Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1–4 and gliomas increasing neuronal excitability2,5–8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron–glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

BACKGROUND The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuro-epithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks. METHODS Registry study of published clinical trials for World Health Organization defined neuro-epithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ2 tests were used for data analysis. RESULTS Among 662 published clinical trials representing 49,907 participants, 62.5% of participants were men and 37.5% women (P<0.0001) representing a mortality specific over-accrual for men (P=0.001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P=0.008), Hispanics (17% of expected mortality, P<0.001) and Asians (33% of expected mortality, P<.001) were underrepresented compared with Whites (114% of expected mortality, P<0.001). Clinical trials meeting accrual benchmarks for race included minority authorship. CONCLUSIONS Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients.

BACKGROUND: High-grade gliomas are fatal with universally poor prognosis. Initiation of effective cancer immune responses requires functional immune cells, especially afferent antigen presenting cells, which are absent from the brain parenchyma.1,2 To address this requirement, two adenoviral vectors expressing HSV1-TK and Flt3L were combined to target human gliomas. This first in human trial assessed safety, cytotoxicity, and immune recruitment to the tumor. METHODS: Eighteen treatment-naive adults with high-grade glioma received injections of HSV1-TK- and Flt3L-expressing adenoviral vectors to the tumor bed after maximal safe resection, at six escalating doses (total 1.1x1010-2x1011 vp), followed by two 14-day courses of valacyclovir, and standard upfront chemoradiation. Key inclusion criteria were: age 18-75, KPS ≥70, and treatment-naive high-grade glioma amenable to gross total resection. Patients were consented pre-operatively. Enrollment occurred intraoperatively, upon pathology confirmation. RESULTS: The treatment was well tolerated without dose-limiting toxicity in patients with glioblastoma (n=17) (3 of the gliosarcoma variant), or anaplastic ependymoma (n=1). The maximal-tolerated dose was not reached. The median overall-survival was 21.3 months (95%CI: 11.1, 26.1). Tissues from subsequent resections from 8 subjects showed elevated markers for CD3+ and CD8+ T cells indicating potential successful anti-glioma immunity recruitment. Multiplex immunohistochemistry on two patients indicated a change in the intratumoral redistribution of CD8+ T cells and microglia/macrophages. CONCLUSIONS: Use of two adenoviral vectors expressing HSV1-TK and Flt3L is safe and well tolerated in newly diagnosed high-grade glioma patients. Promising multiplex immunocytochemical evidence of immune infiltration warrants further efficacy studies, possibly in combination with blockade of the inhibitory tumor microenvironment. (Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, and The Rogel Cancer Center at The University of Michigan; clinicaltrials.gov:NCT01811992)

In recent years, there have been significant advances in understanding the neuronal influence on the biology of solid tumors such as prostate, pancreatic, gastric, and brain cancers. An increasing amount of experimental evidence across multiple tumor types strongly suggests the existence of bidirectional crosstalk between cancer cells and the neural microenvironment. However, unlike cancers affecting many solid organs, brain tumors, namely gliomas, can synaptically integrate into neural circuits and thus can exert a greater potential to induce dynamic remodeling of functional circuits resulting in long‐lasting behavioral changes. The first part of the review describes dynamic changes in language, sensory, and motor networks following glioma development and presents evidence focused on how different patterns of glioma‐induced cortical reorganization may predict the degree and time course of functional recovery in brain tumor patients. The second part focuses on the network and cellular‐level mechanisms underlying glioma‐induced cerebral reorganization. Finally, oncological and clinical factors influencing glioma‐induced network remodeling in glioma patients are reviewed.