"It's Shaking Your Entire Construction as a Human Being": A Qualitative Analysis on Epistemic Injustice and Medical Gaslighting Consequences in Patients Living with Chronic Pain.

The US National Cancer Institute estimated more than 24,000 new central nervous system (CNS) cancer cases each year, with a 5-year survival rate of 33% []. Primary and metastatic brain tumors are commonly treated with the Stupp protocol, which combines fractionated cranial radiation therapy (RT) with adjuvant temozolomide (TMZ) chemotherapy []. Although this regimen improves survival, RT-TMZ treatment is frequently accompanied by debilitating neurocognitive sequelae that markedly diminishes patients' and survivors’ quality of life (QOL). RT-induced cognitive decline (RICD) has been linked to impaired neurogenesis, reduced dendritic complexity, elevated oxidative stress, and chronic neuroinflammation []. TMZ can further exacerbate CNS injury by disrupting hippocampal function, suppressing neural precursor cell proliferation, and increasing anxiety-like behaviors []. Together, the adverse cognitive effects of RT and chemotherapy are referred to as cancer-related cognitive impairments (CRCI) or [–]. CRCI is especially concerning in pediatric brain tumor and low-grade glioma patients, who often experience prolonged post-treatment survival [,,]. Beyond survival, preservation of cognitive function may be the most critical criterion for evaluating therapeutic success in brain cancer care. However, long-term CRCI remains a major unmet clinical need, with a conspicuous lack of effective interventions. Thus, regenerative strategies that restore brain function and cognition after completion of oncologic treatment are clearly needed. This study evaluates the translational potential of extracellular vesicles (EVs) derived from good manufacturing practice (GMP)-grade human neural stem cells (hNSC-EVs) to ameliorate CRCI in a clinically relevant mouse glioma model treated with RT-TMZ. Proliferating human neural stem cells secrete EVs that support cell-to-cell communication and maintain the neural microenvironment [–]. EVs carry bioactive cargo, including proteins, lipids, mitochondrial components, and nucleic acids []. They exhibit low immunogenicity, display a prolonged circulating half-life, cross the blood-brain barrier (BBB) [,], and can remain stable for up to 20 months at 4 °C []. EVs derived from stem or progenitor cells have been shown to promote CNS recovery after stroke and traumatic brain injury [,]. Our prior work using a commercially available hNSC line in an acute 9 Gy RT model demonstrated that transplanted hNSCs improved cognitive outcomes [,]. However, long-term follow-up revealed that only approximately 4.5% of transplanted stem cells survived at 8 months, and very few differentiated into mature, functional neurons []. These findings suggested that direct cell replacement is unlikely to account for the observed neuroprotection, and hNSCs likely exert their therapeutic benefits by secreting trophic factors . Consistent with this view, studies in traumatic brain injury, stroke, and Alzheimer's disease models indicate that the functional benefits of stem cell therapy are largely mediated by EV production and release [,,–]. Indeed, intracranial administration of EVs derived from a commercially available hNSC line has been shown to confer cognitive benefit in an acute RT (9 Gy), non-cancer model [,]. Albeit, none of the previous neuroprotective studies tested the approach to model clinical standard of care for glioma. Building on this foundation, the present study uses a syngeneic murine glioma model and a clinically relevant Stupp protocol to test whether GMP-grade hNSC-derived EVs can mitigate CRCI and neurodegenerative sequelae . Details of all chemicals and materials are provided in .