bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-07. BONE MARROW ABLATIVE CHEMOTHERAPY ASSOCIATED WITH IMPROVED OUTCOMES AMONG PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Abu-Arja Mohammad H , McGlynn Mary Claire , Zaghloul Mohammed Saad , Elhemaly Ahmed , Bertrand Kelsey , Gajjar Amar , Ronsley Rebecca , Cappellano Andrea M , Dassi Natalia , Czogala Malgorzata , Graham Richard , Baglivo Sofi Jares , Dhall Girish , Nagabushan Sumanth , Abdelbaki Mohamed S 
Published: June 2023

Abstract

PURPOSE
Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor outcomes. There is no universal agreement on managing these patients secondary to the rarity of the disease and lack of prospective trials. We aim to explore prognostic factors that may help guide the management of patients with relapsed/refractory CNS NGGCTs.

METHODS
We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. We summarized all data 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) using SPSS software.

RESULTS
We identified 28 patients from 7 centers. Twenty-three patients (82%) were males. The median age at initial diagnosis was 11 years (range: 8-15). Twelve patients (43%) suffered from relapse, and 16 patients (57%) had an initial refractory disease. The median time to first relapse/progression was 29 months (range: 5-26). Eight patients (29%) received bone marrow ablative chemotherapy (HDCx) at relapse/progression. Sixteen patients (57%) received re-irradiation at relapse/progression. Six patients (21%) achieved complete remission (CR) at relapse. Only eight patients (29%) were alive at the last follow-up. The median follow-up time since relapse/progression was 16 months (range: 1 -153 months). HDCx (OR=25, 95%CI: 2.9-2223) – not re-irradiation (OR=7.8 95%CI: 0.795-76.1) – was associated with being alive at the last follow-up. All patients who achieved CR at the end of relapse treatment survived. Only one patient with the refractory disease was alive at the last follow-up.

CONCLUSIONS
Patients with refractory CNS NGGCTs have dismal outcomes. HDCx and achieving CR at the end of relapse therapy are associated with improved survival. A multinational registry is needed to collate standardized data to inform future prospective clinical trials and improve the outcomes of patients with relapsed/refractory CNS NGCCTs.
OUTC-01. ESTABLISHING THE PSYCHOMETRIC VALIDITY OF ATTENTIONAL MEASURES APPLIED TO THE PAEDIATRIC NEURO-ONCOLOGY POPULATION: A SYSTEMATIC REVIEW
Authors: Verity Sarah , Hagan Alexander 
Published: June 2023

Abstract
BACKGROUND: Associated with hydrocephalus, cranial irradiation, and certain chemotherapeutic agents, impairment in attention is a common feature of childhood brain tumour survivorship. Attentional processes are implicated in a number of cognitive functions, supporting sustained and selective attention, inhibition of competing stimuli, and management of divided attention (multi-tasking). Acquired attentional deficit reported in childhood survivors of brain tumour is correlated with reduced academic attainment, slowed intellectual development, poor peer relationships, and lower overall quality of life. Accurate identification of tumour-related attentional impairment is a prerequisite to access appropriate rehabilitative intervention. Despite this, no attentional measures have been adequately normed on the paediatric brain tumour population. As such, there exists little agreement as to which measure is most suitable for current research or clinical practice. AIM: This prospective study will assess the utility of common measures of childhood attention used in the paediatric Neuro-Oncology population. METHOD: Comprehensive database searches will be conducted to identify relevant articles that address the validity, reliability, and capability of attentional measures currently used within paediatric Neuro-Oncology populations. The psychometric properties and clinical utility of each measure will be reviewed using a purpose-developed evaluative tool. The strengths and limitations of particular measures when applied to this clinical population will be discussed. Recommendations for the utility for and against measures in future research or clinical application will be provided. FINDINGS: Analyses of these data continues with an aim to present initial findings by May 2023.
OUTC-03. IMPACT OF TREATMENT EXPOSURES AND SOCIOECONOMIC STATUS ON NEUROCOGNITIVE PERFORMANCE IN CHILDREN WITH BRAIN TUMORS
Authors: Chang Leslie , Patel Palak , Peterson Rachel , Acharya Sahaja 
Published: June 2023

Abstract

PURPOSE
To investigate the impact of treatment exposures and socioeconomic status on neurocognitive performance in children with brain tumors.

METHODS
Eligible patients included those diagnosed with a brain tumor at &lt;22 years of age with ≥ 1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age standardized measures of intellectual function. Neurocognitive outcomes included Wechsler indices of full-scale intelligent quotient (IQ), working memory (WM), and processing speed (PS). Neurocognitive decline was defined as a negative slope. Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models.

RESULTS
Eligible patients (n=152) had a mean neurocognitive follow-up of 50.2 months and median age at diagnosis of 9.6 years. PS was most frequently impaired in patients (37.5%) followed by IQ (20.6%) and WM (16.5%). Patients with public insurance had eight-fold increased odds of impaired IQ compared to those with private insurance (Odds Ratio [OR]: 7.59, p&lt;0.001). Patients treated with CSI had eight-fold increased odds of impaired IQ (OR: 7.86, p=0.003) and almost six-fold increased odds of impaired WM (OR: 5.66, p=0.028) compared to those treated without RT. After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, p=0.012). Patients treated with both chemotherapy and RT demonstrated the greatest decline whereas those treated without either demonstrated no decline in any of the neurocognitive measures.

CONCLUSION
After treatment for pediatric brain tumors, public insurance, an indicator of low socioeconomic status, was associated with impairment in IQ with a large effect size similar to that of CSI. Chemotherapy was associated with decline in IQ with a small effect size. Combined chemotherapy and RT had additive effects on neurocognitive decline in IQ, WM, and PS.
OUTC-04. SUBSEQUENT CNS MALIGNANCY AMONG SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)
Authors: Galvin Robert , Chen Yan , Yuan Yan , Cooney Tabitha , Howell Rebecca , Smith Susan , Arnold Michael , Conces Miriam , Leisenring Wendy , Robison Leslie , Armstrong Gregory , Neglia Joseph , Turcotte Lucie 
Published: June 2023

Abstract
Subsequent malignant neoplasms (SMNs) of the central nervous system (CNS) following childhood cancer are a frequently fatal late effect of cancer therapy. We used the CCSS (5-year childhood cancer survivors, diagnosed 1970-1999) to assess whether temporal changes in therapy have reduced CNS SMN risk. Twenty-year cumulative incidence rates (95% confidence interval) were estimated, and standardized incidence ratios (SIR, 95% CI) were calculated comparing observed to expected rates from SEER. Multivariable models assessed demographic and treatment-related risk factors for CNS SMN. Among survivors diagnosed between 1970-1979 (N=6223), 1980-1989 (N=9680), and 1990–1999 (N=8999) with median follow-up of 40.5, 32.2, and 22.6 years, respectively, 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas. Malignant gliomas (N=131) were the most common SMNs. Cranial radiotherapy (CRT) exposure decreased by treatment decade, with the proportion of survivors receiving no CRT increasing from 23.0% (1970s), to 45.7% (1980s), and 66% (1990s). Decreases in &gt;0–10Gy exposure (39.0% to 14.1%) and 20.1–30Gy (19.2% to 2.4%) were observed while those receiving &gt;30Gy CRT has not substantially changed (12%, 11.1%, and 8.8%, respectively). Twenty-year cumulative incidence and SIR for development of SMN were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant differences between treatment eras, including when stratified by attained age. Multivariate analysis showed increased risk for all CRT dose levels &gt;10Gy and for primary diagnoses of medulloblastoma/PNET (HR 3.6, 2.0-6.6) and astrocytoma (HR 2.4, 1.4-3.9). Three-year cumulative incidences of death after SMN, by treatment decade, were 70%, 73%, and 69%, respectively. In conclusion, CNS SMN incidence has not decreased despite fewer survivors being treated with CRT, and CNS SMNs remain a significant source of mortality for affected patients.
HGG-10. A SAFETY AND EFFICACY STUDY OF NOVOTTF-100A FOR PEDIATRIC HIGH-GRADE GLIOMA: RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE FIRST THREE CASES
Authors: Makimoto Atsushi , Terashima Keita , Nishikawa Ryo , Fujisaki Hiroyuki , Kurihara Jun , Ihara Satoshi , Adachi Jun-ichi , Enokizono Mikako , Morikawa Yoshihiko , Yuza Yuki 
Published: June 2023

Abstract

BACKGROUND
The safety and efficacy of Tumor-Treating Fields (TTFields) therapy for pediatric diffuse high-grade glioma (HGG) are uncertain. Despite differences between adult GBM and pediatric HGG in terms of genetic etiology, both have certain clinical behaviors in common, allowing TTFields therapy to be tested in pediatric HGG.

METHODS
The present study [jRCTs032200423] aims to evaluate the safety of NovoTTF-100A in pediatric HGG and conduct an exploratory analysis of its efficacy. The target population is ten children aged 5 to 17 years with newly diagnosed supratentorial HGG or its first-recurrence following frontline therapy. After completion of surgical resection of the tumor and radiation therapy, all the patients will receive TTFields therapy using NovoTTF-100A for 28 days per course for up to 26 courses until the end-of-therapy criteria (including disease progression) are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various efficacy parameters and quality of life. In total, the ten patients will be enrolled by September 2023.

RESULTS
The planned interim analysis, which was done in October 2022, included 3 female patients aged 14, 17, and 9 years, respectively. All had a histological grade 4 tumor, two of which were radiation-induced secondary HGG. Although the first patient with recurrent disease had early progression after enrollment and experienced disease-related adverse events, no serious, treatment-related toxicities or device-related issues were observed. The second patient had a recurrence after six courses, and the third patient remained through the second course. All 3 patients were able to maintain device usage of 75% or more of the time, in alignment with use recommendations, suggesting treatment feasibility.

DISCUSSION
Based on the results presented above, the study was resumed as the current, multicentric study aimed at obtaining approval for the expanded use of NovoTTF-100A for pediatric HGG.
HGG-13. ONCOGENIC STAT3 AND SHP2 ACTIVATION IN ROS1-FUSION DRIVEN INFANT-TYPE HEMISPHERIC GLIOMAS
Authors: Postlmayr Andreas , De Micheli Andrea , Hofmann Nina , Zuckermann Marc , Stücklin Ana Guerreiro 
Published: June 2023

Abstract
Genomic analyzes identified a subgroup of gliomas – infant-type hemispheric gliomas – that are driven by oncogenic fusions of, amongst others, ROS1 receptor tyrosine kinase with a variety of fusion partners. These fusions result in ligand independent constitutively active oncogenic kinases. In the present study we aim to identify the, yet poorly characterized, alterations in cellular signaling driven by ROS1 fusions leading to tumor formation to enhance our understanding of IHG formation and to identify complementary targets for therapy. To answer these questions, we deploy a combination of biochemical characterization of cellular models as well as in vivo experiments and transcriptomic and phosphoproteomic analyzes. Expression of different ROS1-fusions results in robust tumor formation in two different mouse models, proving their tumorigenic potential. The impact of the fusion partner, which dictates subcellular localization, as shown by immunofluorescence microscopy, on differences in tumor formation has not yet been established. Transcriptomic and phosphoproteomic analyses of ROS1-fusion cellular models revealed diverging effects of the fusions on transcriptomic and proteomic alterations. A common denominator, however, is a significant hyper-phosphorylation of the tyrosine phosphatase SHP2, which we established to be a direct substrate of ROS1. ROS1 fusions, irrespective of the fusion partner, drive non-canonical STAT3 signaling, indicated by direct phosphorylation of STAT3 by ROS1 and upregulation of STAT3 target genes. Characterizing the main signaling pathways using immunoblots did not detect alterations in the PI3K/AKT/mTOR or MAPK pathways. STAT3 signaling is a well characterized pathway for promoting pro-survival, proliferation and stemness cues in development and cancer, making it a paramount candidate for ROS1 driven tumorigenesis as well as an excellent target for targeted therapies.
HGG-22. PROGNOSTIC FACTORS FOR PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH NON-DIPG GRADE 4 GLIOMAS: A CONTEMPORARY POOLED INSTITUTIONAL EXPERIENCE
Authors: Matsui Jennifer , Allen Pamela , Perlow Haley , Johnson Jason , Paulino Arnold , McAleer Mary , Fouladi Maryam , Grosshans David , Ghia Amol , Li Jing , Zaky Wafik , Chintagumpala Murali , Palmer Joshua , McGovern Susan 
Published: June 2023

Abstract

BACKGROUND
WHO grade 4 gliomas are rare tumors in the pediatric and AYA (adolescent and young adult) population. In this study, we evaluate prognostic factors, toxicities, and outcomes in the pediatric versus AYA population.

METHODS
This retrospective pooled institutional study included patients &lt; 30 years old with grade 4 gliomas. Overall survival (OS) and progression free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis.

RESULTS
Ninety-seven patients (n=20 &lt; 15y, n=77 ≥ 15y) were identified with a median age 23.9y at diagnosis. Most had biopsy-proven glioblastoma (91%) and the remainder had diffuse midline glioma, H3K27M-altered (9%). All patients received surgery and adjuvant radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection was associated with better PFS in multivariate analysis [HR 2.00 (1.01–3.62), p = 0.023]. Age ≥15y was also associated with improved OS [HR 0.36 (0.16–0.81), p = 0.014] while female gender [HR 2.12 (1.08–4.16), p = 0.03] and K27M altered histology [HR 2.79 (1.11–7.02), p = 0.029] were associated with worse OS. Only 7% of patients experienced grade 2 toxicity during radiation. Sixty-two percent of patients experienced tumor progression, 28% local and 34% distant. Analysis of salvage treatment found reirradiation was not associated with improved OS, but second surgery and systemic therapy significantly improved survival from the time of tumor progression.

CONCLUSIONS
Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. Diffuse midline glioma was associated with worse OS compared to hemispheric glioblastoma; this may be related to lack of effective targeted therapies. Surgery and systemic therapy were effective salvage options that significantly improved outcome. Better understanding of prognostic factors may guide future treatment within this understudied patient population, and prospective studies are warranted.
HGG-27. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASK FORCE
Authors: Negm Logine , Nobre Liana , Bennett Julie , Chung Jiil , Komosa Martin , Fernandez Nick , Ku Michelle , Johnson Monique , Bianchi Vanessa , Aronson Melyssa , Zhang Cindy , Stengs Lucie , Lim-Fat Mary Jane , Keith Julia , Tsang Derek , Gao Andrew , Munoz David G , Nguyen Lananh , Das Sunit , Levine Adrian , Das Anirban , Resnick Adam , Wheeler David , Hawkins Cynthia , Tabori Uri 
Published: June 2023

Abstract
Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond to immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) or Constitutional Mismatch Repair Deficiency (CMMRD). However, the prevalence of MMRD in gliomas of children, adolescents, and young adults (CAYA), and impact of germline inheritance is unknown. We utilized functional genomic tools on population-based and validation cohorts from 3 large databases (Toronto, St-Jude and CBTN) to determine the prevalence, subgroup, and impact of germline mutations on MMRD-gliomas. Ongoing data on 998 pediatric-gliomas from Toronto reveals that MMRD is extremely rare in pediatric low-grade gliomas (PLGG) but common in pediatric high-grade gliomas (PHGG) (9%, p&lt;0.0001). Similarly, data from St-Jude and CBTN (n=374) reveals that MMRD exists only in PHGG (8%). In both cohorts, MMRD-PHGG are enriched for RAS/MAPK, IDH, and TP53 mutations while pediatric-type fusions, BRAF-V600E and histone mutations are absent. In AYA-HGG (n=884), the most common groups include glioblastomas without chromosome-7/10 alterations (9%) and IDH1-astrocytomas, while MMRD is not present in IDH-oligodendrogliomas. All but 1 CAYA-MMRD-gliomas harbored germline MMR mutations. Data from the IRRDC on 174 patients reveal that LS is more common than CMMRD in gliomas, with the median age of onset 11 and 29 years in CMMRD and LS, respectively (p&lt;0.001). Furthermore, CMMRD gliomas are commonly caused by germline PMS2 and MSH6 mutations, enriched for secondary polymerase mutations (60%, p&lt;0.001), and exhibit ultra-hypermutation. In contrast, LS-gliomas are caused by MSH2 and MLH1 mutations, and enriched for IDH1 mutations (32%, p&lt;0.025) with a lower mutational burden. Our data reveals high prevalence of MMRD in CAYA-HGG with alarming impact of germline predisposition. Specifically, unrecognized LS patients with AYA MMRD-HGG. These findings support universal screening for MMRD in HGG to identify patients for immunotherapy and surveillance.
IMG-02. VISUALIZATION OF TIGIT IN THE GLIOMA MICROENVIRONMENT: THE CREATION OF A PET IMAGING TRACER
Authors: Frederico Stephen , Vincze Sarah , Nisnboym Michal , Li Bo , Sneiderman Chaim , Server ReidAnn , Day Kathryn , LaToche Joseph , Nedrow Jessie , Edwards Wilson , Kohanbash Gary 
Published: June 2023

Abstract
Pediatric high-grade gliomas (HGGs) are aggressive tumors and are one of the drivers of pediatric brain tumor mortality. Few effective treatment options exist for pediatric HGGs beyond surgery and chemoradiation. Additionally, some HGGs, such as diffuse midline glioma, are often surgically inaccessible and respond poorly to chemotherapy leaving radiotherapy as the only treatment for this disease. While immune checkpoint inhibitors (ICIs) have seen success in treating cancers outside the CNS, ICIs for gliomas have shown limited efficacy.
TIGIT is an IC receptor that is expressed on activated T-cells and has a critical role in suppressing T-cell and NK cell function. Prior work by our group has shown TIGIT to be a promising target for adult gliomas. These studies included analysis of transcriptomic data, and preclinical studies in glioma-bearing mice. We therefore assessed pediatric glioma transcriptomic datasets and identified via optimal cutoff analysis that at a specific mRNA threshold, TIGIT expression is associated with worsened survival. As TIGIT expression may be both prognostic and a biomarker for anti-TIGIT ICI therapy, we created a radiolabeled immunoPET tracer capable of binding TIGIT antigen that could be visualized via PET imaging.
Referred to as “89Zr-DFO-TIGIT”, we found this tracer bound TIGIT with moderate immunoreactivity (57.7% ± 3.5%) as determined by bead-based immunoreactivity assays. As proof of feasibility, we injected glioma-bearing mice (GL261 cell line) with 89Zr-DFO-TIGIT which enabled the visualization of TIGIT in the tumor microenvironment via PET imaging. Thereafter, we performed biodistribution studies which found there to be significantly increased 89Zr-DFO-TIGIT in mouse tumor-bearing hemispheres as compared to non-tumor-bearing hemispheres. PET imaging also showed tracer-to-tumor uptake increased from day one to day eight.
Our findings demonstrate the capability of 89Zr-DFO-TIGIT to visualize and quantify TIGIT in the glioma microenvironment, highlighting how this tracer may be of value in pediatric brain tumor immunotherapy studies.
IMG-07. MOLECULAR PROCESSES GIVE RISE TO EMERGENCE OF RADIO-PHENOTYPES ON MRI SCANS OF PEDIATRIC LOW-GRADE GLIOMA
Authors: Kazerooni Anahita Fathi , Kraya Adam , Kim Meen Chul , Haldar Debanjan , Rathi Komal , Mahtabfar Aria , Familiar Ariana , Khalili Nastaran , Naqvi Ammar , Koptyra Mateusz , Bagheri Sina , Anderson Hannah , Ware Jeffrey B , Storm Phillip B , Vossough Arastoo , Resnick Adam C , Davatzikos Christos , Nabavizadeh Ali 
Published: June 2023

Abstract
There is mounting evidence that tumor microenvironmental pressure selects for somatic genetic alterations that contribute to the formation of distinct morphological characteristics, captured on radiology scans as radio-phenotypes. Such phenotypic variations are a source of heterogeneity in clinical manifestation of tumors of the same histology across the patients, and in part, their heterogeneous responses to therapies. Deeper understanding of the associations between genotype and radio-phenotype in pediatric low-grade glioma (pLGG), the most histologically diverse childhood brain tumor, may facilitate precision diagnostic and therapeutic approaches. Here, we categorize pLGGs into distinct and relatively homogeneous imaging subtypes based on radiomic features and further explore the associations of these imaging subtypes with genotype. From multiparametric MRI scans of 167 pLGGs from the Children’s Brain Tumor Network (CBTN), 881 radiomic features and clinical variables (tumor location, age, and gender) were extracted. After dimensionality reduction using principal component analysis (PCA), K-Means clustering was applied on 19 principal components to group the patients into three imaging subtypes. Using whole transcriptomic data from OpenTargets, differential expression and co-expression of network- and pathway-level and immune-related signaling were compared among these three imaging subtypes. Gene Set Enrichment Analysis (GSEA) revealed differentially higher expression of cell cycle regulatory, extracellular matrix (ECM) remodeling, and cell migratory pathways in imaging subtype1 than subtypes 2 and 3, and upregulation of ECM and immune-related pathways in subtypes 1 and 2 compared to subtype3. Based on Gene Sets Net Correlations Analysis (GSNCA), subtype1 exhibited differential co-regulation of TNF/TNFR1 signaling compared to subtype2, and differential co-regulation of RHOG GTPase and TGFB1pathways when compared against subtype3. Subtype2 showed differential co-regulation in NOTCH1 signaling and transcriptional regulatory pathways. Our proposed multi-disciplinary radiomic-genomic analysis approach elucidates the molecular and biological processes in the genotype of the tumors that are associated with emergence of distinct imaging subtypes in pLGG.