Citations

Abstract In epilepsy patients lacking magnetic resonance imaging‐visible lesions such as focal cortical dysplasia (FCD), surgical resections target regions with abnormal electroencephalographic (EEG) activity. However, histopathological identification of subtle cortical architectural abnormalities in these specimens remains challenging. We investigated whether artificial intelligence (AI)‐based morphometric and spatial analysis of NeuN‐stained cortical sections could detect neuronal architectural disorganization in epilepsy resections, including regions without definitive histologic dysplasia. Whole slide images were generated from 83 FCD regions and 19 neurologically normal autopsy controls. Regions of interest were annotated in QuPath as FCD, FCD‐adjacent, FCD‐distant, apparently normal (abnormal EEG without histologic dysplasia), and true normal (autopsy controls). NeuN‐positive neurons were detected using QuPath (90% sensitivity, 12% false positive rate). Spatial and morphometric features—including neuronal clustering, distribution inhomogeneity, and nuclear morphology—were extracted and used to train a multinomial, Least Absolute Shrinkage and Selection Operator‐regularized regression classifier. The classifier achieved 70.6% accuracy in subregion classification and 88.2% accuracy in overall specimen diagnosis. Notably, regions with abnormal EEG but lacking histologic dysplasia exhibited quantifiable architectural disorganization similar to those seen in areas adjacent to FCD and distinct from control tissue. AI‐driven analysis of neuronal morphology and spatial distribution reveals subtle cortical disorganization in epilepsy resections, including in histologically ambiguous regions. Further investigation is warranted to determine if this methodology can enhance the diagnostic yield of neuropathological evaluation and support more precise surgical targeting in epilepsy.

Abstract Despite effective control of inflammation in rheumatoid arthritis (RA), persistent and severe pain remains a challenge. Dysregulated pain processing in the central nervous system may underlie this disconnect. The PainDETECT questionnaire, originally developed to identify neuropathic pain, may capture features of central sensitization. We hypothesized that neuropathic-like pain at diagnosis predicts worse pain prognosis in early RA, independent of baseline pain severity and inflammation. We also explored brain activation patterns using neuroimaging. In this prospective cohort study, adults with newly diagnosed RA completed the PainDETECT questionnaire at baseline. Bodily pain was measured using the SF-36 Bodily Pain Subscale at baseline, 3, 6, and 12 months. C-reactive protein (CRP) was monitored. Linear mixed-effects models examined associations between PainDETECT, as a continuous measure, and bodily pain and CRP over time, adjusting for baseline outcome values. A neuroimaging substudy (n = 27) used task-based functional MRI to assess brain responses to evoked pressure pain. Among 158 participants (mean age 58.4 years; 35% male), 24.7% had likely neuropathic-like pain (PainDETECT ≥19) at baseline. Higher baseline PainDETECT scores were associated with worse bodily pain throughout follow-up in fully adjusted models (β = −0.43; 95% CI: −0.84 to −0.02; P = 0.043), independent of socio-demographics and comorbidities. No association was found between PainDETECT and CRP. On neuroimaging, higher PainDETECT scores correlated with increased activation in the left insula, dorsal anterior cingulate cortex, and left amygdala during evoked wrist pain. Neuropathic-like pain at diagnosis predicts a worse pain prognosis in early RA, independently of inflammation. Early identification may support more targeted and effective pain management.

Abstract Background: Alternative lengthening of telomeres (ALT) is common in isocitrate dehydrogenase (IDH) mutant astrocytomas, but how telomere length variability contributes to genome instability remains unclear. We hypothesized that chromosome arm–specific telomere heterogeneity underlies distinct patterns of somatic structural variation (SV), copy-number alteration (CNA), and extrachromosomal DNA (ecDNA) formation. Methods: Oxford Nanopore long-read whole-genome sequencing (∼20–40x coverage) was performed in a clinical cohort of n = 20 IDH-mutant astrocytomas. Somatic SVs were called with Severus and filtered to a high-confidence tumor-specific set. CNAs were inferred by read-depth segmentation (DNAcopy) and further refined using a long-read CNA framework (Wakhan). Chromosome arm–specific telomere length was estimated with Telogator, and SV breakpoints were annotated for enrichment near subtelomeric and pericentromeric regions. Associations between arm-level telomere length and SV/CNA features (rate and proportion) were tested using linear mixed-effects models with patient as a random effect. High-level amplification regions were defined directly from CNA segments with high copy number, and ecDNA-like circular amplicons were subsequently reconstructed from amplified intervals using Decoil. Results: IDH-mutant astrocytomas displayed pronounced SV heterogeneity, with complex breakends (BNDs) dominating the somatic SV landscape. SVs were spatially patterned, as deletions and insertions preferentially accumulated near subtelomeric and pericentromeric domains, implicating chromosome ends and repeat-rich regions as recurrent substrates for rearrangement. At the tumor level, markedly shortened telomeres were associated with increased SV burden and CNA burden, consistent with telomere attrition as a correlate of genome-wide structural instability in highly rearranged genomes. At higher resolution, telomere length varied substantially across chromosome arms and classified distinct structural outcomes: arms with shorter telomeres were enriched for complex insertional SVs, whereas arms with relatively elongated telomeres more frequently carried focal high-level amplifications and ecDNA-like circular amplicons. Conclusions: These findings reveal a link between arm-specific telomere heterogeneity and the emergence of structural and amplification architectures in IDH-mutant astrocytomas. Telomere remodeling may influence where rearrangements and ecDNA structures arise, offering potential biomarkers of genome instability and tumor evolution. Generative AI was used to improve language clarity; all content was verified by the authors. Citation Format: Maryam Jehangir, Kristen Drucker, T. Rhyker Ranallo-Benavidez, Thomas M. Kollmeyer, Ayse Keskus, Daniel Lachance, Jeanette E. Eckel-Passow, Ofer Shoshani, Mikhail Kolmogorov, Robert B. Jenkins, Floris P. Barthel. Telomere length heterogeneity shapes structural and amplification landscapes in IDH-mutant astrocytoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr PR009.

Abstract Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity and plasticity. GBM tumors contain neoplastic cells within a fluid spectrum of diverse transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we develop scFOCAL (Single-Cell Framework for -Omics Connectivity and Analysis via L1000), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identify compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states, and leverage this capability to predict combination synergy. We validate the significance of these findings in vitro, ex vivo, and in vivo, and use the Olig2 inhibitor CT-179 as a reference drug to identify additional small molecules that would maximize the cell-drug discordance across the GBM transcriptional landscape. Our analysis leads to the combination of Olig2 inhibition with treatment with Depatux-M, of with which we demonstrate synergy in vivo. Our studies suggest that scFOCAL identifies cell states that are sensitive and resistant to targeted therapies in GBM using a measure of cell and drug connectivity, which can be applied to identify new synergistic combinations. Citation Format: Robert K. Suter, Anna M. Jermakowicz, Rithvik Veeramachaneni, Matthew D'Antuono, Longwei Zhang, Rishika Chowdary, Simon Kaeppeli, Madison Sharp, Pravallika Palwai, Vasileios Stathias, Grace Baker, Luz Ruiz, Winston Walters, Maria Cepero, Danielle Burgenske, Edward B. Reilly, Anatol Oleksijew, Mark G. Anderson, Sion Ll. Williams, Michael E. Ivan, Ricardo J. Komotar, Macarena I. De La Fuente, Gregory Stein, Alexandre Wojcinski, Santosh Kesari, Jann N. Sarkaria, Stephan C. Schürer, Nagi G. Ayad. Drug and single-cell gene expression integration identifies heterogeneity-aware synergistic combinations for glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B032.

In adult persons the narcoleptic syndrome consists of narcolepsy proper, cataplexy, sleep paralysis and hypnagogic hallucinations. The characteristics of these phenomena are discussed. The disease is not often recognized in children, although anamnestic evidence suggests that in the majority of patients the onset of the disorder is in childhood or adolescence. Data are presented concerning 16 children in whom narcolepsy was evident. Problems in diagnosis are reviewed and common pitfalls and misinterpretations are discussed. The use of analeptic drugs for treatment is outlined.

BACKGROUND Bertolotti syndrome is an underrecognized cause of chronic low back pain. Back pain generated from Bertolotti syndrome is believed to result from altered weight dissipation mechanics and/or instability of the pseudoarticulation, while local nerve root compression may result in radiculopathy. Here, the authors describe the findings of a patient with treatment-refractory low back pain found to have a cystic lesion arising from a Bertolotti joint causing L5 nerve root compression. To their knowledge, this has not been previously described in the literature. OBSERVATIONS Despite early recognition of Bertolotti syndrome, the patient’s back pain remained resistant to many years of both conservative and surgical management. The novel finding of a cyst arising from the pseudoarticulation complicated the management. The patient is scheduled to undergo further surgery this year. LESSONS This case highlights a pseudocyst associated with a Bertolotti joint. The cyst introduced additional clinical uncertainty to what is already an uncommon and difficult to treat condition. Resection of the Bertolotti joint failed to improve the patient’s symptoms. Postoperatively, a complex hemorrhagic pseudocyst was seen on imaging, possibly due to the pseudoarticulation with persistent motion. Ongoing efforts to characterize Bertolotti syndrome and its associated imaging findings are necessary to better optimize management strategies in these patients. https://thejns.org/doi/10.3171/CASE25948

BACKGROUND Intraneural ganglion cysts (IGCs) are mucinous lesions that originate from adjacent synovial joints. According to the articular theory, synovial fluid tracks from a joint into the parent nerve through an articular branch. In uncommon sites such as the sural nerve, this connection can be difficult to identify. This report illustrates the use of a preoperative intra-articular fluorescein injection as a tool to identify the articular branch during surgery. OBSERVATIONS A 60-year-old woman presented with lateral foot pain, numbness, and a palpable mass along the left sural distribution. MRI showed a large cyst extending along the course of the sural nerve with connection to the subtalar joint. Fluorescein was injected preoperatively into this joint to detect the articular branch intraoperatively with ultraviolet illumination. The connection was transected at the joint origin, and the cyst was decompressed, preserving the parent nerve. Postoperatively, the patient had complete pain relief and sensory recovery, and MRI at 3 and 8 months confirmed resolution of the cyst. LESSONS Sural IGCs conform to the articular theory and can be managed effectively by transection of the articular branch. Preoperative intra-articular fluorescein injection is a useful tool to detect the articular branch that can be difficult to find in sural IGCs. https://thejns.org/doi/10.3171/CASE251018