bluuebunny/crossref_metadata_2025 huggingface dataset:
GCT-21. CENTRAL NERVOUS SYSTEM GERMINOMA - PONDERING THE NEXT STEPS
Authors: AbdelBaki Mohamed S , Bartels Ute
Published: December 2020

Central nervous system germinoma (CNS) represents one successful example where the introduction of chemotherapy into the treatment allowed significant and meaningful reductions in the volume and dose of radiation therapy while maintaining excellent outcomes. However, the long-term toxicities and morbidities of the current therapies, in addition to their substantial negative impact on the social wellbeing of germinoma patients, should clearly indicate that the current achievements are not enough. While stepwise cutback of the radiation therapy needs to be commended, real progress must be achieved in the exploration and investigation of biological and molecular markers. Furthermore, the differences that still exist between the several working groups around the globe in determining the tumor marker cut-offs that help diagnose these tumors illustrate their shortcomings, and therefore the need for newer and more reliable methods. Additionally, efforts should focus on the inclusion of metastatic and basal ganglia/thalamic germinomas in future prospective clinical trials given the lack of evidence on the best treatment strategy for these patients. A comprehensive review of all major CNS germinoma clinical trials will be presented aiming to lay a foundation for researchers and clinicians alike who are currently working on designing innovative approaches for this group of patients. This review also details the current issues of debate, and provides suggestions which may assist in the design of future prospective clinical trials for children with CNS germinomas.
GCT-22. PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT NON-GERMINOMATOUS CNS GERM CELL TUMORS
Authors: Tomiyama Arata , Uchida Eita , Wada Kojiro , Ichimura Koichi
Published: December 2020

Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.
GCT-23. MULTI-INSTITUTIONAL ANALYSIS OF TREATMENT MODALITIES IN BASAL GANGLIA AND THALAMIC GERMINOMA
Authors: Graham Richard T , Abu-Arja Mohammad H , Stanek Joseph , Bartels Ute , Cappellano Andrea , Chi Susan , Cooney Tabitha , Dhall Girish , Finlay Jonathan L , Fisher Michael J , Friedman Gregory , Gajjar Amar , Gauvain Karen , Hoffmann Lindsey M , Hukin Juliette , Margol Ashley , Mueller Sabine , Navalkele Pournima , Ronsley Rebecca , Villeneuve Stephanie , Yeo Kee Kiat , Su Jack M , Gottardo Nicholas G , Allen Jeffrey , Packer Roger , AbdelBaki Mohamed
Published: December 2020

BACKGROUND

Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear.

METHODS

Retrospective multi-institutional analysis was conducted across 18 institutions in four countries.

RESULTS

For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT.

CONCLUSION

In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.
GCT-29. DOES TUMOUR MARKER DECLINE PREDICT OUTCOME IN INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOURS (NGGCTs)?
Authors: Conter Cecile Faure , Lardy-Cleaud Audrey , Murray Matthew , Nicholson James , Guerrini-Rousseau Lea , Palenzuela Gilles , Alapetite Claire , Garre Maria Louise , Kortmann Rolf , Saran Frank , Ajithkumar Thankamma , Pietsch Torsten , Vasiljevic Alexandre , Ricardi Umberto , Timmermann Beate , Muller Jans Enno , Calaminus Gabriele
Published: December 2020

INTRODUCTION

The prognostic impact of tumour marker (TM) decline rate has been demonstrated for extracranial poor prognostic non-seminomatous/germinomatous germ cell tumours (NGGCT). The current series aimed to assess if this finding can be applied to intracranial primaries.

METHODS

Patients were retrieved from the SIOP-CNS-GCT-96 database. They were selected if they had i/assessable values of serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG) before and 18 to 28 days after the first course of chemotherapy and ii/ available data for outcome. Decline rate was calculated using a logarithmic transformation and expressed as time to normalization (TTN) as published by Fizazi (JCO 2004). TTN≤ 9 weeks for AFP and ≤ 6 weeks for HCG were considered as favourable decline rate. Prognostic impact of TTN on outcomes was assessed using the log-rank test.

RESULTS

Out of 149 patients with NGGCT, 59 were evaluable for both HCG and AFP TTN of whom 44 (74%) had a favourable decline rate. After a median follow-up of 88 months (2–251), 20 relapses and 15 deaths occurred. The 5-year PFS rates were 72% and 60% in patients who had a favourable and an unfavourable TTN, respectively (p=0.15). The 5-year OS rates were 77 % and 69%, respectively (p=0.66). Separate analysis of TTN based only on AFP or only on HCG gave similar results.

CONCLUSION

Despite the use of a methodology similar to that used in extracranial NGGCT, no significant impact of serum TM decline on prognosis was observed, but insufficient statistical power cannot be ruled out.
GCT-33. A PHASE 2 TRIAL OF RESPONSE-BASED RADIATION THERAPY FOR PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS: A CHILDREN’S ONCOLOGY GROUP (COG) STUDY. IMPACT OF RAPID CENTRAL RADIOTHERAPY REVIEW ON RADIOTHERAPY QUALITY AND PATTERN OF FAILURE FOR NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Murphy Erin S , Dhall Girish , Fangusaro Jason , Bartels Ute , Fouladi Maryam , Shaw Dennis , Khatua Soumen , Panigraphy Ashok , Souweidane Mark , Gajjar Amar , Williams-Hughes Chris , Onar Arzu , Wu Shengjie , Haas-Kogan Daphne , MacDonald Shannon
Published: December 2020

BACKGROUND

COG ACNS 1123 tested reduced radiotherapy (RT) for non-metastatic, non-germinomatous germ cell tumor (NGGCT) patients. The impact of central review on quality of RT and pattern of failure for NGGCT patients is evaluated.

METHODS

Patients who achieved a complete response (CR) or partial response (PR) to induction chemotherapy were eligible for reduced dose and field RT of 30.6 Gy whole ventricular field (WVI) and 54 Gy tumor-bed total dose. An online contouring atlas was available. Within three days of RT start, WVI plans were submitted for rapid central review. Within one week of RT completion, the complete RT record was submitted. Brain and spine MRIs of relapsed patients were centrally reviewed.

RESULTS

Between 5/2012–9/2016, 107 eligible patients were accrued and 70 met reduced RT criteria. Rapid RT review was performed for 49 (70%) of 70 patients. Forty-four (89.8%) required no modification. All modifications were completed and plans became compliant. Final central review was performed for 66 evaluable patients: 62 (94%) were per protocol; there were 2 major (1 dose and 1 target) and 2 minor deviations. Eight patients progressed; none had deviations. Median time to progression was 3.54 months (range: 1.7–19.1) from RT start. All failures had a spine component; two also had cranial component: one local progression (within the RT boost volume) and one leptomeningeal disease.

CONCLUSION

Providing an online contouring atlas and performing a rapid central review lead to high quality radiotherapy on this prospective trial. The deviations did not contribute to the pattern of failure.
GCT-49. EVALUATION OF THE PERIOPERATIVE AND POSTOPERATIVE COURSE OF SURGERY OF PINEAL GERMINOMA ACCORDING TO THE SIOP CNS GCT 96 TRIAL
Authors: Shabo Ehab , Czech Thomas , Nicholoson James C , Mallucci Conor , Sarikaya-Seiwert Sevgi , Guerini-Rousseau Lea , Piatelli Gianluca , Murray Matthew C , Faure-Conter Cecile , Calaminus Gabriele
Published: December 2020

INTRODUCTION

CNS germinoma, being marker-negative, are diagnosed by surgical biopsy. Here we evaluate the perioperative status and postoperative complications of patients with pineal germinoma who underwent a primary biopsy or resection, treated according to SIOP CNS GCT 96.

METHODS

235 patients with histologically conﬁrmed germinoma were registered, of which 113 were pineal: 55 were biopsied and 58 underwent primary resection. Initial symptoms, tumour size, complications and neurological status were assessed. 111 patients were evaluable.

RESULTS

Pure germinoma was present in 101 patients; 10 had additional teratoma components. The main clinical symptoms at diagnosis were headache (n=98), hydrocephalus (n=93), double vision (n=62), Parinaud syndrome (n=57) and papilloedema (n=44). Tumour size was documented in 81 patients (<2cm, n=14; 2-3cm, n=35; ≥3cm, n=32). 17 patients underwent primary total resection, 14 subtotal resection >50%, 26 subtotal resection <50%, 39 stereotactic biopsy, 11 endoscopic biopsy, 2 open biopsy and 2 not documented. The postoperative neurological status after resection was improved in 23 patients, unchanged in 27, deteriorated in 6 and not documented in one. Clinical status after biopsy improved in 26 patients, was unchanged in 15, deteriorated in 2 and not documented in 11. Postoperatively, 16/57 patients after resection and 5/54 after biopsy developed complications (Parinaud syndrome, double vision and hydrocephalus).

CONCLUSION

Although surgical techniques have improved within recent decades, these results support the practice of biopsy over resection for histological confirmation of germinoma arising at the pineal site. Supported in part by German Cancer Aid.
GCT-58. BRAZILIAN CENTRAL NERVOUS SYSTEM GERM CELL TUMOR CONSORTIUM PROTOCOL
Authors: Cappellano Andréa M , Silva Nasjla S , Mançano Bruna , Almeida Daniela B , Cavalheiro Sergio , Dastoli Patricia A , Silva Frederico A , Epelman Sidnei , Aguiar Simone S , Finlay Jonathan L
Published: December 2020

INTRODUCTION

Primary central nervous system (CNS) germ cell tumors (GCT) account for 2–3% brain tumors children/adolescents in Western hemisphere. The report aim is to present the results of a Brazilian CNSGCT consortium protocol.

METHODS

Since 2013, 45 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels≤200mIU/ml (n=33), four between 100-200mIU/ml and NGGCT (n=12), received carboplatin/etoposide/cyclophosphamide (4–6 cycles), followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous bone marrow transplant (ABMT) was conducted for NGGCT low responders.

RESULTS

Mean age 12.9 years (4.7-20y), 34 males. Diagnosis was made by TM (n=9), surgery (n=19), both (n=15). Two bifocal cases, (-)TM were treated as germinoma. Primary tumor location was pineal (n=20), suprasellar (n=13), bifocal (n=11) and basal ganglia/thalamus (n=1). Fourteen had ventricular/spinal spread. Second-look surgery occurred in 5 patients. For the germinoma group, 26 achieved complete response (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 2/4 cycles, four patients showed CR, 2 failure/progression and 6 partial response (4 (-)TM). Two were submitted to ABMT. Radiotherapy was performed as described, except in three. One recurrence to date. Two patients died (endocrinologic complications/progression). Toxicity was mostly grade ¾ neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 38 months, OS was 100% for Germinoma and 85% NGGCT.

CONCLUSION

The treatment is tolerable and VFI dose reduction to 18Gy seems to preserve efficacy. Further follow-up is warranted to assess the NG group and the slow-responder patients.
GCT-69. VOLUMETRIC CHANGE BEFORE CHEMORADIOTHERAPY AND INFLUENCE OF DIAGNOSTIC RADIATION EXPOSURE IN INTRACRANIAL GERMINOMAS
Authors: Kagawa Naoki , Hirayama Ryuichi , Yokota Chisato , Chiba Yasuyoshi , Fujimoto Yasunori , Nakagawa Tomoyoshi , Umehara Toru , Kijima Noriyuki , Kinoshita Manabu , Kishima Haruhiko
Published: December 2020

BACKGROUND

Spontaneous regression in intracranial germ cell tumors has been reported in some literatures, but the mechanism has not been well known. We retrospectively measured the tumor volume before chemoradiotherapy and analyzed factors that influence reduction of tumor volume.

PATIENTS AND METHODS

Plural MRI scans were done before the first course of chemotherapy regimen in 27 patients with primary intracranial germinomas. Their age ranged from 8 to 31 years. 35 lesions from them were enrolled and included 13 pineal, 4 neurohypophyseal, 4 basal ganglia, 4 bifocal type, and 2 multiple lesions. All regions were verified as pure germinoma or HCG-producing germinoma by histopathological examination. Tumor volume of 35 lesions was analyzed by volumetric assessment based on MRI. Ratio of volumetric change between the first MRI and the scan immediately before chemotherapy was defined as shrinking rate (%). Period between disease onset and the first chemotherapy was 20 to 47 days. Diagnostic radiation dose was calculated in each case.

RESULTS

Initial tumor volume ranged from 0.962 to 72.356 cubic centimeters (mean: 8.27). Diagnostic radiation dose: 40.5 to 910.1 mGy. Shrinking rate ranged from -57.8 to 85.4% (mean: 30.8). In 10 regions, shrinking rate was within 30%. Shrinking rate was significant positively influenced by diagnostic radiation dose (p<0.05) and negatively influenced by initial volume (p<0.05). But, other factors such as age, sex, histopathological parameters did not influence tumor shrinkage.

CONCLUSION

This study shows that the volume of intracranial germ cell tumors is changing dynamically before chemoradiotherapy in many cases. Diagnostic exposure to low-dose radiation influences tumor shrinkage of intracranial germinomas.
GCT-70. INTRACRANIAL GROWING TERATOMA SYNDROME IN CHILDREN
Authors: Febres Maria Carter , Bruggers Carol S , Zhou Holly , Perry Arie , Kestle John , Whipple Nicholas
Published: December 2020

Germ cell tumors account for less than 5% of all intracranial malignancies in children. Intracranial growing teratoma syndrome (GTS) is a rare pathophysiologic process characterized by growth of mature teratoma elements of a non-germinomatous germ cell tumor (NGGCT) during or following treatment with chemotherapy, in addition to normalization of or declining AFP/βHCG of the cerebral spinal fluid (CSF)/serum. A 13-year-old male presented with headache, emesis, and diplopia. MRI of the brain/spine revealed a localized 3.1 x 3.1 x 3.2 cm pineal tumor. Biopsy confirmed NGGCT (germinoma, immature and mature teratoma). Serum AFP (227ng/ul) and βHCG (12 IU/L) and CSF AFP (21ng/ul) and βHCG (31 IU/L) were elevated. Prior to cycle two of chemotherapy, he developed unstable gait and moderate hearing loss. Repeat MRI brain demonstrated tumor enlargement (4.4 x 5.2 x 5.1 cm) and obstructive hydrocephalus, although serum AFP/βHCG had normalized. Gross total resection of tumor confirmed GTS, without residual immature/malignant elements. Following six cycles of multiagent chemotherapy (carboplatin, etoposide, ifosfamide) and proton beam craniospinal irradiation (36 Gy with 18 Gy boost), he remains free of disease at eleven months since diagnosis. The pathogenesis of GTS remains unclear. Care must be taken to avoid misdiagnosing GTS as progressive NGGCT, as treatment and prognosis differ significantly. Second-look surgery, with a goal of complete resection, should be considered in cases of NGGCT when residual tumor grows during or following therapy, as this may represent GTS. Although histologically benign, GTS can be fatal. In patients with GTS, complete resection is usually curative.
GCT-71. SIOP STRATEGY TREATMENT FOR CENTRAL NERVOUS SYSTEM GERM CELL TUMORS IN A MIDDLE INCOME COUNTRY
Authors: Oller Agustina , Sampor Claudia , Baroni Lorena , Freytes Candela , Ponce Nicolas Fernandez , Villanueva Gabriela , Alderete Daniel
Published: December 2020

BACKGROUND/OBJECTIVES

Central nervous system (CNS) germ cell tumors (GCTs) represent 3% of primary paediatric brain tumours in occident. They can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs). The aim is to describe demographic characteristics, Event Free Survival (EFS) and Overall Survival (OS) in patients with GCTs treated at Oncology Unit of Garrahan Hospital (HG).

DESIGN/METHODS

Retrospective analysis of patients with GCTs admitted between September 1st,2000 to September 1st,2019. Variables analysed: age, localization, treatment, relapse and death. Patients were treated per SIOP-CNSGCTs protocol. For statically analysis SPSS (IBM), for EFS/OS Kaplan-Meyer, Long-rank for significance.

RESULTS

Fifty-seven patients were included, comprising 38 Germinomas and 19 NGGCTS. Median age was 146 months (range 11–228). Primary site in localized Germinomas were pineal (16p), suprasellar (7p) and bifocal (7p). Five-year EFS and OS of 100% and 88.5%, respectively. Four patients presented metastatic disease, with an EFS and OS of 60.9% and 66.6%. Tumor site in localized NGGCT were pineal(8p) and suprasellar(5p). Five-year EFS was 81.8% and OS was 80.2%. No patients presented metastatic disease. All patients with high-risk tumor markers at diagnosis relapsed. No significative differences were found in OS neither EFS between groups (Germinomas OS5y 90% vs NGGCTs 74.6%p=0.19[CI95%0.0786–1.689]), (Germinomas EFS5y 78.9% vs NGGCTs5y 81.8%p=0.85[CI95%0.3046–4.230). Global OS and EFS5y was 83% and 72.9%.

CONCLUSION

OS of our cohort is lower than what has been shown in current literature. This result may be related to the lack of resources and lower social economic status in our population.
HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH BRAF V600E-MUTANTATION
Authors: Kimura Yui , Ishi Yukitomo , Watanabe Yuko , Nakano Yoshiko , Yamaguchi Shigeru , Narita Yoshitaka , Ichimura Koichi
Published: December 2020

BACKGROUND

Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan.

RESULTS

Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors.

DISCUSSION

Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.
HGG-05. REGRESSION OF RECURRENT GLIOBLASTOMA AFTER BORON NEUTRON CAPTURE THERAPY AND CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY IN A CHILD
Authors: Chen Hsin-Hung , Chen Yi-Wei
Published: December 2020

A 6 y/o girl with recurrent multifocal glioblastoma received 3 times of boron neutron capture therapy (BNCT) and chimeric antigen receptor (CAR)–engineered T cells targeting the tumor-associated antigen HER2. Multiple infusions of CAR T cells were administered over 30 days through intraventricular delivery routes. It was not associated with any toxic effects of grade 3 or higher. After BNCT and CAR T-cell treatment, regression of all existing intracranial lesions were observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid, but new lesions recurred soon after the treatment. This clinical response continued for 14 months after the initiation of first recurrence.
HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT)
Authors: Aung Le Le
Published: December 2020

INTRODUCTION

Diffuse Leptomeningeal Glioneuronal Tumor (DLGNT) are rare CNS tumors and in infants, they can be lethal. There are several anecdotal reports in infants with low grade gliomas (LGG) with treated with BRAF inhibitors.

METHODS

A six-month old baby girl presented with a 2-week history of absent visual contact and vomiting. Imaging revealed a large 4.7 X 4.2 X 2.8 cm suprasellar charismatic region mass and multiple small extra-axial plaques in spinal canal. The child developed significant ascites post VP shunt requiring shunt externalization, extensive protein infusion support and hospitalization for six weeks. Immunohisto-chemical staining revealed Olig-2 and S-100, GFAP and synaptophysin positive. EMA showed patchy cytroplasmic reactivity in stromal cells and CD99 showed diffuse reactivity in stromal and lesional cells. INI-1, IDH-1, and CD117 were negative. Ki-67 proliferation index was 8–10%. PCR for BRAF V600E/E2/D was detected and KIAA1549-BRAF fusion as negative. This was confirmed by Genome Wide Next Generation Sequencing. While waiting for GNS testing results, the baby received one dose of Vinblastine. However, within seven days of initiating Debrafenib, significant clinical and radiological responses were observed.

CONCLUSION

The baby continues safely on Debrafenib with continued dramatic radiological response. This suggest that there may be a role in early initiation of targeted therapy such as BRAF inhibitors rather than giving standard chemotherapy such as Vinblastine or Carboplatin-Vincristine in extremely ill infants with low grade gliomas.
HGG-12. A CASE OF PEDIATRIC SPINAL HIGH-GRADE GLIOMA WITH NTRK1 GENE FUSION
Authors: Morisako Tamaki , Umebayashi Daisuke , Kamata Kazuaki , Yamamoto Hiroyuki , Yamanaka Takumi , Takeuchi Hayato , Takahashi Yoshinobu , Tatsuzawa Kazunori , Miyachi Mitsuru , Yagyu Shigeki , Iehara Tomoko , Hosoi Hajime , Hashimoto Naoya
Published: December 2020

INTRODUCTION

Tumors arising from the spinal cord are uncommon, especially high-grade tumors in pediatric patients. We report a case of high-grade glioma in the spinal cord harboring NTRK1 gene fusion, who received effective entrectinib therapy. CASE REPORT: A 5-year-old boy presented right hemiparesis and MR imaging revealed an intramedullary enhancing mass at the vertebral body level between C3 and Th1. He underwent microsurgical partial resection and the histological diagnosis was low-grade astrocytoma. After the first-line chemotherapy with vincristine and carboplatin, his right hemiparesis deteriorated and recurrent MR imaging showed growth of the tumor. He underwent microsurgical partial resection again and the histological examination was high-grade glioma with endothelial proliferation and necrosis. The chemoradiotherapy with temozolomide and focal irradiation of 50.4 Gy were given, and his neurological symptom slightly improved. One month later, he presented respiratory disturbance and required assisted ventilation with tracheostomy. MR imaging showed tumor progression invading upward to medulla oblongata. NTRK1 gene fusion was detected in the previous surgical specimen by a gene panel testing, and he received entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK). Since then, no tumor progression has been demonstrated for several months by MRI and he has been stable neurologically.

CONCLUSION

High-grade spinal cord tumors are rare and effective treatment strategies have not been addressed. Although the frequency of the gene fusion is very low in pediatric gliomas, identification of the driver gene aberration like in this case by a gene panel can provide potential targeted therapies for selected patients.
HGG-14. TREATMENT AND PROGNOSTIC FACTORS FOR PEDIATRIC GLIOBLASTOMAS--THE 10 YEARS EXPERIENCE FROM ONE SINGLE CENTER
Authors: Li Juan , Lai Mingyao , Hu Qingjun , Zhou Cheng , Zhou Zhaoming , Shan Changguo , Hong Weiping , Zhang Xing , Zhang Yangqiong , Luo Rishun , Wang Lichao , Lu Ming , Cai Linbo
Published: December 2020

OBJECTIVE

We retrospectively analyzed the clinical features of pediatric glioblastoma patients in our center in the past 10 years.

METHODS

From November 2009 to December 2018, patients with glioblastoma under 18 years were admitted to Guangdong Sanjiu Brain Hospital. Clinical and pathological features were summarized, and the curative effect was evaluated.

RESULTS

A total of 31 pediatric patients were enrolled. The median age is 13.8 years (range 0.8–18), including 19 males and 12 females. To Sep, 2019, the median follow-up time was 18 months(Range 4–80 months). Among them,2 were lost to follow-up,13 died, 16 still survived, and the longest survivor survived for 80 months. The median survival time was 16.4 months, the 2-year survival rate was 38%. In the prognostic factor analysis, the median survival time of patients with surgical resection ≥90% was 18 months (95% CI 15.9–20 months), and for children with resection 90% was 11 months (95% CI 9.9–12 months), P=0.027, with significantly statistically difference. Multivariate analysis showed that tumor resection rate was an independent prognostic factor for survival.

CONCLUSION

The prognosis of pediatric glioblastoma is still dismal. This study demonstrates that prognosis of such patients with GTR or near GTR is better.
HGG-16. EXOSOME-MEDIATED INTER-CLONAL INTERACTIONS IN PEDIATRIC GBM AND DIPG
Authors: Pericoli Giulia , Galardi Angela , Petrini Stefania , Giorda Ezio , Petrilli Lucia Lisa , Paolini Alessandro , Colletti Marta , De Billy Emmanuel , Pascucci Luisa , Peinado Hector , Court Will , Jones Chris , Carai Andrea , Mastronuzzi Angela , Masotti Andrea , Locatelli Franco , Giannatale Angela Di , Vinci Maria
Published: December 2020

Pediatric Glioblastoma (pGBM) and Diffuse Intrinsic Pontine Glioma (DIPG) are highly heterogeneous brain tumors which we demonstrated are comprised by distinct sub-clones interacting in a functional network. Exosomes are known to mediate the crosstalk between tumor and its microenvironment. Based on this, we aimed to investigate the role of exosomes in mediating pGBM and DIPG inter-clonal communication. By using optical barcoding for single cell-tracking, we generated two bulk multicolor patient derived-cell lines (one DIPG H3.3K27M and one pGBM histone WT) from which we obtained two and five single cell-derived clones respectively. The sub-clones demonstrated significantly phenotypic differences in terms of morphology, growth, adhesion, migration and invasion properties. In particular, co-culture experiments, with the two most different clones for both cell-lines, confirmed the cell-cell interaction key role in driving their more aggressive phenotype. Furthermore, we found that pGBM and DIPG sub-clones release exosomes which are actively and differentially up-taken by individual clones. Analysis of the exosomal microRNAs showed a different profile between the two selected clones in each cell-line. In particular, we found a pool of five upregulated microRNAs in 1C5 clone (DIPG cell-line) strongly associated to Wnt-signaling and PI3K-AKT pathway. Similarly, a pool of five upregulated microRNAs for 5E2 clone (pGBM cell-line) were found associated with focal adhesion and PI3K-AKT pathway. Our study may provide novel therapeutic strategies by interfering with the exosome-mediated inter-clonal communication in pGBM and DIPG.
HGG-26. H3G34V MUTATION AFFECTS GENOMIC H3K36 METHYLATION IN PEDIATRIC GLIOMA
Authors: Huang Tina , Piunti Andrea , Bartom Elizabeth , Qi Jin , Hashizume Rintaro , Shilatifard Ali , Saratsis Amanda
Published: December 2020

BACKGROUND

Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas. This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase), resulting in reduced H3K36me on H3G34V nucleosomes relative to wild-type. This contributes to genomic instability and drives distinct gene expressions associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3G34V on genomic H3K36me3 enrichment in vitro.

METHODS

Doxycycline-inducible short hairpin RNA (shRNA) against H3F3A was delivered via lentivirus to established H3G34V mutant pediatric glioma cell line KNS42, and H3G34V introduced into H3.3 wild type normal human astrocytes (NHA). Transfections were confirmed by western blot, fluorescent imaging, and flow cytometry, with resulting H3.3WT and H3K36me3 expression determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to evaluate genomic enrichment.

RESULTS

Complete knockdown of H3G34V was achieved with DOX-induced shRNA, with no change in total H3.3, suggesting disproportionate allelic frequency of genes encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone impacts observed H3K36me3 levels. Distinct H3K36me3 genomic enrichment was observed with H3G34V knock-in.

CONCLUSIONS

We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant pediatric glioma cells and H3G34V mutation transduction in wild-type astrocytes affects H3K36me3 expression. Further evaluation by ChIP-Seq analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with H3G34V transduction, is currently underway.
HGG-35. PEDIATRIC PLEOMORPHIC XANTHOASTROCYTOMA WITH ANAPLASIA TREATED WITH SURGERY AND ADJUVANT CHEMOTHERAPY: A CASE SERIES OF 3 LONG-TERM SURVIVORS
Authors: Ronsley Rebecca , Dunham Christopher , Yip Stephen , Hukin Juliette , Cheng Sylvia
Published: December 2020

OBJECTIVE

Pleomorphic xanthoastrocytoma (PXA) with anaplasia is a rare histological subtype of central nervous system astrocytoma and generally treated as high grade gliomas. The optimal extent of therapy required is unknown. Here we report on 3 pediatric cases of PXA with anaplasia. We also describe molecular features and methylation profile of PXA with anaplasia compared to age-matched PXA without anaplasia.

METHODS

Our institutional database was queried for cases of PXA since 1998 and 3 cases with anaplasia were identified and records reviewed.

RESULTS

2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of PXA with anaplasia was made. Immunohistochemistry demonstrated that two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation. All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients received concurrent temozolamide with radiation followed by maintenance chemotherapy with temozolamide and lomustine for 6 cycles as per the Children’s Oncology Group Protocol ACNS0423. These two patients had a continued complete response. The third patient received temozolamide following radiation and subsequently had recurrent disease at the end of treatment and went on to have a re-resection GTR and achieved complete response after 6 cycles of lomustine, vincristine and procarbazine. All are alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%).

CONCLUSIONS

This rare pediatric tumor is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.
HGG-37. PAEDIATRIC GLIOBLASTOMA CELLS SHOW CRITICAL DEPENDENCIES ON EPIGENOMIC AND EPITRANSCRIPTOMIC CONTROL OF GENE EXPRESSION BY H3.3G34R/V MUTATIONS
Authors: Bjerke Lynn , Mackay Alan , Rogers Rebecca , Grabovska Yura , Molinari Valeria , Temelso Sara , Cole Kristina , Waanders Angela , Carcaboso Angel Montero , Vinci Maria , Jones Chris
Published: December 2020

H3.3G34R/V mutations are restricted to glioblastomas of the cerebral hemispheres, and occur predominantly in adolescents and young adults. We had previously shown these mutations to result in a global re-organisation of the activating mark H3K36me3 to drive transcription of key developmental transcription factors and oncogenes such as MYCN, however the precise mechanism was unclear. Using multiple H3G34R/V samples and ChIP-seq with antibodies specific to both wild-type and mutant histone H3.3, we show a high degree of incorporation of mutant histone into nucleosomes, with only a minority (<15%) remaining wild-type only. Heterogenous G34-mutant nucleosomes displayed significantly elevated H3K36me3 binding, the majority apparently in trans to the mutation on the wild-type H3.3, and expression signatures associated with chromatin modification, cell cycle progression, DNA repair and gene transcription. Super-enhancer analysis by H3K27ac ChIP-Seq highlighted lineage-dependent transcription factors and previously identified targets MYCN and NOTCH1 (both stabilised by FBXW7, down-regulated by loss of chromosome 4q), as well as specific H3K36 lysine demethylases and splicing factors. Whole-genome CRISPR-Cas9 screening of patient-derived H3.3G34R/V cells identified critical dependencies on these latter targets, in addition to a general essentiality for genes involved in RNA processing. Assessment of RNA methylation by MeRIP-seq revealed a strong concordance of m6A-modified RNA and H3K36me3 binding, with differentially modified transcripts in mutant cellsassociated with the 3’-UTR but also the promoter and gene bodies. These data highlight the critical nature of the epitranscriptome in H3.3G34R/V-mutant paediatric glioblastoma, and highlight novel targets for therapeutic intervention.
HGG-39. CLINICAL CHARACTERISTICS AND OUTCOME OF PATIENTS WITH RADIATION-INDUCED GLIOMA
Authors: Ohno Makoto , Miyakita Yasuji , Takahashi Masamichi , Ohmura Takaki , Satomi Natsuko , Tamura Yukie , Matsushita Yuko , Ichimura Koichi , Narita Yoshitaka
Published: December 2020

The development of gliomas subsequent to therapeutic cranial irradiation is a rare but serious complication. The purpose of this study is to understand the clinical characteristics and outcome of patients with radiation-induced glioma (RIG). Between 2001 and 2018, we identified 10 patients with RIG, which satisfied the Cahan’s criteria in our data base. There was no sex predominance (M: 5, F: 5), and the median age of the primary diseased was 13.5 years (range: 1–39). The primary diseases included 2 germinoma, 2 acute lymphoblastic lymphoma, 2 medulloblastoma, 1 diffuse astrocytoma, 1 pilocytic astrocytoma, 1 pituitary adenoma and 1 metastatic tumor from lung cancer. All the patients received cranial radiation (range: 12–60 Gy). The median latency time between primary disease and RIG was 16 years (range: 9–30 years), which was not correlated with age at the time of primary disease (r2= 0.014, p=0.74). Radiation-induced gliomas included 8 glioblastoma and 2 grade III glioma based on histological diagnosis. After surgical removal or biopsy of the RIG, 4 patients underwent chemotherapy alone (nimustine, temozolomide (TMZ), carboplatin and etoposide), and 6 received chemotherapy (nimustine, TMZ, bevacizumab) combined with radiotherapy (range: 40-66Gy). The median progression free survival and survival time from RIG were 10.1 and 27.5 months, respectively. In summary, RIG may occur many years after successful initial treatment using radiotherapy, and the outcome of our patients with RIG supports the use of radiotherapy and/or chemotherapy after surgical resection.
HGG-45. PROTEOMIC ANALYSIS OF PEDIATRIC DIFFUSE ASTROCYTOMAS YIELDS PATHWAYS ASSOCIATED WITH BOTH PROGRESSION-FREE AND OVERALL SURVIVAL
Authors: Sells Blake , Fleming Jessica , Graham Richard , McElroy Joseph , Haque Jahar , Boué Daniel , Becker Aline , Bell Erica , Finlay Jonathan , Chakravarti Arnab
Published: December 2020

Brain tumors are now responsible for more deaths each year than any other childhood cancer. Current studies aim to discover key molecular drivers that can explain prognosis and serve as targets for new therapeutic approaches, reducing morbidity. In this study, we performed LC-MS/MS proteomics on a cohort of 28 primary diffuse astrocytoma formalin-fixed paraffin embedded samples (WHO Grades II-IV) from patients at Nationwide Children’s Hospital with a median follow-up time of 2.3 (0.6–20.2) years. Ingenuity Pathway Analysis was used to analyze the proteomic data after using both age and grade as covariates and only including proteins with p-values less than 0.05. The upregulation of a well-known oncogenic pathway, the Protein Kinase A signaling pathway, was significantly associated with greater risk of progression and death (P=5.5E-07 and P=4.6E-04). Integrin signaling, a pathway commonly suppressed in cancer, was similarly downregulated in those with greater risk of progression and death (P=3.3E-04 and P=1.7E-07). A global upstream analysis of the proteomic data also predicted activation of the oncogene MYCN in those who performed poorly, supporting previous studies. When comparing grade II (n=10) to grade III (n=8) and IV (n=10) primary tumors, the pathway most upregulated in higher histopathological grades was EIF2 Signaling (P=4.9E-49). This pathway has previously been associated with resistance in adult glioblastoma. These pathways, and the proteins detected within, may provide novel means by which to better understand and treat pediatric diffuse gliomas. Ongoing studies are in progress to understand how these pathways drive aggressiveness and differ from adult astrocytomas.
HGG-49. A PEDIATRIC THALAMIC HIGH-GRADE GLIOMA WITH H3F3A K27M AND BRAF V600E DOUBLE MUTATIONS
Authors: Terashima Keita , Sugawa Masahiro , Sakamoto Kenichi , Kiyotani Chikako , Osumi Tomoo , Shioda Yoko , Deguchi Takao , Kato Motohiro , Tomizawa Daisuke , Usami Kenichi , Ogiwara Hideki , Tsutsumi Yoshiyuki , Fuji Hiroshi , Nakano Noriyuki , Yoshioka Takako , Nakano Yoshiko , Ichimura Koichi , Matsumoto Kimikazu
Published: December 2020

CASE

A 18-month-old boy presented with approximately 2 months history of progressive left hemiparesis and left exotropia. MRI study showed a 3–4 cm T1-iso, T2-high tumor at right thalamus to midbrain with little contrast enhancement. The patient underwent endoscopic biopsy of the tumor, which showed relatively dense proliferation of small cells with round nuclei, mitosis of the tumor cell, but no necrosis. Immunohistochemical showed positive stain of GFAP and Olig2. Ki-67 was 34%. The histopathological diagnosis was compatible with high grade glioma. Chemotherapy with vincristine, cyclophosphamide, cisplatin and etoposide was initiated. Molecular testing of the tumor revealed H3F3A K27M and BRAF V600E double mutations in DNA from frozen tumor tissue.

DISCUSSION

The concurrent mutation of H3F3A K27M and BRAF V600E in pediatric glioma is very rare, but there are several cases previously reported in literature. Interestingly those cases are heterogenous in age, location, histopathological subtypes and clinical outcome.
HGG-53. PROJECT HOPE: “PEDIATRIC AND AYA HIGH-GRADE GLIOMA OMICS PROJECT”- A LONGITUDINAL MOLECULAR LANDSCAPE OF HIGH-GRADE GLIOMAS RESOLVED AT SINGLE-CELL LEVEL
Authors: Hack Olivia A , Babikir Husam , Jiang Li , Shamardani Karin , Liu Ilon , Shaw McKenzie , Cunliffe-Koehler Kennedy , Resnick Adam , Prados Michael , Monje Michelle , Diaz Aaron , Filbin Mariella G
Published: December 2020

High-grade gliomas (HGG) are among the most prevalent and fatal cancers in pediatric, adolescent, and young adult (AYA) patients. Especially understudied are older children and young adults, aged 16–39 years. Previously, we profiled primary pediatric HGGs through single-cell transcriptomics and identified the genetic, epigenetic and developmental programs that drive their malignant progression. However, the questions of how these programs compare to those in older HGG patients, what the mechanisms are by which these tumors ultimately evolve to drive recurrence and treatment resistance, and how distinct tumor cell subpopulations bidirectionally communicate with their microenvironment remain to be elucidated. Here, we use single-nucleus RNA sequencing to compare 11 paired, matched high-grade gliomas at diagnosis and recurrence and 15 additional H3K27M primary and recurrent DMG samples in pediatric and AYA patients. In all tumors, we find both undifferentiated and differentiated tumor cells recapitulating distinct glial lineages, as well as diverse microenvironmental cell populations. When longitudinally comparing this tumor architecture within matched pairs, we find substantial differences in transcriptional program expressions. Diagnostic samples include more differentiated, astrocyte-like tumor cells, while cells from recurrent samples more highly express ribosomal and heat-shock protein genes, suggesting tumor progression- and treatment-related shifts. Ongoing sequencing and analysis will allow for unprecedented insight into the evolutionary dynamics of pediatric and AYA high-grade gliomas as well as delineate differences in the biology of DMGs occurring in different age groups. This multi-institutional project was funded by the National Institute of Health.
HGG-54. HISTOLOGICAL AND MOLECULAR CHARACTERIZATION OF HIGH-GRADE BRAIN TUMORS SECONDARY TO TOTAL BODY IRRADIATION FOR HEMATOLOGICAL MALIGNANCIES
Authors: Miele Evelina , Pagliara Daria , Pedace Lucia , Camassei Francesca Diomedi , Cacchione Antonella , Colafati Giovanna Stefania , Carai Andrea , Locatelli Franco , Mastronuzzi Angela
Published: December 2020

INTRODUCTION

Hematopoietic stem cell transplantation (HSCT) is increasingly used in the treatment of acute leukemias (AL), non-Hodgkin lymphomas and other primary malignancies. However, a growing number of neoplasms secondary to HSCT are reported. The combination of total body irradiation (TBI) and high dose chemotherapy (HD-CT) as conditioning regimen is considered a risk factor. We present four children who survived AL, treated with HSCT and conditioning regimens including TBI/HD-CT. These patients developed a high-grade-brain tumor. We analyzed histological and molecular characteristics of neoplasms.

METHODS

Histologically, tumors were assessed for: presence of mitosis, necrosis and vascular proliferation; expression of ki67; expression of neuronal and glial markers, p53 and therapeutic targets. We analyzed the DNA methylation profile (DMP) of all tumors using IlluminaEPICarrays and compared it to the brain tumor classifier which allowed to generate the CNVs.

RESULTS

Morphologically two cases were defined as anaplastic astrocytoma, two cases as glioblastoma. Based on the DMP, all cases were found to belong to the methylation class “glioblastoma, IDH wildtype, subclass midline”, hypermutants, with gain of chromosome 1q and loss of 1p. Two cases showed PDGFRA amplification. All patients were treated with Temozolomide combination therapy +/- Bevacizumab and radiation therapy. At progression three patients were treated with checkpoint inhibitors.

CONCLUSIONS

The improvement of the precision medicine is fundamental in the therapeutic decision of brain tumors and even more in neoplasms secondary to antiblastic treatments. DMP and CNV have proven to be useful tools to complement the histological characterization of the reported cases.