Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment

Medulloblastoma (MB) is the most common malignant central nervous system tumor in pediatric patients. Mainstay of therapy remains surgical resection followed by craniospinal radiation and chemotherapy, although limitations to this therapy are applied in the youngest patients. Clinically, tumors are divided into average and high-risk status on the basis of age, metastasis at diagnosis, and extent of surgical resection. However, technological advances in high-throughput screening have facilitated the analysis of large transcriptomic datasets that have been used to generate the current classification system, dividing patients into four primary subgroups, i.e., WNT (wingless), SHH (sonic hedgehog), and the non-SHH/WNT subgroups 3 and 4. Each subgroup can further be subdivided on the basis of a combination of cytogenetic and epigenetic events, some in distinct signaling pathways, that activate specific phenotypes impacting patient prognosis. Here, we delve deeper into the genetic basis for each subgroup by reviewing the extent of cytogenetic events in key genes that trigger neoplastic transformation or that exhibit oncogenic properties. Each of these discussions is further centered on how these genetic aberrations can be exploited to generate novel targeted therapeutics for each subgroup along with a discussion on challenges that are currently faced in generating said therapies. Our future hope is that through better understanding of subgroup-specific cytogenetic events, the field may improve diagnosis, prognosis, and treatment to improve overall quality of life for these patients.

Glioblastoma multiform with primitive neuronal component, radiological and histology features: a case report

Background Glioblastoma multiform with primitive neuronal component (GBM-PNC) has been recently defined as a rare variant of glioblastoma multiform (GBM), which shows characteristically pathological pattern of less differentiated areas with small blue cell morphology and neuroectodermic immunophenotype. New studies emphasize its characteristics and differences, which have become vitally important due to the changes in therapeutic management. Case presentation We present the case of 57-year-old male patient who onset symptoms were secondarily widespread partial seizures and expression aphasia. Brain magnetic resonance imaging (MRI) reported left enhanced temporal infiltrating lesion, requiring surgery twice throughout two years. At first surgery, pathological samples revealed embryonic tumor of the central nervous system (grade IV, WHO 2016), so PACKER protocol consisting of CSRT (craniospinal radiation) plus weekly vincristine followed by 8 cycles of cisplatin, lomustine and vincristine usually used for medulloblastomas or other primitive neuroectodermal tumors was started. However, due to reappearance of symptoms and progression in MRI, reoperation was performed with definitive diagnosis of GBM-PNC (Grade IV, WHO 2016) and switched to STUPP protocol. Conclusions It is important to take into account the chance of this entity when histological, radiological and intraoperative findings orient toward a primitive neural tumor since the presence of GBM could be overlooked leading to mistakes in diagnosis and the therapeutic orientation.

A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma

PurposeMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma.MethodsWe performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.ResultsTwenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.ConclusionsGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00031590

GERM-02. MANAGEMENT STRATEGY FOR CHEMO-REFRACTORY, PROGRESSIVE PEDIATRIC IMMATURE TERATOMA

Background Localized NGGCT, a heterogeneous entity, treated with chemo-radiotherapy harbors an overall survival of around 93% based. Here, we present a case of a child whose immature teratoma progressed on chemotherapy, while tumor markers remain within normal range. Salvage therapy for progressive immature teratoma is variable, and can include surgery, chemotherapy and/or craniospinal radiation. Case: 10 year old boy with precocious puberty presented to the local Emergency room with tonic-clonic seizures. Imaging showed a localized pineal mass, with mixed cystic and solid components. Biopsy results were diagnostic for mixed germ cell tumor with components of immature teratoma. Prior to the start of chemotherapy, serum and cerebrospinal fluid (CSF) tumor markers showed slight elevation of both alpha feto- protein (AFP) and beta-human chorionic gonadotropin hormone (β-HCG). The patient underwent two cycles of chemotherapy per ACNS1123, stratum 1, with normalization of tumor markers. Unfortunately, near the end of Cycle 2 of chemotherapy, patient presented with clinical signs of herniation, and was noted to have significant progression of pineal mass on imaging. Tumor was gross totally resected, with pathology conclusive for only immature teratoma. Pre- and post-operative tumor markers remained normal. Proton-beam craniospinal radiation was then administered. Patient is now almost 6 months off therapy, with unremarkable serum and CSF tumor markers, as well as serial imaging that remains negative for disease, with neurological development appropriate for age. Conclusion This case highlights the unusual nature of progression of an immature teratoma with no elevation of tumor markers while on chemotherapy. While salvage chemotherapy, in the form of a metronomic regimen or high-dose consolidative regimen, can be considered, these do present quite a bit of short-term and long-term toxicity to the growing child. Craniospinal irradiation followed by close monitoring is a reasonable alternative, with less short-term toxicity, for an entity that is radio-sensitive.

MBCL-14. A STUDY OF LOW-DOSE CRANIOSPINAL RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED AVERAGE-RISK MEDULLOBLASTOMA

INTRODUCTION Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. METHODS We performed a single-arm, multi-institution study, seeking to reduce the late effects of treatment in patients with average-risk medulloblastoma prior to advances in molecular subgrouping. To do so, we reduced the dose of craniospinal irradiation by 25% to 18 gray with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy. RESULTS 28 patients aged 3–30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 78.6% (95% CI 58.4% to 89.8%) and 92.9% (95% CI 74.4% to 98.2%), respectively. The 5-year RFS and OS were 71.4% (95% CI 50.1% to 84.6%) and 85.7% (95% CI 66.3% to 94.4%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities. CONCLUSIONS Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from reduced craniospinal radiation dose of 18 gray without impacting relapse-free or overall survival.

MBCL-04. 5 – AZACYTIDINE IN TREATMENT OF CHILDREN WITH DE NOVO AND RELAPSED METASTATIC MEDULLOBLASTOMA: RESULTS OF INTERCENTER PILOT STUDY

The aim of this study was to estimate treatment toxicity and event-free survival (EFS) according to therapeutic program, MYC/MYC-N gene amplification and MGMT/DNMT (1, 3a, 3b) proteins expression in tumor cells. From 2016 to 2018 twenty four patients were included in trial. Children underwent adjuvant therapy: craniospinal radiation (CSI) or local radiation therapy (RT) to the relapsed site up to 23.4Gy with 5-azacytidine, 2 cycles methotrexate/5-azacytidine/cisplatin/etoposide, 3 cycles 5-azacytidine/temozolomide - for relapsed group (arm A, n = 5); for patients with de novo medulloblastoma: arm B, n = 11 – vincristine/cyclophosphamide/cisplatin/etoposide (OPEC) - based induction, CSI 36Gy + local RT to the tumor bed up to 54Gy with 5-azacytidine, 1 cycle OPEC and 2 cycles thiophosphamide/carboplatin with auto stem cell transplantation (auto-SCT); arm C, n = 8 – cyclophosphamide/cisplatin - based induction, CSI 23.4 Gy followed by 2 cycles 5-azacytidine/thiophosphamide/carboplatin with auto-SCT, local RT with 5-azacytidine. The combination of 5-azacytidine with local RT or temozolomide was safety and tolerability. Arm C was discontinued due to severe gastrointestinal grade 3/4 toxicity, hemorrhagic syndrome after combination of 5-azacytidine with thiophosphamide/carboplatin. EFS was 0% in arm A, 53.0 ± 15.5%, 50.0 ± 17.7% in arms B and C, a median follow-up 8.8 ± 1.1 months (arm A), 18.8 ± 2.5 months (arm B), 25.0 ± 4.4 months (arm C). Addition of 5-azacytidine to RT or chemotherapy did not improve EFS of patients with MYC/MYC-N gene amplification positive tumor. There was not determined any prognostic significance of MGMT/DNMT (1, 3a, 3b) proteins expression in this cohort.

DDEL-17. TRIPLE INTRAVENTRICULAR CHEMOTHERAPY FOR TREATMENT OF RELAPSED CHOROID PLEXUS CARCINOMA

Limited evidence for the optimal management of relapsed choroid plexus carcinoma (CPC) exists, with a few case reports involving surgery, radiotherapy and intravenous chemotherapy. However, the safety and tolerability of intraventricular chemotherapy in this setting has not been widely studied. We describe a case where triple intraventricular chemotherapy was administered to a child with relapsed metastatic CPC. A 7-year-old male with a history of CPC presented with relapsed metastatic disease. At initial diagnosis at 4 years of age, treatment involved gross total resection of an intraventricular mass in the left temporal region followed by chemotherapy and autologous stem cell transplantation (SCT) according to HEADSTART II-D. One year after SCT, craniospinal radiation was delivered following radiological relapse, achieving a partial response. Given previous treatment-limiting myelosuppression, intraventricular chemotherapy via Ommaya® reservoir with thiotepa 5mg, etoposide 0.5mg and topotecan 0.4mg twice a week (non-weight-based dosing) was commenced taking into consideration pharmaceutical formulation aspects for optimal intraventricular drug delivery. After six cycles of intraventricular chemotherapy, palliative radiotherapy was administered due to radiological progression. Following completion, weekly triple intraventricular chemotherapy continued for 9 months. The patient remained out of hospital with the main side effects being fatigue and occasional nausea amenable to ondansetron. This case study demonstrates the safety and tolerability of a triple intraventricular chemotherapy regimen used to delay disease progression and prolong quality of life in a child with relapsed CPC in the palliative setting. This could provide an alternative treatment regimen for patients with relapsed disease.

LINC-16. MEDULLOBLASTOMA IN A BOY WITH RUBINSTEIN-TAYBI SYNDROME: A CASE REPORT

BACKGROUND Rubinstein–Taybi syndrome (RTS) is characterized by multiple congenital anomalies and associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of benign and possibly also malignant tumors, but the correlation remains unclear. Here we present a case of a patient with RTS and medulloblastoma. CLINICAL CASE: A 5-year-old male presented with increased intracranial pressure. An MRI revealed a 4.2 x 4.7 cm mass in the midline of cerebellum arising from the floor of 4th ventricle. The patient underwent a complete resection and pathology revealed medulloblastoma, classic histology. Staging established no disseminated disease. At diagnosis, a peculiar phenotype consisting in mild mental retardation, microcephaly, down-slanting palpebral fissures, broad nasal bridge, highly arched palate, mild micrognathia, screwdriver incisors and wide thumbs and toes was noted. Clinical genetics evaluation was consistent with RTS. Karyotype was performed and normal. Further genetics testing was not done. Treatment consisted in 8 cycles of chemotherapy and craniospinal radiation (2300 cGy to spine, 5500 cGy Total). At the end of treatment, there was no evidence of disease. He was under surveillance for 33 months free of disease, but relapsed with a supratentorial meningeal disease that ultimately resulted in death. CONCLUSION This report highlights the fact that pediatric medulloblastoma can be associated to RTS, in this case associated to classical histology and recurrent disease.

QOL-41. CARDIAC DYSFUNCTION IN MEDULLOBLASTOMA SURVIVORS TREATED WITH PHOTON IRRADIATION

BACKGROUND Medulloblastoma is an aggressive central nervous system (CNS) tumor that occurs mostly in the pediatric population. Treatment includes surgical resection, craniospinal radiation (CSI) and chemotherapy. Children who receive standard photon radiation (RT) are at risk for cardiac toxicities. Potential late effects include coronary artery disease, left ventricular scarring and dysfunction, valvular damage and atherosclerosis. Current survivorship guidelines recommend routine ECHO surveillance for these patients but this comes at significant health care costs over a lifetime. We describe the experience of cardiac dysfunction in medulloblastoma survivors in a multi-institution study. METHODS A retrospective chart review of medulloblastoma patients treated between 1980 and 2010 with radiation at Lurie Children’s Hospital and Dana-Farber/ Boston Children’s Hospital who had an echocardiogram done following completion of therapy. RESULTS 168 patients were treated for medulloblastoma during the study time. Of whom, 80 patients had echocardiogram follow up and 76 received photon irradiation. The latter were included in the study. The mean age at CSI was 8.6 years (range 2.9- 20), and mean number of years post RT at echocardiogram 7.4 years (range 2–16). Mean ejection fraction (EF) was 60.03% and shortening fraction (SF) 33.8%. Four patients (5%) had abnormal results, all of which had EF<50%. CONCLUSION Patients who received craniospinal irradiation for medulloblastoma therapy have relatively normal echocardiograms post treatment. Although RT may result in cardiac risks, echocardiograms may not be the most cost effective or efficacious mode to evaluate the risk in these survivors long term.

Bridging the treatment gap in infant medulloblastoma: molecularly informed outcomes of a globally feasible regimen

Background Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy. Methods In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival. Results Twenty-nine children (range, 0.3–4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551–0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHβ, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633–1) and SHHβ having a PFS of 0.56 (95% CI: 0.42–1). Group 3 had a PFS of 0.50 (95% CI: 0.25–1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5. Conclusions We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.