bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-15. CLINICAL AND MOLECULAR CHARACTERIZATION OF INFANTILE CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
Authors: Fukuoka Kohei , Takami Hirokazu , Satomi Kaishi , Nakano Yoshiko , Inoue Yohei , Miyahara Akira , Matsushita Yuko , Hibiya Yuko , Kato Miho , Takimoto Tetsuya , Nakazawa Atsuko , Yoshioka Takako , Hirato Junko , Nakazato Yoichi , Shibahara Junji , Oka Hidehiro , Kurihara Jun , Koh Katsuyoshi , Matsutani Masao , Nishikawa Ryo , Nagane Motoo , Ichimura Koichi 
Published: June 2024

Abstract

BACKGROUND
The management of infantile central nervous system germ cell tumors (CNS-GCTs) presents unique challenges, including variable clinical presentations such as tumor size and propensity for hemorrhage. Moreover, data on the clinical and molecular features remain limited.

METHODS
We conducted a clinical and molecular analysis of CNS-GCTs in children aged 6 years or younger, registered with the Japan Children’s Cancer Group and the iGCT consortium. DNA methylation analysis was performed using the Illumina Methylation EPIC array to identify potential molecular prognostic indicators.

RESULTS
The cohort comprised 43 patients, with a median age at onset of 6.5 months (0–68 months). Notably, 23 patients (54%) were diagnosed before 1 year of age. The male-female ratio was 27:15. Most common tumor location was cerebellum (13 cases). The median AFP level was 538 ng/ml (0–206460). Pathologically, the tumors were predominantly diagnosed as teratomas and yolk sac tumors. Teratomas were more common in patients diagnosed before 1 year of age, while mixed GCTs were more frequent in those diagnosed after 3 years. Molecular analysis identified four cases as embryonal tumors, including three AT/RTs and one DICER1-mutant intracranial sarcoma. The 3-year overall survival rates varied significantly by diagnosis: mixed GCTs at 100%, teratomas at 90.6%, yolk sac tumors at 30.0%, and embryonal tumors at 0%. Notably, two patients with teratomas developed metachronous tumors more than 10 years post-diagnosis, with both secondary tumors exhibiting mutations in the MAPK pathway absent in the primary tumors.

CONCLUSION
Infantile CNS-GCTs exhibit distinct clinical and molecular profiles compared to those in older children and adults. Not all tumors classified as GCTs based on molecular characterization were GCTs; some were embryonal tumors, potentially impacting treatment strategy. The genetic analysis suggests that some metachronous GCTs may represent second primary tumors rather than recurrences.
GCT-16. LONG-TERM OUTCOMES AND COMPLICATION MANAGEMENT IN CNS GERM CELL TUMORS: INSIGHTS FROM A PHASE II HISTOPATHOLOGY-STRATIFIED TREATMENT TRIAL
Authors: Takami Hirokazu , Nishikawa Ryo , Suzuki Tomonari , Takabatake Kazuhiko , Fujimaki Takamitsu , Okamoto Michinari , Yamaguchi Shigeru , Kanamori Masayuki , Matsuda Kenichiro , Sonoda Yukihiko , Natsumeda Manabu , Ichinose Toshiya , Nakada Mitsutoshi , Muroi Ai , Ishikawa Eiichi , Takahashi Masamichi , Narita Yoshitaka , Higuchi Fumi , Shin Masahiro , Mineharu Yohei , Arakawa Yoshiki , Kagawa Naoki , Kawabata Shinji , Wanibuchi Masahiko , Takayasu Takeshi , Yamasaki Fumiyuki , Fujii Kentaro , Ishida Joji , Date Isao , Miyake Keisuke , Fujioka Yutaka , Kuga Daisuke , Yamashita Shinji , Takeshima Hideo , Shinojima Naoki , Mukasa Akitake , Tanaka Shota , Asai Akio , Matsutani Masao 
Published: June 2024

Abstract

BACKGROUND
This detailed examination merges outcomes from a Phase II clinical trial targeting central nervous system (CNS) germ cell tumors (GCTs) conducted between 1995 and 2003. It evaluates the impact of histopathologically driven treatment modalities on survival, recurrence, and post-treatment life and social outcomes, aiming to delineate the long-term effects of such stratified treatment approaches.

METHODS
The cohort comprised 228 patients, stratified into three groups based on histology: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), each receiving customized chemotherapy and radiation treatments. With a median follow-up duration of 222 months, this longitudinal study scrutinized survival rates, recurrence patterns, and a spectrum of socio-economic and health-related outcomes.

RESULTS
For the germinoma group, the 10- and 20-year event-free survival (EFS) rates stood impressively at 82% and 73%, respectively, with overall survival (OS) rates reaching 97% and 92%. The intermediate prognosis group witnessed 10- and 20-year EFS rates of 76% and 66%, and OS rates of 87% and 70%. The poor prognosis group recorded EFS rates of 49% at both intervals, with OS diminishing to 61% and 53%. Notably, germinomas localized in the basal ganglia exhibited high relapse rates absent initial whole-brain radiation, yet were effectively managed upon subsequent interventions. The comprehensive follow-up illuminated striking disparities in socio-economic achievements: higher educational attainments, more stable employment, and improved health outcomes were predominantly observed among patients without recurrence. Non-recurrent germinoma patients, in particular, showcased enhanced educational and employment status, vividly illustrating the profound impact of disease progression and treatment on life quality.

CONCLUSIONS
The findings highlight the critical importance of customized initial treatments for improving survival and life quality in CNS GCT patients, stressing the need for detailed long-term follow-up to address relapses and complications effectively. The study advocates for personalized care that balances treatment intensity to optimize long-term outcomes, enhancing post-treatment care.
HGG-01. DURABLE RESPONSE TO IMMUNOTHERAPY IN AN ADOLESCENT PATEINT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY CMMRD AND SYNCHRONOUS THREE PRIMARY MALIGNANCIES
Authors: Mobarak NAHLA Aly , Alotabi Fahad , Balbaid Ali Abdullah O , Shakweer Wafa Al , Alrasheed Rana , AlMalki Salman Turbush A , Alharbi Musa , AlFakeeh Ali H 
Published: June 2024

Abstract

BACKGROUND
Familial Cancer Syndrome FCS is of particular concern in Saudi Arabia due to the high rates of consanguinity. Constitutional mismatch repair deficiency Syndrome (CMMRD) is an autosomal recessive FCS with a wide spectrum of malignancies Caused by Biallelic germline mutations in one of 4 mismatch repair genes (MLH1, PMS2, MSH2, and MSH6).

METHODS
we report 13 yr. Saudi boy, previously healthy with multiple café-au-lait (CAL) macules, and Consanguineous parents with a positive family history of Malignancy. presented with progressive headache, vomiting, abdominal pain, weight loss, and microcytic anemia. MRI Brain showed a Large left hemispheric necrotic mass, MRI abdomen: Circumferential gastric body wall thickening Distal transverse colon intraluminal polypoid mass, and liver hypodense lesion. He had a Resection of the brain tumor and Upper GI endoscopy + colonoscopy with polypectomy: which showed an Ugly gastric ulcer, and multiple colonic polyps.

RESULTS
Brain tumor molecular pathology: Gliosarcoma WHO grade 4 with negative IHC expression in PMS2 protein, hypermutant tumor with somatic PMS2 ATRX, TP53, NFI, and PIK3R1 genes mutation. stomach biopsy confirmed invasive gastric adenocarcinoma and Colonic polyp biopsy: Tubulovillous adenoma. Genetic testing Detect pathogenic Biallelic germline PMS2 mutation. He received adjuvant focal Brain radiation therapy 59.4Gy/33 F concurrent with immunotherapy (PD-1) inhibitor Nivolumab. Follow-up Abdominal imaging showed excellent response to immunotherapy with no significant residual lesion. MRI of the brain showed surgical bed multi-cystic lesions with thick nodular enhancement suggestive either of radiation necrosis vs. progressions/pseudoprogression. repeated MRI confirmed further progression of the enhancing surgical cavity lesion which was unresectable. CTLA-4 Inhibitor ipilimumab was added to Nivolumab to optimize therapy. UpToDate our patient is clinically stable on Maintenance Nivolumab with no side effects.

CONCLUSION
Our case confirms immunotherapy’s efficacy for treating CMMRD-related cancers, which can improve survival while reducing toxicity from less effective conventional therapies.
HGG-11. TRANS-SPECIES STUDY OF IDH-MUTANT REPLICATION-REPAIR DEFICIENT HIGH-GRADE GLIOMAS (RRD-HGG) AND RESPONSE TO COMBINED TARGETED AND IMMUNOTHERAPY: AN IRRDC STUDY
Authors: Das Anirban , Fernandez Nicholas R , Bielamowicz Kevin J , Abebe-Campino Gadi , Caspi Shani , Per Nyman , Graham Richard T , Kim John Y , Wilhelmsson Mari , Jorgensen Mette , Michaeli Orli , Fernández Maria Baro , Li Amanda , Levine Adrian , Aamir Zoya , Stengs Lucie , Negm Logine , Bianchi Vanessa , Edwards Melissa , Bennett Julie , Ertl-Wagner Birgit , Dirks Peter , Bouffet Eric , Hawkins Cynthia , Tabori Uri 
Published: June 2024

Abstract

BACKGROUND
IDH-mutant gliomas comprise &lt;10% of HGG in children. RRD-HGG comprise 5-10% of childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact of RRD with childhood IDH-mutant gliomas, and effective therapeutic options for these patients are not well-established.

METHODS
Clinical and multi-omic analyses were performed on IDHmut-RRD-HGG registered to the IRRDC and the glioma taskforce. Tumor development and genomic data were studied from a novel IDHmut-RRD-HGG immunocompetent mouse model. Outcome following ICI and targeted therapy were evaluated.

RESULTS
IDH mut-RRD-HGG accounted for &gt;60% of childhood IDH-mutant-HGG. Conversely, IDH1-mutations were detected in 20% of RRD-HGG. All patients (n=48) harboured germline mutations in MMR genes (CMMRD: 62%, Lynch syndrome: 38%). Contrary to sporadic IDH-mutant-gliomas, the majority (&gt;90%) were high-grade. Diffuse/multifocal involvement, predominantly involving the frontal lobe, was frequent. TMB was lower than IDH-wildtype RRD-HGG (median: 28 mutations/Mb, p&lt;0.05). Secondary POLE/POLD1 mutations were absent. TP53 and ATRX were frequent somatic hits. Copy number changes, particularly loss of CDKN2A/2B, were common. CD8-T-cell infiltration (immunohistochemistry) and tumor inflammation score (transcriptome) were lower than IDH-wildtype RRD-HGG (p&lt;0.05). A novel mouse model (Olig2Cre+/Msh2LoxP/LSL-Idh1R132H) revealed similar lower TMB, diffuse cerebral involvement, slower growth, and low immune infiltrates as compared with IDH-wildtype RRD-HGG models. IDHmut-RRD-HGG demonstrated worse survival as compared to sporadic IDH-mutant-HGG (p&lt;0.001). Within RRD-HGG, ICI monotherapy resulted in inferior survival in IDHmut-RRD-HGG vs IDH-wildtype RRD-HGG (p&lt;0.05). Five patients developed metachronous IDHmut-RRD-HGG while on anti-PD1 treatment for IDH-wildtype RRD-HGG, suggesting intrinsic resistance. Interestingly, an IDH-inhibitor demonstrated objective response in 4/8 IDHmut-RRD-HGG. Furthermore, for IDHmut-RRD-HGG on ICI treatment, the addition of an IDH-inhibitor prolonged survival at 12-months in comparison to those without (p=0.01).

CONCLUSION
Hypermutant RRD-HGG with IDH1;p.R132H harbour unique immuno-biology and do not respond to anti-PD1 monotherapy. The addition of IDH-inhibition demonstrated favourable responses, supporting need for evaluation of the combination in clinical trials.
HGG-17. DECIPHERING GENETICS AND EPIGENETICS OF HIGH-GRADE GLIOMAS WITH BRAF ACTIVATING ALTERATION IS SUPPORTING THE DISCOVERY OF A NEW INTRACRANIAL SARCOMA-LIKE BRAF POSITIVE ENTITY
Authors: Lhermitte Benoit , Wolf Thibaut , Reita Damien , Salmanli Chinar , Chammas Agathe , Deschuyter Marlène , Gauchotte Guillaume , Entz-Werlé Natacha 
Published: June 2024

Abstract

BACKGROUND
The current WHO classification of Central Nervous System tumors recognizes several glioma types driven by the BRAFV600E mutation. These tumors mostly encompass pediatric low-grade gliomas. Nevertheless, a subset of them behaves as anaplastic gliomas and, currently, the unique predictive criterion linked to anaplasia is an elevated mitotic index (more than 2.5 mitoses/mm2). Histologically, the high-grade gliomas harboring BRAFV600E alteration mostly correspond to WHO grade 3 pleomorphic xanthoastrocytoma, IDH wild-type glioblastoma, entering the WHO grade 4 subset like the epithelioid subtype, and the rarer high-grade gliomas with piloïd features. These tumor types share their histomolecular features making differential diagnoses difficult. In this setting, DNA methylation profiling may be very useful to precise the integrative diagnosis. However, some of those high-grade forms failed in our experience to be classified in any methylation class with v11b4 version of the Heidelberg classifier.

METHODS
To understand the reasons explaining this standard classification failure, we investigated with multi-omics approaches (epigenetics, next-generation sequencing, RNAseq, proteomics and metabolomics) a well clinical characterized cohort of 17 high-grade pediatric intracranial tumors harboring this mutation.

RESULTS
Interestingly, almost all tumors show similar morphological features and associated passenger molecular alterations mostly CDKN2A homozygous deletion. When using the new v12.5 brain tumor classifier, the methylation profiling of the 2/17 unclassified tumors was clustering with a new MPNST (Malignant Peripheral Nerve Sheath Tumor) methylation entity. The RNAseq and proteomics analyses were showing a different molecular pattern from standard BRAF-mutated high-grade gliomas, even the clinical, radiological and histomolecular characteristics were comparable.

CONCLUSION
So, methylation profiling should be part of the mandatory molecular assessments to perform when a BRAF-mutated tumor is seen by neuropathologists. Furthermore, the multiomics analyses helped us to define a specific molecular pattern of this new BRAF-driven entity, where frequency and prognosis need to be determined on another larger series.
HGG-32. PNOC008: A PILOT TRIAL TESTING THE CLINICAL BENEFIT OF USING MOLECULAR PROFILING TO DETERMINE AN INDIVIDUALIZED TREATMENT PLAN IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA (EXCLUDING DIFFUSE INTRINSIC PONTINE GLIOMA)
Authors: Franson Andrea T , Kilburn Lindsay B , Cooney Tab M , Stoller Schuyler , Reddy Alyssa T , Banerjee Anu , Packer Roger J , Bendel Anne E , Skrypek Mary M , Minturn Jane E , Abdelbaki Mohamed S , Whipple Nicholas S , Chan Priya , Crawford John R , Crotty Erin E , Waanders Angela J , Elster Jennifer D , Raabe Eric H , George Elizabeth , Pinto Soniya N , Vossough Arastoo , Kraya Adam A , Prados Michael , Kline Cassie , Nazarian Javad , Solomon David A , Long-Boyle Janel R , Molinaro Annette M , Waszak Sebastian M , Mueller Sabine 
Published: June 2024

Abstract

BACKGROUND
Children and young adults diagnosed with high-grade glioma (HGG) face extremely poor prognoses. Despite multiple clinical trials testing new treatments in this population, a survival advantage has yet to be achieved. Herein we assessed, in a single-arm, multi-center pilot trial, the feasibility of molecular profiling of primary HGG tumor tissue to create an individualized treatment plan with up to four FDA approved medications.

METHODS
Patients aged &lt;21 years with newly diagnosed, localized, hemispheric HGG (Stratum A) or midline HGG (non-DIPG; Stratum B) were eligible. Tumor tissue underwent comprehensive molecular profiling (targeted gene panel, whole exome, and whole transcriptome sequencing). Based on detailed review of the molecular data by a dedicated tumor board, an individualized treatment plan that combined up to four FDA approved drugs was recommended. Circulating tumor DNA (ctDNA), imaging, and quality of life (QOL) measures were collected at multiple timepoints.

RESULTS
Fifty-five patients enrolled between 2018 and 2023 (median age 11 years [range 2-20], n=31 female, n=29 Stratum A). The most common integrated diagnoses included H3K27-altered diffuse midline glioma (n=17), H3/IDH-wildtype diffuse pediatric-type HGG (n=16), and H3G34-mutant diffuse hemispheric glioma (n=12). Median overall survival (OS) from the time of study enrollment was 26.5 months in Stratum A (lower 95% CI: 18.7) and 21.7 months in Stratum B (lower 95% CI: 16.8), with a median follow-up of 35.4 months for all patients (lower 95% CI: 32.5). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophils (n=28), decreased platelets (n=22), and decreased white blood cells (n=16). As of December 2023, seven patients remain on therapy. Central imaging, ctDNA, and QOL analyses are underway.

CONCLUSIONS
A personalized treatment recommendation for children and young adults with HGG based on comprehensive transcriptomic and genomic analysis is feasible. Current survival data are encouraging, and molecular subgroup analyses are ongoing.
HGG-33. HIGH GRADE TRANSFORMATION OF CNS TUMOR WITH BCOR:CREBBP FUSION: A CASE REPORT
Authors: Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Shatara Margaret , Cluster Andrew , Abdelbaki Mohamed S , Brossier Nicole M 
Published: June 2024

Abstract

BACKGROUND
The discovery of unique EP300:BCOR and CREBBP:BCORL1 fusions has extended the spectrum of BCOR altered CNS tumors previously associated with BCOR internal tandem duplication (ITD). Due to the rarity of CNS tumors with BCOR alterations, there is limited information on the clinical outcomes and the effective treatment strategies.

METHODS
Literature review and retrospective chart analysis

RESULTS
An 18-year-old male who presented with seizures was found to have a left temporal mass. Histologic diagnosis was low grade glioneural tumor harboring a pathogenic CREBBP:BCOR1 fusion, matching to CNS tumor with EP300:BCOR/BCORL1 fusion by methylation. A re-resection aimed at gross total resection was then performed. Histologic examination revealed residual glioma with focal high-grade transformation, Ki67 up to 35% and CDKN2A loss via FISH analysis. The patient was treated with focal radiation to 54Gy. He remains disease- and seizure-free 1 month post radiation therapy. This case displayed some similarities to previously reported cases, including oligodendroglial- or ependymoma-like features, positivity for Olig2 and/or GFAP, presence of calcifications, and branching capillary networks. However, this case had less frequent mitoses than previously reported cases. In a series of 21 patients with BCOR altered tumors, BCOR-fusion tumor patients had a more favorable PFS compared to BCOR-ITD tumors. In a reported case series of high grade BCOR altered CNS tumors, 5 out of 8 patients remained alive, all of whom received radiation therapy as a primary treatment or at relapse. There is one prior report of an EP300:BCOR tumor undergoing high-grade transformation; increased mitoses, cellularity, and necrosis were observed. This case was lacked necrosis.

CONCLUSIONS
The optimal treatment for BCOR altered tumors of the CNS is largely unknown given the limited reported cases. Radiation therapy in addition to gross total resection may be an effective treatment leading to more favorable PFS and OS.
HGG-38. COMBINING TARGETED THERAPY AND RADIATION OUTPERFORMS SINGLE TREATMENTS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Chan Kenneth Chun-Ho , Hofmann Nina , Roscher Mareike , Euler-Lange Rosemarie , Steimel Kevin , Fransisca Mathea , Cais Alessia , Dokic Ivana , Jones David T W , Burhenne Jürgen , Kurth Ina , Pfister Stefan M , Zuckermann Marc 
Published: June 2024

Abstract

BACKGROUND
Pediatric-type diffuse high-grade gliomas (pHGGs) are a diverse group of central nervous system tumors in children and adolescents with typically fatal outcomes. Addressing this disease requires new treatment approaches to enhance both survival and quality of life for affected patients. Recently, targeting oncogenic receptor tyrosine kinases (RTKs) has provided promising initial responses in different pHGG subtypes. However, even in these cases, the disease invariably relapses.

METHODS
We utilized murine tumor cell cultures carrying oncogenic alterations in different RTKs, such as an NTRK fusion, an ALK fusion and activating FGFR1 mutations to evaluate the synergy of radiotherapy and a variety of specific small molecule inhibitors using viability and apoptosis assays. By conducting pharmacokinetic analyses in murine models, we quantified the availability of selected compounds in the mouse brain in vivo, informing downstream preclinical experiments.

RESULTS
We found that concomitant radiation potentiated the antitumor effect of all tested targeted compounds, mostly outperforming calculated additivity of single treatments. Of note, the level of potentiation was comparable between different inhibitors targeting the same RTK, but was highly dependent on the underlying tumor genotype. Using erdafitinib or futibatinib and a dose of 2 Gy in a FGFR1-driven pHGG model, the combined treatment resulted in a remarkably high late apoptosis rate of 90%, warranting ongoing in vivo studies. Through pharmacokinetic analyses, we identified that among all tested small-molecule-inhibitors, only lorlatinib and futibatinib reach clinically relevant concentrations in the murine brain.

CONCLUSIONS
Our preliminary data showed that the combination of targeted therapy and radiation elicits encouraging anti-tumor effects in different pHGG cultures. We are currently performing preclinical in vivo studies using immunocompetent orthotopic mouse models to evaluate benefits of combined treatment. Our data will inform future clinical trials and hopefully improve the prognosis and quality of life for a fraction of pediatric patients diagnosed with pHGG.
HGG-45. HIGH GRADE GLIOMA PRESENTING AS A SYNCHRONOUS CANCER IN A PATIENT WITH DIFFUSE LARGE B CELL LYMPHOMA: A UNIQUE TREATMENT DILEMMA
Authors: Kendel Nicole , Wilson Yelena , Wright Erin N 
Published: June 2024

Abstract

BACKGROUND
Patients with synchronous tumors pose significant treatment dilemmas. We present a pediatric patient found to have concomitant Diffuse Large B-cell Lymphoma (DLBCL) and a High Grade Glioma (HGG). His unique presentation and family history uncovered a familial diagnosis of Lynch Syndrome.

CASE
A 7-year-old male presented with acute appendiceal rupture. Surgical resection identified an appendiceal mass consistent with localized DLBCL. While undergoing staging evaluations, the patient complained of new onset blurry vision with normal neurologic and ophthalmologic exams. Subsequent imaging was concerning for a high-grade lesion. Biopsy confirmed HGG and he underwent gross total resection. Family history included a brother with relapsed leukemia status post bone marrow transplant and multiple first cousins with lymphoma and gastrointestinal cancers.

RESULTS
While awaiting genetics and mutational analysis, we initiated treatment. The HGG was treated with focal radiation to the tumor bed starting 2 weeks after resection. Lymphoma therapy was initiated concurrently per the REBOOT regimen with the goal of decreasing doxorubicin dosing during radiation. Lumbar punctures and intrathecal chemotherapy were deferred until completion of radiation. Biopsy of residual abdominal masses following consolidation 1 showed &lt;5% viable cells and therapy was intensified to ANHL1331, Group C1. Evaluation of both lesions identified hypermutation (mutational burden &gt; 150mutations/Mb). Two unique germline mutations of PMS2 were also identified, consistent with Lynch syndrome. After completion of above therapy, the patient received maintenance therapy with nivolumab checkpoint inhibition. The patient developed severe neutropenia leading to cessation of nivolumab and quick progression of his HGG.

CONCLUSION
Synchronous tumors pose significant treatment dilemmas given the need to treat multiple lesions while balancing side effects. While checkpoint inhibitors may provide a way to address multiple lesions, our patient had unacceptable side effects limiting the utility of this therapy.