Diffuse Pontine Research Articles

INNV-34. APPLICATION OF 200 KHZ TUMOR TREATING FIELDS (TTFIELDS) IN PATIENTS WITH INFRATENTORIAL HIGH-GRADE GLIOMA: CASE SERIES

Abstract BACKGROUND 200 kHz Tumor Treating Fields (TTFields) therapy is FDA-approved for supratentorial newly-diagnosed and recurrent glioblastoma. However, reports of its application in patients with infratentorial high-grade glioma (HGG) are rare. Based on computational modeling, the therapeutic field strength (~1 V/cm peak-to-peak) is thought to be achievable for infratentorial HGG. METHODS Two patients with infratentorial HGG received off-label 200 kHz TTFields therapy with the Optune® device (Novocure, Ltd.). To reduce impaired range of motion of the neck, the electrode transducer arrays were “skeletonized” by cutting a portion of the adhesive material surrounding them. Application of the electrode arrays was performed with the neck in flexion, to further promote neck range of motion. Cloth tape was used for reinforcement as necessary. Electrode arrays were changed every 2-3 days. We report the results of patient survival and adverse events. RESULTS Patient 1: 22-year-old man with high-grade diffuse pontine glioma with recurrences and prior treatments (including radiation, temozolomide, lomustine, and dopamine receptor D2 [DRD2] antagonist), tolerated TTFields combined with systemic treatment (initially with a bi-functional DNA alkylating agent; subsequently with temozolomide and bevacizumab) for 5 months with stable disease for 4 months. He experienced grade 1 rash of the neck. Patient 2: 58-year-old woman with diffuse glioma of the brainstem (H3K27M-mutated) with multiple recurrences and prior treatments (including concurrent radiation and temozolomide, and DRD2 antagonist), tolerated TTFields combined with systemic treatment (lomustine and bevacizumab). The TTFields infratentorial layout was iteratively modified with respect to placement of the electrode transducer arrays, for improved tolerability. With the TTFields+systemic combination therapy, the patient was stable for 8 months with no local TTFields-related side effects. CONCLUSIONS We provide initial post-marketing evidence that off-label use of 200 kHz TTFields in infratentorial HGG is safe and feasible. Prospective studies are necessary to validate the efficacy of this approach.

A review of sonodynamic therapy for brain tumors.

Sonodynamic therapy (SDT) is gaining attention as a promising new noninvasive brain tumor treatment that targets and selectively kills tumor cells, with limited side effects. This review examines the mechanisms of SDT and ongoing clinical trials looking at optimization of sonication parameters for potential treatment of glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). The results in the first patient with recurrent GBM treated at the Mayo Clinic are briefly discussed. The authors of this literature review used electronic databases including PubMed, EMBASE, and OVID. Articles reporting relevant preclinical and clinical trials were identified by searching for text words/phrases and MeSH terms, including the following: "sonodynamic therapy," "SDT," "focused ultrasound," "5-ALA," "ALA," "brain tumors," "diffuse pontine glioma," "glioblastoma," and "high grade glioma." Preclinical and clinical trials investigating the specific use of SDT in brain tumors were reviewed. In preclinical models of high-grade glioma and GBM, SDT has shown evidence of targeted tumor cell death via the production of reactive oxygen species. Emerging clinical trial results within recurrent GBM and DIPG show evidence of successful treatment response, with minimal side effects experienced by recruited patients. So far, SDT has been shown to be a promising noninvasive cancer treatment that is well tolerated by patients. The authors present pilot data suggesting good radiological response of GBM to a single SDT treatment, with unpublished observation of a lack of off-target effects even after multiple (monthly) sonication outpatient treatments. The scope of the clinical trials of SDT is to investigate whether it can be the means by which the fatal diagnosis of GBM or DIPG is converted into that of a chronic, treatable disease. SDT is safe, repeatable, and better tolerated than both chemotherapy and radiotherapy. It has been shown to have an effect in human cancer therapy, but more clinical trials are needed to establish standardized protocols for sonosensitizer delivery, treatment parameters, and combination therapies. The most appropriate timing of treatment also remains to be determined-whether to prevent recurrence in the postoperative period, or as a salvage option in patients with recurrent GBM for which redo surgery is inappropriate. It is hoped that SDT will also be developed for a wider spectrum of clinical indications, such as metastases, meningioma, and low-grade glioma. Further clinical trials are in preparation.

Uraemic brainstem encephalopathy mimicking ocular myasthenia: a case report

BackgroundUraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in brainstem uraemic encephalopathy.Case presentationA 22-year-old Sri Lankan man with end stage renal failure presented with acute onset diplopia and drooping of eyelids progressively worsening over one week. The patient had not complied with the prescribed renal replacement therapy which was planned to be initiated 5 months previously. On examination, his Glasgow coma scale score was 15/15, He had a fatigable asymmetrical bilateral ptosis. The ice-pack test was negative. There was a complex ophthalmoplegia with bilateral abduction failure and elevation failure of the right eye. The diplopia did not worsen with prolonged stare. The rest of the neurological examination was normal. Serum creatinine on admission was 21.81 mg/dl. The repetitive nerve stimulation did not show a decremental pattern. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse midbrain and pontine oedema with T2 weighted/FLAIR hyperintensities. The patient was haemodialyzed on alternate days and his neurological deficits completely resolved by the end of the second week of dialysis. The follow up brain MRI done two weeks later demonstrated marked improvement of the brainstem oedema with residual T2 weighted/FLAIR hyperintensities in the midbrain.ConclusionsUraemia may rarely cause an isolated brainstem encephalopathy mimicking ocular myasthenia, which resolves with correction of the uraemia.

Bickerstaff’s brainstem encephalitis: a rare case of neurologic complication in Ulcerative Colitis

Bickerstaff’s brainstem encephalitis is a rare autoimmune disorder that presents with ataxia, ophthalmoplegia, disturbance of consciousness and quadriplegia. A 45-year-old man with a history of ulcerative colitis (UC) taking mesalazine (5-aminosalicylic acid) visited the emergency room presenting with ataxia, ophthalmoplegia and a progressively worsening cognitive impairment. Cerebrospinal fluid analysis showed mild elevation in protein and white blood cell count and increased intracranial pressure. Anti-GQ1b autoantibodies were found positive in the patient’s serum and contrast-enhanced brain magnetic resonance imaging showed diffuse leptomeningeal enhancement and pontine lesions. Based on these findings and the patient’s clinical course and history, he was diagnosed with Bickerstaff’s brainstem encephalitis. Mesalazine was discontinued and high-dose steroid pulse therapy was started, followed by intravenous immunoglobulin, which resulted in gradual improvement of the neurologic symptoms. When an ulcerative colitis patient presents with progressive cognitive impairment, quadriplegia and disturbance of consciousness and gait, Bickerstaff brainstem encephalitis should be considered in the differential diagnosis and prompt immunotherapy may lead to favorable prognosis.

Brainstem tumors in children: a monocentric series in the light of genetic and bio-molecular progress in pediatric neuro-oncology.

Brainstem tumors represent a challenge. Their management and prognosis vary according to anatomopathological findings and genetic and bio-molecular fingerprints. We present our experience with pediatric brainstem tumors. All patients admitted for a brainstem tumor at the Pediatric Neurosurgical Unit at Hôpital Femme Mère Enfant hospital between January 1997 and December 2019 were considered. Patients data were obtained through a retrospective review of the medical records; follow-up was from the last outpatient consultation. One hundred and twelve patients were included. Eighty-five patients (75.9%) had open surgery or stereotactic biopsy. Thirty-five patients were treated for hydrocephalus. Sixty-six received an adjuvant treatment. Several protocols were adopted according to the SFOP and SIOP during this time period. The overall survival rate was 45% with a median follow-up of five years (range 1-18 year). However, the survival rate was very different between the diffuse intrinsic pontine gliomas (DIPG) and the others tumor types. If we exclude the DIPG (59 patients), of which only 1 was alive at 3 years, the survival rate was 90.6% (only 5 deaths over 53 patients) with a median follow up of 5 years. Our series confirms that benign tumors of the brainstem have a good survival when treated with surgical removal ± adjuvant therapy. Diffuse pontine gliomas continue to have a dismal prognosis. Individualized treatment based on molecular fingerprints may help to select the best adjuvant therapy and hence potentially improve survival.

P20.15.A DESCRIPTIVE ANALYSIS OF A SERIES OF H3 K27-ALTERED DIFFUSE MIDLINE GLIOMAS IN CHILDREN AND ADULT POPULATION

Abstract BACKGROUND Molecular biomarkers have gained importance in providing diagnostic information for brain and spinal cord tumors. Diffuse midline gliomas (DMG) are now defined as H3 K27-altered. H3 K27M mutations were first described in pediatric diffuse pontine gliomas but can also be encountered in adult gliomas. The H3 K27M mutation often co-occurs with mutations in TP53, PDGFR, or ACVR1 and is mutually exclusive to IDH1/2 mutations and 1p/19q co-deletion. Surgical resection is often not feasible for its localization and the benefit of temozolomide (TMZ) is not clear as they are MGMT unmethylated; all of it conferring a poor prognosis. It has been suggested that pediatric patients (pts) have worse outcomes. Our aim was to describe pts with H3 K27-altered gliomas to better understand the characteristics of this population. MATERIAL AND METHODS We analyzed clinical, histological and molecular features of 6 adults and 10 pediatric pts diagnosed with H3 K27M-mutant gliomas between May 2016 and January 2021 in a tertiary hospital in Barcelona. RESULTS For adults, mean age at diagnosis was 34.6 years (range = 20 - 55 years). For children, mean age was 11.2 years (range = 4 - 17 years). Male-to-female ratio was 1:1. Tumors involved thalamus (adult = 3; pediatric = 3), pons (adult = 1; pediatric = 6), and pineal region (n = 1). Ki67 range was 2-60% (pediatric mean 32%, adult mean 20%). A molecular panel was analyzed in 8 pediatric pts and 1 adult. No EGFR amplifications were detected.Three of them had TP53 mutations and 2 had PDGFRA amplification. Only 2 pediatric pts had MGMT methylation. Regarding treatment, 9 pediatric and 4 adult pts underwent radiotherapy and TMZ as first-line, with a mean time to intervention of 5.6 months. One child went through palliative care. As a second-line treatment, re-irradiation was used in 3 pediatric pts and irinotecan-bevacizumab was used in 2 adults. One adult received up to 4 different treatments (TMZ chemoradiotherapy followed by adjuvant TMZ, irinotecan-bevacizumab, lomustine and metronomic TMZ).All 9 pediatric pts died, with a mean OS of 12.0 months. Among adults, 2 pts died, 10.5 and 31.2 months after diagnosis, 1 has progressed to first-line and is receiving PCV as second-line treatment, and 1 has completed Stupp regimen with stable disease as best response. CONCLUSION Although the sample size is limited, our cohort data resembles what has been previously reported in terms of clinical and molecular characteristics: diagnosed in young adults and pediatric pts, characterized by a midline location, a low rate of MGMT promoter methylation, frequent TP53 and PDGFR alterations, and poor prognosis. There is currently no consensus on optimal treatment sequence or best treatment for these pts. Collaborative effort and participation in clinical trials are needed to keep advancing in this poor prognosis disease.

P17.03.A MAGIC-G1: A PHASE 1 DOSE-ESCALATION TRIAL OF WEEKLY INTRATUMORAL ADMINISTRATION OF THE SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)

Abstract BACKGROUND One of the biggest challenges in treating rGBM is achieving high local drug concentration. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming the blood-brain barrier, while also limiting systemic toxicity. MTX110 (Midatech Ltd), a water-soluble formulation of panobinostat, has demonstrated cytotoxic activity in GBM cell lines, as well as safety and efficacy in two pediatric diffuse pontine glioma trials. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumor, thus avoiding systemic administration and therefore toxicity. MATERIAL AND METHODS Eligibility includes adult rGBM patients with a single enhancing lesion ≤3cm in maximal diameter; ≥4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥60%. MTX110 is continuously infused over 48hrs weekly at a rate of 0.5mL/h, via a CED catheter implanted into the enhancing disease recurrence connected to a fully internalized pump system. After safety of a single patient treated at 60μM has been established, 3-6 patients will be treated with MTX110 at 90μM as a single agent (Cohort 1). Patients in cohort 2 will receive MTX110 in combination with lomustine at a starting MTX110 dose of 60 μM and following the same dose-escalation approach. RESULTS As of March 30, 2023, the 1st patient was treated in monotherapy at 60μM and has received 12 weekly infusions of MTX110. No dose-limiting toxicities were observed. Observed study related adverse events (AEs) included: grade 1 cognitive disturbance, headache, and seizure; grade 2 candida wound infection, erythema of the scalp, bruising, and hemiparesis; and grade 3 abdominal seroma at pump insertion site. Enrolment is ongoing and the next patient will receive the 90 μM dose. CONCLUSION Weekly intratumoral administration of MTX110 via a fully internally implanted CED pump system is feasible. Updated results will be presented.

Systemic cellular viroimmunotherapy for canine high-grade gliomas

BackgroundOncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade...

Conventional and Cross-Channel MR Radiomic Features do Not Predict Histone H3 Status in DIPG: Genomic and Clinical Evaluation of a Multi-Institutional Cohort

<h3>Purpose/Objective(s)</h3> Genomic profiling of diffuse pontine glioma (DIPG) has suggested distinct and clinically relevant molecular subgroups based on the presence and type of histone H3K27M mutation. Recent studies have demonstrated improved safety for biopsy, but sampling carries risks. We evaluated the impact of radiomic features on the molecular classification of 154 histologically confirmed and centrally reviewed DIPG. <h3>Materials/Methods</h3> Automatically segmented and manually reviewed tumor volumes were used to compute single & cross channel radiomic features from T1, T2, FLAIR, and T1+gadolinium MR sequences obtained from histone H3 WT (N=30) and H3K27M-mutant (N=124) DIPG. Radiomic feature stability was assessed when multiple pretreatment MRs were available using the concordance correlation coefficient. Random Forest, Logistic Regression, XGBoost, and Deep Learning classifiers were used to build predictive models of H3K27M status in a training dataset, after exclusion of correlated features. Model accuracy was assessed in the remaining validation dataset. <h3>Results</h3> Two hundred and twelve of 456 imaging features (46.4%) demonstrated stability (CCC, p<0.05) between pretreatment scans. Accuracy varied by method, but none surpassed the No Information Rate (82%). Model accuracy was not improved by efforts to remedy class imbalance (resampling and class weight adjustment). Several cross channel radiomic features were consistently selected by the models, indicating some predictive utility, although cross institutional scanning techniques were confounding. <h3>Conclusion</h3> While early efforts with single institutional data were encouraging, differences in MR technique and class imbalance seemed to limit the identification of stable radiomic features predictive of H3 status in this multi-institutional cohort. Biopsy remains key for determining trial eligibility and directing precision medicine.

DIPG-35. Personalized treatment for molecularly heterogeneous Diffuse midline glioma, H3 k27-altered Paediatric case

Abstract Diffuse midline glioma, H3 k27-altered (DMG) is a type of Paediatric- type diffuse high grade gliomas according to the 2021 WHO CNS tumors Classification. Diffuse intrinsic pontine glioma (DIPG) is another acceptable related term when it located in the pons with fatal prognosis. The combination of H3K27M with BRAF V600 mutations rarely reported in DMG although more commonly in Paediatric-type low grade gliomas (Diffuse low-grade glioma, MAPK pathway-altered). We present a twenty-month-old boy, previously healthy, presented with 2 weeks history of unsteady gait, drooling, cranial nerves palsy MRI imaging showed diffuse pontine mass with classic radiological features of DIPG. 2.6 x 1.6 x 3.2 (AP x TV x CC) with no evidence for spinal metastases. Patient underwent right retro sigmoid approach and open biopsy of lesion he received focal Radiation Therapy 54GY/30fx as stander of care of DIPG with mild neurogical improvement Pathological &amp; molecular Diagnosis was Diffuse midline glioma, H3 k27-altered with Co-occurrence BRAF V600E mutation. Two months after end of radiation, he presented with vomiting, and neurological deterioration with new right-side hemiplegia. Imaging studies showed interval increase in the pontine lesion with increased edema causing narrowing of the fourth ventricle, no active hydrocephalus. He was started on combination therapy BRAF inhibitor Dabrafenib and MEK Inhibitor Trametinib as maintenance therapy the patient gradually showed Marked neurological and clinical improvement. A 6-month MRI after start of targeted therapy showed favorable treatment response with complete resolution of the previous diffusion restriction, reduced tumor volume on MR perfusion ,reduced perilesional edema otherwise almost stabilization of nonenhancing pontine lesion. The poor prognosis of recurrent DIPG is well known but our patient is clinically and radiologically stable with excellent quality of life and well tolerating the therapy . Our case show that personalized treatment approach that address molecular heterogeneity of H3K27M glioma are safe and feasible

Osmotic demyelination syndrome despite appropriate gradual correction of moderate hyponatraemia.

Osmotic demyelination syndrome characteristically follows rapid correction of hyponatraemia. We present a young woman with a subacute progressive brainstem syndrome and diffuse pontine signal abnormality on MR imaging, diagnosed as osmotic demyelination syndrome. The case posed a diagnostic challenge due to comorbid Behçet's disease and the absence of significant fluctuation in her serum sodium concentration. Osmotic demyelination syndrome is not limited to patients with rapidly corrected hyponatraemia, especially when there are other risk factors. These factors, all present in this patient, include hypokalaemia, hypophosphataemia, malnutrition, harmful alcohol use and liver dysfunction.

A rare case of undulatory rhythmic lingual myoclonus in a patient with intracranial hemorrhage and diffuse pontine lesion

We describe a 35-year-old man, who suffered a severe intraventricular hemorrhage and was admitted to the intensive care unit of our tertiary clinic. Two weeks after the incident, while in ICU, a neurological examination revealed persistent, undulating, rhythmic, myoclonic tongue movements. The diagnostic evaluation via CT scan, MRI and EEGs elicited a diffuse brainstem lesion as well as multiple corpus callosum lesions as a considerable underlying etiology. This case presentation attempts to update the current investigation of the rare phenomenon of lingual myoclonus.

Role of Dynamic Parameters of 18F-DOPA PET/CT in Pediatric Gliomas.

PET with 18F-DOPA can be used to evaluate grading and aggressiveness of pediatric cerebral gliomas. However, standard uptake parameters may underperform in circumscribed lesions and in diffuse pontine gliomas. In this study, we tested whether dynamic 18F-DOPA PET could overcome these limitations. Patients with available dynamic 18F-DOPA PET were included retrospectively. Static parameters (tumor/striatum ratio [T/S] and tumor/cortex ratio [T/N]) and dynamic ones, calculated on the tumor time activity curve (TAC), including time-to-peak (TTP), slope steepness, the ratio between tumor and striatum TAC steepness (dynamic slope ratio [DSR]), and TAC shape (accumulation vs plateau), were evaluated as predictors of high/low grading (HG and LG) and of progression-free survival and overall survival. Fifteen patients were included; T/S, T/N, TTP, TAC slope steepness, and DSR were not significantly different between HG and LG. The accumulation TAC shape was more prevalent in the LG than in the HG group (75% vs 27%). On progression-free survival univariate analysis, TAC accumulation shape predicted longer survival (P < 0.001), whereas T/N and DSR showed borderline significance; on multivariate analyses, only TAC shape was retained (P < 0.01, Harrell C index, 0.93-0.95). On overall survival univariate analysis, T/N (P < 0.05), DSR (P < 0.05), and TAC "accumulating" shape predicted survival (P < 0.001); once more, only this last parameter was retained in the multivariate models (P < 0.05, Harrell C index, 0.86-0.89). Dynamic 18F-DOPA PET analysis outperforms the static parameter evaluation in grading assessment and survival prediction. Evaluation of the curve shape is a simple-to-use parameter with strong predictive power.

Clinical profile and management of sixth nerve palsy in pediatric patients (0-15 years) in Southern India - A hospital-based study.

Purpose:This study was done to evaluate the clinical profile in pediatric patients (0–16 years) presenting with acute onset esotropia due to sixth nerve palsy and its management options in a tertiary care set up of Southern India.Methods:A total of 12 patients presenting to our OPD with acute onset esotropia due to sixth nerve palsies were included in this retrospective study. All patients were observed for 6 months and managed with prism and/or patching while waiting for spontaneous resolution and later managed surgically. Neuroimaging was done in all cases.Results:The mean deviation of esotropia at presentation was 30.17 ± 5.7 Prism Diopter (range 12–50 Prism Diopter 95% CI, SD 10.11). Mean age of the patients during presentation was 8.6 ± 2.4 years (range: 1–15 years, SD 4.27). Among the common causes of sixth nerve palsy in our study population were trauma and idiopathic intracranial hypertension followed by tumor and miscellaneous causes. Only three patients underwent surgical correction of residual deviation after a waiting period of 6 months for self-resolution. Spontaneous resolution was observed in 41.6% patients, and surgical correction (unilateral resection–recession) was done in 25% of the patients with good surgical outcome.Conclusion:At 1-year follow up, the motor outcome was satisfactory except for one patient who had diffuse pontine glioma and had worsening neurological symptoms on follow-up.

Endoscopic third ventriculostomy for the management of hydrocephalus secondary to posterior fossa tumors: A retrospective study.

Background: Endoscopic third ventriculostomy (ETV) is an effective alternative to ventriculoperitoneal shunting as well as external ventricular drainage for the urgent management of acute hydrocephalus. We performed this study to investigate the efficacy and safety of ETV before tumor resection in managing hydrocephalus in patients with posterior fossa brain tumors (PFBT) in our neurosurgery department.Methods: We conducted this retrospective observational study between February 2018 and February 2020 on all cases diagnosed with PFBT associated with triventricular obstructive hydrocephalus. We retrospectively reviewed the demographic characteristics, operative procedures, and radiological investigations of all cases. During the follow-up period, clinical, as well as radiological success were evaluated.Results: Twenty-two ETV procedures were performed in 22 cases of PFBT (mean age = 22.1 years, SD = 11.4). Of the 22 cases, 8 cases (36.4%) had ependymoma, 7 cases (31.8%) had cerebellar astrocytoma, and 5 cases (22.7 %) had medulloblastoma, while 2 cases (9.1%) had diffuse pontine gliomas. The median follow-up duration was 9 months (range 3–13 months). The most commonly reported clinical presentation was the significant intracranial pressure increase. All operations were performed successfully in all cases. Only two ETV post-tumor resection failures were documented during the follow-up period.Conclusion: Preoperative ETV has shown to be an effective long-term cerebrospinal fluid diversion procedure to manage PFBT-associated hydrocephalus, with a relatively low rate of complications. Further prospective studies are required to assess the regular use of ETV before complete tumor resection.

Pediatric brain tumor cell lines exhibit miRNA-depleted, Y RNA-enriched extracellular vesicles.

Medulloblastoma (MB) and diffuse infiltrative pontine glioma (DIPG) are malignant pediatric tumors. Extracellular vesicles (EVs) and their bioactive cargoes have been implicated in tumorigenesis. Most studies have focused on adult tumors, therefore the role of EVs and the noncoding RNA (ncRNA) landscape in pediatric brain tumors is not fully characterized. The overall aim of this pilot study was to isolate EVs from MB and DIPG patient-derived cell lines and to explore the small ncRNA transcriptome. EVs from 3 DIPG and 4MB patient-derived cell lines were analyzed. High-throughput next generation sequencing interrogated the short non-coding RNA (ncRNA) transcriptome. Known and novel miRNAs were quantified. Differential expression analysis, in silico target prediction, and functional gene enrichment were performed. EV secretomes from MB and DIPG patient-derived cell lines demonstrated discrete ncRNA biotypes. Notably, miRNAs were depleted and Y RNAs were enriched in EV samples. Hierarchical cluster analysis revealed high discrimination in miRNA expression between DIPG and MB cell lines and RNA-Seq identified novel miRNAs not previously implicated in MB or DIPG pathogenesis. Known and putative target genes of dysregulated miRNAs were identified. Functional annotation analysis of the target genes for differentially expressed EV-and parental-derived miRNAs revealed significant cancer-related pathway involvement. This hypothesis-generating study demonstrated that pediatric brain tumor-derived cell lines secrete EVs comprised of various ncRNA cargoes. Validation of these findings in patient samples may provide new insights into the pediatric brain tumor microenvironment and identification of novel therapeutic candidates.

A patient with pediatric diffuse pontine astrocytoma: good local control after gamma knife radiosurgery

A patient with pediatric diffuse pontine astrocytoma: good local control after gamma knife radiosurgery

DIPG-72. LONG-TERM SURVIVAL OF A CLASSIC DIFFUSE INTRINSIC PONTINE GLIOMA TREATED WITH NIMOTUZUMAB

BACKGROUNDLong-term survival in diffuse intrinsic pontine glioma is rare, and typically associated with atypical imaging and/or atypical clinical course. Although most patients harbor hotspot mutations in H3.1/3-K27M, a proportion of patients have alternate mutations, despite a typical clinicoradiological course. Herein we describe a long-term survivor with a classical presentation, treated with nimotuzumab, highlighting the challenges associated with such cases. CASE REPORT: A 5 year old male, diagnose in 2012 with a 10 day history multiple cranial neuropathies and a right hemiparesis. Cranial MRI revealed a poorly delimited diffuse pontine tumor and secondary hydrocephalus. Tumor biopsy was not performed due to the classic clinical presentation, and he received 54Gy/30 of radiation plus concomitant weekly nimotuzumab 150mg/m2. Initial tumor dimensions were 43x31x28mm. Nimotuzumab 150mg/m2 was continued every 2 weeks. Image assessment at week 12 of treatment revealed 16.9% volume increase, 4 weeks after radiotherapy completion. Nevertheless, subsequent neuroimaging at 24th, 36th, 60th, 96th and 108th weeks of nimotuzumab therapy showed a sustained and progressive tumor cytoreduction of 47.5%, 59%, 62.2%, 63.8% and 67%, respectively, when compared with post-radiotherapy dimensions. Currently, the patient is 13y old, good school performance, no neurologic disabilities. The last MRI at 394 weeks of nimotuzumab revealed dimensions of 21x19x14mm which corresponds to 70% of reduction compared with initial volume.CONCLUSIONSOur case of progressive cytoreduction over two years of a classic DIPG, diagnosed in the era prior to the discovery of the K27M mutation, highlights the challenges associated with long-term survival of this devastating entity.

DIPG-23. SINGLE CASE REPORT OF LOW DOSE RADIOTHERAPY AND CHEMOTHERAPY IN THE TREATMENT OF DIPG

A 3 year-old girl, was noted to have progressive gait problem since Nov. 2017 and brought to hospital for checkup. Brain MRI on Jan. 2018 showed T2 hyperintensity infiltrative pontine lesion, favoring diffuse infiltrative pontine glioma and mild obstructive hydrocephalus, received VP-shunting on Jan. 15, 2018. Due to the refusal of surgical biopsy for tissue proof, we started the radiotherapy from Jan. 24, 2018, using Rapidarc technique with 6MV photon energy to treat the brain stem lesion, ended on Feb. 24, 2018 with total dose of 25.5Gy in 17 fractions as our usual practice. Following the completion of radiotherapy, we started the adjuvant chemotherapy using 1-week on, 1-week off regimen of temozolomide using dosage of 75 mg/sq-m/day, and this patient’s general condition returned back to nearly normal. Serial follow-up images of brain MRI on 04/30/2018, 08/01/2018, 11/30/2018, 02/26/2019, 05/30/2019, 08/28/2019 showed slow progression of the pontine lesion, without the development of contrast enhanced new lesion. She maintained the functional independent until Sep. 2019, she was noted to have symptoms of ataxic gait, esotropia and choking on drinking liquid. We started the retreatment of radiotherapy from Oct.7, 2019, using same technique, ended on Nov. 5, 2019 with total dose of 30Gy in 20 fractions. The symptoms improved partially after the treatment, with residual weakness over left extremity. We are still treating the patient with adjuvant temozolomide, and she has survived most of time functionally independent in these 2 years.

EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.