Glioblastoma remodelling of human neural circuits decreases survival.

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.

Interactive Effects of Molecular, Therapeutic, and Patient Factors on Outcome of Diffuse Low-Grade Glioma.

PURPOSE: In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible. METHODS: In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR. RESULTS: Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis. CONCLUSION: Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.

Neuro-Oncology Patients as Human Research Subjects: Ethical Considerations for Cognitive and Behavioral Testing for Research Purposes.

Language, cognition, and behavioral testing have become a fundamental component of standard clinical care for brain cancer patients. Many existing publications have identified and addressed potential ethical issues that are present in the biomedical setting mostly centering around the enrollment of vulnerable populations for therapeutic clinical trials. Well-established guides and publications have served as useful tools for clinicians; however, little has been published for researchers who share the same stage but administer tests and collect valuable data solely for non-therapeutic investigational purposes derived from voluntary patient participation. Obtaining informed consent and administering language, cognition, and behavioral tasks for the sole purpose of research involving cancer patients that exhibit motor speech difficulties and cognitive impairments has its own hardships. Researchers may encounter patients who experience emotional responses during tasks that challenge their existing impairments. Patients may have difficulty differentiating between clinical testing and research testing due to similarity of task design and their physician's dual role as a principal investigator in the study. It is important for researchers to practice the proposed methods emphasized in this article to maintain the overall well-being of patients while simultaneously fulfilling the purpose of the study in a research setting.

Tribute to William Edward Hunt and Robert McDonald Hess Jr.: Pioneers in the Clinical Classification of Ruptured Intracranial Aneurysms.

William Edward Hunt (1921-1999) and Robert McDonald Hess Jr. (1931-2019) were pioneers in revolutionizing the early surgical management of ruptured intracranial aneurysms. Early on in his career as a professor of neurosurgery at Ohio State University, Dr. Hunt adopted a systematic method to identify clinical symptoms of patients presenting with subarachnoid hemorrhage as candidates for either immediate or delayed surgery. As an Ohio State University neurosurgery resident, Dr. Hess was an active key collaborator in Dr. Hunt's aneurysm studies. Described as a modification of the Botterell classification system, the Hunt-Hess scale grading the survival risk of undergoing immediate intracranial aneurysm surgery was implemented and validated across an 18-year consecutive patient series at White Cross Hospital, Columbus, Ohio. Dr. Hunt and Dr. Hess demonstrated that for patients with subarachnoid hemorrhage on admission with Hunt-Hess grades I and II, indicating retained consciousness and minimal neurological deficits, immediate surgical management afforded a <20% mortality rate. In comparison, patients with grade III or higher had a >50% mortality rate, suggesting that conservative management should be instead pursued. As the principal investigator, Dr. Hunt was widely regarded internationally as an expert in the field of treating intracranial aneurysms, eventually serving as a World Federation of Neurosurgical Societies (WFNS) committee member to also publish a universal subarachnoid hemorrhage grading scale. To pay tribute to Drs. Hunt and Hess for their substantial contributions, we present historical vignettes of their lives along with highlighting the role of the Hunt-Hess classification system in transforming management of ruptured aneurysms.

Shunt Treatment for Coccidioidomycosis-Related Hydrocephalus: A Single-Center Series.

OBJECTIVE: Coccidioidomycosis is a fungal infection endemic to the southwestern United States. Hydrocephalus can develop after intracranial dissemination, and management of this disease entity is difficult. We present our institutional experience with shunting coccidioidomycosis-related hydrocephalus. METHODS: A cohort of patients with coccidioidomycosis-related hydrocephalus undergoing an intracranial shunt placement were retrospectively identified over a 24-year period. Demographics and treatment characteristics were obtained from the electronic medical record. RESULTS: Thirty patients undergoing 83 procedures were identified, with a median follow-up of 19.4 months. The average age of the cohort was 43 years at the time of initial shunt placement. Most patients (66.7%) had ≥1 shunt failure, and the average number of revisions required was 2.6 for patients who had shunt failure. The average shunt valve pressure threshold required was 5.5 cm H2O, and patients who harbored the disease for a longer period (>7 months) had a lower pressure setting for initial shunt valves. Shunts without an antisiphon component were more likely to be failure free on multivariate analysis (odds ratio, 9.2; 95% confidence interval, 2.4-35.7). Death was associated with a longer diagnosis-to-shunt time interval, and patients having been diagnosed with intracranial disease for more than 10 months before shunt placement had significantly higher rates of death on follow-up. CONCLUSIONS: Patients with coccidioidomycosis-related hydrocephalus typically have normal to low pressure setting requirements, high shunt failure rates, prolonged hospitalizations, and mortality. In this disease context, shunt valves without an antisiphon component are associated with lower shunt failure rates.

Complementary networks of cortical somatostatin interneurons enforce layer specific control.

The neocortex is functionally organized into layers. Layer four receives the densest bottom up sensory inputs, while layers 2/3 and 5 receive top down inputs that may convey predictive information. A subset of cortical somatostatin (SST) neurons, the Martinotti cells, gate top down input by inhibiting the apical dendrites of pyramidal cells in layers 2/3 and 5, but it is unknown whether an analogous inhibitory mechanism controls activity in layer 4. Using high precision circuit mapping, in vivo optogenetic perturbations, and single cell transcriptional profiling, we reveal complementary circuits in the mouse barrel cortex involving genetically distinct SST subtypes that specifically and reciprocally interconnect with excitatory cells in different layers: Martinotti cells connect with layers 2/3 and 5, whereas non-Martinotti cells connect with layer 4. By enforcing layer-specific inhibition, these parallel SST subnetworks could independently regulate the balance between bottom up and top down input.