Cerebrospinal Fluid Dissemination Research Articles

TMOD-03.BRAFV600E MUTATION INDUCES TWIST1 UPREGULATION ASSOCIATED WITH MIGRATION AND CEREBRAL FLUID DISSEMINATION IN GLIOBLASTOMA

Abstract INTRODUCTION BRAFV600E-mutant glioblastoma (GBM) with epithelioid features frequently show cerebrospinal fluid dissemination (CSFD), which results in poor prognoses. BRAF mutation is worth investigating since BRAF or downstream MEK inhibitors show dramatic response for BRAFV600E-mutant GBM including CSFD. This suggests BRAF mutation could play a role for inducing the clinical manifestation of CSFD found in newly diagnosed and recurrent BRAFV600E-mutant GBM. Because, BRAFV600E-mutant GBM often recur with CSFD, elucidating the mechanism by which BRAFV600E-mutant GBM exhibits CSFD is important to improve prognosis. (Objective) To elucidate the molecular mechanism of CSFD involved in BRAFV600E-mutant GBM. METHODS We introduced the heterozygous BRAFV600E mutation in human induced pluripotent stem cells (iPSC) in the context of GBM genetic alterations, CDKN2A/2B, and PTEN deletion, TERT promoter mutation and with EGFRvIII overexpression. We implanted these iPSC-derived neural progenitor cells into immunodeficient mouse brains to establish a BRAFV600E-mutant GBM model. At the same time, we created a model with the same genetic background without BRAFV600E. We compared their gene expression, pathology, and migration patterns to identify BRAFV600E specific characteristics. RESULTS RNA sequencing revealed BRAFV600E-mutant tumors upregulated migration, and downregulated cell-to-cell adhesion genes. TWIST1 was one of the most upregulated genes, and was validated by qPCR. Concomitant with TWIST1 expression we detected downregulation of E-cadherin. The BRAFV600E GBM model histologically showed a cluster-like invasion phenotype, while non-BRAF tumors showed homogenous invasion with typical GBM pathological findings. Immunohistochemical staining showed relatively high TWIST1 expression in cluster-like tumor cells of BRAFV600E tumors. Upon re-engraftment of primary tumor-derived cells, secondary BRAFV600E tumors presented leptomeningeal dissemination. TWIST1 knockdown resulted in a decrease in the migratory ability of our BRAFV600E model in vitro, and is under investigation in vivo. CONCLUSION BRAV600E mutation induces TWIST1 upregulation, and might facilitate migration and CSFD. This work nominates TWIST1 and its regulated genes as targets for BRAFV600E-mutant GBM with CSFD.

Long-Term Outcomes of Stereotactic Radiosurgery for Pineocytomas: An International Multicenter Study.

Pineocytomas are grade 1 tumors arising from the pineal parenchyma. Gross total resection can potentially cure these benign lesions but can be associated with morbidity. This study was designed to provide multi-institutional data to evaluate the results of stereotactic radiosurgery (SRS) for pineocytomas. Centers participating in the International Radiosurgery Research Foundation were asked to review their database and provide data for patients who had SRS for histology confirmed grade 1 pineocytomas, for whom clinical and imaging follow-up of at least 6 months was available. In total, 38 patients underwent SRS as part of the management of a pineocytoma. The median age at SRS was 39 years (range 8-76). SRS was performed as primary approach in 68%, adjuvant after partial resection 19%, and at recurrence in 13% of patients. The median margin dose was 15 Gy (range 11-25 Gy). The median treatment volume was 3.35 cc (range 0.1-17.9 cc). Local tumor control was achieved in 92% of patients, with a mean actuarial progression-free survival of 21.6 years (median not reached). At last follow-up, 82% were still controlled, 8% had local recurrence, and 10% had cerebrospinal fluid dissemination. Tumor control was significantly better when SRS was used as primary care compared with the adjuvant or recurrent setting (P = .016). Five patients (13%) died during follow-up, all from tumor progression. The actuarial mean survival duration was 24.3 years, with a 5-year survival rate of 91%, and an estimated rate of 76% at 29 years. Larger tumor volume at SRS was found to be correlated to increased risk of death (P = .045). Transient symptomatic adverse radiation effects were observed in 4 patients (11%). SRS appears safe and effective for the management of pineocytomas. Long-term tumor control is achieved in most cases. SRS can be offered to selected patients as an alternative to surgical resection.

Outcomes of five cases of retinoblastoma with optic nerve invasion on imaging

PurposeTo investigate the timing of enucleation, treatment course, and outcome for retinoblastoma (RB) with optic nerve (ON) invasion on imaging.Study designRetrospective clinical study.MethodsOf the 160 patients with RB who presented to the National Center for Child Health and Development in Japan between 2005 and 2022, ON invasion on imaging at the initial presentation was seen in five patients. The clinical, computed tomography (CT), and magnetic resonance imaging (MRI) findings, and treatment courses were reviewed retrospectively.ResultsMRI showed ON invasion in all five patients (three with unilateral RB, 2 with bilateral RB); in two patients CT detected no invasion. Enucleation was performed in four patients, three of whom underwent neoadjuvant therapy and one had a positive ON resection margin following the enucleation as initial treatment. One patient did not undergo enucleation due to cerebrospinal fluid dissemination. All enucleated patients underwent adjuvant chemotherapy. Four patients underwent radiotherapy. During follow-up (mean, 89.4 months), four patients survived and one died.ConclusionMRI is recommended to evaluate ON invasion and determine the timing of enucleation for RB. The appropriate choice of neoadjuvant or adjuvant therapy would be helpful to avoid radiotherapy for RB with ON invasion on imaging.

The many faces of myxopapillary ependynomas.

Myxopapillary ependymomas (MPE), classified as grade 2 tumors by the WHO, are rare spinal neoplasms. Despite their slow growth and generally benign nature, MPE have a high recurrence rate and potential for cerebrospinal fluid dissemination. This study aims to identify the MRI characteristics and pathological patterns of MPE and investigate potential correlations between the MRI characteristics and specific histopathological patterns. We assessed 13 patients (7 men; mean age, 45.1 years) with pathologically proven MPE. MRI images were reviewed for tumor location, size, T1 and T2 signal characteristics, contrast enhancement, hemosiderin cap presence, vertebral scalloping, drop metastasis, and prominent intradural flow voids. Four histopathological patterns (microcystic, solid, hemorrhagic, and high hyalin content) were defined and segmented, with surface areas measured and percentages calculated relative to the total tissue surface. Most tumors were in the lumbar region (84.61%), with MRI revealing typical features such as T2 hyperintensity (100%) and contrast enhancement (92.3%). A rare non-enhancing MPE was noted. Large tumors exhibited a microcystic pathology pattern, with two cases with this pattern showing drop metastasis on MRI. Smaller tumors typically presented a solid pathology pattern with homogenous MRI signals. This study underscores the diverse MRI presentations of MPE and suggests a potential link between microcystic patterns in pathology and large MPE with drop metastasis.ABBREVIATIONS: MPE= myxopapillary ependymoma.

ACTION: a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma.

H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma. ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.

Long-term survival after cordectomy in a case of spinal cord diffuse midline glioma, H3K27-altered: illustrative case.

Spinal cord diffuse midline glioma, H3K27-altered, is an extremely rare entity with a poor prognosis. However, its optimal treatment remains poorly defined. Although cordectomy was introduced in the early 20th century, its efficacy has been questioned and shrouded behind the scenes. A 76-year-old male with recent-onset paraparesis of the lower extremities and paresthesia presented to our outpatient clinic. Magnetic resonance imaging revealed an intra-axial spinal cord tumor extending from T12 to L2. The patient underwent laminectomy and partial tumor resection, and the surgical specimen was histologically diagnosed as a diffuse midline glioma, H3K27-altered. Although standard chemoradiotherapy was implemented, the patient experienced local tumor recurrence 2 years later and underwent cordectomy at T9. The patient was alive at the 4-year follow-up after cordectomy without tumor recurrence. According to the literature, patients with lesions in the lower thoracic cord below T8 achieved a longer survival than those with lesions in the upper thoracic cord above T5. Cordectomy benefits selected cases of high-grade spinal cord gliomas. Maximal prevention of cerebrospinal fluid dissemination by tumor cells is indisputably important, and tumors located below the lower thoracic spine may be the key to success in establishing a long-term prognosis after cordectomy.

10179-NI-8 CLINICORADIOLOGICAL CHARACTERISTICS OF H3 K27-ALTERED THALAMIC GLIOMAS

Abstract BACKGROUND Diffuse midline glioma (DMG), H3 K27-altered (CNS WHO grade 4, 2021), exhibits diverse imaging features, and its characteristics have not yet been established. METHODS We retrospectively analyzed the imaging features and progression patterns of cases with H3p.K27M mutation in the thalamus, as part of the Kansai Molecular Diagnosis Network for CNS Tumors. RESULTS Among the H3p.K27M mutation cases accumulated from May 2007 to July 2022 (total 109 cases), 47 cases were located in the thalamus. The main tumor location was as follows: right side 23 cases, left side 19 cases, bilateral 4 cases and unknown 1 case. The tumor border was well-defined in 18 cases (38.3%), indistinct in 26 cases (55.3%), and uncertain in 3 cases (6.4%). Contrast enhancement was observed in 36 cases (76.6%), necrosis in 29 cases (61.7%), cyst formation in 11 cases (23.4%), peritumoral brain edema in 15 cases (31.9%), ventricular enlargement in 28 cases (59.6%), and evidence of cerebrospinal fluid dissemination on imaging in 8 cases (17.0%). The degree of tumor progression from the main tumor to the surrounding area was scored from 1 to 5 (mean: 3.5, median: 4). SURVIVAL RESULTS Among 43 cases with confirmed overall survival (OS) and progression-free survival (PFS), the median OS was 19.2 months (95% CI: 13.2-25.2), and the median PFS was 9.8 months (95% CI: 5.4-14.2). In univariate analysis, favorable prognostic factors were preoperative KPS 80 over(p = 0.007), and tumor progression score of 2 or less (p = 0.01). However, in multivariate analysis, only a tumor progression score of 2 or less remained the sole independent factor (p = 0.03, HR: 3.89, 95% CI: 1.14-13.3). DISCUSSION AND CONCLUSION A large-scale prospective study is needed, but in H3 K27M-mutant thalamic gliomas, the extent of tumor progression before surgery may be a prognostic factor.

P11.46.A ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. MATERIAL AND METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.

TIPS-08 ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with international sites opening imminently.

Multifocal primary central nervous system angiosarcoma: illustrative case.

Angiosarcoma is a malignant mesenchymal tumor derived from vascular endothelial cells in which a primary intracranial origin is extremely rare. Most previous reports of primary central nervous system (CNS) angiosarcoma have been solitary cases. The authors report a case of primary CNS angiosarcoma that caused the development of multiple disseminated cerebral hemorrhagic lesions within a short period of time. This rapid progression of symptoms resulted in the death of the patient. During surgery, several nodules suggestive of a tumor were removed from just below the surface of the brain, mixed into the hematoma. A pathological examination revealed atypical cells mimicking blood vessels in the subarachnoid space that were positive for specific vascular endothelial markers. In this case, multifocal angiosarcoma occurred on the brain surface and ventricles, suggesting cerebrospinal fluid dissemination. If multiple cerebral hemorrhages are found on the brain surface, multifocal angiosarcoma should also be considered.

Survival and Clinical Characteristics of Patients with Glioblastoma with Primitive Neuronal Component (P13-13.004)

<h3>Objective:</h3> Evaluate the survival and clinical characteristics of patients with diagnosis of glioblastoma with primitive neuronal component (GBM-PNC) on initial diagnosis compared to patients diagnosed with GBM-PNC at recurrence following prior diagnosis of malignant glioma without primitive component. <h3>Background:</h3> A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). At initial diagnosis, GBM-PNC is associated with increased responsiveness to platinum-based therapies and high rates of cerebrospinal fluid dissemination. It is unknown if the same characteristics and risks exist when primitive neuronal component develops at recurrence after an initial diagnosis with a malignant glioma. <h3>Design/Methods:</h3> The University of Washington pathology database was queried between the years of 2005 to 2021 to identify patients with a pathological diagnosis of GBM-PNC. Clinical and radiographic data were abstracted. Descriptive statistics and survival analysis were preformed. <h3>Results:</h3> 20 patients with diagnosis of GBM-PNC were identified and 16 had appropriate clinical information for inclusion. 11 patients were diagnosed with GBM-PNC at initial surgery and 6 were diagnosed at surgery for presumed recurrent malignant glioma. For patients found to have GBM-PNC at recurrence, the median overall survival was 40months compared to only 17months for patients diagnosed at initial surgery. Patients diagnosed at recurrence, also had longer time to first progression of 26.5months compared to 12months for patients initially diagnosed with GBM-PNC. The 4 patients who had intracranial progression leading to diagnosis of GBM-PNC all had cystic appearance on MRI. 33% of patients diagnosed with GBM-PNC at recurrence developed leptomeningeal dissemination. <h3>Conclusions:</h3> Patients who are diagnosed at GBM-PNC at recurrence of a prior malignant glioma have improved survival compared to patients who have a primitive neuronal component of the malignant glioma diagnosed at initial resection. This pathology was associated with a cystic radiographic appearance when intracranial. <b>Disclosure:</b> Dr. McGranahan has nothing to disclose. Patrick Cimino has nothing to disclose. Ms. Costanza has nothing to disclose.

Abstract CT060: ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma

Abstract Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease. Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023. Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT060.

Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy: analysis of recurrence patterns and predictive factors

BackgroundRadiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution.MethodsThe treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed.ResultsPlan 1 (n = 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n = 55) showed a median PFS and OS of 9.4 and 36.5 months (p = 0.418; p = 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p = 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n = 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05).ConclusionIn our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.

Clinicoradiologic Characteristics of Intradural Extramedullary Conventional Spinal Ependymoma.

Distinguishing intradural extramedullary (IDEM) spinal ependymoma from myxopapillary ependymoma is challenging due to the location of IDEM spinal ependymoma. This study aimed to investigate the utility of clinical and MR imaging features for differentiating between IDEM spinal and myxopapillary ependymomas. We compared tumor size, longitudinal/axial location, enhancement degree/pattern, tumor margin, signal intensity (SI) of the tumor on T2-weighted images and T1-weighted image (T1WI), increased cerebrospinal fluid (CSF) SI caudal to the tumor on T1WI, and CSF dissemination of pathologically confirmed 12 IDEM spinal and 10 myxopapillary ependymomas. Furthermore, classification and regression tree (CART) was performed to identify the clinical and MR features for differentiating between IDEM spinal and myxopapillary ependymomas. Patients with IDEM spinal ependymomas were older than those with myxopapillary ependymomas (48 years vs. 29.5 years, p < 0.05). A high SI of the tumor on T1W1 was more frequently observed in IDEM spinal ependymomas than in myxopapillary ependymomas (p = 0.02). Conversely, myxopapillary ependymomas show CSF dissemination. Increased CSF SI caudal to the tumor on T1WI was observed more frequently in myxopapillary ependymomas than in IDEM spinal ependymomas (p < 0.05). Dissemination to the CSF space and increased CSF SI caudal to the tumor on T1WI were the most important variables in CART analysis. Clinical and radiological variables may help differentiate between IDEM spinal and myxopapillary ependymomas.

PATH-41. THE DEVELOPMENT OF PRIMITIVE NEURONAL COMPONENT AT FIRST PROGRESSION OF MALIGNANT GLIOMA, A CASE SERIES

Abstract A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). These tumors are associated with higher rates of isocitrate dehydrogenase (IDH) mutations and increased responsiveness to platinum-based therapies, however they are also associated with a high rate of cerebrospinal fluid (CSF) dissemination. We review four patients treated at our institution with a prior diagnosis of malignant glioma who were found to have GBM-PNC at resection of recurrent disease and evaluate the clinical significance of the development of a primitive neuronal component. Of the 4 patients, 3 had previously been diagnosed with glioblastoma with a disease-free interval after radiation and temozolomide of 17.8 years, 2.4 years, and 1.6 years. The 4th patient was diagnosed 2 years prior with a WHO grade 2 IDH mutant astrocytoma and had only been treated surgically prior to disease progression. At recurrence, all patients developed cystic masses adjacent to prior surgical site in frontal lobe and/or temporal lobe. While no patients had spinal cord symptoms, as a result of the primitive component found at re-resection 3 out of 4 patients underwent spinal cord imaging. Two patients were found to have cauda equina enhancement favored to represent CSF dissemination. This is in line with the 40% CSF dissemination reported in other case series of diagnosis of GBM-PNC and far greater than 1.1% reported for glioblastoma. In this case series, the of development of primitive neuronal component at malignant glioma recurrence was associated with radiographic appearance of a cystic mass with significant vasogenic edema as well as high rates of CSF dissemination. The clinical implication of platinum responsiveness will also be presented.

RTID-01. ONC108: A RANDOMIZED PHASE 3 STUDY OF ONC201 IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of objective response in ONC201-treated patients enrolled in one of five open-label trials has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. METHODS ONC108 is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients will be randomized to receive once-weekly ONC201 or placebo following standard frontline radiotherapy. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed with the response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lanksy performance status ≥ 70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥ 10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible.

Refining M1 stage in medulloblastoma: criteria for cerebrospinal fluid cytology and implications for improved risk stratification from the HIT-2000 trial

BackgroundMedulloblastoma is the most common malignant paediatric brain tumour, and cerebrospinal fluid (CSF) dissemination (M1 stage) is a high-risk prognostic factor. Criteria for CSF evaluation and for differentiating M0 from M1 stage are not clearly defined, and the prognostic significance of M1 stage in this context is unknown. Patients and methodsCSF investigations from 405 patients with medulloblastoma of the prospective multicenter trial HIT-2000 (HIirnTumor-2000) were reviewed. Data from 213 patients aged ≥4 years were related to 5-year progression-free (5y-PFS) and overall survival. ResultsPatients with cytological tumour dissemination only (M1 stage only) aged ≥4 years (n = 18) and patients with radiologically detected metastases (M2/3, n = 85) showed a worse 5y-PFS than M0 patients (n = 110) without signs of metastatic disease (5y-PFS 61.1% and 59.6% vs 80.7%; p < 0.02 and p < 0.01, log rank). Patients with positive samples drawn early after surgery who turned negative within 14 days postoperatively (n = 9) and patients with atypical cells (n = 6) showed a 5y-PFS similar to M0 patients. No tumour cells were detected in samples containing <10 nucleated cells. Analysis of cytological criteria showed a better predictive value for tumour cell clusters than ≥2 individual tumour cells. ConclusionBased on our results, we suggest that CSF medulloblastoma staging should be performed 14 days postoperatively by lumbar puncture, and specimens should contain at least 10 nucleated cells. Cytological tumour dissemination alone (M1 stage only) appears a high-risk prognostic factor associated with an outcome comparable to M2/M3 stage. Tumour cell clusters seem to have a greater impact on prognosis than single tumour cells. This should be validated further.

Leptomeningeal disease and tumor dissemination in a murine diffuse intrinsic pontine glioma model: implications for the study of the tumor-cerebrospinal fluid-ependymal microenvironment.

BackgroundLeptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor–CSF–ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG.MethodsA Nestin-Tva model of DIPG utilizing the 3 most common DIPG genetic alterations (H3.3K27M, PDGF-B, and p53) was used for this study. All mice underwent MR imaging and a subset underwent histopathologic analysis with H&E and immunostaining.ResultsTumor dissemination within the CSF pathways (ventricles, leptomeninges) from the subependyma was present in 76% (25/33) of mice, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region-specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles.ConclusionsThis is the first study to report CSF pathway tumor dissemination associated with subependymal tumor in an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF–tumor–ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.

ML-16 First clinical experience of administration of Tirabrutinib for the patients with newly diagnosed primary central nervous system lymphoma

Tirabrutinib (TIR), a Burton’s tyrosine kinase inhibitory drug, has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). The authors recently encountered three patients with newly diagnosed refractory PCNSL using TIR.Three patients, 48, 78 and 88 years-old males, diagnosed with PCNSL by histologically verification were firstly treated with high dose Methotrexate based chemotherapy (HD-MTX) and/or radiotherapy, however these cases were refractory for these standard treatments, demonstrated early cerebrospinal fluid dissemination or accompanied with severe adverse event. The authors decided to administrate TIR to these patients with a full informed consent. TIR demonstrated dramatic reduction of the volume of tumor on MRI within one month after administration of TIR, and improved the patient’s performance status. However, one case demonstrated liver dysfunction and multiple brain abscess due to aspergillus infection, and one case demonstrated early progression of the tumor 49 days after starting TIR.Administration of TIR for the patients with newly diagnosed refractory PCNSL demonstrated a rapid and dramatic clinical response, and presented with several clinical implications for this complicated condition.

BT-1 An autopsy case of multicentric malignant glioma, H3K27M mutant

Introduction: In 2016, the World Health Organization (WHO) defined diffuse midline glioma, H3K27M mutant (WHO Grade 4) as a tumor with K27M mutation in histone H3.3 (H3F3A) or H3.1 (HIST1H3B/C) that develops mainly in the midline regions of the central nervous system. Here, we report a rare case of the abovementioned disease with remote multiple lesions in addition to the midline regions that was diagnosed on the initial visit. Case: The 52-year-old man, suffered from dysarthria, dysphagia, gait disturbance, and headache that gradually worsened over several months. Non-contrast-enhanced lesions were noted in the pons(swelling and involvement of the basilar artery trunk), cerebellum, thalamus, fornix, periventricular area, hippocampus, medial aspect of bilateral frontal lobes, and distally in the right frontal cortex and apical region of the left temporal lobe. The open biopsy was performed for left cerebellar surface lesion, and the pathological and genetic diagnosis was diffuse midline glioma, H3K27M mutant. Extended focal radiation at 50Gy/25fr and corpus callosal/cerebellar boost at 10Gy/5fr were performed. The lesions were markedly reduced, and neurological symptoms were also alleviated. However, 20 months after the initial visit, neurological symptoms had worsened and cerebrospinal fluid dissemination occurred, after that died at 29 months. An autopsy revealed tumor invasion mainly in the midline regions of the cerebrum and in the cerebellum, brain stem, pituitary gland, entire spinal cord, and cauda equina. Immunostaining of the distally cerebral cortex lesions showed that with a negative result for H3G34V. Discussion/Conclusion: It was suggested that caution is required for primary differential diagnosis may be presented at multiple lesions such as remote cerebral cortex of diffuse midline glioma, H3K27M-mutant.