ITVT-03. Use of Functional MRI and DTI for Surgical Planning of Maximal Extent of Resection of CNS Tumors - A Single Neurosurgical Center’s Experience

Use of functional neuroimaging capabilities such as fMRI, DTI, MRP, MRS, AS-PET-CT, SPECT, and TMS as noninvasive tools to visualize intrinsic brain and spine morphology in relation to function have developed over the past 30 years. Amongst these imaging modalities, functional magnetic resonance imaging (fMRI) is of particular interest since it follows the physiological coupling between neuronal electrical activity and metabolic structural (cellular) activity as it relates to tissue vascularity and perfusion states. As an adjunct to this modality, MRI-based diffusion tensor imaging (DTI) allows further detailed radiographic assessment of fiber tracts in the brain in relationship to the surgical lesion of interest. In addition, combination of other imaging modalities including MR perfusion and intraoperative tools such as neuronavigation and direct cortical stimulation can help guide the extent of maximal safe resection. Herein we present a case series from our neurosurgical institution of primary intra-axial, extra-axial, supratentorial, and brainstem tumors resected using fMRI and DTI for presurgical planning allowing for maximal safe extent of resection and outcomes.

Fifteen-year trends and differences in mortality rates across sex, age, and race/ethnicity in patients with brainstem tumors

Background Localization of tumors to the brainstem carries a poor prognosis, however, risk factors are poorly understood. We examined secular trends in mortality from brainstem tumors in the US by age, sex, and race/ethnicity. Methods We extracted age-adjusted incidence-based mortality rates of brainstem tumors from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2018. Trends in age-adjusted mortality rate (AAMR) were compared by sex and race/ethnicity among the younger age group (0-14 years) and the older age group (>15 years) respectively. Average AAMRs in each 5-year age group were compared by sex. Results This study included 2,039 brainstem tumor-related deaths between 2004 and 2018. Trends in AAMRs were constant during the study period in both age groups, with 3 times higher AAMR in the younger age group compared to the older age group. Males had a significantly higher AAMR in the older age group, while no racial differences were observed. Intriguingly, AAMRs peaked in patients 5-9 years of age (0.57 per 100,000) and in patients 80-84 years of age (0.31 per 100,000), with lower rates among middle-aged individuals. Among 5-9 years of age, the average AAMR for females was significantly higher than that of males (p=0.017), whereas the reverse trend was seen among those 50-79 years of age. Conclusions Overall trends in AAMRs for brainstem tumors were constant during the study period with significant differences by age and sex. Identifying the biological mechanisms of demographic differences in AAMR may help understand this fatal pathology.

Brainstem tumors in children: a review

The brainstem is defined as the portion of the neural axis between the diencephalon and the cervical spinal cord. Brainstem gliomas (BSGs) can occur anywhere within this region and account for 10% to 15% of primary pediatric intracranial tumors. The development of neuroimaging allied to the refinement of surgical tools, such as improved magnification and visualization of the surgical field with more powerful surgical microscopes and sources of light, followed by the introduction of ultrasonic aspirator, anesthetic and intraoperative neurophysiological monitoring provided the neurosurgeon with conditions for a much safer surgical management of these tumors. This article reviews the current state of knowledge with regard to tumors arising in the brain stem in children, the therapeutic options available and provides recommendations with regard to management.

EPID-18. TRENDS IN INCIDENCE AND SURVIVAL OF MALIGNANT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN THE NETHERLANDS

BACKGROUND Variation in survival of pediatric central nervous system (CNS) tumors is large between countries. Within Europe, the Netherlands had one of the worst reported survival rates of malignant CNS (mCNS) tumors during 2000–2007. METHODS Using the Netherlands Cancer Registry, we evaluated trends in incidence and survival of pediatric mCNS tumors (behavior /3, 5th digit in the morphology code) diagnosed between 1990–2017. RESULTS 839 newly-diagnosed mCNS tumor patients <18 years were registered between 1990–2017. Incidence of mCNS tumors remained stable (average incidence rate, 21.6 per million person-years). However, an increased incidence of malignant gliomas, NOS was found (Estimated Annual Percentage Change (EAPC) 11.6% p<0.001). This appears to be related to a registration shift between 1990–1999 and 2000–2009 as brainstem tumors increased (+25%, n=79) for astrocytomas and other gliomas but decreased (-31%, n=32) for unspecified intracranial and intraspinal neoplasms. Overall, 5-year observed survival (5Y-OS) of mCNS tumors increased from 51% in 1990–1999 to 61% in 2010–2017 (P-for-trend<0.001). This increase was not constant over time, as 5Y-OS for the period 2000–2009 was 47%. The only significant decrease in survival was found for malignant astrocytomas and other gliomas with a 5Y-OS of 56% in 1990–1999 decreasing to 48% in 2010–2017 (P-for-trend<0.001). CONCLUSION Between 1990–2017 incidence of mCNS tumors in the Netherlands remained stable and survival increased. However, a decrease in survival was seen for malignant astrocytomas and other gliomas, which is partially explained by the registration shift of brainstem tumors. The impact of this shift on survival for all mCNS tumors is subject to further research.

ETMR-04. EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES: THE MD ANDERSON CANCER CENTER EXPERIENCE

BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) are rare tumors that are molecularly diagnosed by C19MC amplification. Rarity of this tumor has precluded profiling uniform therapeutic strategy. METHODS Retrospective review after institutional approval, identified 10 pediatric case of ETMR, treated at MD Anderson Cancer Center during the period of 2005 to 2019. RESULTS Median age of at diagnosis was 4.6 years. Tumor sites include frontal or parietal lobes (3), spine (3) and posterior fossa involving the brainstem (4). All patients received a combination of chemotherapy and radiation. 4 patients had metastasis at the presentation. 9 patients received focal radiation but only 6 of them received Craniospinal irradiation (CSI). Average dose of radiation was 50 Gy. Surgical resection was performed in all cases except the brainstem tumors. 7 children had recurrence including all the patients with metastasis at diagnosis (median time: 9.4 months), 1 passed away secondary to hemorrhage in brainstem and data was not available for 2 patients. 5/6 patients who received CSI had recurrence. CONCLUSIONS To-date no well-defined treatment regimens exists for these neoplasms, resulting in poor overall survival. Preclinical drug screen have shown the efficacy of topotecan, actinomycin D, and volasertib as potential new therapeutic candidates, though this has not translated successfully into the clinical arena. Given the limited success with current conventional therapeutic methods, molecular interrogation in addition to histopathological diagnosis are essential upfront, as it could provide clues to targeted therapy. Defining molecularly-based treatment with less toxicities and increased survival are warranted.

DIPG-44. A GAIN OF FUNCTION Ezh2 MUTATION DELAYS DIFFUSE INTRINSIC PONTINE GLIOMA PROGRESSION

BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) remains an incurable pediatric brain cancer. The oncohistone H3K27M implicated in 80% of the cases, is also predicted to target Enhancer of Zeste Homolog 2 (Ezh2), the catalytic component of the Polycomb Repressor Complex 2 (PRC2). There are no reported mutations of Ezh2 and its function in DIPG is not fully determined. This work aims to address the role of Ezh2 in DIPG. METHODS Brainstem tumors were established by intracranial injections of Nestin;Tv-a; Ezh2Y641F/+ (NTv-a; Ezh2Y641F/+) neonatal pups using Replication Competent Avian Sarcoma leucosis virus long terminal repeat with splice acceptor (RCAS) viruses, expressing PDGF-B, p53 shRNA, and RCAS-CRE/Y. Immunohistochemical staining for Ki-67 and H3K27me3 were performed on the Discovery ULTRA (Ventana). RESULTS Ezh2 overexpression (Ezh2Y641F/+, RCAS CRE) conferred a survival advantage of approximately 10 days (n=20 mice/group, p<0.001). H3K27me3 levels were significantly upregulated in RCAS CRE group (50% vs 20% in RCAS Y, n=4 tumors/group, p<0.03), with a concomitant lower Ki-67 staining (30% vs. 55% in RCAS Y, n=3 tumors/group, p<0.05). Interestingly, pathological review categorized more RCAS-CRE tumors as ‘atypical’. RNA-sequencing of virus-infected neural precursor cells revealed a suppression of inflammatory/interferon gene signature in the Ezh2 overexpression group. CONCLUSIONS AND FUTURE DIRECTIONS: Enhanced Ezh2 activity appears to delay DIPG pathogenesis. Ongoing work aims to highlight the contribution of differentially expressed gene signatures that contribute to this phenotype.

Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

Background Diffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem. Methods Syngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models. Results Expression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity. Conclusions Virus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.