Citations

Abstract Post-traumatic headache (PTH) is the most common consequence of mild traumatic brain injury (mTBI) and often resembles migraine. In 20% to 30% of migraine patients, headaches are preceded by aura, transient visual or sensory disturbances, which are caused by cortical spreading depression (CSD) that can induce headache pain. However, whether mTBI promotes the development of aura and CSD and their possible contributions to PTH remains unclear. We examined the incidence of new-onset aura in individuals with PTH who had no history of aura. Thirty-two percent (35/108) developed new aura symptoms within 60 days of injury, suggesting that mTBI can sensitize the cortex to the induction of CSD. To test this, we combined electrophysiology, neuroimaging, and behavioral assays in a mouse model of mTBI-induced PTH. After closed-head mTBI, injured mice exhibited a 160% increase in CSD induction probability (ie, lowered threshold) and became sensitized to CSD induction by brief exposure to stress, a common headache trigger. When evoked optogenetically, CSD produced prolonged periorbital and hind paw allodynia, consistent with headache-like pain. Subcutaneous onabotulinumtoxinA administered to the scalp after mTBI did not alter CSD susceptibility but completely abolished optogenetic CSD-induced allodynia. These findings suggest that mTBI elicits sensitization to CSD induction and promotes the emergence of aura in humans, likely contributing to PTH. It is important that, even after mTBI-induced sensitization, onabotulinumtoxinA decoupled CSD from pain behaviors, suggesting efficacy in treating PTH associated with aura.

Imaging is important for evaluation and diagnosis of nail pathologic disorders, and knowledge of imaging protocols and characteristics supports informed treatment planning and effective monitoring of therapeutic outcomes in cutaneous and systemic disease contexts.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with a poor prognosis of 15 months despite aggressive therapies. GBM malignancy is often driven by a high degree of inter- and intra-tumoral heterogeneity that is dynamic through time and regulated by interactions between tumor cells and their neural microenvironment. For instance, GBM tumors located near the lateral ventricles (LV) of the brain grow more aggressively and result in significantly worse patient survival, compared to tumors that grow far from the LV. This suggests that interactions between GBM and cells in the LV microenvironment may regulate tumor malignancy. Understanding the mechanisms underlying GBM malignancy near the LV is essential to determine if regulation of tumor biology is driven by the presence of healthy neural cells, and to ultimately develop therapeutic approaches that target GBM-LV interactions. Here, we tested the hypothesis that region-specific cellular identities and activation of unique transcriptional programs regulate GBM malignancy near the LV. Paired primary biopsies were collected from 14 GBM patients. Image-guided biopsies proximal and distal to the brain’s LV (LV-proximal GBM and LV-distal GBM, respectively) were processed for bulk RNA sequencing, single-nucleus RNA sequencing, and in situ spatial transcriptomic (Xenium) analyses. We found significant inter-patient and intra-tumoral transcriptional heterogeneity in GBM samples collected proximal and distal to the LV. After accounting for tumoral and patient heterogeneity, we found that proximal GBM tumors exhibit an increased immune-related gene signature, compared with tumors distal to the LV. Single-nucleus RNA sequencing and in situ spatial transcriptomic analyses showed no significant differences in the proportion of cellular states or identities between proximal and distal GBM samples. However, within each cellular identity, significant differences in gene expression were identified between proximal and distal GBM, suggesting that distinct cell-specific transcriptional pathways characterize regional differences in GBM biology. Our results suggest that GBM tumors near the LV have increased interactions with immune cells that lead to the enrichment of immune-related transcriptional pathways, compared to tumors growing far from the LV. This work will inform the development of therapies that target GBM-immune cell interactions to decrease tumor malignancy and improve individual patient outcomes. Citation Format: Maria F. Gonzalez-Aponte, Jhan C. Salazar, Aura Figueroa-Gonzalez, Emily S. Norton, Paola Suarez-Meade, Hugo Guerrero-Cazares. Integrating RNA sequencing and spatial transcriptomic analyses reveals drivers of glioblastoma malignancy near the brains’ lateral ventricles [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 B035.

Abstract Glioblastoma (GBM), the most common malignant primary brain tumor in adults, has a median survival of 15 months and 5-year survival rate of only 6.9%. Standard of care, including radiation and chemotherapy, can induce cellular senescence in the brain. The senescence-associated secretory phenotype (SASP) significantly affects glioma microenvironment as these secreted factors exhibit both anti-and pro-tumorigenic effects. However, it is currently unknown whether senescence in the surrounding GBM microenvironment could be beneficial or detrimental to tumor outcomes. Using cell-specific proteomics, we identified upregulation of cathepsin B (CTSB) expression in patient-derived brain tumor initiating cells (BTICs) co-cultured with human fetal neural progenitor cells (NPCs). In matched patient tumor biopsies, sequencing of lateral ventricle (LV)-proximal regions revealed increased CTSB expression compared to LV-distal counterparts. Remarkably, LV-proximal GBMs induced a senescent phenotype and reduced differentiation in subventricular zone (SVZ) NPCs through CTSB secretion. We hypothesize that senescent NPCs in the SVZ contribute to a pro-tumorigenic microenvironment that promotes tumor aggressiveness in LV-proximal GBM. To model this in vitro, senescence was induced in NPCs using recombinant CTSB (100 nM) and hydrogen peroxide (250 µM, 2 hours). Treated NPCs showed increased β-galactosidase activity and increased expression of SASP factors IL-1α, IL-6, and CTSB. Senescent NPCs significantly increased BTIC migration and proliferation (p<0.05) both in co-culture and through conditioned media, suggesting this effect may be mediated by soluble factors. These findings support the hypothesis that senescent NPCs promote BTIC malignancy in LV-proximal GBM and identify CTSB as a potential mediator of this interaction.

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median survival of 8-14 months and 5-year survival rate of 6.9%. Its aggressive nature arises mostly from molecular heterogeneity and resistance to standard of care (SOC), including radiation and temozolomide (TMZ). Recurrence is nearly inevitable, driven by highly invasive brain tumor initiating cells (BTICs). Our previous studies revealed that exposing BTICs to cerebrospinal fluid (CSF) from GBM patients increases cell migration and proliferation compared to non-cancer CSF. Transcriptomic analysis identified the upregulation of the SERPINA3 gene, which encodes alpha-1-antichymotrypsin (ACT). Silencing of SERPINA3 reduces BTIC migration and proliferation and abolishes the promigratory response to GBM-derived CSF, highlighting SERPINA3 as a potential therapeutic target. ACT has been reported to bind to DNA, although the implications of this interaction are unknown. We have previously observed higher levels of intranuclear ACT in human GBM compared to non-cancer brain tissues. We hypothesize that the nuclear localization of SERPINA3 in GBM contributes to increased malignancy, opening the possibility of therapeutically targeting its intranuclear transport. Here, we determined the intracellular localization of ACT in BTICs and GBM and compared it to non-cancer tissues. Additionally, we evaluated whether SOC affected intranuclear localization of ACT. Patient-derived BTICs were treated with TMZ, radiation, and a combination of both, to assess changes in ACT expression via Western Blot, PCR, and ICC. A decrease in cell confluency was correlated with a significant decrease (p<0.05) in SERPINA3 mRNA and overall protein expression when BTICs were treated with TMZ alone or in combination. Interestingly, confocal microscopy revealed a significant increase (p<0.05) in its nuclear localization, particularly with TMZ treatment, indicating a change in its intracellular distribution. Overall, nuclear translocation of SERPINA3 increases in response to SOC with potential implications as a treatment resistance mechanism.

BACKGROUND AND OBJECTIVES: Patients with brain arteriovenous malformations (BAVMs) sometimes experience migraine-like chronic headaches. Reportedly, this symptom is common in occipital lobe BAVMs; however, the exact prevalence has not been clarified, and the details of visual auras have been scarcely reported. Furthermore, no comprehensive studies exist on the improvement of migraine associated with visual auras in occipital lobe BAVMs after stereotactic radiosurgery (SRS). Therefore, this study investigated the prevalence of headache with visual aura in patients with occipital lobe BAVMs and evaluated the impact of SRS on preexisting symptoms. METHODS: As a single-center retrospective cohort study, a total of 104 patients with occipital lobe BAVMs treated with SRS from 1990 to 2024 were analyzed. Pre-SRS and post-SRS symptoms of headache and visual aura were documented. The outcomes measured were headache severity, frequency, aura characteristics, and BAVM obliteration rates. RESULTS: Of the 104 patients, 41 (39%) reported chronic headache pre-SRS, and 37 (36%) experienced migraine with visual aura. Compared with pre-SRS, 90% (28/31) of the patients experienced a >50% reduction in headache severity and frequency at a median follow-up of 11 months, and 89% (25/28) experienced a >50% reduction in aura frequency. Complete headache remission was achieved in 35% (13/31) of patients. Complete obliteration of BAVMs was confirmed in 75% (76/102) of the patients at a median of 33 months. A smaller nidus volume was associated with both complete headache remission and BAVM obliteration, whereas age and sex were not significant predictors of headache outcome. CONCLUSION: Patients with occipital lobe BAVMs frequently experience migraine-like headaches with visual aura, which may be more prevalent than in the general population. SRS for occipital lobe BAVMs could not only achieve favorable BAVM obliteration with minimal adverse effects but also significantly improve migraine-like symptoms, including visual aura, particularly in patients with smaller nidus volumes.

Abstract Recent advances in the field of immuno‐oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high‐throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi‐marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.