Glioblastoma multiforme (GBM) is a devastating tumour with abysmal prognoses. We desperately need novel approaches to understand GBM biology and therapeutic vulnerabilities. Extracellular vesicles (EVs) are membrane-enclosed nanospheres released locally and systemically by all cells, including tumours, with tremendous potential for intercellular communication. Tumour EVs manipulate their local environments as well as distal targets; EVs may be a mechanism for tumourigenesis in the recurrent GBM setting. We hypothesized that GBM EVs drive molecular changes in normal human astrocytes (NHAs), yielding phenotypically tumour-promoting, or even tumourigenic, entities. We incubated NHAs with GBM EVs and examined the astrocytes for changes in cell migration, cytokine release and tumour cell growth promotion via the conditioned media. We measured alterations in intracellular signalling and transformation capacity (astrocyte growth in soft agar). GBM EV-treated NHAs displayed increased migratory capacity, along with enhanced cytokine production which promoted tumour cell growth. GBM EV-treated NHAs developed tumour-like signalling patterns and exhibited colony formation in soft agar, reminiscent of tumour cells themselves. GBM EVs modify the local environment to benefit the tumour itself, co-opting neighbouring astrocytes to promote tumour growth, and perhaps even driving astrocytes to a tumourigenic phenotype. Such biological activities could have profound impacts in the recurrent GBM setting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

The differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.

The present quantitative study extends our investigation of cetartiodactyls by exploring the neuronal morphology in the giraffe (Giraffa camelopardalis) neocortex. Here, we investigate giraffe primary visual and motor cortices from perfusion-fixed brains of three subadults stained with a modified rapid Golgi technique. Neurons (n = 244) were quantified on a computer-assisted microscopy system. Qualitatively, the giraffe neocortex contained an array of complex spiny neurons that included both "typical" pyramidal neuron morphology and "atypical" spiny neurons in terms of morphology and/or orientation. In general, the neocortex exhibited a vertical columnar organization of apical dendrites. Although there was no significant quantitative difference in dendritic complexity for pyramidal neurons between primary visual (n = 78) and motor cortices (n = 65), there was a significant difference in dendritic spine density (motor cortex > visual cortex). The morphology of aspiny neurons in giraffes appeared to be similar to that of other eutherian mammals. For cross-species comparison of neuron morphology, giraffe pyramidal neurons were compared to those quantified with the same methodology in African elephants and some cetaceans (e.g., bottlenose dolphin, minke whale, humpback whale). Across species, the giraffe (and cetaceans) exhibited less widely bifurcating apical dendrites compared to elephants. Quantitative dendritic measures revealed that the elephant and humpback whale had more extensive dendrites than giraffes, whereas the minke whale and bottlenose dolphin had less extensive dendritic arbors. Spine measures were highest in the giraffe, perhaps due to the high quality, perfusion fixation. The neuronal morphology in giraffe neocortex is thus generally consistent with what is known about other cetartiodactyls.

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BACKGROUND:Despite spinal cord stimulation's (SCS) proven efficacy, failure rates are high with no clear understanding of which patients benefit long term. Currently, patient selection for SCS is based on the subjective experience of the implanting physician.OBJECTIVE:To develop machine learning (ML)–based predictive models of long-term SCS response.METHODS:A combined unsupervised (clustering) and supervised (classification) ML technique was applied on a prospectively collected cohort of 151 patients, which included 31 features. Clusters identified using unsupervised K-means clustering were fitted with individualized predictive models of logistic regression, random forest, and XGBoost.RESULTS:Two distinct clusters were found, and patients in the cohorts significantly differed in age, duration of chronic pain, preoperative numeric rating scale, and preoperative pain catastrophizing scale scores. Using the 10 most influential features, logistic regression predictive models with a nested cross-validation demonstrated the highest overall performance with the area under the curve of 0.757 and 0.708 for each respective cluster.CONCLUSION:This combined unsupervised–supervised learning approach yielded high predictive performance, suggesting that advanced ML-derived approaches have potential to be used as a functional clinical tool to improve long-term SCS outcomes. Further studies are needed for optimization and external validation of these models.

The hormonally active nature of intracranial meningioma has prompted research examining the risk of tumorigenesis in patients using hormonal contraception. Studies exploring estrogen-only and estrogen/progesterone combination contraceptives have failed to demonstrate a consistent increased risk of meningioma. By contrast, the few trials examining progesterone-only contraceptives have shown higher odds ratios for risk of meningioma. With progesterone-only contraception on the rise, the risk of tumor recurrence with these specific medications warrants closer study. We sought to determine whether progesterone-only contraception increases recurrence rate and decreases progression-free survival in pre-menopausal women with surgically resected WHO Grade I meningioma. Comparative analysis of 67 pre-menopausal women taking hormone-based contraceptives (progesterone-only medication, n = 21; estrogen-only or estrogen/progesterone combination medication, n = 46) who underwent surgical resection of WHO Grade I intracranial meningioma was performed. Differences in demographics, degree of resection, adjuvant therapy and time to recurrence were compared between the two groups. Compared to patients taking combination or estrogen-only contraception, those taking progesterone-only contraception demonstrated a greater recurrence rate (33.3 vs. 19.6%) with a reduced time to recurrence (18 vs. 32 months, p = 0.038) despite a significantly shorter follow-up (p = 0.014). There were no significant demographic or treatment related differences. The results from this study suggest that exogenous progesterone-only medications may represent a specific contraceptive subgroup that should be avoided in patients with meningioma.

BACKGROUND AND IMPORTANCE Dural arteriovenous fistulas (DAVFs) may present unique challenges for treatment depending on the anatomy and pattern of venous drainage. If endovascular techniques are to be employed, the DAVF must be amenable to transvenous or transarterial therapy. When access of peripheral vasculature does not provide a straightforward path, less conventional options may be available. This case highlights a novel, technically simple, and effective approach for the treatment of a subset of DAVFs, with venous drainage through calvarial diploic veins, that would make endovascular treatment otherwise challenging or impossible. CLINICAL PRESENTATION We present a case of a 66-yr-old female patient who was diagnosed with a symptomatic DAVF located along the sphenoid ridge with a large intraosseous channel containing the draining vein of the fistula. This lesion was successfully treated with transcranial endovascular embolization via direct intraosseous cannulation of the calvarial diploic vein. This novel approach obviated the need for a full-thickness craniotomy, afforded only minimal bone loss, and preserved the integrity of the dura. A 3-mo follow-up angiogram confirmed complete cure of the DAVF with no residual arteriovenous shunt. At 20 mo postembolization, the patient was symptom free, with no reported neurologic deficits. Complete diagnostic work-up, treatment planning in a multidisciplinary environment, and a novel approach for endovascular embolization utilizing a hybrid operating suite played key roles in the successful implementation of this technique. CONCLUSION This is the first report of direct intraosseous cannulation of a calvarial diploic vein for successful transcranial endovascular embolization of a symptomatic DAVF.