ITVT-07. Robotic alignment module Cirq for navigated brainstem tumor biopsies

BACKGROUND With the incorporation of the robotic alignment module Cirq (Brainlab, Germany) into our neurosurgical armamentarium, we aimed to know our baseline accuracy in stererotactic biopsies. We therefore retrospectively reviewed our data on biopsy accuracy for brain(stem) tumors using the non-robotic alignment instrument Varioguide (Brainlab, Germany). Because of unexpectedly large deviations from the intended target, we sought to improve our registration accuracy when we introduced Cirq. Intraoperative 3D CT with bone fiducials was added to the pre-operative 3D T1 MRI with skin fiducials. This made it possible to compare surgical devices as well as registration methods. AIMS To share our experience with the new robotic alignment module Cirq for navigated brain(stem) tumor biopsies and to evaluate its target accuracy with bone fiducial registration, as compared to the previously used Varioguide with skin fiducial registration. METHODS All patients (0–18 years old) that underwent a brain(stem) biopsy in our institution were included. Over 2018–2020, data were collected retrospectively (cohort Varioguide with 3D T1 MRI registration with skin fiducials). From 2021, data were collected prospectively (cohort Cirq with both 3D T1 MRI registration with skin fiducials and intraoperative CT registration with bone fiducials). For both cohorts, Euclidian distances were calculated between the intended target and the obtained target. For the prospective cohort, registration errors were calculated for bone versus skin fiducials. PRELIMINARY REUSLTS The deviation from the intended target was much smaller in the Cirq cohort versus the Varioguide cohort. Within the Cirq cohort, registration errors were submillimetric for bone fiducial registration as compared to several millimeters for skin fiducial registration. CONCLUSION: The Cirq robotic arm is convenient, safe and highly accurate, especially when combined with intraoperative 3D CT bone fiducial registration. Skin fiducial registration does not offer the level of precision that is mandatory in brainstem tumor biopsies.

Brainstem tumor as a cause of headache triggered by Valsalva maneuver

Expansive lesions of the posterior fossa or the malformation in the occipitocervical transition can cause headache triggered by Valsalva maneuver, usually of sudden onset and of significant intensity, which usually lasts for a short time. Brainstem tumor is rarely related to cause headache, hence the interest in documenting this patient's case in this article.

“MASSIVE BI-FRONTAL EXTRADURAL HEMORRHAGE FOLLOWING EXTERNAL VENTRICULAR DRAIN (EVD) PLACEMENT”-A CASE REPORT

One of the most important lifesaving procedures performed regularly in neurosurgical intensive care units is the insertion of an External Ventricular Drain (EVD).Complications arising from EVDs include hemorrhage, misplacement, dislodgement, blockage, and infection. We present a case of massive bi-frontal extradural hemorrhage following external ventricular drain (EVD) placement. A 23 years old male, diagnosed with dorsally exophytic midbrain and pontine glioma presented with headache, repeated vomiting and became drowsy. Non-contrast CT scan of head showed brainstem tumor with hydrocephalus. An EVD was inserted through right frontal twist drill craniostomy. Patient improved only to deteriorate 2 hours later. Repeat NCCT head showed massive bifrontal extradural hemorrhage. Immediate bi-frontal craniotomy and surgical evacuation of extradural hemorrhage was done. Complications of EVD insertions are many therefore preferably EVD insertion should be carried out in operation theratre and multiple attempts should be avoided, also controlled drainage of csf should be done.

DDEL-11. CONVECTION-ENHANCED DELIVERY OF EZH2 INHIBITOR FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA

BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. OBJECTIVE This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models. METHODS The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography–mass spectrometry (LC/MS). We treated mice bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. RESULTS LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P=0.0475). CONCLUSION Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.

ET-03 Convection-enhanced delivery of EZH2 inhibitor for the treatment of diffuse midline glioma

Background: Diffuse midline glioma (DMG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. Objective: This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DMG xenograft models. Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography mass spectrometry (LC/MS). We treated mice bearing human DMG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = 0.0475). Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DMG.

Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

Imaging features and classification of peritumoral edema in vestibular schwannoma

Background Peritumoral edema (PTE) is rarely present in patients with vestibular schwannomas (VS). We studied the correlation between radiological tumor characteristics and the presence of edema, describe its magnetic resonance imaging features and classify the different edema patterns. Methods We analysed 605 consecutive patients treated for VS at our Institute. PTE was found in 30 patients, studied on fluid attenuated inversion recovery sequences and categorised as involving the brachium pontis, cerebellum and/or brainstem. Tumor volume, shape, surface, internal structure and axis of growth were evaluated and compared to a matched series of 30 patients without PTE. Results In our population of patients, 5% showed PTE. Edema involved the brachium pontis in 22 cases (88%), cerebellum in 15 (60%) and brainstem in 3 (12%). PTE was classified as mild (one region involved), moderate (two regions) and severe (three regions). Edema was present not only perpendicular to the major tumor growth axis but also parallel to it (91%). The difference between the two groups in regards to tumor shape and surface was not significant. We found no correlation between tumor and edema volumes. Conclusions VS can cause PTE, but its incidence is less frequent than in skull base meningiomas. PTE involves most frequently the brachium pontis, followed by the cerebellum and brainstem. Its occurrence correlates with tumor size but not with other radiological VS features. PTE is not always located perpendicular to the major axis of tumor growth, which indicated that the compressive theory proposed for meningiomas is not plausible explanation for its manifestation.

NIMG-08. 2-HYDROXYGLUTARATE MAGNETIC RESONANCE SPECTROSCOPY IN BRAINSTEM TUMOR PATIENTS IN VIVO

Evaluation of 2-hydroxyglutarate (2HG) by magnetic resonance spectroscopy (MRS) has significant application in assessing the isocitrate dehydrogenase (IDH) mutational status in brain tumor patients noninvasively. This clinical role of 2HG MRS may be demonstrated most clearly in patients with brainstem lesions, where surgical biopsy presents high risk of permanent neurological injury. We conducted 2HG MRS in 20 subjects with a radiographically identified brainstem tumor (13 male and 7 female, age 20 - 73, median age 38). Proton MRS data was acquired from the T2-FLAIR volume using a 2HG-tailored MRS protocol (PRESS TE 97 ms). The millimolar concentration of 2HG was estimated with reference to water. Excluding data with unacceptable quality, data from 16 patients were included in subsequent analysis. The 16 patients were clearly divided into two groups in terms of 2HG level. The tumors in 5 patients showed a clearly discernible 2HG signal (2.25 ppm) while those in 11 patients did not. The 2HG estimation ranged from 2.1 to 6.3 mM in the 5 patients (IDH mutation) and from 0 to 0.7 mM in the 11 patients (most likely IDH wildtype). The mean concentration of 2HG differed significantly between the groups (p=3.3×10−6). One tumor was confirmed to be IDH mutated from autopsy. A representative case for 2HG MRS utility was a patient in whom 2HG was estimated to be 5.3 mM in the first MRS scan and the clinical decision was made to follow with 2HG MRS without surgery and chemoradiation therapy. The patients had 22 follow-up MRS scans for 5.4 years (scan intervals ~3 months), during which the tumor was stable clinically and radiographically. The present study demonstrates the clinical utility of 2HG MRS in brainstem tumors. 2HG MRS provides reliable estimation of 2HG and can be utilized for evaluating the IDH mutation status in brainstem lesion noninvasively.