Meningiomas’ Management: An Update of the Literature

Meningiomas are the most common primary intracranial tumors in the adult population [1]. They are generally considered benign lesions but after the 2007 WHO classification, the proportion of atypical meningiomas has steeply increased. Surgery is considered the mainstay of the treatment and a complete resection is considered curative in WHO grade I meningiomas. The role of adjuvant treatments like radiotherapy (stereotactic radiosurgery or conventional external beam irradiation) and chemotherapy in more aggressive cases is still discussed, above all in WHO grade II meningiomas. We would like to expose the most important advances in meningiomas’ management in accordance with the recent literature evidences

BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of developing rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres, and identified 6 distinct response patterns. To uncover emerging actionable vulnerabilities that can be targeted with a second drug, we extracted the 169 significantly disturbed DNA Damage Response genes and inspected their response pattern. The most prominent candidate with consistent downregulation, was the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a known resistance factor for alkylating agent therapy in glioblastoma. BETi not only reduced MGMT expression in GBM cells, but also inhibited its induction, typically observed upon temozolomide treatment. To determine the potential clinical relevance, we evaluated the specificity of the effect on MGMT expression and MGMT mediated treatment resistance to temozolomide. BETi-mediated attenuation of MGMT expression was associated with reduction of BRD4- and Pol II-binding at the MGMT promoter. On the functional level, we demonstrated that ectopic expression of MGMT under an unrelated promoter was not affected by BETi, while under the same conditions, pharmacologic inhibition of MGMT restored the sensitivity to temozolomide, reflected in an increased level of γ-H2AX, a proxy for DNA double-strand breaks. Importantly, expression of MSH6 and MSH2, which are required for sensitivity to unrepaired O6-methylguanine-lesions, was only briefly affected by BETi. Taken together, the addition of BET-inhibitors to the current standard of care, comprising temozolomide treatment, may sensitize the 50% of patients whose glioblastoma exert an unmethylated MGMT promoter

Anterior Petrosectomy With Intertentorial Approach

Background and objectives: The extradural anterior petrosal approach (EAPA) can present a challenge because it deals with critical structures in a narrow, confined corridor. It is associated with several potential approach-related risks including temporal lobe and venous injuries. Tentorial peeling has the potential to largely eliminate these risks during the approach and may offer more options for tailoring the dural opening to the anatomic region that one wants to expose. Methods: Anatomic dissections of five adult injected non-formalin-fixed cadaveric heads were performed. Anterior petrosectomy with intertentorial approach (APIA) through a tentorial peeling was completed. Step-by-step documentation of the cadaveric dissections and diagrammatic representations are presented along with an illustrative case. Results: Tentorial peeling separates the tentorium into a temporal tentorial leaf and posterior fossa tentorial leaf, adding a fourth dural layer to the three classic ones described during a standard EAPA. This opens out the intertentorial space and offers more options for tailoring the dural incisions specific to the pathology being treated. This represents a unique possibility to address brainstem or skull base pathology along the mid- and upper clivus with the ability to keep the entire temporal lobe and basal temporal veins covered by the temporal tentorial leaf. The APIA was successfully used for the resection of a large clival chordoma in the illustrative case. Conclusion: APIA is an interesting modification to the classic EAPA to reduce the approach-related morbidity. The risk reduction achieved is by eliminating the exposure of the temporal lobe while maintaining the excellent access to the petroclival region. It also provides several options to tailor the durotomies based on the localization of the lesion

Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain

Purpose: Experimental evidence suggests that lactate is neuroprotective after acute brain injury; however, data in humans are lacking. We examined whether exogenous lactate supplementation improves cerebral energy metabolism in humans with traumatic brain injury (TBI). Methods: We prospectively studied 15 consecutive patients with severe TBI monitored with cerebral microdialysis (CMD), brain tissue PO2 (PbtO2), and intracranial pressure (ICP). Intervention consisted of a 3-h intravenous infusion of hypertonic sodium lactate (aiming to increase systemic lactate to ca. 5mmol/L), administered in the early phase following TBI. We examined the effect of sodium lactate on neurochemistry (CMD lactate, pyruvate, glucose, and glutamate), PbtO2, and ICP. Results: Treatment was started on average 33±16h after TBI. A mixed-effects multilevel regression model revealed that sodium lactate therapy was associated with a significant increase in CMD concentrations of lactate [coefficient 0.47mmol/L, 95% confidence interval (CI) 0.31-0.63mmol/L], pyruvate [13.1 (8.78-17.4)μmol/L], and glucose [0.1 (0.04-0.16) mmol/L; all p<0.01]. A concomitant reduction of CMD glutamate [−0.95 (−1.94 to 0.06) mmol/L, p=0.06] and ICP [−0.86 (−1.47 to −0.24) mmHg, p<0.01] was also observed. Conclusions: Exogenous supplemental lactate can be utilized aerobically as a preferential energy substrate by the injured human brain, with sparing of cerebral glucose. Increased availability of cerebral extracellular pyruvate and glucose, coupled with a reduction of brain glutamate and ICP, suggests that hypertonic lactate therapy has beneficial cerebral metabolic and hemodynamic effects after TBI

ICAR: endoscopic skull‐base surgery

n/