bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETMR-29. PRIMARY CNS SARCOMAS IN CHILDREN AND ADOLESCENTS: EXPERIENCE OF AN INSTITUTION
Authors: de Oliveira Milena Reis Santos , Rodrigues Jessica Benigno , Almeida Daniela Barbosa , Cavalheiro Sergio , Dastoli Patricia , Devanir Marcos , Silva Frederico , Seixas Maria Teresa , Toledo Silvia , Lima Fernanda Teresa , Cappellano Andrea Maria , Silva Nasjla Saba 
Published: June 2024

Abstract

BACKGROUND
Soft tissue sarcomas represent 6% of childhood cancers, less than 0.2% of CNS tumors are primary intracranial sarcomas. Their origin is pluripotential primitive mesenchymal cells.

OBJECTIVE
to evaluate clinical and genetic characteristics and report the experience of a rare CNS tumor.

METHODS
review of CNS tumors database at IOP/GRAACC/UNIFESP for the period 2008-2024, searching for all types of sarcomas that involved the CNS.

RESULTS
case series included 7 male, 2 female patients; average age at diagnosis 11.3 years. Supratentorial was the most common site of occurrence (66.6%), posterior fossa and intramedulary (2 and 1 cases, respectively) were found. One PF sarcoma presented as a second neoplasm after 2 years finished treatment for medulloblastoma, the other was diagnosed just after metilation. The presenting symptoms varied with tumor location, specially hemiparesis, seizure and headache. Gross total resection was achieved in 7 cases (77.7%), 1 after second look surgery. Histology and immunohistochemistry studies revealed: spinocellular sarcoma, fusocellular and myxoid sarcoma, gliosarcoma, meningeal sarcoma, Ewing sarcoma, condrosarcoma and synovial sarcoma. Work-up excluded other primary tumor origin outside CNS. Analyses for genetic characteristics were performed by Next Generation Sequencing in 6 patients (66.6%) and the following alterations were found: NRAS, TP53, JAK3, NF2, C11orf95-RELA fusion, PDGFRA. Some of these, by now, with no significant meaning for the disease. All patients underwent multimodal treatment. Chemotherapy involved mainly ICE Protocol (55.5%), but also Head Start Protocol and Ewing Sarcoma Protocol. Follow-up ranged from 13 months to 12 years, 90% of patients are alive, 2 (28.5%) dealing with endocrinal issues after focal radiotherapy. The mean overall survival was 61.4 months.

CONCLUSION
CNS primary sarcomas were mostly observed in the supratentorial region and in older children, with male predilection. Multimodal treatment seems to benefit patients’ outcomes. More patients and longer follow-up periods are needed to further elucidate the biological features of these tumors.
EPEN-07. USP7 IS AN INTERACTION PARTNER OF EZHIP AND POTENTIAL DRUGGABLE TARGET IN PFA EPENDYMOMAS
Authors: Jenseit Anne , Camgöz Aylin , Mauermann Monika , Mack Norman , Schwalm Benjamin , Mohr Jacqueline , Wittenburg Sophie , Steinebach Christian , Gütschow Michael , Peterziel Heike , Friedenauer Aileen , Jaunecker Carola , Lötsch-Gojo Daniela , Oehme Ina , Pfister Stefan M , Kool Marcel 
Published: June 2024

Abstract

BACKGROUND
Ependymomas (EPN) arise in the supratentorial brain (ST-EPN), posterior fossa (PF-EPN), or the spinal cord (SP-EPN), in children and adults. Among the three molecular PF-EPN groups, PFAs are characterized by young median age at diagnosis, a balanced genome and poor outcome. Recently, enhancer of zeste inhibiting protein (EZHIP) has been identified as potential driver of PFAs. By inhibiting EZH2, EZHIP prevents the distribution of the epigenetic repressor mark H3K27me3. Without known enzymatic functions though, EZHIP isn´t the urgently needed drug target. We therefore focused on essential and potentially druggable interaction partners.

METHODS
We investigated protein-protein interactions using co-immunofluorescence, co- immunoprecipitation and proximity-based assays. We utilized CRIPSR/Cas9 and shRNAs-based methods, mutagenesis and PROTAC treatments followed by Western Blot or mass spectrometry for functional analyses. Viability and apoptosis after drug treatments was assessed in vitro by metabolic readouts, synergy was determined using matrix layouts.

RESULTS
We identified ubiquitin-specific protease 7 (USP7), a known cancer regulator with multiple inhibitors available as direct interaction partner of EZHIP in PFA. We confirmed their interaction in PFA cells and showed that the EZHIP-USP7 interaction is independent of EZH2, a separate interactor of both. Functionally, we show that USP7 de-ubiquitinates EZHIP, preventing its degradation and thus stabilizing it, mediated via the six lysine residues present in EZHIP. We reveal a vulnerability of PFA cells to genetically engineered losses of EZHIP and USP7. Moreover, USP7 inhibitors highly affected the survival and induced apoptosis in different PFA cell lines at a low micromolar IC50 in vitro. Mid-throughput drug library screens additionally identified BET inhibitors as synergistic partners. In vivo treatments with the combination of USP7 and clinically achievable doses of BET inhibitors in PFA PDX models are ongoing.

CONCLUSIONS
USP7 de-ubiquitinates and thus stabilizes EZHIP, which qualifies it as a candidate therapeutic target in pediatric PFA ependymoma.
EPEN-18. MULTI-OMICS APPROACH REVEALED A TIGHT BLOOD-BRAIN BARRIER IN EPENDYMOMA
Authors: Sundheimer Julia K , Benzel Julia , Federico Aniello , Knoll Maximilian , Gansert Cornelia , Statz Britta , Scheuermann Sophia , Seitz Christian , Kool Marcel , Pfister Stefan M , Maaß Kendra K , Pajtler Kristian W 
Published: June 2024

Abstract

BACKGROUND
A major challenge in the treatment of brain tumors is the limited penetration of many drugs through the blood-brain barrier (BBB). BBB characteristics include endothelial cells connected by tight junction proteins (e.g. Claudin5, ZO1, occludin) and the expression of efflux transporters (e.g. P-gp) with the physiological role to limit the accumulation of potentially toxic substances in brain tissue. Our study aims to enhance our understanding of the BBB composition across different molecular groups of ependymoma (EPN) with the goal of leveraging this knowledge to improve therapeutic strategies against these tumors.

METHODS
We applied a multi-omics approach integrating single-nuclear RNA sequencing and ultra-high content imaging to unravel BBB composition at both transcriptomic and proteomic levels. Patient-derived xenograft (PDX) models were utilized to explore differences in BBB penetration between tumor and healthy brain tissue following drug treatments.

RESULTS
Expression of tight junction and transporter proteins revealed strong dependencies specific to molecular groups, but were independent of the corresponding brain regions. Human tissue of ST-EPN-ZFTA exhibited highest expression of claudin5, while both ST-EPN-ZFTA and PF-EPN-A represented upregulation of occludin and ZO1 in comparison to healthy tissue. These findings on claudin5 and ZO1 were further confirmed in PDX models. Single-cell data analysis from patients localized the expression of relevant BBB factors to tumor-associated endothelial cells. Treatment of PDX models with drugs revealed disparities in drug penetration between EPN tumors and healthy brain regions. Notably, for most drugs BBB penetration was lower in ST-EPN-ZFTA tumors than healthy brain region.

CONCLUSIONS
Molecular BBB specifics may contribute to drug resistance of aggressive EPN particularly in ST-EPN-ZFTA tumors, which presented high tight junction expressions and lower drug penetration. This resource aims to improve BBB penetration prediction in EPN, to identify combination therapies targeting BBB components and to select innovative drug delivery approaches.
METB-13. GERMLINE GENETIC TESTING IN CHILDREN WITH CNS TUMORS; FIRST-EVER EXPERIENCE FROM JORDAN
Authors: Amer Shrouq , Shanap Mayada Abu , Amayiri Nisreen 
Published: June 2024

Abstract

BACKGROUND
It is expected that 10-15% of children with CNS tumors have an underlying cancer predisposition syndrome (CPS). This has important implications on treatment, cancer screening and family counseling. There is no published data on this genetic risk from Jordan.

METHODS
We retrospectively reviewed the medical charts of the Jordanian children &lt;18 years old at the time of diagnosis with CNS tumors, and were treated at King Hussein Cancer Center/Jordan between January 2021 and December 2023. We reviewed their clinical characteristics and tumor diagnoses, then applied the updated Jongmans’ criteria and MIPOGG criteria and linked that with their germline genetic testing result if performed.

RESULTS
We identified 198 children (53% males); median age at diagnosis was 7years (range, 0-18 years). Consanguinity was found in 30% of families, and 35% had first/second degree relatives with cancer. Most common diagnoses were LGG (41%), HGG (22%) and medulloblastoma (14%). Most tumors were non-metastatic (90%) at initial diagnosis. Fifty-five percent of patients fulfilled the updated Jongmans’ criteria and 36% the MIPOGG criteria, however germline genetic testing was only performed for 34 patients (17%). Pathogenic germline variants were found in 15 patients (44%); 6 LGG (NF1 (3), TSC2, PTPN11, MUTYH), 4 medulloblastoma (SDHB, TP53, BRCA2, CHEK2), 4 HGG (MSH6 (3), TP53), and one had pathogenic NF2 gene. The presence of CPS affected the management received: children with NF1 were treated without tumor biopsy, the child with TSC2 received everolimus, and 3 children with MSH6 received checkpoint inhibitors instead of temozolomide. The underlying CPS also predicted prognosis e.g. rapid clinical deterioration in the TP53-mutated-SHH-medulloblastoma. Partial screening was provided to children with NF1, TSC, NF2, TP53 and BMMRD mutations.

CONCLUSIONS
High proportion of our patients fulfilled the criteria for referral to genetic clinic, but less than half were referred. Increasing awareness of these criteria is important. Identification of CPS impacted treatment and prognosis, yet families’ perceptions and attitudes toward these CPS need to be captured.
GCT-02. OPTIC PATHWAY PRIMARY GERMINOMA: DON´T MISS THE DIAGNOSIS
Authors: Campo Regina M Navarro-Martin del , Huerta-Hurtado Alma M , Saldaña-Alcalá David , Orozco-Alvarado Ana L 
Published: June 2024

Abstract

BACKGROUND
Germ Cell tumors usually arise in the midline of brain; location in optic pathway (OP) is extremely rare. This case illustrates an OP primary Germinoma.

METHODS
A 9 years old female debuted with diminished visual acuity, it was diagnosed and treated as optic neuritis without improvement, a MRI evidenced a gadolinium enhancement with a very subtle thickening on the optic chiasm, along 3 non conclusive vascular like images in the left Virchow space. A differential diagnosis between endophytic Optic pathway glioma and germ cell tumor was made.

RESULTS
Assessment of AFP and Sub HCG in both blood and CFS was negative, endocrine evaluation confirmed Diabetes insipidus. A stereotaxic biopsy was performed and Pathology confirmed a Pure Germinoma. Non metastatic disease was confirmed as negative Spine MRI and acellular CFS. As a relevant familiar History the father had testicular Germinoma in his teenage. She was treated with 9 weeks of Carboplatin/V16 and radiotherapy as follows: whole ventricular 24 Gy and primary site 16.5 Gy for a total dose of 40.05 Gy. She is free of tumor at 3 follow up years with improvement in visual acuity and arginine vasopressin dependence.

CONCLUSIONS
This case illustrates a germ cell tumor primary arising in the optic pathway and aware us to consider it as a differential diagnosis with non-exophytic optic pathway Glioma being the biopsy mandatory to establish the correct diagnosis
GCT-11. CENTRAL NERVOUS SYSTEM GERM TUMORS (CNS GCTS): RESULTS FROM A SINGLE INSTITUTION IN BRAZIL - SÃO PAULO UNIVERSITY
Authors: Barreto Juliana S , Campoy Mirela L , de Azambuja Alessandra M P , Ribas Felippe G O , Sanders Felipe H , Baraldi Helena E , Weltaman Eduardo , Ferracioli Suely F , Lucato Leandro T , Casal Yuri R , Novak Estela M , Gimenez Thamiris M , Komatsu Mariana M , Cristofani Lilian M , Filho Vicente Odone 
Published: June 2024

Abstract

INTRODUCTION
Central Nervous System Germ Tumors (CNS GCTs) are broadly classified as germinomatous (commonly called germinoma) and non-germinomatous germ cell tumors (NGGCTs) based on clinicopathological and laboratory characteristics, including tumor markers.

OBJECTIVES
Compare data from patients admitted from 2000 to 2023, with the usual presentation in the literature, identifying possible specific variables.

METHODOLOGY
Retrospective study involving 27 patients admitted to the institution without previous treatment.

RESULTS
In western countries, GCTs account for 3% to 4% of primary brain tumors in children, with a peak incidence between 10 and 19 years of age. In Japan and other Asian countries, one series reported that the incidence of GCTs in the CNS consists of approximately 15% of all pediatric CNS tumors. The genetic or environmental reasons for these differences remain unknown. In general, males have a higher incidence of GCT than females. Male patients have a preponderance of primary tumors of the pineal region. The data collected by our institution are compatible with those in the literature.

CONCLUSION
Our discussion and data analysis on GCTs are comparable to those presented in the literature, with the majority of cases treated being: adolescents between 10 and 15 years old, predominantly male and with a satisfactory response to therapy.
GCT-17. EXPLORING NEW THRESHOLDS FOR BETA-HCG IN CENTRAL NERVOUS SYSTEM GERMINOMA
Authors: Krawczyk Malgorzata A , Acar Simge , Wang Jinli , Bartels Ute , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Human chorionic gonadotropin (beta-HCG) levels in serum and cerebrospinal fluid (CSF) are critical in the management of patients with germinoma. The threshold for beta-HCG diagnosis is a topic of debate and differs in Europe, ≤50 IU/L, North America ≤100 IU/L, and ≤200 IU/L in Brazil/Japan.

METHODS
We conducted a meta-analysis of English-language publications (1990-2023) to assess how beta-HCG cut-off levels impact treatment outcomes. Standard descriptive statistics summarized all data.

RESULTS
Forty-nine patients with biopsied germinoma were identified. Eighteen had beta-HCG level of 50-100 IU/L (cohort 1), 21 had 100-200 IU/L (cohort 2), and 10 had &gt;200 IU/L (cohort 3). In cohort 1, treatment with chemotherapy plus radiotherapy was administered to 9 patients. Eight of them received radiotherapy like germinoma treatment (≤30Gy), primarily employing whole ventricle irradiation (WVI). Nine patients received radiotherapy alone with total dose 30-59.6Gy. Fifteen patients in cohort 2 received chemotherapy plus radiotherapy. Eight of them received radiotherapy ≤30Gy for different fields [WVI – 4, whole brain (WB) – 3, cerebrospinal irradiation (CSI) – 1). In 7 patients the dose of radiotherapy exceeded 30Gy (local radiotherapy – 4, CSI – 3). Radiotherapy alone was used in 5 patients, chemotherapy alone – 1 patient. In cohort 3, radiotherapy only was primarily used. Six patients received CSI (50-54Gy), one – CSI+WB+local radiotherapy (12.8Gy+27.2Gy+50.6Gy). One patient received combined treatment and 2 patients received chemotherapy alone. Relapses occurred in each cohort. In cohort 1 – 2 metastatic relapses (1 after WVI 24Gy, 1 after radiotherapy &gt;30Gy). Three children from cohort 2, who received chemotherapy plus radiotherapy were diagnosed with relapse (1 after WB 23.4Gy, 2 after radiotherapy &gt;30Gy). In cohort 3 two metastatic relapses were diagnosed – only after chemotherapy.

CONCLUSIONS
Relapse rates across all beta-HCG level are similar. However, study groups are small and treatment regimens vary, warranting further investigation.
GCT-21. MULTINATIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Abu-Arja Mohammad Hatim , McGlynn Mary Claire , Zaghloul Mohammed Saad , Elhemaly Ahmed , Bertrand Kelsey , Gajjar Ammar , Ronsley Rebecca , Cappellano Andrea M , Dassi Natalia , Czogala Malgorzata , Graham Richard , Knowles Truman , Meuller Sabine , Dhall Girish , Nagabushan Sumanth , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor prognosis. We explored prognostic factors to guide the management of these patients.

METHODS
We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. Data were summarized using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI).

RESULTS
We identified 31 patients from eight centers. The median age at initial diagnosis was 11 years (interquartile range (IQR): 9-15.3). Twenty patients (64.5%) suffered a relapse, and 11 patients (35.5%) had refractory disease. The median follow-up time since relapse/progression was 17.5 months (range:1-295). The median time to relapse/progression was 12.1 months (IQR: 5.5-27.5). Ten patients (32.3%) received high-dose chemotherapy (HDCx) with stem cell rescue. Sixteen patients (51.6%) received re-irradiation at relapse/progression. Nine patients (29%) achieved complete remission (CR). Ten patients (32.3%) were alive at the time of the last follow-up. Among the ten survivors, the median serum and cerebrospinal fluid (CSF) alpha-fetoprotein levels were 2.3 ng/dl (range: 0-17) and 2.1 ng/dl (range: 0-55), respectively, the median serum and CSF beta-human chorionic gonadotropin were 23 IU/L (0-168) and 139 IU/L(0-601), none underwent gross total resection, eight received HDCx, and seven received radiotherapy (craniospinal irradiation (n=6), abdominal radiotherapy (n=1)). HDCx (OR=19.8, 95%CI: 2.7-145.7; p=0.01) and achieving CR at the end of relapse treatment (OR=160, 95%CI: 8.9-2880.5; p=&lt;0.001) were associated with a survival benefit. Re-irradiation (OR=3.3 95%CI: 0.53-20.9; p=0.24) was not associated with a survival benefit.

CONCLUSIONS
A subset of patients with relapsed NGGCTs are salvageable at relapse. HDCx and achieving CR at the end of relapse therapy were associated with a survival benefit. More studies are required to identify these patients who would benefit from salvage therapy.
GCT-22. MEDICAL AND SURGICAL VARIABLES ASSOCIATED WITH RELAPSE IN CENTRAL NERVOUS SYSTEM (CNS) NONGERMINOMATOUS GERM CELL TUMORS (NGGCTS): SECONDARY ANALYSIS OF STRATUM 1 OF THE CHILDREN’S ONCOLOGY GROUP ACNS1123 PHASE 2 CLINICAL TRIAL
Authors: Nagabushan Sumanth , Yan Rachel , Lin Tong , Onar-Thomas Arzu , Souweidane Mark M , Dhall Girish 
Published: June 2024

Abstract

BACKGROUND
ACNS1123 was a Phase 2 trial that evaluated the survival benefit of whole ventricular irradiation (WVI) instead of craniospinal irradiation in children with localized CNS NGGCTs who achieved a complete/partial radiographic response (CR/PR) to induction chemotherapy with negative tumor markers (beta-HCG/AFP) in serum and cerebrospinal fluid (CSF). Patients who did not achieve a CR/PR were considered inevaluable and removed from study therapy post-induction.

METHODS
In unplanned, exploratory analyses, we evaluated the association of age &lt;15/&gt;15-years at diagnosis, tumor location (pineal/suprasellar/bifocal/ventricular), tumor markers (beta-HCG/AFP) in serum and cerebrospinal fluid (CSF) at baseline (&gt;/&lt;1000), and rate of decline during induction in CR/PR and &lt;CR/PR patients. Since most evaluable patients with relapse experienced distant failure in the spine, we assessed the impact of surgical variables, such as endoscopic third ventriculostomy (ETV)/biopsy/resection/combination, on spinal relapse in patients with or without disease progression.

RESULTS
66 of 107 eligible patients achieved CR/PR with negative tumor markers while 41 patients did not. Bifocal tumors appeared to demonstrate a higher hazard for disease progression compared to suprasellar tumors (Hazard Ratio=5.4; p=0.0279). Otherwise, we did not find an association with progression-free-survival for any of the analyzed medical variables. Of 66 evaluable patients who received WVI, eight patients experienced relapse, with all patients demonstrating disease in the spine. No significant association was detected between any surgical variable (ETV/biopsy/resection) and spinal failure among evaluable patients who did or did not relapse; however, we had very limited power for these analyses due to very few events.

CONCLUSION
Current reliance on conventional parameters appears inadequate to identify biomarkers of response as well as relapse. Innovative approaches such as comprehensive genomic profiling of primary and recurrence tumor specimens could inform somatic clonal evolution and potential targeted therapies.
GCT-23. LONG-TERM FOLLOW-UP AND SURVIVALS OF PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS (NGGCT) ENROLLED ON ACNS1123: A CHILDREN’S ONCOLOGY GROUP (COG) STUDY
Authors: Dhall Girish , Wang Yu , Onar-Thomas Arzu , Shaw Dennis , MacDonald Shannon , Murphy Erin , Khatua Soumen , Bartels Ute , Fangusaro Jason 
Published: June 2024

Abstract

BACKGROUND
ACNS1123 was a Phase 2 study to determine whether irradiation could be safely reduced without impacting survival in a subgroup of NGGCT patients.

METHODS
Patients with localized disease who achieved a complete (CR) or partial response (PR) to induction chemotherapy were eligible to receive reduced dose/volume of irradiation to 30.6Gy whole ventricular field with 54Gy tumor-bed boost.

RESULTS
107 eligible NGGCT patients were accrued. The median age of patients at enrollment was 11 years (3.7-21.6). Eighty patients (75%) were male. Location was pineal in 58 (55%), suprasellar in 37 (35%), ventricles in 6 (6%), and bifocal in 6 patients (6%). Sixty-six (61.7%) patients achieved a CR/PR post-induction and were eligible and evaluable for the primary objective and received reduced dose and volume of irradiation. Eight patients progressed; 6 had a distant spinal relapse (outside the irradiation field) and 2 had a local plus distant relapse. As of December 31, 2023, the median follow-up time for eligible and evaluable patients was 5.6 years (0.9-7.9) from enrollment. Except for an unrelated death due to SARS-CoV-2 at 5.5 years from enrollment, there were no grade 3 or higher adverse events at the 60-month follow-up timepoint and no disease progressions beyond 2 years. The 5-year progression-free and overall survival for all eligible and evaluable patients are 87.9% (95% CI:79%-94.8%) and 92.4% (95% CI:82.8%- 96.8%), respectively.

CONCLUSION
Although the study was closed prematurely due to the concern of increased spinal relapse, the current data suggest that most patients with localized NGGCT and a CR/PR to chemotherapy will survive long-term, and, in fact, have similar survival (PFS and OS) to patients enrolled on ACNS0122 who received full dose craniospinal irradiation. The key to future biologic studies and clinical trials is identifying at diagnosis those patients at high risk for relapse.