difference in OS after the BM diagnosis. OS did not differ between patients with BM and patients with extracranial metastases only, following the diagnosis of metastatic disease. Conclusions: Our findings support that independently of the chronicity of BM diagnosis, patients with SCLC have poor survival once the diagnosis of BM is conferred.

While the central nervous system (CNS) tumor classification has increasingly incorporated molecular parameters, there is a paucity of literature reporting molecular alterations found in intraventricular glioblastoma (IVGBM), which are rare. We present a case series of nine IVGBMs, including molecular alterations found in standardized next-generation sequencing (NGS). We queried the clinical charts, operative notes, pathology reports, and radiographic images of nine patients with histologically confirmed IVGBM treated at our institution (1995–2021). Routine NGS was performed on resected tumor tissue of two patients. In this retrospective case series of nine patients (22% female, median (range) age: 64.3 (36–85) years), the most common tumor locations were the atrium of the right lateral ventricle (33%) and the septum pellucidum (33%). Five patients had preoperative hydrocephalus, which was managed with intraoperative external ventricular drains in three patients and ventriculoperitoneal shunts in one patient. Hydrocephalus was managed with subtotal resection of a fourth ventricular IVGBM in one patient. The most common surgical approach was transcortical intraventricular (56%). Gross total resection was achieved in two patients, subtotal resection was achieved in six patients, and one patient received a biopsy only. Immunohistochemistry for IDH1 R132H mutant protein was performed in four cases and was negative in all four. Genetic alterations common in glioblastoma, IDH-wildtype, were seen in two cases with available NGS data, including EGFR gene amplification, TERT promoter mutation, PTEN mutation, trisomy of chromosome 7, and monosomy of chromosome 10. Following surgical resection, four patients received adjuvant chemoradiation. Median survival among our cohort was 4.7 months (IQR: 0.9–5.8 months). Management of IVGBM is particularly challenging due to their anatomical location, presentation with obstructive hydrocephalus, and fast growth, necessitating prompt intervention. Additional studies are needed to better understand the genetic landscape of IVGBM compared to parenchymal glioblastoma and may further elucidate the unique pathophysiology of these rare tumors.

Patients with radiographically detectable lesions in their brain or other symptoms compatible with brain tumors pose challenges for diagnosis. The only definitive way to diagnose such patients is through brain biopsy, an invasive and dangerous procedure. In this study, we present a new workflow termed “CSF-BAM” that simultaneously identifies B-cell or T-cell receptor sequences, aneuploidy, and mutations using amplification of both strands of the DNA from cerebrospinal fluid (CSF) samples. We applied CSF-BAM to a validation set of 209 samples from patients with brain cancers. Among the 129 samples from patients with the most common aggressive cancer types, the sensitivity of detection was 81%. None of 30 CSF-BAM assays were positive in CSF samples from patients without brain cancers (100% specificity). CSF-BAM provides an integrated approach to identify neoplasia in the central nervous system, provides information about the genetics and immune environment, and has the potential to inform patient management. Significance: There is a paucity of technologies beyond surgical biopsy that can accurately diagnose central nervous system neoplasms. We developed a novel, sensitive, and highly specific assay that can detect brain cancers by comprehensively identifying somatic mutations, chromosomal copy-number changes, and adaptive immunoreceptor repertoires from samples of CSF. See related commentary by Weiss, p. 1976.