bluuebunny/crossref_metadata_2025 huggingface dataset:
EPEN-34. THE CRISPR-Cas9 SYSTEM-MEDIATED ENDOGENOUS GENE REARRANGEMENT INDUCED C11orf95-RELA FUSION IN VITRO AND IN VIVO THAT LED TO THE DEVELOPMENT OF EPENDYMOMA-LIKE TUMOR
Authors: Takadera Mutsumi , Ozawa Tatsuya , Satomi Kaishi , Yamamoto Tetsuya , Ichimura Koichi
Published: December 2020

Recent large-scale genomic studies of ependymal tumors have identified recurrent RELA and YAP1 fusion genes in supratentorial ependymomas. The formation of the C11orf95-RELA fusion gene has been attributed to massive genomic rearrangement involving chromosome 11q termed Chromothripsis in many cases. However, the causal relationship has not been clarified experimentally. In this study, we developed a system to reproduce the oncogenic gene rearrangement using the CRISPR-Cas9 system and examined whether consequent endogenous ependymoma fusion genes are competent to form brain tumors in mice. Initially, to investigate whether C11orf95-RELA fusion can be formed by inducing the relevant gene rearrangement in vitro, we designed multiple guide RNAs on the human and mouse genomic loci and introduced them into cultured cells. RT-PCR and immunoblot analyses detected endogenous C11orf95-RELA fusion transcript and protein in both human and mouse cultured cells. Subsequently, we lentivirally introduced the gRNAs into a mouse brain. Brain tumor formation was observed from around 2 months after the lentivirus injection, thus indicating successful gene rearrangement followed by C11orf95-RELA fusion expression in vivo. Analysis of the tumor tissue confirmed the expression of the endogenous C11orf95-RELA fusion gene. These results suggested that a gene rearrangement is a primary mechanism to form the C11orf95-RELA fusion which is the direct driver of tumorigenesis. Our system to simulate a genomic event will provide significant insights into the understanding of the tumorigenic mechanism in ependymomas.
EPEN-39. CLINICAL STRATIFIED TREATMENT OF LOCALIZED PEDIATRIC INTRACRANIAL EPENDYMOMA WITH COMBINED LOCAL IRRADIATION AND CHEMOTHERAPY WITHIN THE PROSPECTIVE, MULTICENTER E-HIT TRIAL – THE MOLECULAR SUBGROUP MATTERS
Authors: von Hoff Katja , Obrecht Denise , Wening Janna , Mynarek Martin , Gerber Nicolas U , Benesch Martin , Juhnke B - Ole , Bison Brigitte , Warmuth-Metz Monika , Timmermann Beate , Faldum Andreas , Schüller Ulrich , Pfister Stefan M , Kool Marcel , Pietsch Torsten , Kortmann Rolf-D , Kwiecien Robert , Pajtler Kristian W , Witt Hendrik , Rutkowski Stefan
Published: December 2020

BACKGROUND

Pediatric ependymoma is a heterogenous disease. Subgroup-specific clinical information on prospectively treated patients will help to improve treatment stratification.

METHODS

Within the population based, prospective, multicenter E-HIT-trial (2001–2011) patients with localized ependymoma confirmed by neuropathological central-review, received hyperfractionated local radiotherapy (68Gy, 2x1Gy/day) followed by chemotherapy (stratum-A), or chemotherapy followed by local radiotherapy (54Gy, 1.8Gy/day) (children < 4years, stratum-B), or age-adapted radiotherapy with pre-/post-irradiation chemotherapy (residual tumor, diagnosis after 2005, stratum-C). Retrospective classification of DNA-methylation was available for n=164 E-HIT-trial participants, and n=80 patients with comparable treatment and prospective registration in the subsequent HIT-interim-registry (2012–2014). FINDINGS: For 291 E-HIT-trial patients, 5-year progression-free (PFS) and overall survival (OS) were 61±3%, and 81±2%. Five-year PFS/OS after complete resection were 71±4% and 87±3% in stratum-A (n=127), and 64±5% and 86±4% in stratum-B (n=86). Outcome was poor after incomplete resection, irrespective of treatment-stratum (n=78, 5-year PFS/OS: 43±6%, 68±5%). In the pooled trial- and registry-cohort, there were 152 patients with PF-EPN-A (5-year PFS/OS: 44±4%, 77±4%), 40 of them with 1q-gain (5-year PFS/OS: 28±7%, 66±8%), 21 with PF-EPN-B (5-year PFS/OS: 90±7%, 100%), 59 with ST-EPN-RELA (5-year PFS/OS: 63±7%, 87±5%), and 4 with ST-EPN-YAP1 (2 progression/relapse, no death).

CONCLUSION

Outcome differed between molecular subgroups and insufficient survival rates were achieved for patients with PF-EPN-A with 1q-gain, despite combined radio- and chemotherapy treatment. Treatment reduction in the context of a clinical trial may be considered for PF-EPN-B.
EPEN-43. TARGETING INTRA-TUMOUR HETEROGENEITY IN PAEDIATRIC EPENDYMOMA: AN INTEGRATED OMICS STUDY TOWARDS PATIENT-TAILORED THERAPY
Authors: Pandele Alina , Woodward Alison , MacArthur Donald , Kamaly-Asl Ian , Barrett David A , Grundy Richard G , Kim Dong-Hyun , Rahman Ruman
Published: December 2020

Ependymoma (EPN) is the second most common malignant paediatric brain tumour, which despite extensive genomic sequencing, no novel therapeutic options have been discovered. Multi-omics are anticipated to reveal dysregulated pathways that may be predictive of patient-specific biomarkers. Given the close association between gene expression, active biochemical signaling and metabolism, there is an unmet scientific challenge to determine whether EPN gene expression correlates with aberrant metabolic pathways, thus presenting therapeutic vulnerabilities. We first compared two distinct subgroups of EPN, PF-A and ST-RELA, identifying 115 metabolites and 1580 upregulated genes between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. We next integrated transcriptomics and metabolomics, comparing 28 intra-tumour tissue regions from eight primary PF-A EPN patients. Polar metabolites and RNA were simultaneously extracted from the same population of cells. RNAseq identified dysregulated genes and liquid chromatography-mass spectrometry (LC-MS) detected 98 significantly altered metabolites between 18 multi-regions, the majority mapping onto the arginine and proline pathways. Integration of genes and metabolites using pathway-based network analysis revealed 124 aberrant gene-metabolite interactions between intra-tumour regions, with large numbers occurring in the glucogenesis and glycine metabolic pathways in 6/8 patients. These may represent ubiquitous and therapeutically relevant metabolic pathways critical for EPN survival. Additionally, patients presented at least one unique intra-tumour genomic-metabolomic interaction, applicable for patient-tailored therapy. This is the first exploration of EPN multi-omic integration and intra-tumour heterogeneity. Selected drug targets predicated on aberrant gene-metabolite networks will be validated in multi-region patient-derived cell lines and orthotopic models using repurposed therapeutics.
EPEN-51. CHILDHOOD INTRACRANIAL EPENDYMOMA: A MULTI-CENTER RETROSPECTIVE ANALYSIS
Authors: Pickle Emily Owens , Aguilar-Bonilla Ana , Khallouq Bertha Ben , Stapleton Stacie , Sandler Eric , Langevin Anne-Marie , Libes Jamie , Hanif Iftikhar , Smith Amy
Published: December 2020

Ependymoma is a heterogeneous disease which is resistant to improvement. Current challenges are the unreliability of histologic classification, the uncertain role of adjuvant chemotherapy, and a lack of clinical trials integrating molecular and clinical diagnostics into risk-guided therapy. Ependymoma can show surprising latency, reoccurring many years after the original diagnosis. In this study, we performed a retrospective analysis of ependymoma cases treated at six centers over a period of 12 years. A total of 73 cases were submitted from six sites; 68 cases were retained for review. Median age at diagnosis was 4.1 years and gender was reported as male (50%) and female (50%). Histologic grade was reported as Grade II (49%) and Grade III (50%)(not reported: 1). Anatomic location reported as supratentorial (27%) and infratentorial (73%). Metastatic disease was reported in 9% of patients. At diagnosis, gross total resection was achieved in 59% of cases. Twenty-eight percent of patients have died, 59% of patients are alive (with and without disease), and 13% of patients are lost to follow-up. Maximal safe surgical resection is currently the best predictor of long-term survival but was achieved in only 60% of cases. Biology-based therapy will be the next step towards improving the prognosis of pediatric ependymoma.
EPID-01. TRENDS OF INCIDENCE IN PEDIATRIC BRAIN TUMORS IN KUMAMOTO PREFECTURE, JAPAN
Authors: Itoyama Takashi , Shinojima Naoki , Yamamoto Takahiro , Fujimoto Kenji , Makino Keishi , Mukasa Akitake
Published: December 2020

BACKGROUND/PURPOSE

One of the most problematic issues Japan has is a declining birthrate resulting in an aging society. There are some reports on the trends of incidence in brain tumors in the elderly, whereas few reports on those in the children. The aim of this study is to investigate the trends of incidence in childhood primary brain tumors.

METHODS

The population of children aged <15 years was available from Kumamoto Prefecture’s annual census between 1990 and 2017. During the period 301 childhood primary brain tumors (124 gliomas, including astrocytic tumors and ependymomas, 35 embryonal tumors, 34 germ cell tumors, 22 craniopharyngioma, and 86 others) were registered with the Kumamoto Brain Tumor Data Bank, and investigated.

RESULTS

The average of the annual incidence rate per 100,000 child populations was 3.90 for total brain tumors, 1.63 for gliomas, 0.44 for embryonal tumors, 0.42 for germ cell tumors, 0.26 for craniopharyngioma, and 1.15 for others. Divided into the first half from 1990 to 2003 and the second half from 2004 to 2017, there was no significant difference in the incidence of brain tumors aged <15 years between the two periods. However, the average of the annual incidence rate/100,000 child populations was 3.02 in the first half, while significantly increased in the second half of 4.78 (p=0.00075, t-test). DISCUSSION &

CONCLUSIONS

The average number of children aged <15 years in Kumamoto Prefecture was 31,2737.9 from 1990 to 2003, while decreased remarkably to 251460.2 from 2004 to 2017. A decrease in the number of children may affect increasing the incidence rate of pediatric brain tumors.
EPID-06. DIAGNOSTIC INTERVAL TIME OF PEDIATRIC CNS TUMORS: A REPORT OF THE CANCER IN YOUNG PEOPLE IN CANADA (CYP-C) DATABASE
Authors: AlNajjar Mohammad , Goel Divya , Larouche Valerie , Erker Craig , Cheng Sylvia , Barber Randy , Strother Douglas , Sung Lillian , Lafay-Cousin Lucie
Published: December 2020

INTRODUCTION

CNS tumors are the second most common neoplasm in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors are limited and outdated. We aimed at evaluating the diagnostic interval time(DIT) for Canadian children, and identifying factors possibly associated with prolonged DIT.

METHODS

Using the CYP-C database, we analyzed data from children <15 years, diagnosed with CNS tumors between 2001–2015. DIT was defined as time in weeks, elapsed from the first contact with a healthcare provider to confirming diagnosis. We described DIT according to patient’s demographics, socioeconomic, geographic factors as well as tumor-related criteria.

RESULTS

Patients from all Canadian provinces, except Ontario, had available timepoints to calculate DIT. The cohort included 842 patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas had the longest mean DIT and embryonal tumors had the shortest(14.6 and 3.6 weeks p<0.01). ATRT and medulloblastoma had a mean DIT of 1.3 and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4 versus 16.1 weeks, p<0.01). Metastatic disease, infratentorial tumors, or age £36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1 and 8.6). Sex, annual income(QAIPPE), and distance from tertiary center did not influence DIT.

CONCLUSION

The current diagnostic interval time for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These results only reflect the healthcare system’s contribution toward diagnosis confirmation, but not the patient interval before seeking medical attention.
ETMR-05. SINGLE-CELL RNA-SEQ OF ETMR REVEALS CELL PROGRAMS OF DEVELOPMENTAL HIERARCHY AND CELLULAR DIVERSITY IN THE TUMOR MICROENVIRONMENT
Authors: de Faria Flavia W , Interlandi Marta , Moreno Natalia , Graf Monika , Melcher Viktoria , Albert Thomas K , Kerl Kornelius
Published: December 2020

Embryonal tumors with multilayered rosettes (ETMR) are deadly brain malignancies affecting young children. No standard treatment is available and the median survival is less than 12 months. Molecularly, the disease is characterized by the miRNA C19MC cluster amplification, with the expression of multiples miRNAs related to a stem cell program. The discoveries on the purely molecular mechanisms of the disease did not help to create a bridge for new treatment strategies so far and the cellular diversity of ETMR remains poorly understood. In this study, we used single-cell RNA sequencing of murine and human tumors to describe ETMR cellular heterogeneity. Our findings support that intra-tumoral heterogeneity is mainly characterized by 4 cellular programs defining a developmental hierarchy related to different metabolic states: 1) Early quiescent NSC-like cells supported by fatty-acid oxidation 2) Late NSC and NP-like proliferative cells fueled by glycolytic metabolism; 3) Post-mitotic neuroblast-like cells, relying on oxidative-phosphorylation; 4) NSC-like proliferative cells, with metabolic plasticity and capable of performing the three types of metabolism. Tumor-specific ligand-receptor interaction analysis revealed that ETMR exchange with microglia and vascular mural cells (MC) signals related to extracellular matrix (ECM) organization (Cxcl12-CxCr4), stem cell signaling (BMPs-BMP receptors), anti-apoptosis and survival (Ntf3-Ntrk), not seen in the control brain. In addition, the vascular MC showed a cancer-associated fibroblast (CAF) phenotype, with potential prognostic implications, as previously demonstrated for other tumors. This study provides new findings to build up a more robust understanding of ETMR biology and opens space for further studies in the field.
ETMR-07. ETANTR: A RARE TUMOR IN A RESOURCE-LIMITED SETTING
Authors: Hoveyan Julieta , Avagyan Manushak , Avagyan Anna , Papyan Ruzanna , Iskanyan Samvel , Danielyan Samvel , Hovhannisyan Garik , Khachatryan Parandzem , Tamamyan Gevorg , Bardakhchyan Samvel
Published: December 2020

INTRODUCTION

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare aggressive brain tumor with low survival rates. There are about 80 cases reported in literature since 2000 when it was first described. There is no standard treatment scheme for ETANTR yet. CASE REPORT: A 2 years old boy presented with a month-long of headache and inability to hold his head. CT scan and MRI revealed a large mass in the right frontal lobe with midline shift. Subtotal tumor resection was done. Histological and immunohistochemical analyses was consistent with ETANTR in one laboratory and PNET in another. The second opinion suggested by the Center of Pediatric Oncology, Hematology and Immunology in Moscow the diagnosis ETANTR was confirmed. Taking into account certain similarities with medulloblastoma was decided to provide treatment according to HIT-2014 protocol. Control MRI done after 2 cycles of Block SKK Carboplatin/Etoposide found tumor progression and for that reason patient underwent second surgical resection. Considering the age of the child radiation therapy was not expedient and the decision was to continue treatment with HIT 2014 intensified regimen, which includes Cisplatin, Vincristine, Etoposide, Cyclophosphamide and intravenous High dose Methotrexate with intrathecal Methotrexate. Aiming to evaluate the effectiveness of treatment we are planning to perform MRI after this 2nd cycle of intensified regimen.

DISCUSSION

There are difficulties in diagnosis of rare types of cancers in Armenia. Since there is no approved treatment for ETANTR, there is a need for ongoing research to improve its prognosis.
ETMR-08. INTERNATIONAL CONSENSUS PROTOCOL FOR EMBRYONAL TUMOR WITH MULTILAYER ROSETTES
Authors: Hanson Derek , Andre Nicolas , Chi Susan , Filbin Mariella , Fisher Michael , Hoffman Lindsey , Khatib Ziad , Kool Marcel , Narendran Aru , Pizer Barry , Slavc Irene , Vogel Timothy , Ziegler David , Kieran Mark
Published: December 2020

Embryonal tumors with multilayer rosettes (ETMR) are rare and highly-aggressive central nervous system (CNS) neoplasms which occur primarily in young children and carry a dismal prognosis. To date, no large clinical investigations have been conducted to determine the optimal therapy for ETMR. Data from retrospective case series suggest that our most aggressive standard therapies are not sufficient for cure in the majority of cases. New treatment approaches incorporating pre-clinical data and the known biology of ETMR are therefore urgently needed. A German drug screen using the patient-derived ETMR BT183 cell line and its xenograft revealed anti-tumor activity of topotecan, doxorubicin, and actinomycin D; three agents used infrequently for treating infant CNS tumors. Additional results from a small series of ETMR patients suggest that optimization of induction chemotherapy using these active agents may improve response and survival outcomes. In 2019, an international panel of pediatric neuro-oncology experts convened to advance therapy for ETMR. A consensus protocol was developed incorporating maximal safe surgical resection, induction chemotherapy with active pre-clinical agents, intrathecal chemotherapy, radiotherapy, and high-dose chemotherapy. This international consensus protocol represents the first prospective clinical investigation specific to ETMR and will be available through a treatment registry globally and as a clinical trial at select centers. The study aims to improve survival by providing aggressive, optimized therapy for ETMR and will serve as a platform to explore new biologically-promising agents. The investigation will also provide valuable prospective outcome data and correlative biological studies to serve as baseline comparators for future clinical trials.
ETMR-17. SINGLE-CELL TRANSCRIPTOME ANALYSIS OF ETMR PATIENT SAMPLES
Authors: Hovestadt Volker , Shaw McKenzie L , Beck Alexander , Lambo Sander , Hack Olivia A , Gojo Johannes , Madlener Sibylle , Mayr Lisa , Haberler Christine , Czech Thomas , Hanson Derek R , Koschmann Carl , Jabado Nada , Huang Annie A , Slavc Irene , Pfister Stefan M , Alexandrescu Sanda , Bernstein Bradley E , Kool Marcel , Filbin Mariella G
Published: December 2020

Brain tumors are comprised of cells with heterogeneous genetic and transcriptional states, resulting in substantial phenotypic diversity. This diversity is particularly evident in embryonal tumor with multilayered rosettes (ETMR), which shows a striking bi-phasic pattern for which it is named. A better understanding of its underlying molecular makeup is urgently needed to develop more effective therapeutic strategies that eliminate all malignant cell types underlying ETMR initiation, maintenance, progression, and relapse. Furthermore, the cellular origin of ETMR is currently poorly understood. We used plate-based single-cell RNA sequencing to assess the intratumoral heterogeneity in 6 fresh and 4 snap-frozen surgical biopsies, following a workflow that we have previously established to study pediatric high grade gliomas, medulloblastomas, and ependymomas. Computational analyses conducted on >4,000 single cells identified cellular hierarchies ranging from a proliferative, undifferentiated cell population to more differentiated, predominantly neural-like progeny in all samples. Patient-derived cell line and xenograft models partially recapitulated this hierarchy. We further integrated transcriptional programs identified in single cells with available datasets of the developing normal brain, as well as with programs identified in other pediatric brain tumor entities, to inform both putative cellular origins and ETMR-specific oncogenic pathways. These timely results provide unparalleled insights into the molecular underpinnings of the phenotypic heterogeneity observed in ETMR. Analyses aimed at further integrating malignant cell type abundances with genetic alterations and clinical annotations, and therapeutical targeting of malignant cell populations using in-vitro models are currently ongoing.
ETMR-19. SINGLE CELL ANALYSES OF ETMRs REVEAL THAT C19MC+ POPULATION DRIVES CELL CYCLE PROGRESSION AND STEM CELL MAINTENANCE
Authors: Mumal Iqra , Xu Liming , Yao Fupan , Suwal Tannu , Fan Xiaolian , Lu Mei , Huang Annie
Published: December 2020

Embryonal tumors with multilayered rosettes (ETMRs) are highly fatal diseases characterized by recurrent amplification of C19MC, an oncogenic miRNA cluster. While C19MC was discovered as a major driver of ETMRs, its direct role in ETMRs remains unknown. As ETMRs exhibit significant heterogeneity in C19MC expression, we employed single cell transcriptomics to investigate features of C19MC+ population. We conducted single-nuclei RNAseq of 23,269 cells from 6 primary and 2 matched recurrent ETMRs. We also conducted single-cell RNAseq of human neural stem cells (hNSC-5miR) and ETMR cell line (A664-5miR) with stable expression of 5 C19MC miRNAs. Bulk RNAseq (n=27), H3K27Ac ChiP-seq (n=5) and ATAC-seq (n=5) corroborated scRNAseq data and identified core transcription factors (TFs) of C19MC+ population. C19MC+ population (24%) mapped to neuro-epithelial cells and exhibited signatures of cell cycle and stem cell maintenance, consistent with bulk-RNAseq data. The C19MC+ population overlaps with MKI67+ cycling (57%) and PROM1+ stem cell population (56%). Interestingly, interrogation of hNSC-5mir and A664-5miR showed a larger MKI67+/PROM1+ population compared to controls. Likewise, hNSC-5miR/A664-5miR in vitro and in vivo experiments showed increased proliferation/stemness. C19MC+ population is characterized by SHH, WNT, mTOR, Hippo and IGF-signalling and driven by MEIS1, SOX11, ZNF521, RFX4 and NR2F2 TFs. Recurrent ETMRs exhibit a persistent but smaller C19MC+ population. Intriguingly, recurrent tumors were more quiescent with a smaller proliferative population. C19MC is directly involved in driving cell cycle and stemness in ETMRs. Cellular and molecular features of primary and recurrent ETMRs were remarkably different, suggesting that C19MC plays a different role upon recurrence.
GCT-02. THE LONG-TERM OUTCOMES AND SEQUELAE ANALYSIS OF INTRACRANIAL GERMINOMA FROM 187 PATIENTS IN THE SINGLE INSTITUTE: NECESSITY FOR THE ADAPTATION OF RADIOTHERAPY DOSE AND VOLUME
Authors: Lee Joo Ho , Kim Il Han , Eom Keun-Yong , Kim Seung Ki , Wang Kyu-Chang , Kim Tae Min , Heo Dae Seog , Kang Hyoung Jin , Shin Hee Young
Published: December 2020

PURPOSE

We aimed to refine the radiotherapy (RT) volume and dose determinant for disease failures and long-term sequelae in the intracranial germinoma.

METHODS

The main treatment for intracranial germinoma was craniospinal RT only (n=51) during 1981–1992 and RT with upfront chemotherapy (CRT) (n=152) during 1992–2015 in Seoul National University Hospital. All 187 cases were confirmed histologically. RT fields included craniospinal, whole-ventricle (WV), whole-brain (WB), and focal radiotherapy. RT dose was dependent on the M status and combination of chemotherapy. The median follow-up duration was 115 months (range, 3–358).

RESULTS

The 10-year overall and recurrence-free survival was 94.5% and 91.4%. The complete response rate after chemotherapy was 62.6%. For the patients with complete response, WV RT 16–20 Gy, and focal boost of 25–36 Gy after upfront chemotherapy showed no in-field recurrence. The causes of death were progression (n=3), 2nd malignancy (n=6), treatment-related complications (n=7), and others (n=8). For non-sellar tumors, the rate of hormonal replacement treatment was significantly related to WB RT and WB/WV RT dose ≥ 30 Gy (p=.030, and .026). After a latency of the median 20 years, ten patients (5.3%) developed 2nd malignancy. WB RT and WB/WV dose ≥ 30 Gy were significantly correlated with the 2nd malignancy (p=.024, and .004). The rate of severe neurocognitive dysfunction was significantly associated with WB/WV dose ≥ 30 Gy (p=.027).

CONCLUSION: CONCLUSION

RT with or without upfront chemotherapy exhibits the excellent control rate of disease. However, the intensity and volume of RT are critical for managing treatment toxicities. Adaptation and further de-intensification of RT should be followed.
GCT-09. HEALTH AND SOCIAL ISSUES IN THE LONG-TERM GERM-CELL TUMOR SURVIVORS
Authors: Matsutani Tomoo , Horiguchi Kentaro , Ikegami Shiro , Hirono Seiichiro , Murai Hisayuki , Saeki Naokatsu , Iwadate Yasuo
Published: December 2020

Germ cell tumor (GCT) is a rare juvenile CNS tumor that is more frequent in eastern Asia. Most survivors require continuous medical care for hormone replacement, maintenance of shunting devices, and late radiation-induced effects. In the present study, we retrospectively analyzed medical records of long-term GCT survivors, and make the health and social issues clear. Ninety-two GCT patients were treated in our institute from 1982 to 2018, and 81 patients, of which medical records are available, are included. The median follow-up period is 12.2 years, and 47 patients (58.1%) are followed for more than ten years. The overall survival rate is gradually decreasing more than ten years follow-up, such as 10-, 15- and 25-years survival are 92.3, 87.7, and 73.3%, respectively. In the long-term follow-up, eight subsequent malignancy and seven cerebrovascular events are recorded. These events occurred 20 years or more after the treatments, and six CNS malignancies were observed in survivors irradiated with 50Gy or more. As social issues, forty-two of 50 adult survivors had been employed after the treatments, but only thirty-four (70.8%) are still working. Of note, only nine (18.8% of adults) survivors got married. All four married women require any hormone replacement, while only one of 4 men requires the replacement. Long-term follow-up of GCT survivors revealed subsequent malignancy and social problems. A recent attempt to decrease the dose of irradiation might overcome some issues. As a conclusion, GCT survivors require a supporting program for not only health but also social issues.
GCT-12. INTRACRANIAL GROWING TERATOMA SYNDROME: CLINICAL IMPLICATION FROM SINGLE UNIVERSITY EXPERIENCES
Authors: Kim Chae-Yong , Kwon Ji-Yeon , Go Kyeong-O , Hwang Kihwan , Han Jung Ho , Choi Hyoung Soo , Kim You Jung , Choi Byung Se , Kim In Ah , Choe Gheeyoung , Kim Seung-Ki , Phi Ji Hoon , Wang Kyu-Chang , Cho Byung-Kyu
Published: December 2020

In general, intracranial germ cell tumors (GCT) are sensitive to chemotherapy, radiation therapy, and have favorable outcomes. However, a rare chemotherapeutic retro conversion phenomenon, known as intracranial growing teratoma syndrome (iGTS), shown a poorer prognosis. We analyze the diagnostic characteristics and the result of treatment response for the patients with iGTS treated in our institutes (SNUH and SNUBH, from 1997 to 2019). The electronic medical records and PACS were used for reviewing the clinical information, follow-up MRI images, tumor markers (alpha-fetoprotein, human chorionic gonadotropin, in serum or cerebrospinal fluids), and pathological findings. Out of 328 intracranial GCT patients, seventeen were finally identified as iGTS. Sixteen out of 17 patients were non-germinomatous GCTs, and 1 were germinomas. Initial pathology was common in order of immature teratoma (26.7%), other than immature teratoma (11.5%), and germinoma (0.5%). All of the tumors showed typical ‘honeycomb appearance’ in their follow-up MRI images. Sixteen out of 17 tumors were surgically resected as 2nd look surgery. Among them, 13 tumors were gross totally resected. Twelve were alive without evidence of recurrences during follow-up periods, and the other was dead from the progression of the disease. Among the other than the gross total resection group (n=4), two patients were dead, one recurred the tumor, and the other is following up with stable disease after adjuvant radiation therapy. Early detection and total resection of the tumor as possible might be meaningful for favor prognosis, especially in non-germinomatous GCTs patients.
GCT-24. RELAPSE PATTERN AND QUALITY OF LIFE IN PATIENTS WITH LOCALIZED GERMINOMA ORIGINATING FROM BASAL GANGLIA REGION
Authors: Li Bo
Published: December 2020

BACKGROUND

The optimal radiation field in localized basal ganglia (BG) germinoma was not well defined, mostly due to unknown relapse patterns. In our institute, both focal radiotherapy (FR) and craniospinal irradiation (CSI) plus boost were considered in this population until whole-brain radiotherapy (WBRT) plus boost became an option in 2008. Thus, a retrospective study was conducted to address the issue. Furthermore, the health-related quality of life (HRQOL) was also evaluated.

METHODS

Patients who were diagnosed as localized BG germinoma between 2000 and 2017 were studied. HRQOL was evaluated by PedsQL 4.0 (≤15 years) and SF-36 (>15 years) questionnaires based on the age at last follow-up.

RESULTS

Among 161 patients included, 35 patients received FR, 109 patients received WBRT plus boost, and 17 patients received CSI plus boost. After a median follow-up of 83 months (range, 13 to 214 months), 15 patients relapsed in FR group, 4 in WBRT group and 0 in CSI group. The 5-year DFS was 74.3%, 97.2%, and 100%, respectively (p<0.001). Among 15 patients who relapsed after FR, 14 had positive radiological findings, in which 6 (42.8%) had lesions documented at the periventricular area, and 7 (50.0%) in the frontal lobe. HRQOL data were available in 69 patients, which generally scored low. In 38 patients evaluated by SF-36, those receiving CSI had significantly lower mental component scores than those receiving WBRT (p=0.027) or FR (p=0.011).

CONCLUSIONS

Patients with localized BG germinoma present a unique relapse pattern. WBRT, which covers at-risk areas, showed both better disease control and HRQOL.
GCT-26. PROGNOSTIC FACTORS IN PATIENTS WITH BASAL GANGLIA GERM-CELL TUMORS: A RETROSPECTIVE ANALYSIS OF THE SINGLE CHINESE INSTITUTE EXPERIENCE FROM 2009 TO 2019
Authors: Hu Qingjun , Li Juan , Lai Mingyao , Zhou Cheng , Zhou Zhaoming , Shan Changguo , Hong Weiping , Zhang Yangqiong , Wang Lichao , Cai Linbo
Published: December 2020

OBJECTIVE

To evaluate the clinical factors related to the prognosis of basal ganglia germ cell tumors.

METHODS

A retrospective analysis of 52 cases of the basal ganglia germ cell tumors treated from January 2009 to January 2019 in the department of oncology of Guangdong Sanjiu Brain Hospital. The median age: 12 years (range: 5–32), The median course of disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were 31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%) with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed.

RESULTS

To October 15, 2019, the median follow-up time was 30.4 months (range 2–124 months). The 5-year survival rate was 85%, and the 5-year progression-free survival rate was 84%. Multivariate analysis found whether serum AFP was greater than 100mIU / ml, (with HR: 11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(with HR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR: 16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival.

CONCLUSION

The pathological type, degree of surgical resection, and response to initial treatment can all affect survival.
GCT-35. SALVAGE CRANIOSPINAL IRRADIATION FOR RECURRENT GERMINOMAS
Authors: Kanamori Masayuki , Saito Ryuta , Sonoda Yukihiko , Kumabe Toshihiro , Tominaga Teiji
Published: December 2020

BACKGROUND

The treatment strategies for recurrence has not been established.

PURPOSE

To clarify the tumor control and complications of salvage craniospinal irradiation (CSI) for recurrent germinoma.

METHODS

We retrospectively reviewed the medical record. Among 153 germinomas treated in Tohoku University Hospital since 1983, 22 had recurrence of germinoma. At first recurrence, 7 cases received CSI, whereas 15 cases did chemotherapy and/or radiation therapy other than craniospinal field (non- CSI). CSI was performed at 24 Gy/ 12 fractions or 30 Gy/ 25 fractions.

RESULTS

CSI had statistically significant better recurrence-free survival rate after recurrence than non-CSI (100% vs 33%, p<0.001: log-rank test). In addition, tumor control was obtained in all of four cases with the failure after non- CSI treatments for recurrence. The late complications of these 11 cases were examined. The local dose before CSI was 24- 50 Gy, and the median interval from last irradiation to CSI was 33 months. Median follow- up period after CSI was 126 months. Three patients developed newly developed visual or cognitive deficits. These patients received high-dose irradiation at initial treatment or multiple treatment before CSI. There were no late complications in the cases which had prior chemotherapy and 24 Gy of irradiation to whole ventricle only before CSI.

CONCLUSION

Low dose CSI for the first recurrence of germinoma is effective and safe in the cases treated by chemotherapy and low dose irradiation to whole ventricle only.
GCT-36. TREATMENT RESULTS AND RADIATION-INDUCED TUMORS IN CASES OF CENTRAL NERVOUS SYSTEM GERM CELL TUMOR: A LONG-TERM FOLLOW-UP STUDY IN KUMAMOTO PREFECTURE
Authors: Yamamoto Takahiro , Makino Keishi , Nakamura Hideo , Kuroda Jun-ichiro , Itoyama Takashi , Takezaki Tatsuya , Ota Kazutaka , Shinojima Naoki , Mukasa Akitake
Published: December 2020

INTRODUCTION

Central nervous system germ cell tumor (GCT) is one of the pediatric brain tumors. Although there have been epidemiological studies in the past, long-term prognosis and the late effects remained unclear. In this study, we examined GCT over the past 41 years in Kumamoto prefecture.

METHODS

Epidemiological features and complications with radiation-induced tumors were searched in patients diagnosed with GCT in the 41-year period from 1977 to 2018.

RESULTS

There were 93 patients diagnosed with GCT. These cases were divided into 14-year periods before and after incorporation of chemotherapy into the treatment, and the results for germinomas were compared. An improvement in the 10-year survival rate from 12 of 23 cases (52.2%) between 1977 and 1991 to 19 of 28 cases (67.9%) between 1992 and 2006 was observed. The 10-year survival rate for germinoma cases that received medical treatment during a more recent 5-year period between 2004 and 2009 increased to over 90%. However, 10.3% of all long-term survivors of GCT developed radiation-induced glioblastoma. The examination results showed that regardless of the tumor type, patients who received a high dose of radiation during their initial treatment developed the complication of radiation-induced glioblastoma within 10 to 25 years after their initial treatment.

CONCLUSION

This study suggests that the long-term survival rates for GCT are improving but the rate of radiation-induced glioblastoma in these cases are too high to be ignored. Long-term follow-up of at least 10 years is essential to effectively evaluate the details of treatment for pediatric brain tumors.
GCT-38. RELAPSE PATTERNS OF INTRACRANIAL GERMINOMAS BEFORE AND AFTER ENDOSCOPIC ERA
Authors: Tsurubuchi Takao , Takano Shingo , Muroi Ai , Hara Kei , Matsuda Masahide , Akutsu Hiroyoshi , Mizumoto Masashi , Fukushima Hiroko , Suzuki Ryoko , Yamaki Yuni , Ishikawa Eiichi , Matsumura Akira
Published: December 2020

PURPOSE

We evaluated the relapse patterns of CNS germinomas before and after introducing neuroendoscopic biopsy in 2000.

METHODS

We retrospectively assessed the relapse patterns of 57 patients treated as pure germinoma or germinoma with STGC between 1980 and 2019 at University of Tsukuba, partially containing the patients of the previous report (Takano S et al., World Neurosurg, 2015). Median age was 15 y.o.(7y.o.~38y.o.), and men was 80.7%. Tumor locations were pineal 35, sellar 19, basal ganglia 3, others 11. Group A;1980~1999 was 20, and group B;2000~2019 was 37. From 1980 to 1994, whole brain irradiation(WB) 30.6 Gy plus whole ventricle irradiation(WV) 19.8 Gy. From 1995 to 1999, WV 26~30.6 Gy with Chemotherapy(Chem) or Chem alone. Since 2000, Chem for 3 kurr with WV 24~30.6 Gy, and 6–19.8 Gy as local boost to residual lesion.

RESULTS

Follow up periods were median 121 M(4.5M~386M; group A), and median 89 M(4 M~231 M; group B). Six patients(30%) recurred in the group A, as ex field 4(1;brain and extramedullary, 1;brain and paranasal sinus, 1;LV & third ventricle, 1;extramedullary), in field 1(LV). Chem only 1(LV & third ventricle). Two patients(5.4%) recurred in the group B, as ex field 2(1;intramedullary, 1;extramedullary). The group A showed CR;18, PR;1, Dead;1(Dissemination), and the group B showed CR;35, PR;1 Dead;1(Encephalopathy).

CONCLUSION

WV and Chem prevented extrafield recurrence keeping good quality of life. Neuroendscopy biopsy with ETV did not increase CSF seeding.
GCT-43. GAIN OF SHORT ARM OF CHROMOSOME 12 IS A MOLECULAR MARKER TO PREDICT PROGNOSIS AND REPRESENTS AN EARLY EVENT IN TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMORS
Authors: Satomi Kaishi , Takami Hirokazu , Fukushima Shintaro , Nakazato Yoichi , Tanaka Shota , Saito Nobuhito , Kanamori Masayuki , Kumabe Toshihiro , Kobayashi Keiichi , Nagane Motoo , Iuchi Toshihiko , Yoshimoto Koji , Mizoguchi Masahiro , Tamura Kaoru , Maehara Taketoshi , Sakai Keiichi , Sugiyama Kazuhiko , Yokogami Kiyotaka , Takeshima Hideo , Nonaka Masahiro , Asai Akio , Nishikawa Ryo , Matsutani Masao , Ichimura Koichi
Published: December 2020

Gain of short arm of chromosome 12 (12p) is commonly observed in testicular germ cell tumors (tGCTs) and also seen in intracranial GCTs (iGCTs). However, little is known about the clinical significance of 12p gain in iGCTs. We have collected over 200 fresh frozen tissue samples of iGCTs through the Intracranial Germ Cell Tumor Genome Analysis Consortium in Japan. Firstly, we analyzed DNA methylation profile in 83 iGCTs, 3 tGCTs (seminomas) and 6 normal control samples using Infinium Human Methylation 450K BeadChip array (Illumina, CA, USA) in order to determine 12p gain status. Then, fluorescence in situ hybridization (FISH) study was carried out on 3 mixed iGCT cases using 12p/CEP12 probe (Abbott Molecular, Abbott park, IL, USA). Lastly, 58 iGCTs with clinicopathological information were analyzed for progression-free survival (PFS) and overall survival (OS). Gain of 12p was observed in 100% (3/3) of seminoma, 14% (3/22) of germinoma, 17% (1/6) of mature teratoma, 25% (1/4) of immature teratoma, 55% (11/20) of mixed germ cell tumor, 100% (4/4) of yolk sac tumor, 100% (1/1) of embryonal carcinoma, and 100% (1/1) of choriocarcinoma. In total, 45% (37/83) of iGCT showed 12p gain. Different histological components in each mixed GCT shared the same 12p copy number status within each mixed GCT case. Both PFS and OS were significantly worse in iGCTs with 12p gain (PFS: P=0.027, OS: P=0.0012). Gain of 12p can be a molecular marker to predict prognosis and represents an early event in tumorigenesis prior to histological differentiation in iGCTs.
GCT-46. MULTI-KINASE INHIBITORS AS NOVEL THERAPEUTIC AGENTS AGAINST INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Uchida Eita , Ozawa Tatsuya , Takahashi Masamichi , Nishikawa Ryo , Ichimura Koichi , Tomiyama Arata
Published: December 2020

Central nervous system germ cell tumors (CNS GCTs) are rare intracranial malignancies developing in adolescents and young adults which relatively frequently occur in East Asia region of the world including Japan. However, among CNS GCTs, non-germinomatous germ cell tumors (NGGCTs) are highly resistant to the current chemoradiotherapies, and the prognosis of CNS NGGCTs is still extremely poor. Therefore, development of novel therapeutic strategy against CNS NGGCTs is urgently needed. In this study, we screened small molecule inhibitors of kinases specifically targeting cell membrane receptors, such as receptor tyrosine kinases, and their related molecular signaling, which could effectively exert antitumor effects against NGGCT cells. As the NGGCT model cells, the Tcam2 cell, a mixed germ cell tumor cell line composed of germinoma and embryonal carcinoma components, and the YST1 cell, a novel yolk sac tumor cell line established in our institute, were used. As a result, effective induction of cell death in both cell lines was confirmed only by treatment with two multi-kinase inhibitors. Immunoblotting revealed these multi-kinase inhibitors suppressed activation of various kinases concurrently. Furthermore, these multi-kinase inhibitors also triggered cell death in the Tcam2 cell stably expressing mutant KIT, the most common oncogenic driver genes of CNS GCTs, suggesting that these inhibitors would be also effective against CNS GCTs harboring activated KIT mutants. In vivo studies of these multi-kinase inhibitors using CNS GCT xenografts are currently on going.
GCT-50. LONG-TERM OUTCOMES OF INTRACRANIAL GERMINOMA IN A SINGLE INSTITUTION
Authors: Yamamoto Etsuko , Arakawa Yoshiki , Umeda Katsutsugu , Mineharu Youhei , Uto Megumi , Takita Junko , Mizowaki Takashi , Miyamoto Susumu
Published: December 2020

The treatment for intracranial germinoma has been well-established. Complete removal is not necessary, but radiation therapy is important. As the prognosis of patients with germinoma has become better, side effect of radiotherapy and chemotherapy must be well considered. The aim of this study was to evaluate the outcome of intracranial germinomas at Kyoto University Hospital from 1979 to 2019. 64 patients were diagnosed as intracranial germinoma. Patients with hCG > 100 IU/l and/or AFP > 10 ng/ml were excluded. Patients, who were histologically diagnosed as germinoma without information of hCG and AFP, were included. Follow-up time was from 2 to 486 months (median 136 months). Recently, germinoma patients were diagnosed with biopsy and received low dose whole-ventricle irradiation with intensity modulated radiation therapy (IMRT) (total 24-30Gy) and chemotherapy dominated by platinating agent. 10-year PFS was 80.21% (high dose radiation alone), 86.36% (high dose radiation with chemotherapy) and 100% (low dose radiation with chemotherapy). Many recurrent sites were out of irradiation areas. Late cognitive dysfunction was identified in 6 patients, and 5 of them were treated with high dose radiation. Patients with intracranial germinoma can obtain long-term survival. It is important to prevent recurrence without increasing late iatrogenic complications. Low dose radiotherapy and chemotherapy is highly effective, and it potentially reduces late adverse effects.
GCT-52. TRANSCRIPTOME OF CENTRAL NERVOUS SYSTEM GERM CELL TUMOR REVEALS ITS PATHOGENESIS AND CONTRASTS WITH TESTICULAR COUNTERPARTS IN INTEGRATED OMICS ANALYSIS
Authors: Takami Hirokazu , Elzawahry Asmaa , Kato Mamoru , Fukuoka Kohei , Mamatjan Yasin , Suzuki Tomonari , Yanagisawa Takaaki , Matsushita Yuko , Nakamura Taishi , Yamasaki Kai , Mukasa Akitake , Saito Nobuhito , Kanamori Masayuki , Kumabe Toshihiro , Tominaga Teiji , Kobayashi Keiichi , Nagane Motoo , Iuchi Toshihiko , Tamura Kaoru , Maehara Taketoshi , Sugiyama Kazuhiko , Nakada Mitsutoshi , Kanemura Yonehiro , Nonaka Masahiro , Asai Akio , Yokogami Kiyotaka , Takeshima Hideo , Narita Yoshitaka , Shibui Soichiro , Nakazato Yoichi , Totoki Yasushi , Shibata Tatsuhiro , Nishikawa Ryo , Matsutani Masao , Ichimura Koichi
Published: December 2020

Germ cell tumors (GCTs) are unique neoplasms in that they arise from the migrated cells which were supposed to be directed to gonads. They occur in the central nervous system (CNS), as well as gonadal organs such as testis and ovary. Our genomic analysis revealed that they are characterized by mutations in MAPK and PI3K pathways, chromosomal instability and global hypomethylation in germinoma. However, there were plenty of cases which lacked driver alterations and their pathogenesis is yet to be fully unraveled. Here we aimed to uncover CNSGCT’s pathogenesis from a transcriptomic perspective. Genome-wide transcriptional analysis was performed for 58 CNS and 3 testicular GCTs. This demonstrated that germinoma had a transcriptional profile characteristic to primordial germ cells (PGCs) at early embryogenesis, whereas non-germinomatous germ cell tumors (NGGCTs) showed that with differentiation into various tissues. Integration of transcriptome and methylome corroborated the above finding that pluripotency/meiosis-genes were unmethylated and highly expressed in germinoma compared with NGGCT. Co-analysis with transcriptome of various developmental stages of embryonic cells revealed germinoma and NGGCT had similarities in expression to PGC and embryonic stem cells, respectively. Multi-omics analysis with testicular GCTs (n=134) from TCGA showed shared genomic backgrounds between germinoma-seminoma and NGGCT-nonseminomatous GCT (NSGCT) in mutation and methylation profiles, and contrast in the chromosomal instability, which was more highlighted in testicular GCTs. These new insights into molecular profiles of GCTs lead to a better understanding of the complex pathogenesis of GCTs, and will hopefully provide a clue to future development of new treatments.
GCT-59. EPIDEMIOLOGY OF PEDIATRIC INTRA-CRANIAL GERM CELL TUMORS: COMPARING THE INCIDENCE OF INTRA-CRANIAL GERM CELL TUMORS IN THE NATIVE JAPANESE POPULATION AND IMMIGRANT JAPANESE POPULATIONS ABROAD
Authors: Plant Ashley , Suzuki Tomonari , Coronado Rosdaili Diaz , Epelman Sidnei , Sakamoto Luis , Cheng Sylvia , Yanagisawa Takaaki , Rosner Bernard , Chi Susan , Kieran Mark
Published: December 2020

Pediatric intra-cranial germ cell tumors (iGCTs) occur at an incidence of 0.6–1.2 cases/million/year in Western countries. The incidence is reported up to 5 times higher in the Japan. It is unknown whether this increased incidence is due to tumor biology or environment. The incidence of iGCTs in children ages 0–19 years was evaluated from 12/1/96-12/1/2016 in stable Japanese immigrant populations living abroad compared to current native Japanese registry data. Medulloblastoma incidence was used as a control to account for assumptions in the data. A review of the Brain Tumor Registry of Japan from 1984–2004 revealed an incidence of 2.5 cases/million/year and a lower incidence of medulloblastoma at 1.1 cases/million/year. Sites outside of Japan included Vancouver, Canada, Lima, Peru, and San Paolo, Brazil and together included a population of 853,174 Japanese persons. Within this population, 0 cases of iGCT were identified over a 20-years. The ratio of medulloblastoma to iGCT cases in Japan was identified as 1:2 while the ratio was 2:1, 6.5:1, and 5:1, respectively, in the other three locations. The data suggests increased incidence in the native Japan may not translate to higher incidence in immigrant Japanese populations abroad and a clear genetic component was not found in this preliminary data set. A more precise and comprehensive study is needed to determine the cause of this difference in incidence. This study also emphasizes the importance of national and state registries and is a call to collaborate on state and country level epidemiology studies.