bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract
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

Abstract
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

Abstract
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 &gt; 100 IU/l and/or AFP &gt; 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

Abstract
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

Abstract
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.
GCT-61. CORRELATION OF PATTERNS OF DISEASE RECURRENCE WITH RADIOTHERAPY TECHNIQUES AND DOSE IN INTRACRANIAL GERM CELL TUMOURS (icGCT): LESSONS FROM THE UK COHORT OF SIOP GCT96 STUDY
Authors: Ajithkumar Thankamma , Mandeville Henry , Carceller Fernando , Ronghe Milind , Foord Tina , Lowis Stephen , Kwok-Williams Michelle , Calaminus Gabriele , Murray Matthew , Nicholson James 
Published: December 2020

Abstract

BACKGROUND
There are global variations in radiotherapy approaches for icGCT. An understanding of patterns of disease recurrence correlated with radiation techniques and doses is important in standardising and improving the quality of radiotherapy using high-precision techniques.

METHODS AND RESULTS
Data from 20 patients with tumour recurrence after treatment within the SIOP GCT96 study in the UK were analysed. Seven (35%) patients had germinoma and 13 (65%) had non-germinoma. Twelve patients had local recurrence, 5 had metastatic and 3 had local and metastatic disease. Radiotherapy details were retrieved in only 8 patients (40%). Six patients had received focal radiotherapy and two craniospinal radiotherapy. Of the patients who received focal radiotherapy, 4 had recurrence within the radiation portal, one had periventricular recurrence and one had marker-positive recurrence with no radiological lesions. Both patients who received CSI recurred within the CSF space. The main reasons for poor retrieval of treatment details were difficulty in retrieving archived information and that the study was conducted during a period before PACS or electronic radiotherapy records.

CONCLUSION
This study highlights the importance prospective data collection and analysis to understand the patterns of recurrence in icGCT. Even within a prospective study, radiotherapy techniques varied between centres. There is therefore an urgent need for centralised radiological review and prospective radiotherapy quality assurance measures in future clinical trials.
GCT-65. INCIDENCE AND OUTCOME OF INTRACRANIAL MALIGNANT GERM CELL TUMOURS DIAGNOSED IN WESTERN DENMARK IN THE LAST DECADE
Authors: Lassen-Ramshad Yasmin , Mikkelsen Torben Stamm , Rosthoej Steen , Henriksen Louise Tram , Tuckuvienne Ruta , Kristensen Ines Ackerl , von Oettingen Gorm , Cortnum Soeren , Als Anne-Birgitte , Safwat Akmal , Agerbaek Mads 
Published: December 2020

Abstract

INTRODUCTION
Intracranial malignant germ cell tumours (iGCT) are rare brain tumours mainly diagnosed in children and younger adults.

MATERIAL AND METHODS
A retrospective analysis was performed by chart review of patients treated for iGCT in the northern and central region of Denmark. Teratoma only patients were not included in the study.

RESULTS
20 patients with iGCT were diagnosed from 2008–2019 in Western Denmark. The cumulative incidence was 1.05 per 100.000. The yearly incidence was 0.1 per 100.000. Mean age at diagnosis was 18 years (range 8–36 years), 17 were males and 3 were females. 13 patients presented with germinoma and 7 patients with non germinomateous germ cell tumours (NGGCT). Three patients had disseminated disease, two with germinoma and one with NGGCT. All patients had received radiotherapy and 18 patients were treated with multidrug chemotherapy including platinum and etoposide before irradiation. Two patients experienced recurrent disease, both non disseminated at diagnosis, one patient with germinoma and one patient with NGGCT. Both received salvage treatment including high dose chemotherapy with stem cell transplantation and reirradiation. Two NGGCT patients died, one patient after development of an anaplastic astrocytoma in the radiation field five years after radiotherapy and one patient after intracranial hemorraghe 18 months after salvage treatment for recurrent disease. Overall survival was 90%, 100% for GCT and 71% for NGGCT.

CONCLUSION
The outcome of patients with iGCT in Western Denmark was comparable to the literature. A nationwide study of epidemiology and outcome of iGCT in Denmark is planned.
GCT-67. CENTRAL NERVOUS SYSTEM GERMINOMA IN TWO CAUCASIAN AMERICAN SIBLINGS WITH AUTISM SPECTRUM DISORDER
Authors: Toll Stephanie , Gorsi Hamza 
Published: December 2020

Abstract

BACKGROUND
Central nervous system germ cell tumors (CNS-GCT) account for approximately 5% of all pediatric brain tumors. These tumors are pathologically heterogeneous, but have recurrent somatic mutations in KIT and rare germline variants in a Japanese cohort. Chromosomal abnormalities, specifically Klinefelter Syndrome, are associated with increased tumor development and familial cases have been reported, but no germline tumor syndromes are known. We describe a pair of siblings, both with autism spectrum disorder (ASD) that developed CNS-GCT, which previously has not been described outside of Japan. CASES: We report two siblings with ASD who developed CNS germinomas within two months of each other. The older brother, with basal ganglia and hypothalamic tumors, underwent surgical resection followed by treatment per ACNS0232 with chemotherapy and whole-ventricular irradiation (WVI). The younger sibling, with a midbrain tumor, also received ACNS0232, but due to poor response required additional chemotherapy and WVI. Both siblings are without evidence of disease 7 years after end of therapy. Genetic testing, including chromosomal microarray, karyotyping, and whole genome sequencing did not elucidate any variant identified as causative at that time.

CONCLUSIONS
CNS-GCT are rare tumors, diverse in both histopathologic diagnosis and clinical outcomes. Currently there are known somatic alterations and germline chromosomal disorders associated with increased tumor development, but no known inheritable causes. Despite this, familial CNS-GCT have been reported in patients of Japanese descent. The description of two Caucasian American siblings with ASD and CNS-GCT is novel, refuting that familial CNS-GCT are limited to the Japanese population.
HGG-27. ANTI-CANCER POTENTIAL OF ARGINASE FOR HIGH-GRADE GLIOMA IN VITRO & IN-VIVO
Authors: Fung M K L , Chan S , Sun S , Zhang P D , Leung G K K , Chan G C F 
Published: December 2020

Abstract

BACKGROUND
High-grade glioma is currently incurable. It was reported that glioma may be auxotrophic to arginine due to the lack of urea cycle genes expressions, suggesting arginase may be a potential agent for high grade glioma. AIM: We investigated the efficacy of pegylated arginase I (pegArg-I) or in combination with other anti-cancer drugs for high-grade glioma in vitro and in vivo.

METHODS
4 high-grade glioma cell lines (U87, U373, U138, D54) were treated with pegArg-I in vitro. The molecular mechanism of pegArg-I-induced cytotoxicity was tested in U87. The ultra-morphological changes of pegArg-I-treated U87 was investigated by both scanning and transmission electron microscopy. Orthotopic glioma xenograft model with luciferase-transfected U87 cell line was tested for anti-cancer efficacy of peg-Arg I in vivo.

RESULTS
We showed that pegArg-I induced significant cell death in all 4 cell lines in vitro. Temozolomide, difluoromethyornithine and chloroquine (CQ) were then tested together with pegArg-I in U87 in vitro. We found that only CQ showed additive effect with pegArg-I against glioma in vitro. Such additive cytotoxic effect may be associated with enhanced autophagy and necrosis as shown in transmission electron microscopy and autophagy markers’ expression by Western blotting. PegArg-I prolonged the survival of glioma mice, suggesting its possible anti-glioma efficacy. However, CQ+pegArg-I didn’t show further significant anti-cancer efficacy in vivo.

CONCLUSION
PegArg-I may be useful in slowing the progression of glioma, but additional drug candidate which works synergistically with pegArg-I remains to be explored.
HGG-31. UNIQUE BIOLOGICAL CHARACTERISTICS OF RADIATION-INDUCED GLIOMAS
Authors: Váňová Kateřina , Vícha Aleš , Krsková Lenka , Zámečník Josef , Malinová Běla , Sumerauer David , Mišove Adéla , Libý Petr , Zápotocký Michal 
Published: December 2020

Abstract
Radiation-induced gliomas (RIGs) are the most common secondary solid tumours with very unfavourable prognosis. We aimed to describe different clinical and molecular biological characteristic of RIGs from primary gliomas. We reviewed clinical data of ten patients with RIGs. In patients with available samples, we used the whole genome methylation array and performed targeted sequencing for specific mutations. Between 2000–2018, we diagnosed RIG in 10 patients (M/F 2/8) aged 5–12 years at primary diagnosis of different solid tumours and acute leukaemia. These patients developed RIG with a median 9.5 years (ranging 3–31) after primary diagnosis. Eight patients died within 1 year after diagnosis of RIG and 2 patients are still alive more than 4 years from this diagnosis. According to Heidelberg DNA methylation-based classification, most RIGs belong to the IDH-wild type glioblastoma subclass midline which biologically corresponds to diffuse midline glioma (DMG). However, compared to primary DMGs they do not carry the characteristic H3K27M mutation. One patient developed anaplastic ganglioglioma with BRAF-V600E mutation and methylation profile identical to pleomorphic xanthoastrocytoma (alive for 4 years after diagnosis of RIG). In half of the patients from the group DMGs IDH wild type, examined by methylation array, PDGFRA amplification was found. Our data shows that most RIGs are midline IDH-wild type glioblastomas with poor prognosis that are biologically different from primary DMGs. PDGFRA amplifications are potentially targetable by kinase inhibitors in order to order to prognosis of these patients.
HGG-32. UNCOVERING THERAPEUTIC VULNERABILITIES IN MISMATCH REPAIR-DEFICIENT GLIOMAS
Authors: Boynton Adam , Pal Sangita , Touat Mehdi , Currimjee Naomi , Qian Kenin , Bellamy Charlotte , Ho Patricia , Berstler Jim , Ligon Keith , Beroukhim Rameen , Bandopadhayay Pratiti 
Published: December 2020

Abstract

INTRODUCTION
We have observed that approximately 26% of recurrent gliomas acquire hypermutation following treatment with temozolomide (TMZ). Intriguingly, 91% of these tumors harbor mutations in mismatch repair (MMR) genes. Strategies to target MMR-deficient gliomas thus stand to impact a large number of patients.

METHODS
We ablated the MMR genes MSH2, MSH6, MLH1, and PMS2 using an all-in-one sgRNA-CRISPR/Cas9 expression vector to generate panels of isogenic MMR knockouts in patient-derived glioma cell lines. We have characterized the phenotype of these MMR-deficient glioma cells, and leveraged high-throughput drug screens to identify therapeutic vulnerabilities induced by loss of MMR.

RESULTS
We demonstrate that sgRNA-CRISPR/Cas9 targeting of either MSH2 or MLH1 – the two obligatory components of the MutSα and MutLα complexes, respectively – also results in loss of protein expression of their respective binding partner MSH6 or PMS2. Moreover, we show that loss of each MMR component confers resistance to TMZ while maintaining sensitivity to the alkylating nitrosourea CCNU. Furthermore, we show that long-term TMZ treatment of MSH2 and MSH6 knockouts in an MGMT-methylated line induces hypermutation with enrichment of C &gt; T mutations but not in MMR wild-type controls. Lastly, loss of MSH2 or MLH1 confers differential dependencies to small molecule inhibitors.

CONCLUSIONS
CRISPR/Cas9 knockout of individual MMR pathway members allows us to systematically study the response of MMR-deficient cells to alkylating agents in an isogenic context. MMR deficiencies in glioma confer dependencies to small molecule treatment, which may inform future therapies for MMR-deficient tumors.