A craniotomy over the superior cerebellar convexity for approaches to this region typically involves a small infratentorial craniotomy and then drilling down of the bone to expose some portion of the transverse/sigmoid sinuses. The authors describe the anatomy of the region and the method for a two-part paramedian occipital and suboccipital craniotomy (supra and infratentorial) that may have time-saving, safety, and cosmetic advantages. For this technique, a supratentorial craniotomy is used to expose the transverse sinus from above, and subsequently, dissection across the sinus over the cerebellar convexity can be done under direct vision. The two bone pieces are joined on the inner table side while plates for fixation above the superior nuchal line can be counter-sunk to avoid post-operative pain from the prominence of screws. There is no need for cranioplasty materials since there is no burring down of bone for adequate exposure of the transverse sinus. The technique has been used by two senior surgeons over the years convincing them of the speed, safety, and utility of the technique. Here, the authors present a single example of the technique.

Objective

Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1^mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1^mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons.

Methods

Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1^mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5.

Results

Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1^wt) patients and in 59%-74% of IDH1^mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1^mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5.

Conclusions

The D2HG product of IDH1^mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1^mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1^mut inhibitors may improve antiepileptic therapy in patients with IDH1^mut gliomas.

Background

Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p/19q status.

Methods

We analyzed 412 histologic oligodendroglial tumors with use of 1p/19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p/19q was performed. Polysomy was defined as more than two 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p/19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS).

Results

In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p/19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p/19q loss had significantly better PFS and OS than did the group with 1p/19q maintenance (P < 0.0001 each). Patients with 1p/19q loss and polysomy showed significantly shorter PFS survival than patients with 1p/19q codeletion only (P < 0.0001), but longer PFS and OS than patients with 1p/19q maintenance (P < 0.01 and P < 0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% polysomic cells. Polysomy had no prognostic significance on PFS or OS in patients with 1p/19q maintenance.

Conclusions

The presence of polysomy in oligodendroglial tumors with codeletion of 1p/19q predicts early recurrence and short survival in patients with 1p/19q codeleted tumors.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments.