bluuebunny/crossref_metadata_2025 huggingface dataset:
LINC-05. PRIMARY CENTRAL NERVOUS SYSTEM EWING SARCOMA IN PEDIATRIC AND AYA PATIENTS: 2 INSTITUTIONS EXPERIENCE IN BUENOS AIRES ARGENTINA
Authors: Palomar Roberto Nicolas , Yorio Florencia , Alessandro Lucas , Arakaki Naomi , Muggeri Alejandro , Lombardi Mercedes Garcia , Diez Blanca
Published: December 2020

INTRODUCTION

Ewing Sarcoma (ES) is defined by molecular markers, being t(11;22)(q24;q12) the most frequent. Intracranial ES usually shows as metastases from extracranial sites. Primary central nervous system (CNS) lesions are extremely rare.

MATERIAL AND METHODS

Retrospective review of clinical records from patients with primary CNS ES, assessed at 2 institutions in Argentina between 2007–2019. Translocation was evidenced in all cases through molecular testing. Clinical characteristics, imaging, histopathology, and treatment response were evaluated. Extracranial and osseous lesions were excluded.

RESULTS

15 patients. Median age at beginning of symptoms: 8 yo (2–20). Most patients had intracranial hypertension syndrome (14/15). In brain MRI, 5/15 supratentorial lesions, 4/15 posterior fosa, 1/15 medullary, 2/15 supra and infratentorial, and 3/15 lesions diffuse leptomeningeal infiltration. Histopathologic findings showed diffuse pattern with small round blue cells in most cases, other patterns were also described. CD99 marked positive in all cases. Misdiagnosis with glial tumors (4/15), medulloblastoma (6/15) and infectious diseases (3/15); led to median delay to accurate diagnosis of 3 months (range 0–67). After correct diagnosis patients were treated with standard ES treatment (6 VIDE cycles plus radiotherapy) in 14/15 patients. Vincristine, irinotecan and temozolamide was used as second line treatment in all relapse cases whenever possible. EFS was 22 months (2- 65). OS at 5 years of follow-up was 46,67% (mean OS 31 mo).

CONCLUSION

Even though molecular assessment led to accurate diagnosis in all cases, treatment response and outcome showed two different groups of patients with long and very short survival. Adaptative therapy should be considered.
LINC-13. THE STATE OF PEDIATRIC NEURO-ONCOLOGY IN ARMENIA
Authors: Bardakhchyan Samvel , Tananyan Armen , Danielyan Samvel , Arakelyan Jemma , Mkhitaryan Sergo , Bedirian Karen , Safaryan Liana , Arustamyan Mikayel , Tamamyan Gevorg
Published: December 2020

BACKGROUND

Every year in Armenia we have approximately 80–90 new pediatric cancer cases from which 10–15 are brain tumors (PBT). Here we try to summarize the current state of pediatric neuro-oncology in Armenia. DISCUSSION: In Armenia pediatric neuro-oncology is still in its first steps. Surgical treatment of PBTs is performed only in one medical center – “Sourb Astvatsamayr” Medical Center, with 7 practicing pediatric neurosurgeons. Radiation therapy service with two linear accelerators is located at the “National Oncology Center”, however there are no dedicated pediatric radiation neuro-oncologists, and 2 specialists are treating pediatric tumors. Chemotherapy for all pediatric cancers currently is performed at the Pediatric Cancer and Blood Disorders Center of Armenia, established in February 2019 as a result of merging of all pediatric oncology units in the country. Among the 11 practicing pediatric hematologist/oncologists no one is dedicated specifically to PBTs. Since September 2017 we have started discussing all PBT cases (up to now 18 cases) through the telemedicine with St. Jude Children’s Research Hospital (SJCRH). In Sept 2019 neuro-oncology multidisciplinary team was created with the involvement of local and foreign specialists. On a weekly basis the multidisciplinary team discusses all new and problematic cases. The team also concentrates on adaptation of diagnostic and treatment guidelines for pediatric CNS tumors, creation of educational materials for different stakeholders, and identification of current problems and their possible solutions.

CONCLUSION

To the best of our knowledge this is the first report summarizing the current state of pediatric neuro-oncology in Armenia.
LINC-18. FOLLOW-UP EVALUATION OF A WEB-BASED PEDIATRIC BRAIN TUMOR BOARD IN LATIN AMERICA
Authors: Obando Mariel Rosabal , Osorio Diana S , Lassaletta Alvaro , Madrid Andrés Morales La , Bartels Ute , Finlay Jonathan L , Qaddoumi Ibrahim , Rutkowski Stefan , Mynarek Martin
Published: December 2020

BACKGROUND

Since 2013, pediatric oncologists from Latin America have discussed neuro-oncology cases with experts from North America and Europe in a web-based “Latin American Tumor Board” (LATB). This descriptive study evaluates the feasibility of the recommendations rendered during the Board.

METHODS

An electronic questionnaire was distributed to physicians who received recommendations between October 2017 and October 2018, two months after their case presentation on the LATB. Physicians were asked regarding the feasibility of each recommendation given during the Board. Baseline case characteristics of all presented cases were obtained from anonymized minutes prepared after the presentations.

RESULTS

36 physicians from 15 countries answered 103 of 142 questionnaires (72.5%), containing 283 recommendations. Physicians followed 60% of diagnostic procedural recommendations and 70% of therapeutic recommendations. Overall, 96% of respondents considered the recommendations applicable and useful. The most difficult recommendations to follow were genetic and molecular testing, pathology review, locally adapted chemotherapy protocols administration, neurosurgical interventions and access to molecular targeted therapies. The most cited reasons for not implementing the recommendations were lack of resources, inapplicable recommendations to that low-to-middle income country (LMIC) setting, and lack of parental consent.

CONCLUSION

The recommendations given on the LATB are frequently applicable and helpful for physicians in LMIC. Nevertheless, limitations in availability of both diagnostic procedures and treatment modalities affected the feasibility of some recommendations. Virtual tumor boards offer physicians from LMIC access to real time, high-level subspecialist expertise and provide a valuable platform for information exchange among physicians worldwide.
LINC-27. PAEDIATRIC SUPRASELLAR TUMOURS: CLINICAL EXPERIENCE FROM A SINGLE TERTIARY CENTRE IN KUALA LUMPUR, MALAYSIA
Authors: Alias Hamidah , Loh C-Khai
Published: December 2020

INTRODUCTION

The outcome of suprasellar tumours in children varies with the diagnosis and morbidity is significant. We herein report the clinical features of children with suprasellar tumours treated at our centre.

METHODS

Clinical data were collected by retrospective review from January 2000 to December 2019. The patients were identified from the paediatric haematology and oncology unit registry.

RESULTS

There was a total of 103 children with brain tumour and suprasellar tumours comprise of 14.6% (n=15). Median age at presentation was 7 years old. Male to female ratio was 3:2. Majority of cases was low grade glioma, 40% (n=6) and germ cell tumour(GCT) 33.3% (n=5) followed by craniopharyngioma, 13.3% (n=2) and Rathke cleft cyst, 6.7% (n=1). All patients had tissue diagnosis except one with secreting GCT and one with unsatisfactory tissue sample. Mean duration of follow up was 7.4 years. One patient with germinoma was lost to follow-up after radiotherapy. Three out of 13 (23%) patients died; 2 with GCT from disease progression; 1 craniopharyngioma after 11 years of unknown cause. All survivors have significant morbidity; 70% have moderate to severe visual impairment, 90% have at least two pituitary hormones deficiency, 20% have neurological deficit and 1 was surgically related. Two boys have precocious puberty not related to disease progression. Two with GCT with diabetes insipidus had history of thromboembolism (stroke and pulmonary embolism).

CONCLUSIONS

Suprasellar tumours in children at our centre pose a significant long-term complications and multidisciplinary team management and follow up is required to improve the morbidity.
LINC-28. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OUTCOMES OF CHILDREN WITH MEDULLOBLASTOMA TREATED AT THE NATIONAL CANCER INSTITUTE (INCA) IN RIO DE JANEIRO, BRAZIL
Authors: Oigman Gabriela , Osorio Diana , Stanek Joseph , Finlay Jonathan , Vianna Denizar , Ferman Sima
Published: December 2020

BACKGROUND

Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. Brazil is an upper-middle income country according to World Bank, with features of LMIC and HIC.

METHODS

We conducted a retrospective review of 126 children (0–18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively; overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method.

RESULTS

The male/female ratio was 1.42 and the median age at diagnosis was 7.9 years. Headache (79%) and nausea/vomiting (75%) were the most common presenting symptoms. The median time from onset of symptoms to surgery was 50 days. The OS for standard-risk patients was 69% and 53% for high-risk patients. Patients initiating radiation therapy within 42 days after surgery (70.6% versus 59.6% p=0.016) experienced better OS. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.025). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage.

CONCLUSIONS

These findings suggest that socioeconomic factors, education, early diagnosis and continuous data collection, besides oncological treatment must be adressed to improve the survival of children with MB.
LINC-31. TREATMENT OUTCOME IN CHILDREN WITH MEDULLOBLASTOMA IN MEDIUM-INCOME COUNTRY: AN EXPERIENCE FROM A SINGLE TERTIARY CENTRE IN KUALA LUMPUR, MALAYSIA
Authors: Loh C-Khai , Alias Hamidah , Lau Doris
Published: December 2020

INTRODUCTION

Medulloblastoma is the most common malignant brain tumour in children. The overall outcome has improved however, this was not translated to developing nations.

METHOD

This was a retrospective review of patients from January 2000 to December 2017. Treatment was given using modified SIOP PNET 4 protocol: cranio spinal irradiation (CSI), a total of 54G with vincristine followed by 8 cycles of adjuvant chemotherapy. Prior to year 2007, patients had CSI with or without adjuvant chemotherapy. Those <3 years old received modified UKCCSG/SIOP CNS protocol with 2 weekly chemotherapy for a duration of 392 days followed by CSI when required. All patients had MRI brain and spine, and tissue histopathological examination but without molecular subtype.

RESULTS

Medulloblastoma comprised of 30% (n=31) out of total 103 brain tumour cases. Mean age at presentation was 7.6 years old (SD 4.4) with male to female ratio of 2:1. Average time of symptoms was 4.8 weeks. Majority, 77.4% was high risk and 19.4% was standard risk. There was high treatment abandonment rate (35.5%, n=11). Three patients returned and completed treatment after multiple surgeries in an average of 9 months. Three years OS and EF were 69.6% and 74.8%, respectively. Six patients aged < 3years; half had advance disease on palliative care post surgery. Other survivors had severe learning difficulty and two had second malignancy (meningioma and thyroid carcinoma) at average 15.5 years after diagnosis.

CONCLUSION

Strategy to reduce treatment abandonment is crucial. Moreover, multidisciplinary management and molecular stratification are important in improving the outcome.
LINC-33. MULTIMODALITY MANAGEMENT OF PAEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA- UPDATED EXPERIENCE FROM A REGIONAL CANCER CENTRE IN NORTH INDIA
Authors: Biswas Ahitagni , Roy Swarnaditya , KN Yousra , Bakhshi Sameer , Suri Vaishali , Sharma Mehar , Julka Pramod
Published: December 2020

Paediatric primary central nervous system lymphoma(PCNSL) constitutes 1% of all PCNSLs. Data pertaining to paediatric PCNSL (2016–19) was abstracted by retrospective chart review. We identified 7 paediatric patients with PCNSL. None had congenital or acquired immunodeficiency. The median age at presentation was 13 years. The male to female ratio was 4:3. The median ECOG performance status was 2. On neuro-imaging, 3 patients had solitary and 4 patients had multiple lesions. CSF cytology showed atypical cells in 1 patient. None had ocular involvement. Systemic lymphoma work-up was negative in all. Biopsy and resection of tumour were done in 4 patients each. Histopathology revealed DLBCL in 6 and B-cell NHL in 1 patient. All patients underwent induction chemotherapy (median-5 cycles)- modified DeAngelis protocol (IV Methotrexate-2.5g/m2,IT Methotrexate-12 mg,Vincristine,Procarbazine and Rituximab-375mg/m2 every 2 weeks) in 6 and single agent Methotrexate -3.5g/m2 every 3 weeks in 1 patient. Severe haematological toxicities included grade 3 neutropenia, leucopenia and febrile neutropenia in 2,1 and 1 patient respectively. Radiotherapy(RT) was administered in all-whole brain RT(36-45Gy/20-25fractions/4-5weeks) in 6 patients and craniospinal RT(36Gy/18fractions/3.5weeks) followed by whole brain RT(9Gy/5fractions/1week) in 1 patient(with positive CSF cytology). Subsequently consolidation chemotherapy with 2 cycles of Cytarabine(3g/m2 IV D1-2 every 3 weeks) was administered in 5 patients. After a median follow-up of 14 months(mean-18.2 months), all patients are in complete radiological remission. Paediatric PCNSL is a rare tumour entity and multimodality management with high dose Methotrexate and Rituximab based chemo-immunotherapy and cranial radiotherapy leads to excellent early clinical outcome.
LINC-34. OPTIC NERVE INFILTRATION: RARE MANIFESTATION OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA IN REMISSION
Authors: Rahmartani Ludi Dhyani
Published: December 2020

BACKGROUND

Optic nerve infiltration in acute lymphoblastic leukemia is a rare manifestation. This infiltration may appear months in advance as an isolated sign of extramedullary relapse and considered as one of the significant clinical findings of central nervous system leukemia. AIM: To describe a case of rapidly progressive optic nerve infiltration in a girl with ALL in remission. CASE: A 13-year-old girl in full remission following treatment for B-cell acute lymphoblastic leukemia presented with decreased vision and proptosis on the left eye. She completed the chemotherapy course two years before. On physical examination, we found the optic disc swelling in her left eyes. There were no signs of relapse from the hematological, cerebrospinal fluid analysis, and bone marrow aspiration. The orbital CT found a mass on the left retrobulbar (size 29x48x32 mm), suspected of optic nerve glioma. The mass has grown rapidly in a month, and she lost her left sight. The involved eye was exenterated (60x55x40 mm). The histopathology and immunohistochemistry showed the B-cell acute lymphoblastic lymphoma. Unfortunately, the patient could not come for further follow up due to the COVID-19 large-scale social distancing. Two months later, she came with pallor and pain in all of her body. The bone marrow aspiration showed leukemic relapse and she is undergoing chemotherapy.

CONCLUSION

Optic nerve infiltration by leukemia requires both diagnostic certainty and urgent management. A routine ophthalmic assessment is recommended in patients with a history of acute lymphoblastic leukemia to diagnose optic nerve involvement due to leukemic infiltration.
LINC-36. TRILATERAL RETINOBLASTOMA: A REPORT OF FOUR CASES
Authors: Rahmartani Ludi Dhyani
Published: December 2020

Retinoblastoma is the most common primary malignant intraocular cancer that usually develops in early childhood. About 5% of those patients are at risk of developing trilateral retinoblastoma (TRB). In developing countries, most of them came in the late stage; therefore, ocular and patient survival rates are lower than in developed countries. From 2015–2019, we found four cases of trilateral retinoblastoma. Two of them had bilateral retinoblastoma, and two had unilateral retinoblastoma. They all presented with leukocoria and had no family history of retinoblastoma. The mean age was 13.8 months (range 9–24 months of age). The diagnosis of trilateral retinoblastoma was made from initial head CT/MRI. They were treated conservatively with high dose VEC chemotherapy, and three of them have died during treatment. Trilateral retinoblastoma is usually fatal and needs multidisciplinary treatment care. In developing countries, it is important to evaluate distant metastasis. Head CT or MRI from the initial diagnosis to exclude the trilateral retinoblastoma.
LINC-43. FACTORS LEADING TO DIAGNOSTIC DELAY FOR CHILDREN WITH PRIMARY TUMORS OF CENTRAL NERVOUS SYSTEM (CNS) IN QATAR
Authors: Yousif Tayseer , Saleh Ayman , Maaz Ata
Published: December 2020

INTRODUCTION

Median time to diagnosis for primary CNS tumors for children in Qatar has been reported to be 28 days. However, a wide variation in diagnostic times is seen. This study was undertaken to analyze the factors leading to delay in diagnosis.

METHODS

Data were retrospectively analyzed for children who had diagnostic delay (more than 28 days) from September 2006 to February 2020. Presenting symptoms, number and type of healthcare contacts and presenting symptom interval (PSI) were reviewed. Parental delay (PSI-1) was defined as the date of onset of first symptom to the date of first healthcare contact. Healthcare delay (PSI-2) was defined as date of first healthcare contact to the date of diagnostic scan.

RESULTS

Twenty-four patients were identified with diagnostic delay. Median age at diagnosis was 48.2 (range 5.4–171.6) months with an equal sex distribution. Fifteen (62.5%) patients were older than 3 years, 13(54%) patients had low grade glioma, 16 (66.7%) had supratentorial tumors and 12 (50%) presented with raised intracranial pressure. Diagnosis was made after a median 3 (range 1–8) healthcare contacts. Nineteen (79%) patients presented to primary care. Median PSI was 132 (31–783) days. Parental delay (PSI-1) was 35 (0–496) days, while healthcare delay (PSI-2) was 41 (0–562) days. Endocrine (241 days) and oculo-visual (184 days) symptoms were associated with the longest PSI.

CONCLUSIONS

There was no significant difference between parental and healthcare delay. Endocrine and oculo-visual symptoms were associated with longest PSI. Increased awareness is required for early recognition of signs suggestive of CNS tumors.
MBCL-03. RESULTS OF HIGH-DOSE THIOTEPA, CARBOPLATIN AND ETOPOSIDE WITH AUTOLOGOUS HEMATOPOIETIC STEM-CELL TRANSPLANTATION FOR PATIENTS WITH RECURRENT MEDULLOBLASTOMA
Authors: Gevorgian Asmik , Tolkunova Polina , Kazantsev Ilya , Iukhta Tatiana , Kozlov Andrew , Zvyagintseva Darya , Morozova Elena , Zubarovskaya Ludmila , Afanasiev Boris , Zheludkova Olga , Punanov Yury
Published: December 2020

AIM

Medulloblastoma is a highly lethal disease when it recurs. Very few patients survive with second line conventional treatment after relapse. This study evaluated the use of high-dose thiotepa, carboplatin and etoposide with autologous hematopoietic stem-cell transplantation (HSCT) in patients with recurrent medulloblastoma.

METHODS

From 2010 to 2019, 60 patients at the age 4–32 years (median, 12) with recurrent medulloblastoma were received high-dose chemotherapy (HDCT) with auto-HSCT after induction second line chemotherapy. HDCT included thiotepa 150 mg/m2 #4; carboplatin 500 mg/m2 #4; etoposide 250 mg/m2 #4 and +/- etoposide 1 mg intraventricular on days #5 if patient had Ommaya reservoir; followed by HSCT. At the moment of HDCT 24 patients were in complete response (CR), 31 patients were in partial response (PR) and 5 patients had stable disease (SD) after second line conventional chemotherapy.

RESULTS

The median follow-up is 65 months (range, 24–227). The median time to engraftment after auto-HSCT was day +11 (range, 8–39). Five-year overall survival (OS) was 58% and disease free survival (DFS) was 46%. DFS was significantly better among patients in CR or PR 50% in compared to children in SD 20% at the moment of HDCT (p=0,002). Transplant related mortality were 12%, there were 7 patients died because of severe complications within 14 days after transplantation.

CONCLUSIONS

HDCT with auto-HSCT in pediatric patients with recurrent medulloblastoma may be a feasible option for cases who had CR or PR after induction chemotherapy. It is ineffective as a salvage therapy in refractory patients.
MBCL-11. TIME TO RADIOTHERAPY IMPACTS SURVIVAL IN PEDIATRIC AND ADOLESCENT NON-METASTATIC MEDULLOBLASTOMA TREATED BY UPFRONT RADIOTHERAPY – A REPORT FROM THE HIT 2000 TRIAL
Authors: Dietzsch Stefan , Placzek Felix , Pietschmann Klaus , von Bueren André O , Matuschek Christiane , Glück Albrecht , Guckenberger Matthias , Budach Volker , Welzel Jutta , Pöttgen Christoph , Schmidberger Heinz , Heinzelmann Frank , Paulsen Frank , Pazos Montserrat , Schwarz Rudolf , Hornung Dagmar , Martini Carmen , Grosu Anca Ligia , Meyer Frank Michael , Jablonska Karolina , Dunst Juergen , Kapp Karin S , Dieckmann Karin , Timmermann Beate , Pietsch Torsten , Warmuth-Metz Monika , Kwiecien Robert , Benesch Martin , Gerber Nicolas U , Pfister Stefan M , Clifford Steven C , von Hoff Katja , Klagges Sabine , Rutkowski Stefan , Kortmann Rolf-Dieter , Mynarek Martin
Published: December 2020

PURPOSE

To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma.

METHODS AND PATIENTS

382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients.

RESULTS

Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors.

CONCLUSION

Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.
MBCL-12. MOLECULAR SIGNATURES AND TUMOR INFILTRATING IMMUNOLOGICAL CELLS ASSOCIATED WITH ASIAN MEDULLOBLASTOMA PATIENT SURVIVAL
Authors: Liang Kung-Hao , Wu Kuo-Sheng , Lee Yi-Yen , Liang Muh-Lii , Fen Jun-Jeng , Wong Tai-Tong
Published: December 2020

BACKGROUND

Medulloblastoma is an aggressive pediatric brain tumor with surgery and post-resection radiotherapy plus chemotherapy as the major type of treatment currently.

METHODS

A cohort of 52 medulloblastoma patients were treated in Taipei Medical University Hospital and Taipei Veterans General Hospital. Among them, 28 (53.85%) are male. The average age at presentation is 7.21 ± 4.15. Genome-wide RNA profiling were performed on fresh-frozen surgical samples. Tumor infiltrating immune cell percentages were inferred by the cibersort immune deconvolution algorithm.

RESULTS

A total of 13 leading genes, including DLL1, ASIC2, SLC22A17, TRPM3, RPS2P5 and KCNC3, were found to be significantly associated with overall survival (All P < 0.001). A risk score was constructed, which is indicative of overall survival (Hazard Ratio [HR] = 2.720, 95% confidence interval [CI] = 1.798 ~ 4.112, P < 0.001) and recurrence-free survival (HR = 1.645, CI = 1.337 ~ 2.025, P < 0.001). After adjustment of clinical factors, the score remained significantly associated with overall survival (HR = 2.781, CI = 1.762 ~ 4.390, P < 0.001) and recurrence-free survival (HR = 1.604, CI = 1.292 ~ 1.992, P < 0.001). The percentage of Natural Killer and T follicular helper (Tfh) cells were higher in patients with better overall survival (P = 0.046 and 0.001, respectively). Furthermore, the Tfh percentage is also positively associated with mutation burdens in the expressed exonic regions (P < 0.001).

CONCLUSION

Higher mutation burdens are correlated with higher levels of tumor infiltrating Tfh cells, which is indicative of better post-surgery prognosis.
MBCL-14. A STUDY OF LOW-DOSE CRANIOSPINAL RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED AVERAGE-RISK MEDULLOBLASTOMA
Authors: Mochizuki Aaron , Janss Anna , Partap Sonia , Fisher Paul , Li Yimei , Fisher Michael , Minturn Jane
Published: December 2020

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-15. IMPACT OF MOLECULAR SUBGROUPS ON OUTCOMES FOLLOWING RADIATION TREATMENT RANDOMIZATIONS FOR AVERAGE RISK MEDULLOBLASTOMA: A PLANNED ANALYSIS OF CHILDREN’S ONCOLOGY GROUP (COG) ACNS0331
Authors: Michalski Jeff , Northcott Paul , Li Yimei , Billups Catherine , Smith Kyle , Burger Peter , Merchant Thomas , Gajjar Amar , Fitzgerald T J , Vezina Gilbert , Fouladi Maryam , Packer Roger , Tarbell Nancy , Janss Anna
Published: December 2020

The COG conducted a randomized trial for average-risk medulloblastoma (AR-MB). Patients age 3–21 years were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT) after receiving CSI. Patients age 3–7 years were also randomized to standard dose CSI (23.4Gy, SDCSI) or low dose CSI (18Gy, LDCSI). 464 evaluable patients were available to compare PFRT vs. IFRT and 226 for SDCSI vs. LDCSI. 380 cases had sufficient tissue for DNA methylation-based molecular classification: 362 confirmed medulloblastoma; 6 non-medulloblastoma; 12 inconclusive. Molecular subgrouping confirmed the following representation amongst the evaluable cohort: 156 Group 4 (43.1%), 76 Group 3 (21.0%), 66 SHH (18.2%), 64 WNT (17.7%). Five-year event-free survival (EFS) estimates were 82.5±2.7% and 80.5±2.7% for IFRT and PFRT, respectively (p=0.44). Five-year EFS estimates were 71.4±4.4% and 82.9±3.7% for LDCSI and SDCSI, respectively (p=0.028). EFS distributions differed significantly by subgroup (p<0.0001). Group 3 had the worst outcome, while WNT had the best outcome. There was a significant difference in EFS by RT group among SHH patients; SHH patients receiving IFRT arm had better EFS compared to PFRT (p=0.018). There was a significant difference in EFS distributions by CSI group in Group 4 patients; young Group 4 patients treated with SDCSI had better EFS compared to LDCSI (p=0.047). As previously reported, IFRT is noninferior to PFRT in all patients with AR-MB but LDCSI is worse than SDCSI in younger children. Significant differences in outcome by study randomization and molecular subgroup are observed.
MBCL-16. EFFICACY OF CARBOPLATIN GIVEN CONCOMITANTLY WITH RADIATION AND ISOTRETINOIN AS A PRO-APOPTOTIC AGENT IN MAINTENANCE THERAPY IN HIGH-RISK MEDULLOBLASTOMA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Leary Sarah , Packer Roger , Jaju Alok , Heier Linda , Burger Peter , Smith Kyle , Michalski Jeff , Li Yimei , Billups Catherine , Hwang Eugene , Gajjar Amar , Pollack Ian , Fouladi Maryam , Northcott Paul , Olson James
Published: December 2020

BACKGROUND

Metastasis, residual disease, and diffuse anaplasia are high-risk features in medulloblastoma.

METHODS

This was a randomized phase 3 study. Patients age 3–21 years with high-risk medulloblastoma received (+/-) daily carboplatin with 36Gy craniospinal radiation and weekly Vincristine followed by six cycles of maintenance chemotherapy with Cisplatin, Cyclophosphamide and Vincristine (+/) 12 cycles of isotretinoin during and following maintenance. The primary endpoint was event-free survival, with exact log-rank test to compare arms. Retrospective molecular analysis included DNA methylation and exome sequencing.

RESULTS

Of 294 medulloblastoma patients enrolled, 261 were eligible by central review of radiology and pathology, median age 8.6 years (range 3.3–21.2), 70% male, 189 (72%) with metastatic disease, 58 (22%) with diffuse anaplasia, 14 (5%) with >1.5cm2 residual disease. The 5-year EFS and OS for all subjects was 63%+4 and 73%+3, respectively. Isotretinoin randomization was closed due to futility. 5-year EFS was 66 + 5 with carboplatin versus 59 + 5 without (p=0.11), with effect exclusively observed in Group 3 subtype: 73%+8 with carboplatin versus 54%+9 without (p<0.05). Overall survival differed by molecular subgroup (p=0.006): WNT 100%, SHH 54%+11, Group 3 74%+6, Group 4 77%+5 at 5 years. MYC amplification or isochromosome 17 were unfavorable in Group 3 (p=0.029). Chromosome 11 loss or chromosome 17 gain were favorable in group 4 (p<0.001). No survival difference was observed with TP53 mutation in SHH subtype in this high-risk cohort.

CONCLUSIONS

Therapy intensification with carboplatin improved survival for high-risk group 3 medulloblastoma. These findings further support an integrated clinical and molecular risk stratification for medulloblastoma.
MBCL-27. ASSOCIATION OF MEDULLOBLASTOMA WITH CHARCOT-MARIE-TOOTH DISEASE
Authors: Watanabe Kenichiro , Komatsu Kazuyuki , Kawaguchi Koji , Makino Risa , Takachi Takayuki , Ogura Taemi , Horikoshi Yasuo , Ishizaki Ryuji , Iwafuchi Hideto , Tashiro Yuzuru
Published: December 2020

Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary neurological disorders and damages peripheral nerves that results in motor and sensory disturbance. Association of medulloblastoma (MBL) with CMT has been rarely reported. A one-year-old male was referred to our hospital because of cerebellar mass. He had partial resection of the tumor, and was pathologically diagnosed as having desmoplastic nodular medulloblastoma. He received chemotherapy according to the HIT protocol, however, developed severe peripheral neurotoxicity in the initial stage of the treatment. Reinvestigation of family history revealed his mother, grandmother, and aunt had muscle weakness. We suspected he had an inherited neurological disease including CMT, and discontinued administration of vincristine. Fluorescence in situ hybridization analysis detected duplication of PMP22 gene located on 17p11.2, confirming the diagnosis of CMT1A. He completed the rest of chemotherapy without vincristine, and remained in complete remission for four years from the end of treatment. In the literature, there are reports of patients with CMT who developed MBL and were complicated with severe peripheral neurotoxicity due to the use of vincristine. The present case, along with previous reports, suggests that medulloblastoma can develop in patients with CMT and reminds the importance of recalling the possibility of CMT when patients develop severe chemotherapy-induced peripheral neurotoxicity upon use of vincristine. Desmoplastic nodular medulloblastoma may be successfully treated by chemotherapy without vincristine.
MBCL-32. HIGH-DOSE CHEMOTHERAPY WITH STEM CELL RESCUE FOR RECURRENT PREVIOUSLY IRRADIATED MEDULLOBLASTOMA
Authors: Salnikova Ekaterina , Vilesova Irina , Merishavyan Artur , Druy Alexander , Yasko Ludmila , Sysoev Andrey , Nechesnyuk Alexey , Borodina Irina , Karachunsky Alexander , Novichkova Galina , Papusha Ludmila
Published: December 2020

BACKGROUND/OBJECTIVES

Relapse of medulloblastoma (MB) is highly lethal in previously irradiated patients. As one of therapeutic options for recurrence MB, high-dose chemotherapy with stem cell rescue (HDSCR) is suggested. The aim of our work was to evaluate the effectiveness of this therapy.

DESIGN/METHODS

We retrospectively analyzed the data of 8 pts with previously irradiated relapse MB using HDSCR. Initially, M0-stage was verified in 4 cases. Histological diagnoses were desmoplastic (2 pts), classic (2 pts), anaplastic (2 pts) and MB NOS (2 pts). Molecular genetic analyses was performed in 6 cases: Group 3 was verified in 2 cases (1-classic, 1-anaplastic), Group 4 – in 3 cases (1-classic, 1-anaplastic, 1-desmoplastic). Time to first PD was from 15 to 86 months (median=29,4 months). Local relapse was revealed in 1 pt, metastatic – in 5 pts, mixed – in 2 pts.

RESULTS

All pts were treated according HIT-REZ 2005 (3–5 cycles without/with intraventricular etoposide), with CR achieved in 3 pts and PR in 5 pts. HDCT regimens consisted of carboplatin, etoposide, thiotepa and temozolomide. 2 pts received re-irradiation – focal RT (1) and CSI (1). 7/8 patients died, 1 pt alive with PD. Time from HDCT to death was 5–15 months (median=9,6 months).

CONCLUSIONS

HDSCR for recurrent previously irradiated MB is ineffective. Use of other methods should be considered in these cases.
MBCL-36. HOW TO INCREASE SURVIVAL IN 7 TO 10% OF PATIENTS WITH AVERAGE-RISK MEDULLOBLASTOMA WITHOUT NEW THERAPIES: EARLY PROSPECTIVE NEURORADIOLOGY SCREENING EXPERIENCE FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Gottardo Nicholas , Leary Sarah , Kang Guolian , Gossett Jeffrey , Fouladi Maryam , Kessel Sandy , Sabin Noah , Jaju Alok , Harreld Julie
Published: December 2020

BACKGROUND

Previous Children’s Oncology Group (COG) average-risk medulloblastoma studies retrospectively identified that 7 to 10% of patients were wrongly staged; either due to the presence of unequivocal residual disease greater than 1.5cm2 or metastatic disease. Notably, these patients had an inferior survival. The current COG front-line average-risk study for WNT-driven medulloblastoma patients, ACNS1422, is a reduced-intensity therapeutic protocol. Given the potentially devastating consequences of dose reduction in a wrongly staged patient, ACNS1422 is utilizing optimized MRI sequences, including thin slices with no gap and post contrast T2 FLAIR sequences, combined with a rapid central neuroradiology review.

RESULTS

The study opened on October 2 2017. As of 31 December 2019, a total of 34 patients have undergone central neuroradiology review. In 27/34 (79%) repeat scans were requested due to technically inadequate sequences (majority due to missing post contrast T2 FLAIR, slice thickness and gap issues). Of 19 repeat scans received, four patients (12%) were wrongly staged as average-risk; three patients were identified with residual disease >1.5cm2 (in 2 residual disease was confirmed at second resection) and one patient had widespread spinal metastases previously obscured by motion. In addition, metastatic disease was excluded in another patient, reported as having metastatic disease.

CONCLUSION

Our data is consistent with previous reports revealing that approximately 10% of patients are wrongly staged as average-risk. The early experience of ACNS1422 reveals that the optimized MRI sequences combined with a rapid central neuroradiology review are very valuable in a cooperative group setting to more accurately stage patients.
MBCL-48. OUTCOMES OF TREATMENT BASED ON THE ST. JUDE MEDULLOBLASTOMA-96 REGIMEN FOR JAPANESE CHILDREN WITH MEDULLOBLASTOMA
Authors: Fujimura Junya , Suzuki Tomonari , Watanabe Yuko , Niizuma Hidetaka , Saito Ryuta , Kanamori Masayuki , Sonoda Yukihiko , Watanabe Atsuko , Tanaka Ryuhei , Fujiwara Megumi , Yaguchi Akinori , Ishibashi Takeshi , Tomita Osamu , Kondo Akihide , Shimizu Toshiaki , Yanagisawa Takaaki , Tominaga Teiji , NIshikawa Ryo , Arai Hajime
Published: December 2020

Medulloblastoma is a type of malignant embryonal tumor in childhood that is considered to require multiagent chemotherapy followed by radical resection and craniospinal irradiation (CSI). However, the outcomes of chemotherapy for this tumor in Japan are unclear. Here, we performed a multicenter retrospective study to determine the prognosis of pediatric medulloblastoma patients in Japan treated with the St. Jude medulloblastoma-96 (SJMB96) regimen. Thirty patients with newly diagnosed medulloblastoma received treatment with the SJMB96 regimen at Juntendo University Hospital in Tokyo (n=10), Saitama Medical University International Medical Center in Saitama (n=10), and Tohoku University Hospital in Miyagi (n=10) from 2011 to 2018. All patients underwent tumor resection and CSI, with radiation doses of 23.4Gy for standard-risk patients (n=11) and 39.6Gy for high-risk patients (n=19). Six weeks after radiation therapy, patients received four cycles of high-dose chemotherapy with autologous peripheral blood stem cell transplantation according to the SJMB96 regimen. We found that 5-year overall survival was 80.8% among standard-risk patients and 74.2% among high-risk patients. No treatment-related deaths occurred. Eight patients who experienced recurrence died within 80 months of diagnosis. As these treatment outcomes are comparable to those previously reported outside of Japan, our findings indicate that this regimen is a therapeutic option for medulloblastoma patients in Japan.
MBCL-51. POST-AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION (AuHCT) PRACTICES FOR YOUNG CHILDREN WITH MALIGNANT BRAIN TUMORS
Authors: Rahim Mahvish , Auletta Jeffrey , Dhall Girish , Finlay Jonathan , Coven Scott
Published: December 2020

BACKGROUND

“Head Start” protocols have used autologous hematopoietic stem cell transplant (AuHSCT) for infants and young children with malignant brain tumors in order to avoid cranial irradiation. The post-AuHSCT practice for children with a brain tumor diagnosis varies greatly. The goal of this research study is to explore practices and attitudes about post-AuHSCT care for children with brain tumors. DESIGN: An anonymous REDCap survey link was provided to all site primary investigators and additional support personnel at “Head Start” institutions. The survey questions defined the role of the medical provider completing the form and explored the various practices relating to transition, management, communication and overall satisfaction.

RESULTS

Twenty-one individual replies have been received so far. The majority report that prophylactic medicines were discontinued upon WBC recovery; however, management of discontinuation was split evenly between the neuro-oncology and stem-cell transplant teams. Nearly half of responders follow T-cell recovery following transplant without immunology guidance. Post-AuHCT vaccination practices are highly variable, with no clear consensus. Lastly, most responders reported adequate ease of transition and communication between the neuro-oncology and transplant teams.

CONCLUSIONS

This work underscores the need for both multidisciplinary communication for children with brain tumors in the post-AuHCT period and for the development of standardized vaccination and other prophylaxis practices.
MBRS-08. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLAR GRANULE NEURON PROGENITORS, THE CELL OF ORIGIN FOR MEDULLOBLASTOMA, FOR APOPTOSIS BY INDUCING PRO APOPTOTIC BIM
Authors: Cleveland Abigail , Gershon Timothy
Published: December 2020

Medulloblastomas, unlike other malignant brain tumors, are typically sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH-subgroup medulloblastoma, are also highly sensitive to radiation. In early life, CGNPs proliferate in response to Sonic Hedgehog (SHH) signaling, and hyperactivation of SHH signaling in CGNPs can lead to the development of SHH-subgroup medulloblastoma. We propose that SHH activation induces radiation sensitivity along with tumorigenesis. We have previously shown that the proapoptotic protein BAX is required for radiation sensitivity of both SHH-driven medulloblastomas and CGNPs in mice, and that BCL-xL supplies critical regulation of BAX, preventing spontaneous cell death. Here, we show that SHH signaling increases the radiation sensitivity of CGNPs by inducing the proapoptotic protein BIM. We found that BIM expression depends on SHH activity, and that genetic deletion of Bim decreases the radiation-sensitivity of CGNPs. Mechanistically, we show that BIM binds to anti-apoptotic proteins BCL-xL and MCL-1, where it may alter the balance of BAX and BCL-xL interactions. Consistent with our mechanistic model, human medulloblastoma patients with high BIM expression show a better prognosis. Based on these observations, we propose that SHH-induced BIM mediates the typical radiation sensitivity of SHH-driven medulloblastoma. Finding ways to enhance BIM activity may open new opportunities for targeted medulloblastoma therapy.
MBRS-13. MiR-1253 POTENTIATES CISPLATIN RESPONSE IN PEDIATRIC MEDULLOBLASTOMA BY REGULATING FERROPTOSIS
Authors: Kanchan Ranjana K , Perumal Naveenkumar , Atri Pranita , Venkata Ramakanth Chirravuri , Thapa Ishwor , Nasser Mohd Wasim , Batra Surinder K , Mahapatra Sidharth
Published: December 2020

Despite improvements in targeted therapies, few group 3 medulloblastoma patients survive long-term. Haploinsufficiency of 17p13.3 is a hallmark of these high-risk tumors; included within this locus is miR-1253, which has tumor suppressive properties in medulloblastoma. Therapeutic strategies capitalizing on the anti-neoplastic properties of miRNAs can provide promising adjuncts to chemotherapy. In this study, we explored the potentiation of miR-1253 on cisplatin cytotoxicity in group 3 MB. Overexpression of miR-1253 sensitized group 3 MB cell lines to cisplatin, leading to a pronounced downregulation in cell viability and induction of apoptosis. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. In silico analysis revealed an upregulation of several ABC transporters in high-risk MB tumors. When compared to cell lines overexpressing miR-1253, the ABC transporter ABCB7, which regulates both apoptosis and ferroptosis, was revealed as a putative target of miR-1253 with poor survival that may facilitate its chemosensitizing effects by modulating mitochondrial ROS and HIF1α-driven NFκB signaling. We observed high expression of ABCB7 and GPX4, ferroptosis regulators, in MB patients with poor overall survival. MiR-1253 negatively regulated the expression of ABCB7 in Group 3 MB cell lines and induced cytoplasmic ROS and mitochondrial O2-, suggesting ROS-mediated induction of ferroptosis through regulation of ABCB7 and GPX4. Treatment with ROS and ferroptosis inhibitors rescued miR-1253 transfected cells treated with cisplatin. We conclude that miR-1253 induced ROS and potentiated the ferroptotic effects of cisplatin via targeting miR-1253/ABCB7/GPX4/mtROS axis.
MBRS-17. EXAMINING THE ROLE OF LHX9 IN GROUP 3 MEDULLOBLASTOMA
Authors: Injac Sarah , Huang L Frank , Mack Stephen , Braun Frank , Du Yuchen , Kogiso Mari , Lindsay Holly , Parsons D William , Zhao Hong , Lau Ching C , Wong Stephen T C , Li Xiao-nan
Published: December 2020

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite major advances in our understanding of the biology of MB, novel treatments remain urgently needed. Using a chemical-genomics driven drug repositioning strategy, we identified the cardiac glycoside family of compounds as potential treatments for Group 3 MB. We subsequently demonstrated that single-agent treatment with digoxin prolongs survival in a patient-derived xenograft model (PDOX) of Group 3 MB to a degree comparable to radiation therapy, a mainstay in the treatment of MB. Finally, we examined the mechanism of digoxin-mediated cell killing using RNA-seq. This work identified LHX9, a member of the LIM homeobox family of transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially and temporally restricted expression and LHX9 has been proposed as a core transcription factor (TF) in the regulatory circuitry of Group 3 tumors. Loss of function of other core TFs has been shown to impact MB growth. The role of LHX9 in MB, however, has not been previously experimentally evaluated. We now report that knockdown of LHX9 in MB-derived cell lines results in marked growth inhibition raising the possibility that loss of LHX9 plays a major role in digoxin-mediated cell killing and that LHX9 represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting this devastating disease.