bluuebunny/crossref_metadata_2025 huggingface dataset:
EPEN-54. ACNS0831, PHASE III RANDOMIZED TRIAL OF POST-RADIATION CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED EPENDYMOMA AGES 1 TO 21 YEARS
Authors: Smith Amy , Onar-Thomas Arzu , Ellison David , Owens-Pickle Emily , Wu Shengjie , Leary Sarah E S , Fouladi Maryam , Merchant Thomas , Gajjar Amar , Foreman Nicholas
Published: December 2020

PURPOSE

The primary objective of this study is to determine the EFS and OS of children with gross total and near totally resected ependymoma (EPN) treated with post-operative focal radiation therapy (RT) followed by randomization to either RT alone or RT + 4 cycles of maintenance chemotherapy with vincristine, cisplatin, cyclophosphamide and etoposide. Secondary objectives include estimating the EFS and OS of children not randomized, evaluation of neurobehavioral and quality of life (QoL) endpoints, and EPN biomarkers.

RESULTS

479 patients enrolled, 451 were eligible. Of 325 eligible randomized patients, 161 were randomized to RT alone and 164 to RT + maintenance chemotherapy. Age range (1–21 years, median 4.9 years). The planned primary analysis was based on intent-to-treat, irrespective of actual treatment received. Based on the data available as of 12/31/2019, estimated 3-year EFS in the RT + maintenance chemotherapy vs. RT arms were 78% vs. 72%, respectively, which did not meet statistical criteria to establish the benefit of maintenance chemotherapy post RT (1-sided log-rank p-value=0.074). Due to significant noncompliance (30.5% in the RT + maintenance vs 4.3% in the RT arm), a planned secondary “as treated” analysis was performed. With median follow-up of 42.6 months among patients without events, the 3 year EFS estimates for patients who received any chemotherapy (n=114) vs. those who received RT only (n=196) were 80% vs. 71%, respectively (1-sided p-value = 0.0121).

CONCLUSION

Early results in this randomized trial suggest that there may be some EPN patients who benefit from maintenance chemotherapy. Genomic analyses are ongoing.
EPID-04. MORBIDITY IN PAEDIATRIC BRAIN TUMOURS: 17 YEARS’ EXPERIENCE IN A TERTIARY NEUROSURGICAL UNIT
Authors: Goh Chun Peng , Nga Vincent Diong Weng , Ho Cindy Wei Li
Published: December 2020

The treatment of paediatric brain tumours has shown significant improvement over the last 2 decades. The aim of our study is to evaluate the prevalence of various effects among this population within our institution. 102 patients diagnosed with a brain tumour at the age of 0–18 years between 2002 and 2018 were identified within a single paediatric institution. Data was collected retrospectively based on electronic medical records. Medulloblastoma (20.6%) was the most common subtype followed by pilocytic astrocytoma (18.6%) and craniopharyngioma (11.8%). Overall, the 5-years survival rate was approximately 77%. Endocrine dysfunction was reported in 36% of the population, mainly due to tumour located in suprasellar region and irradiation causing progressive pituitary dysfunction. Neurological disorders such as epilepsy, weakness, cranial nerves palsy, visual and hearing impairment were present in 46% of the population. Importantly, 20.4% of patients who received chemotherapy had some degree of sensorineural hearing loss. 16% of the population suffered from impaired neurocognition which is likely an underestimation as screening could not be performed on all patients. Other significant complications are infections (12%) and ventriculoperitoneal shunt dysfunction (7%). Most of these effects can be attributed to direct injury to the developing brain caused by the tumour or related to its treatment during surgical excision and the long term side effects of chemotherapy and radiation therapy. Morbidities in various domains can pose significant challenges to survivors of paediatric brain tumours. Active screening and surveillance of these effects can help improve the health outcomes of survivors of paediatric brain tumours.
EPID-11. ESTABLISHING A BASELINE TIME-FRAME FOR SYMPTOM ONSET TO DEFINITIVE DIAGNOSIS FOR CHILDREN WITH NEWLY-DIAGNOSED CNS TUMORS: AN EXPANDED, MULTI-INSTITUTIONAL COLLABORATIVE STUDY
Authors: Eccles Eamon , Han Yan , Liu Hao , Walker David , Rush Sarah , Finlay Jonathan , Coven Scott
Published: December 2020

BACKGROUND

We have previously documented the presence of diagnostic delays in children with central nervous system (CNS) tumors in the United States. This study serves to expand and validate the previously established baseline from symptom onset to definitive diagnosis in children with newly-diagnosed CNS tumors. DESIGN: The medical records of children with newly-diagnosed CNS tumors were retrospectively reviewed from January 2004 to December 2017 at Nationwide Children’s Hospital, Akron Children’s Hospital and Riley Hospital for Children at IU Health. Records were reviewed for age, gender, tumor type, presenting symptoms, number of healthcare visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis and any associated genetic syndromes.

RESULTS

Of the 768 patients with newly-diagnosed CNS tumors, the median time interval from symptom onset to definitive diagnosis was 40.5 days while the mean symptom interval was 144 days (range < 1 to 5,475 days). The median age of diagnosis was 7 years, with a male predominance (57%). This expanded cohort continues to reveal that pediatric brain tumor patients most often seek care at the primary care level, although many patients were seen in various multiple subspecialty clinics prior to diagnosis.

CONCLUSIONS

This multi-institutional cohort study updates our previously documented single state time interval and provides a consistent Midwest “benchmark” to improve awareness for children with brain tumors through the adaptation of the UK ‘HeadSmart,’ now renamed ‘BrainFirst.’ Additionally, future work could include a prospective registry to better examine potential risk factors for delays in diagnosis.
EPID-17. A SINGLE INSTITUTE EXPERIENCE IN THE REGISTRATION STUDY OF PEDIATRIC SOLID TUMOR IN JAPAN CHILDREN’S CANCER GROUP
Authors: Furukawa Keiko , Mineharu Yohei , Arakawa Yoshiki
Published: December 2020

A larger scale prospective registration study has been conducted nationwide in Japan since 2011, called as “registration study in pediatric solid tumor”, in Japan Children’s Cancer Group (JCCG). In this study, clinical data and surgical specimen are collected into the National Center for Child Health. Kyoto University Hospital has participated in this study since IRB approval in 2011. We reviewed our registered patients to the registration study and assessed the current status. 40 patients with pediatric brain tumors participated in this study from 2011 to 2020. There were 13 intracranial germ cell tumors, 9 medulloblastomas, 6 gliomas in 4 diffuse midline gliomas, 4 pilocytic astrocytoma, and 4 other types of tumor. The informed consent was obtained from 36 patients by pediatricians and 3 patients by neurosurgeons. Twenty-five surgical specimens were collected for central review. The reasons of no surgical specimens were nonsurgical management in 6 patients and no enough FFPE sample in 3 patients. There was no discrepancy between central review and institutional diagnosis. The status of clinical data entry was complete in 13 patients and uncomplete in 9 patients. These registration data including pathological diagnosis, molecular diagnosis, treatment, clinical information in patients with pediatric brain tumor are very important to realize current status. To conduct this study certainly, the collaboration among pediatrician, neurosurgeon, and supporting staff should be needed in collecting specimens and clinical data.
ETMR-04. EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES: THE MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Gupta Sumit , Ragoonanan Dristhi , Itzep Nelda , Sandberg David , Fuller Greg , Ketonen Leena , Meador Heather , Zaky Wafik , Khatua Soumen
Published: December 2020

BACKGROUND

Embryonal Tumor with Multilayered Rosettes (ETMR) are rare tumors that are molecularly diagnosed by C19MC amplification. Rarity of this tumor has precluded profiling uniform therapeutic strategy.

METHODS

Retrospective review after institutional approval, identified 10 pediatric case of ETMR, treated at MD Anderson Cancer Center during the period of 2005 to 2019.

RESULTS

Median age of at diagnosis was 4.6 years. Tumor sites include frontal or parietal lobes (3), spine (3) and posterior fossa involving the brainstem (4). All patients received a combination of chemotherapy and radiation. 4 patients had metastasis at the presentation. 9 patients received focal radiation but only 6 of them received Craniospinal irradiation (CSI). Average dose of radiation was 50 Gy. Surgical resection was performed in all cases except the brainstem tumors. 7 children had recurrence including all the patients with metastasis at diagnosis (median time: 9.4 months), 1 passed away secondary to hemorrhage in brainstem and data was not available for 2 patients. 5/6 patients who received CSI had recurrence.

CONCLUSIONS

To-date no well-defined treatment regimens exists for these neoplasms, resulting in poor overall survival. Preclinical drug screen have shown the efficacy of topotecan, actinomycin D, and volasertib as potential new therapeutic candidates, though this has not translated successfully into the clinical arena. Given the limited success with current conventional therapeutic methods, molecular interrogation in addition to histopathological diagnosis are essential upfront, as it could provide clues to targeted therapy. Defining molecularly-based treatment with less toxicities and increased survival are warranted.
ETMR-09. THE ROLE OF RADIATION FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Kondo Akihide , Suzuki Mario , Fujimura Junya
Published: December 2020

BACKGROUND

Embryonal tumor with multilayered rosettes (ETMR) is a challenging tumor. The prognosis of the patients suffering from this tumor is extremely poor. We have survival cases of more than 12 months. However, the status of illness is different. In order to clarify the cause of this difference, we reviewed our treatments in this study. TREATMENT COURSE: We have two cases. Both have relapsed after the same chemotherapy after the same radiation therapy. After the recurrence we used protocols that were included extended resection, second radiation therapy with bevacizumab.

METHODS

We compared molecular biological evaluations for the initial and recurrent tumors. The resection rate at the time of second removal and the intensity of radiation therapy intensity were compared.

RESULTS

We succeeded to remove the tumors with the confirmation of intraoperative MRI. No apparent differences could be seen in molecular biological characters of tumors before and after treatment. There was a difference between the period until radiation therapy and the irradiation methods.

CONCLUSIONS

This tumor is untreatable only by resection. We need the second radiation therapy with bevacizumab. It was presumed that tumor should be irradiated quickly with appropriate irradiation field and dose.
ETMR-13. NFI GENES IN ETMR TUMORIGENESIS AND NEURODEVELOPMENT
Authors: Bunt Jens , Lambo Sander , Lim Jonathan , Mauermann Monika , Pfister Stefan , Richards Linda , Kool Marcel
Published: December 2020

Embryonal tumors with multilayered rosettes (ETMRs) are aggressive pediatric embryonal brain tumors with a universally poor prognosis. These tumors are commonly characterized by amplification of C19MC, but other miRNA-related aberrations, such as DICER mutations or MIR17HG amplifications, are also observed. Nevertheless, it remains unknown how these aberrations are driving the tumorigenesis. We applied miRNA target prediction to investigate the downstream targets shared by these aberrations affecting normal brain development and tumorigenesis. The nuclear factor one (NFI) family of transcription factors were found to be top candidates shared by both miRNA clusters. These genes are expressed at very low levels in ETMRs, in contrast to other brain tumors. During normal brain development these genes are expressed in radial glial progenitors and are required for the transition of proliferation to differentiation. Since radial glial progenitors are the potential cell-of-origin of ETMRs, we hypothesize that downregulation of NFI is required for the proliferative, undifferentiated state of ETMRs. Indeed, mouse models with deletion of an Nfi family member display sustained proliferation and delayed differentiation of radial glial progenitors during development. This leads into brain overgrowth, which has also been observed in humans with intellectual disabilities caused by NFI haploinsufficiency. When multiple Nfi family members are simultaneously targeted in mice, the progenitors are retained and both neurogenesis and gliogenesis are inhibited, resulting in a neuropathology similar to that of human ETMR tumors. Hence, downregulation of NFI genes resulting from miRNA aberrations could contribute to the developmental state and possibly tumorigenesis of ETMRs.
ETMR-18. TARGETING Lin28 IN ETMR WITH ODC1 INHIBITOR DFMO
Authors: Goodyke Austin , Kelly Shannon , Zagorski Joseph , VanSickle Elizabeth , Maser Tyler , Sortwell Caryl , Kemp Christopher , Nagulapally Abhinav , Dykema Karl , Saulnier-Sholler Giselle
Published: December 2020

Embryonal tumor with multilayered rosettes (ETMR), is an aggressive brain tumor primarily occurring in young patients (<4 years of age) and characterized by C19MC amplification and Lin28 overexpression. These genetic hallmarks have been shown to participate in driving ETMR in a C19MC-Lin28-MYCN circuit. Reducing Lin28 disrupts this circuit and reduces cell viability in ETMR models. Investigation of therapeutic agents targeting this pathway is required to provide new treatment options for this deadly disease. We present data showing the effect of DFMO (α-difluoromethylornithine) in ETMR, an ODC1 inhibitor known to reduce Lin28 in neuroblastoma. DFMO treatment of the ETMR cell line BT-183 resulted in a significant reduction of intracellular Lin28 protein levels (P<0.05) as indicated by flow cytometry. In concert with this reduction in Lin28, there was a as significant reduction in viable cells (P<0.05), and the number of CD133+ cells were reduced 2-fold (P<0.05). High throughput drug testing of BT-183 identified a number of additional therapeutic agents with potential therapeutic efficacy for ETMR and combining these with cytostatic agent DFMO demonstrated the potential use of these drugs in combination. These in vitro data were complemented by testing of DFMO in an in vivo stereotaxic xenograft ETMR model, with inhibition of tumor burden monitored by bioluminescent imaging of the tumors. Together this work shows that Lin28 targeting agents such as DFMO merit further examination and integrating these types of agents into treatment strategies for ETMR may lead to better outcomes.
GCT-03. TREATMENT OUTCOMES, PHYSICAL DEVELOPMENT AND QUALITY OF LIFE OF PATIENTS WITH BIFOCAL GERM CELL TUMOURS
Authors: Li Bo
Published: December 2020

BACKGROUND

The optimal radiation field in patients with bifocal germ cell tumours(GCTs) is controversial, especially in non-metastatic cases. Accordingly, we analysed the survival, growth, and health-related quality of life (HRQOL) data of patients with bifocal GCTs.

METHODS

The data of 87 patients diagnosed with bifocal GCTs at our hospital during the last 10 years were collected. The WHO AnthroPlus software—used to monitor the growth of persons aged 5–19 years—was employed to calculate the Z-score of height (ZSOH) at diagnosis and the last follow-up. The absolute change in the ZSOH was defined as |ZSOH last follow-up - ZSOH diagnosis|. The Pediatric Quality of Life Inventory 4.0 was used to evaluate HRQOL.

RESULTS

The median follow-up was 49 months (range,6–134 months). Among 49 patients with non-metastatic germinoma, those receiving cranial spinal irradiation(CSI; n=12) or whole-brain radiotherapy (WBRT; n=34) had comparable disease-free survival (DFS;p=0.54), but better DFS than those receiving focal radiotherapy(n=3;p=0.016). Furthermore, among 17 patients with non-metastatic non-germinomatous GCTs, DFS was not significantly different between those treated with CSI(n=4) and those receiving WBRT(n=13;p=0.11). Twenty-nine patients had paired ZSOH data at both diagnosis and the last follow-up. Patients receiving CSI(p=0.026) or >40Gy(p=0.048) experienced a significant decline of absolute change in the ZSOH. HRQOL analysis(n=35) did not reveal difference between patients receiving CSI and those not receiving CSI.

CONCLUSIONS

Given the comparable DFS and HRQOL but negative impact on growth, CSI could be spared, especially in patients with non-metastatic bifocal germinoma.
GCT-06. DIAGNOSIS OF A RARE CASE OF RECURRENT GERM CELL TUMOR BY CSF PLACENTAL ALKALINE PHOSPHATASE PRESENTING WITH DIFFUSE INTRAAXIAL ABNORMALITY IN THE LOWER BRAINSTEM
Authors: Yamada Hiroki , Abiko Tomohiro , Fujiwara Hirokazu , Yoshida Kazunari , Sasaki Hikaru
Published: December 2020

INTRODUCTION

Germ cell tumors in the central nervous system (CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in and across the lower brainstem, which was diagnosed by the elevated placental alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy at the previous hospital for bifocal suprasellar and pineal lesions with the provisional diagnosis of germinoma without histological confirmation. Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slight contrast enhancement across the ventral side of the medulla oblongata to the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were all negative. Since the image findings were atypical for recurrent germ cell tumor, some kind of myelitis was initially suspected. Therefore, steroid pulse therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating the recurrence of germinoma. Accordingly, platinum-based chemotherapy was administered, and the imaging findings, patient’s symptoms, and CSF PLAP began to improve. The patient is to be treated with radiotherapy following chemotherapy.

CONCLUSION

We report a rare case of CNS germ cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.
GCT-18. CLINICAL FEATURES OF GERM CELL TUMORS IN CHILDREN
Authors: Higa Nayuta
Published: December 2020

INTRODUCTION

Here, we discuss the presentation, histology, therapy, and outcome of germ cell tumors in children.

METHODS

Treatment outcome and management was assessed for children diagnosed with germ cell tumors from 2007 to 2017 at Kagoshima University.

RESULTS

Twenty-six patients (20 boys, 6 girls) with a mean age of 11.5 ± 4.9 years were included in this study. Patient tumor types included: germinoma (n = 19); immature teratoma (n = 3); yolk sac tumor (n = 3); choriocarcinoma (n = 1); embryonal carcinoma (n = 1). The most common patient clinical features were headache and vomiting associated with hydrocephalus. The median follow-up period was 96.5 months. Tumor location was pineal (n=9), bifocal (n=6), suprasellar (n = 5), basal ganglia (n=2), frontal lobe (n=2), and cerebellum (n=2). Surgical procedures included stereotactic biopsy (n=13), endoscopic third ventriculostomy and biopsy (n=8), and tumor decompression (n=5). All patients with germ cell tumors underwent adjuvant chemotherapy and radiation therapy; patients with germinoma or immature teratoma were still alive, while patients with embryonal carcinoma, yolk sac tumor, or choriocarcinoma had poor prognosis with a median survival of 16 months.

CONCLUSIONS

Patients with germinoma had a relatively good prognosis, while patients with embryonal carcinoma, yolk sac tumor, or choriocarcinoma had a poor prognosis. A multidisciplinary approach including surgical strategy based on location, appropriate radiation planning, and chemotherapy is needed for effective treatment and improved outcomes.
GCT-30. TREATMENT OF PRIMARY INTRACRANIAL GERM CELL TUMORS: SINGLE INSTITUTION EXPERIENCE OF 74 CASES WITHOUT HISTOLOGICAL CONFIRMATION
Authors: Guo Chengcheng , Yang Qunying , Wang Jian , Mou Yonggao , Chen Zhongping
Published: December 2020

BACKGROUND AND OBJECTIVE

Primary intracranial germ cell tumors (PIGCTs) are a group of heterogeneous tumors. It is very difficult to treat those patients without pathological diagnosis. This study retrospectively analyzed the clinical data and outcomes of patients with clinically diagnosed (without histologically confirmed) PIGCTs in SunYat-sen University Cancer Center.

METHODS

Patients who were clinically diagnosed as PIGCTs without histological diagnosis through surgical resection or biopsy were included in this study. Patients were analyzed for clinical characteristics, treatment patterns, outcomes and adverse effects.

RESULTS

From May 2002 to July 2014, 74 patients clinically diagnosed with PIGCTs received chemotherapy and/or radiotherapy at the Sun Yat-sen University Cancer Center. The median age was 16.5 years old (4–45 years old, majority was teenagers). The most of tumors were found in male, and located in the pineal and suprasellar regions. When the patients were grouped into diagnostic chemotherapy group (57 cases), diagnostic radiotherapy group (5 cases) and gamma knife radiosurgery group (12 cases) based on their initial anti-tumor therapy. The 5-year survival rates were 84.3%, 75.0% and 75.0%, respectively. There was a trend that the chemotherapy group got a better survival. Patients were allocated to secretory tumor group (49 cases) and non-secretory tumor group (25 cases) based on their levels of tumor makers (α-FP and β-hCG). The 5- year survival rates were 80% and 77.8% (P value = 0.966), respectively.

CONCLUSION

Clinical diagnosed PIGCT (without histological confirmation) patients may obtain good responses when receiving comprehensive treatments of chemotherapy combined with radiotherapy.
GCT-34. ELUCIDATION OF THE MECHANISMS OF TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMOR BY WHOLE GENOME SEQUENCE
Authors: Yamagishi Yuki , Takami Hirokazu , Narushima Daichi , Matsushita Yuko , Sugihara Eiji , Nishikawa Ryo , Kato Mamoru , Ichimura Koichi ,   Intracranial Germ Cell Tumor Genetic Analysis Consortium
Published: December 2020

Intracranial germ cell tumors (iGCT) are heterogenous group of primary brain tumors that consist of various subtype, and driver genetic alterations in iGCTs remain largely unknown. We have previously reported in a study of whole exome sequence that iGCTs frequently harbored mutations in the KIT gene and its downstream MAPK/PI3K pathway, regardless of tumor subtype. However, no mutations were detected in about one-quarter of germinomas and half of non-germinomatous germ cell tumors. A genome-wide methylation profiling revealed that only germinomas exhibited extreme DNA hypomethylation among iGCTs. Moreover, in mixed iGCT tumors which contained more than one tumor subtypes, each component exhibited distinct methylation status depending on the subtype, while they shared the same mutations. These data suggested that not only mutations in the coding region as previously reported, but also genetic alterations in regulatory regions including promoters and enhancers as well as non-coding RNA genes may be involved in the tumorigenesis of iGCTs. In order to comprehensively search for driver gene alterations, we performed whole genome sequence in 18 paired tumor blood samples from iGCT tumors (16germinomas and two yolk sac tumors (YST)) registered in the Intracranial Germ Cell Tumor Genome Analysis Consortium. In a preliminary analysis of four cases, YSTs harbored a significantly higher number of structural abnormalities, compared with germinomas. Of note, 62 structural abnormalities were clustered within the small genomic region of 95Mb at 1q21-44 in one YST case, suggesting a possibility of chromothripsis. A full analysis of somatic alterations is underway and will be reported.
GCT-40. PROGNOSTIC FACTORS FOR PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM (CNS) NON-GERMINOMATOUS GERM CELL TUMORS (NGGCTs)
Authors: Abu-Arja Mohammad H , Osorio Diana S , Stanek Joseph R , Finlay Jonathan L , AbdelBaki Mohamed S
Published: December 2020

BACKGROUND

Patients with relapsed CNS NGGCTs experience poor outcomes. Our aim to explore prognostic factors that may guide future clinical trials.

METHODS

A review of clinical trials that included patients with relapsed CNS NGGCTs was performed.

RESULTS

Seventy-four patients were identified; only 14 patients (19%) were long-term survivors. Patients who relapsed >24 months after initial diagnosis had a survival rate of 47% compared with 15% of patients who relapsed in <24 months after initial diagnosis (p= 0.015). Patient with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level <25 ng/ml at relapse had a survival rate of 40% compared with 0% among patients with serum/CSF AFP level >25 ng/ml at relapse (p= 0.0015). Patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy had a survival rate of 59% compared with 3% among patients who had less than CR/CCR by the end of therapy (p= 0.0001). Patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) at relapse had a survival rate of 33% compared with 9% of patients who did not receive HDCx/AuHCR at relapse (p=0.056). The extent of surgical resection, receiving radiotherapy, and beta-human chorionic gonadotropin levels at relapse were not statistically associated with improved outcomes.

CONCLUSION

Timing of relapse (>24 months after initial diagnosis), serum/CSF AFP <25 ng/ml at relapse, achieving CR/CCR after treatment were associated with a positive impact on survival. Receiving HDCx/AuHCR at relapse was associated with an improved outcome trend among the patients.
GCT-41. RESPONSE-BASED RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED CENTRAL NERVOUS SYSTEM LOCALIZED GERMINOMA: A CHILDREN’S ONCOLOGY GROUP (COG) PROSPECTIVE PHASE 2 CLINICAL TRIAL
Authors: Bartels Ute , Fangusaro Jason , Shaw Dennis , Bhatia Aashim , Omar-Thomas Arzu , Wu Shengjie , MacDonald Shannon , Murphy Erin , Souweidane Mark , Fouladi Maryam , Gajjar Amar , Dhall Girish , Khatua Soumen
Published: December 2020

BACKGROUND

The objective of stratum 2 of COG ACNS1123 was to evaluate children and young adults (3–21 years) with localized central nervous system (CNS) germinoma and investigate whether simplified pre-irradiation chemotherapy followed by response based dose-reduced whole ventricular irradiation (WVI) would maintain a high progression-free survival (PFS) while reducing long term treatment burden.

METHODS

Pre-irradiation chemotherapy consisted of 4 cycles of carboplatin and etoposide every 21 days followed by response-based irradiation (XRT). Patients with a complete response (CR) to pre-XRT chemotherapy received 18Gy WVI + 12Gy boost to the tumor bed. Patients with partial response (PR) but less than 1.5 cm residual proceeded to 24Gy WVI + 12Gy boost. All patients were also enrolled on COG ALTE07C1 to prospectively evaluate and longitudinally model the cognitive, social and behavioral functioning.

RESULTS

During a total accrual time of 45.5 months from 05/2012 to 06/2018, 137 eligible patients were enrolled. Median age was 14.09 years (4.95–21.46), 73% were male, and 45.26% had elevated βhCG in serum and/or cerebrospinal fluid. Twenty-nine patients (21.17%) did not have tissue biopsy. Eleven patients underwent second-look surgery; 7 had mature teratoma and 4 had non-viable tumor. Eighty-one patients (59.13%) had a CR. There were 4 relapses in patients receiving 18Gy WVI + boost, but no deaths. No unexpected treatment-related events were observed. The estimated 3-year PFS was 94.4 ±2.7% among 74 evaluable subjects.

CONCLUSION

This study shows promise in XRT reduction for patients with localized CNS germinoma and CR. Long-term survival outcomes and ALTE07C1 data are being evaluated.
GCT-44. A CASE OF INTRACRANIAL GERMINOMA WHICH RECURRED IN THE SPINAL CORD 13 YEARS AFTER THE INITIAL TREATMENT
Authors: Murota Yasuhiro , Kiyokawa Juri , Ishikawa Mariko , Yamaoka Hiroto , Kaneko Satoshi , Yoshimura Masataka , Hirota Shin , Yamamoto Shinji
Published: December 2020

BACKGROUND

Central nervous system germinoma occurs most often in early teens, accounting for 15% of childhood brain tumors. Here, we report a case of germinoma which recurred in the spinal cord 13 years after complete remission. CASE DESCRIPTION: A 15-year-old boy presented with diabetes insipidus (DI). MRI showed a pineal gland tumor and ventriculomegaly. Biopsy was performed and the histological examinations revealed PLAP and c-kit positive pure germinoma. Ki67 LI was 64.4%. Gamma knife radiosurgery and 3 courses of ICE chemotherapy brought disappearance of the tumor. However, it recurred in lateral ventricles. Forty-Gray whole brain radiation resulted in complete remission of the tumor. For the sake of DI treatment and MRI examinations, he kept periodical visit to our hospital. Thirteen years later, when he was 28y/o, he complained paresthesia in the right upper extremity. MRI demonstrated gadolinium-enhance mass lesion in the cervical spinal cord. Recurrence of the tumor and multiple sclerosis were the principal differential diagnosis. Pulse steroid therapy did not make any change, and radiation therapy to the cervical spinal cord led to tumor disappearance. Nevertheless, the tumor recurred on the dorsal medulla oblongata one and a half years later. Biopsy of the tumor clarified that the tumor was germinoma. ICE chemotherapy which was limited to three courses due to severe bone marrow suppression was carried out. MRI proved no enhanced mass lesion in the central nervous system.

DISCUSSION

Germinoma may recur even after long period of remission, demonstrating that long-term follow-up is indispensable.
GCT-47. TREATMENT STRATEGIES FOR GIANT IMMATURE TERATOMAS IN INFANTS
Authors: Miwa Tomoru , Kono Maya , Shima Haruko , Shimada Hiroyuki , Yoshida Kazunari
Published: December 2020

INTRODUCTION

Immature teratomas are the most frequent fetal brain tumors and show a poor prognosis. At onset, the tumor is often already giant with deep origins such as suprasellar or pineal region, and easy bleeding is also considered to be a cause of poor prognosis. On the other hand, it is also known that the prognosis is improved in total removal cases.

METHODS

We investigated the best treatment strategy based on two cases of total removal of giant immature teratomas in infants.

RESULTS

1.5 month after birth at onset (median), maximum diameter of 75 mm (median). A giant tumor centered around the third ventricle with hydrocephalus. First, biopsy (+septostomy) was performed using an endoscope. The tumor showed easily bleeding. In addition, external ventricular drainage was taken out of the lower abdomen subcutaneously by long tract. After chemotherapy (carboplatin and etoposide), tumor removal was performed by using drainage tract. Both cases showed not easily bleeding at that time and the tumor was safely removed. Regarding the deep blind spot, using a flexible endoscope was effective. They showed no recurrence after total removal (median 50 months).

DISCUSSION

There have been reports of cases in which chemotherapy for immature teratomas suppressed tumor growth and reduced bleeding and safely removed totally. In infants giant immature teratomas, chemotherapy before tumor removal can be expected to reduce bleeding, and further increase body weight during that period. In addition, long-term placement of ventricular drainage by long tract during the chemotherapy can prevent brain development delay due to hydrocephalus.
GCT-51. IMMUNE CHECKPOINT MOLECULES AND TUMOR INFILTRATING LEUKOCYTES IN THE TUMOR MICROENVIRONMENT ARE ASSOCIATED WITH THE GROWTH OF INTRACRANIAL GERMINOMAS
Authors: Nishimoto Masaaki , Ohara Kentaro , Kamamoto Dai , Tamura Ryota , Miwa Tomoru , Yoshida Kazunari , Sasaki Hikaru
Published: December 2020

The role of immune checkpoint molecules and the tumor immune microenvironment in the development of intracranial germ cell tumors remains unclear. In the present study, we investigated the expression of immune checkpoint molecules, as well as the number of tumor-infiltrating lymphocytes (TILs), in intracranial germinomas to determine whether there were any correlations between the statuses of these immune-related molecules/cells and clinical manifestations in patients with germinoma. The 8 patients were categorized based on the duration between symptom onset and pathological diagnosis into the long-term onset (LTO) group (> 1 year of symptoms, 3 patients) and the short-term onset (STO) group (< 1 year of symptoms, 5 patients). Compared with STO tumors, LTO tumors were significantly associated with a lower ratio of programed cell death ligand-1 (PD-L1)–positive tumor cells (p = 0.012), higher number of infiltrating CD3- and CD8-positive lymphocytes (p = 0.016, 0.003, respectively), and lower ratio of programed cell death-1 (PD-1)–positive cells per CD8–positive lymphocytes (p = 0.047). LTO germinomas were significantly smaller in size than STO tumors and tended to be present in patients with atypical tumor location. Our data suggest that the tumor immune microenvironment, including PD-1/PD-L1 signaling, is associated with the growth of intracranial germinomas. Immune checkpoint inhibitors might be a reasonable treatment option for recurrent germinomas or as replacement for radiotherapy in patients with intracranial germinomas.
GCT-56. ACUTE MYELOID LEUKEMIA FOLLOWING CHEMORADIOTHERAPY FOR INTRACRANIAL GERMINOMA: A CASE REPORT
Authors: Nakaya Masato , Koda Yuya , Yamaguchi Kentaro , Yoshida Kazunari , Sasaki Hikaru
Published: December 2020

INTRODUCTION

Therapy-related acute myeloid leukemia (t-AML) is known as　possible complication of chemotherapy, especially topoisomerase Ⅱ　inhibitor,　alkylating agents, and platinum agents. Although there are many reports of therapy-related leukemia associated with gonadal germ cell tumor, few cases have been reported on central nervous system (CNS) germ cell tumor. CASE REPORT: A 35-year old gentleman presented with diplopia. CT and MR imaging showed enhancing nodules on his right hypothalamus and around fourth ventricle, and differential diagnoses included sarcoidosis and germinoma. Biopsy for fourth ventricle lesion was performed via transvermian approach, and histopathological diagnosis was germinoma. He was treated by 3 cycles of CARE chemotherapy (carboplatin and etoposide) followed by craniospinal irradiation (CSI, 24Gy). After completion of chemoradiotherapy, he was followed up every half year by MRI, and there had been no evidence of tumor recurrence. Two years after chemoradiotherapy, however, the patient presented with bleeding tendency, which led to the diagnosis of AML. Based on the history of chemoradiotherapy and the presence of t(16;21)(q24; q22), t-AML was diagnosed. Complete remission was successfully achieved by chemotherapy consisting of idarubicin and cytarabine.

DISCUSSION

t-AML was diagnosed after chemoradiotherapy in a patient with CNS germinoma probably due to the administration of　topoisomerase II inhibitor, etoposide. The prognosis of t-AML is known to be poorer as compared with de novo AML. Therefore, intensive therapy such as allogeneic stem cell transplantation should be considered in younger patients.

CONCLUSION

A possibility of t-AML should be kept in mind following chemotherapy for CNS germ cell tumors.
GCT-62. DISSECTING INTRATUMORAL HETEROGENEITY OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS BY SINGLE-CELL RNA-SEQUENCING
Authors: Nakano Tomoyuki , Matsushita Yuko , Onuki Ritsuko , Shiokawa Daisuke , Imamura Kiyomi , Horiuchi Terumi , Uchida Eita , Kimura Yui , Ihara Satoshi , Suzuki Tomonari , Tsurubuchi Takao , Ishikawa Eiichi , Nakamura Taishi , Yoshida Makiko , Kawamura Atsufumi , Fukuoka Kohei , Jun Kurihara , Miyakita Yasuji , Narita Yoshitaka , Kobayashi Keiichi , Nagane Motoo , Takami Hirokazu , Nishikawa Ryo , Kato Mamoru , Suzuki Yutaka , Ichimura Koichi
Published: December 2020

BACKGROUND

Central nervous system germ cell tumor (CNSGCT) is a rare pediatric brain tumor. However, they are found at a relatively high incidence in East Asia. Germinoma is sensitive toward radiotherapy and chemotherapy; however, non-germinoma GCTs (NGGCT) often show poor response. Some cases are a mixture of germinoma and NGGCT (mixed GCT), and they sometimes change histological subtypes at recurrence. Previous report demonstrated that a germinoma and NGGCT component within the same mixed GCT tissue shared the same gene mutation, whereas the genome-wide methylation profiles were distinct from each other. The methylation profiles of germinoma was similar to the primordial germ cells (PGC) at the migration phase, supporting a model that PGC is the cell of origin for CNSGCT. However, tumor heterogeneity hinder information of the mixed bulk RNA-sequence data, causing difficulty in elucidating the mechanism of tumor development. The purpose of this study was to investigate the tumor cells subpopulations at the resolution of individual cells by single-cell RNA-seq.

RESULTS

Fresh surgical tumor tissue was immediately dissociated mechanically and enzymatically. Tumor cells are separated from CD45-labelled lymphocytes by FACS, and libraries were generated by Chromium Single cell 3’ Reagent Kit. Total of 11 tumor samples were collected and sequenced. Unsupervised Clustering showed individual clusters. One of the clusters had high expression of Oct-4, which is a marker of germinoma. The other clusters showed different subtypes of cells representing the heterogeneity of CNSGCT. Further analysis including a pseudo-time course analysis is underway to identify the lineage of tumor cell development.
GCT-66. FINAL REPORT OF THE PROSPECTIVE NEXT/CNS-GCT-4 CONSORTIUM TRIAL (GemPOx FOLLOWED BY MARROW-ABLATIVE CHEMOTHERAPY) IN PATIENTS WITH REFRACTORY/RECURRENT CNS GERM CELL TUMORS
Authors: Shatara Margaret , Blue Megan , Stanek Joseph R , Liu Allison Y , Osorio Diana S , AbdelBaki Mohamed S , Prevedello Daniel , Puduvalli Vinay , Giglio Pierre , Gardner Sharon , Allen Jeffrey , Wong Kenneth E , Dhall Girish , Finlay Jonathan L
Published: December 2020

BACKGROUND

We report the responses, toxicities and long-term outcomes of gemcitabine, paclitaxel and oxaliplatin (GemPOx) regimen administered, in responsive patients, prior to single cycle marrow-ablative chemotherapy (thiotepa, etoposide and carboplatin) with autologous hematopoietic progenitor cell rescue (HDCx+AuHPCR).

METHODS

Since December 2009, 11 recurrent/refractory patients (10 MMGCT, 1 germinoma; 10 males; mean age 16.5 years, range 7–46 years) have been treated with up to four cycles of gemcitabine (800mg/M2), paclitaxel (170mg/M2) and oxaliplatin (100mg/M2) administered on one day at 14 days intervals.

RESULTS

All 11 patients were enrolled on a prospective multi-center trial, which was closed in October 2019. Three patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions, two developed disease progression (PD), and one was withdrawn after one cycle for severe paclitaxel neurotoxicity followed by rapid tumor progression and death. One patient with PD after one cycle had pathologically-confirmed metastatic transformation to pure embryonal rhabdomyosarcoma, and rapidly expired. A second patient, with pure pineal choriocarcinoma, progressed after the second GemPOx cycle, ultimately died of tumor progression. Eight of the 11 responsive patients subsequently underwent HDCx+AuHPCR; five of these received some form of radiotherapy. Seven patients (six MMGCT, one germinoma) are alive and disease-free without recurrence for a mean of 94 months (range 74–118 months) since completion of therapy.

CONCLUSION

GemPOx is an effective re-induction regimen for patient with recurrent CNS germ cell tumors, with acceptable toxicities; when followed by marrow-ablative chemotherapy and subsequent irradiation/re-irradiation, the regimen produces encouraging long-term disease-free survival.
GCT-73. EXPRESSION PROFILING OF INTRACRANIAL GERM CELL TUMORS REVEALS UPREGULATION OF RAS THROUGH mRNA-microRNA SIGNALING PATHWAY
Authors: Taylor Aaron M , Shen Jianhe , Ren Lingzhao , Terashima Keita , Huang Lei , Snyder Elizabeth M , Adesina Adekunle , Su Jack , Nishikawa Ryo , Nakamura Hideo , Ng Ho-Keung , Wong Stephen T C , Braun Robert E , Man Tsz-Kwong , Lau Ching C
Published: December 2020

Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumors in children in the U.S. and 11% in Japan and East Asian countries. IGCTs are separated into two distinct subtypes based on histology: germinomas and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtype classification difficult, and previous gene expression studies are limited. We performed mRNA expression profiling (Human Genome U133 Plus 2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49 IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups that delineated germinomas from NGGCTs. Employing stepwise model building in each data set separately, we were able to separate these groups using only mRNA probes for the LIN28B and L1TD1 genes, and two microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B directly binds and suppresses the let-7 microRNA family, which suppress the KRAS oncogene, previously found to be mutated in ~19% of IGCTs. L1TD1 is required for human stem cell renewal and directly interacts with LIN28B for its RNA binding function. LIN28B and L1TD1 are both known to be upregulated in other systemic germ cell tumors, but this has not yet been documented in IGCTs. In conclusion, these results show that intracranial germinomas have similar gene expression compared to systemic seminoma, and suggest a mechanism by which activation of LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently upregulates KRAS.
HGG-38. A COMPARATIVE PROTEOMIC-ANALYSIS OF THE CELL MEMBRANE FRACTIONS OF HISTONE 3 MUTATED BRAIN TUMOURS TO IDENTIFY NOVEL THERAPEUTICS
Authors: Pickering James , Rahman Ruman , Grundy Richard , Layfield Robert , Haque Farhana
Published: December 2020

Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome. We therefore analysed the cell surface proteomics of pHGG and DIPG, in order to identify novel targets for therapy. We have at first isolated the cell membrane fractions from a range of patient cells carrying different histone 3 mutations (G34R, G34V, K27M), relative to wild type histone 3. A comparative quantitative mass-spectrometry analyses of these cell surface membrane fractions is then performed to identify specific targetable factors, which can be then be used for tumour specific precision-therapy. Results of these experiments will be presented.
HGG-48. ROS1 INHIBITOR ENTRECTINIB USE IN RELAPSE/REFRACTORY INFANTILE GLIOBLASTOMA WITH POSITIVE ROS1 FUSION - A CASE REPORT WITH PROMISING RESPONSE
Authors: Ku Dennis Tak-Loi , Shing Matthew Ming-Kong , Chan Godfrey Chi-Fung , Fu Eric , Yau Ping-Wa , Luk Chung-Wing , Cheng King-Fai , Ho Wilson Wai-Shing , Ng Ho-Keung , Po Yin-Chung , Ling Alvin Siu-Cheung
Published: December 2020

INTRODUCTION

Infantile glioblastoma is rare with poor prognosis. Recent molecular study for infantile hemispheric high grade glioma found its association with ALK/ROS1/NTRK/MET pathway. This suggested the potential use of targeted therapy for refractory / relapse patients. CASE: A newborn presented with apnea, CT brain showed intracranial haemorrhage. MRI then showed a left parietal tumour with bleeding and mass effect. Craniotomy achieved subtotal resection. Chemotherapy VCR/CPM alternating with CDDP/VP-16 was given for one year. Patient was stable with static residual tumour during chemotherapy. However patient developed status epilepticus two weeks after off treatment. MRI showed significant tumour progression which required 2nd & 3rd debulking surgery. Molecular assay by nanostring panel showed BRAF-KIAA1549 fusion. MEK inhibitor Trametinib was tried for 3 months and stopped as disease progression. Further molecular assay by RNASeq showed presence of ROS1 fusion (ZCCHC8-ROS1) while absent of BRAF fusion. Patient underwent 4th debulking surgery as impending herniation while waiting for the targeted therapy. It was complicated with right hemiplegia and facial nerve palsy postoperatively. Finally, ROS1 inhibitor Entrectinib was started 2 weeks later. It was well tolerated without significant adverse reaction. Patient made dramatic neurological recovery including improved facial nerve palsy, able to walk unaided and self feed. MRI brain 1 and 3 months after Entrectinib showed interval reduction in residual tumour. Patient is currently progression-free for 6 months.

CONCLUSION

Early molecular study for infantile glioblastoma is useful to guide novel therapy. Molecular result may varies between different panels or change over time, to be interpreted with caution.
HGG-52. SUSTAINED RESPONSE TO CRIZOTINIB MONOTHERAPY IN AN INFANT WITH GOPC-ROS1 FUSED CONGENITAL HEMISPHERIC GLIOMA
Authors: Lulla Rishi , Svokos Konstantina , Pelton Kristine , Anthony Douglas , Touat Mehdi , Ligon Keith L
Published: December 2020

Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of GOPC-ROS1 fused congenital hemispheric glioma with a sustained response to crizotinib. An infant born at 28 weeks gestation was diagnosed with a large hemispheric mass at 2 weeks of life. The tumor was partially resected at 7 weeks of life. Histological evaluation confirmed a neoplasm with a spindle cell growth pattern, hypercellularity, nuclear pleomorphism, endothelial proliferation and necrosis consistent with glioblastoma. Fresh tissue was submitted for targeted panel sequencing (Oncopanel) which identified the presence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed by copy number analysis which showed a focal intragenic deletion with a breakpoint in ROS1 on 6q22. Given the lack of preclinical native models for ROS1 and other congenital kinase-driven gliomas, live cells were utilized to attempt to establish a patient derived cell line (organoid/neurosphere model) and intracranial patient derived xenograft model, the results of which are pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1 and crizotinib was started at 280 mg/m2/dose twice daily at 6 months of life with progressive tumor noted on imaging. Three months after initiating therapy, a 56% reduction in the tumor size and subsequent imaging revealed additional response. Our report is the first to demonstrate clinical response to crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe the development of a renewable resources for future analysis.