bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-13. Clinical management and functional and survival outcomes in pediatric craniopharyngioma, a patient and family perspective
Authors: Marshall Emily , Cheng Sylvia , Crowley Julia , McCormack Shana , Rood Brian , Hankinson Todd , DeCuypere Michael , Lam Sandy , Goldman Stewart , Boekhoff Svenja , Muller Hermann L , Velasco Ryan , Storm Phillip B , Resnick Adam , Prados Michael , Mueller Sabine , Kline Cassie , Malbari Fatema 
Published: June 2022

Abstract
Craniopharyngiomas are rare, histologically benign, sellar/parasellar tumors with significant tumor and therapy related morbidity and impairment in quality of life (QOL). We report survey results from patients/families affected by childhood-onset craniopharyngioma to identify opportunities for improvement in management. An anonymous REDCap survey was distributed via social media and clinic visits to patients/families of craniopharyngioma survivors. Survey questions investigated perspectives on clinical management and functional and survival outcomes at initial diagnosis and recurrence. A total of 159 patients/families completed the survey, 40% (n=64) reported craniopharyngioma recurrence. For primary craniopharyngioma, maximal safe resection was the most frequent treatment reported (n=84), followed by partial resection (n=40), radiation (n=8), biopsy (n=5), and chemotherapy (n=3). Most patients (n=120) decided on a treatment plan within one week, 63 (40%) decided in one day. For recurrent craniopharyngioma, maximal safe resection and radiation were the most frequent interventions (n=33 each), followed by partial resection (n=13), chemotherapy (n=4) and biopsy (n=2). Multiple treatment options and/or participation in a clinical trial were offered to similar numbers of patients across primary and recurrent diagnoses (~21% for each). Most recurrent craniopharyngioma patients decided on management within one week (n=43). Long term effects related to tumor and treatment were identified as the primary concern in all respondents. The most common deficits for all patients were neuro-endocrine followed by vision and neurocognition problems. Neuro-endocrine complications were self-reported as the biggest impact on QOL. Families reported that they would prefer treatment options with the potential for improved QOL, even if these options also carried an increased risk of recurrence. Craniopharyngioma continues to be predominantly treated with surgery and radiation initially and with recurrence. Survivors have multiple comorbidities, with an interest in targeted therapies that preserve QOL. Novel therapies to prevent co-morbidities and provide long term benefits are necessary and upcoming.
RARE-21Sox2 plays an important role in choroid plexus tumor development
Authors: Faltings Lukas , Sarowar Tamanna , Virga James , Singh Navleen , Kwa Brightlyn , Zhao Haotian 
Published: June 2022

Abstract
Choroid plexus (CP) tumors are rare primary brain neoplasms found most commonly in children and are thought to arise from CP epithelial cells. Sox2 is a transcription factor that not only plays a role in development in the ventricular zone, CP, and roof plate, but also contributes to cancer stemness, tumorigenesis, and drug resistance. Gene expression studies demonstrate aberrant Sox2 expression in human CP tumors, suggesting a role in tumor development. A subset of CP tumors exhibit abnormal NOTCH pathway activity. Using animal models, we previously show that sustained NOTCH activity leads to CP tumors. Immunofluorescence, RT-qPCR, and RNA scope assays have revealed increased Sox2 levels in NOTCH-driven CP tumors compared to wild type CP in mice. To investigate the role of Sox2 in CP tumors, we eliminated Sox2 expression in NOTCH-driven CP tumors. Loss of Sox2 almost completely blocked NOTCH-driven CP tumor growth in these mice, supporting a role for Sox2 in these tumors. Ciliation regulation is one proposed functional pathway for tumorigenesis in CP tumors. Using immunofluorescence assays for cilia (ARL13b) and aquaporin transport protein 1 (AQP1) in combination with super resolution microscopy, we observe a stark contrast between wild type CP epithelial cells which are multiciliated and homogeneously express AQP1, indicative of normal epithelial differentiation, compared to NOTCH-driven CP tumors consisting of mono-ciliated cells with loss of AQP1 expression. In Sox2-deficient NOTCH-driven CP tumors, we observe tumor cells remain mono-ciliated and AQP1-negative, indicating that Sox2 loss does not affect the ciliation machinery. Together this warrants further study into the mechanisms of Sox2 functions in CP tumors. By unraveling the role of Sox2 in CP tumors, we may better understand their origin and biology to ultimately design improved treatment options.
RARE-24. The use of novelin vitro models to study adamantinomatous craniopharyngioma disease biology and drug response
Authors: Trudeau Tammy , Prince Eric , Chatain Oscar , Chee Keanu , Jackson Eric , Limbrick David , Naftel Robert , Feldstein Neil , Grant Gerald , Ginn Kevin , Niazi Toba , Smith Amy , Kilburn Lindsay , Chern Joshua , Drapeau Annie , Lam Sandi , Johnston James , Dudley Roy , Staulcup Susan , Hankinson Todd 
Published: June 2022

Abstract
BACKGROUND: Challenges around the design and investigation of cell culture models of adamantinomatous craniopharyngioma (ACP) have arisen from the cellular heterogeneity of these tumors, with populations that harbor disparate requirements in culture. Novel approaches to in vitro modeling of ACP are needed. METHODS: Intraoperatively collected tumor specimens were mechanically digested and plated under conditions tailored to the cell population of interest. ACP tumor-derived fibroblasts and epithelial cells were isolated using serum-containing and keratinocyte-specific media respectively. ACP-derived epithelial cells were immortalized via SV40 virus transfection and puromycin treatment for stable cell-line generation. Cell line validation included immunofluorescence with markers appropriate for the cell population of interest. RNA sequencing of cell lines was compared to ACP transcriptome reference data. Cell typing was conducted using short tandem repeat sequencing. RESULTS: ACP fibroblasts and ACP epithelial cells maintained spindle-like and cobblestone morphologies respectively, even after 4 passages. Immunofluorescence staining confirmed high levels of Vimentin expression in ACP-derived fibroblasts, and panCK and B-catenin in ACP-derived epithelial cells. Point mutation in exon 3 of the CTNNB1 gene was identified in ACP-derived epithelial cells. CONCLUSION: Initial limits related to cell line development in ACP may be addressed through the isolation and culture-specific ACP cell populations. This experience demonstrates the maintenance of validated markers of the cell populations of interest ex vivo. While preliminary, such cell lines offer promise as tools for the identification and study of potential therapeutic vulnerabilities in ACP.
RARE-26. Evaluating the clinical utility of DNA methylation profiling for choroid plexus tumors
Authors: Macrae Cassie , Gampel Bradley , Yeo Kee Kiat , Lidov Hart , Chi Susan , Wright Karen , Fehnel Katie , Baird Lissa , Aldape Ken , Alexandrescu Sanda , Clymer Jessica 
Published: June 2022

Abstract
INTRODUCTION: Choroid plexus tumors (CPT) are rare, potentially aggressive CNS tumors with defined histologic criteria for grading. In recent years, several patients within our practice have demonstrated discordance between histological diagnosis and clinical behavior. DNA methylation profiling has emerged as a potential diagnostic adjunct for aiding clinical planning and treatment approach. In this study, we sought to retrospectively evaluate the clinical utility of DNA methylation profiling within our cohort of patients with CPT. METHODS: We performed a retrospective chart review of all patients with choroid plexus tumors treated at Dana-Farber / Boston’s Children’s Cancer and Blood Disorder Center between 1990-2021, evaluating the histology, treatment approach, and clinical outcome. Available tissue samples were sent to the National Institute of Health for DNA methylation profiling. RESULTS: Seventeen patients with CPT were identified. Median age at diagnosis was 1.8 years (range: 0.4-27.7). Histologic diagnosis included choroid plexus papilloma (CPP; n=4), atypical choroid plexus papilloma (aCPP; n=5), and choroid plexus carcinoma (CPC, n=8). DNA methylation in an initial subset placed these tumors with the pediatric type A (n=5), pediatric type B (n=6), and adult (n=1) subgroups. For one patient, methylation profiling returned as unclassifiable (possibly representing an alternative diagnosis). Discrepancies with the histologic grade were noted in several cases: one patient diagnosed with CPP grouped with pediatric type B CPT on methylation analysis, had rapid recurrence, and a diagnosis of CPC was made on a re-resection specimen; another patient with aCPP with concerning features was classified as pediatric type A by methylation, and is without evidence of disease after initial complete resection. Survival outcomes based on histologic diagnosis and molecular subgroups are compared and reported. CONCLUSION: DNA methylation profiling is a useful tool for the diagnosis of CPT and may have the potential to guide clinical planning and management.
RARE-31. Radiation induced malignancy associated with pediatric craniopharyngioma: a single institution experience
Authors: Chien Franklin , Schniederjan Matthew , Castellino R C , Janss Anna , Esiashvili Natia , Eaton Bree , Indelicato Daniel , Mazewski Claire 
Published: June 2022

Abstract
BACKGROUND: Therapy for pediatric craniopharyngioma, a rare suprasellar tumor, includes surgical resection with consideration for intracranial radiation. Radiation is associated with increased risk of secondary malignancies. Between 2000 and 2021, 81 pediatric patients with craniopharyngioma were treated at our institution; 3 of 54 (5.6%) who received radiation therapy(RT) developed secondary malignancy within the treatment field. CASE DESCRIPTIONS: In all 3 cases, initial imaging demonstrated cystic/solid suprasellar mass and underwent resection; pathology revealed calcifications and wet keratin consistent with craniopharyngioma. None had known cancer predispositions. The first patient (male), presented at 4-years-old with headaches. He underwent subtotal resection (STR) with cyst fenestration(w/CF) and received 55.8Gy photon 3D-Conformal RT. Six-years later, the tumor progressed (edge of RT field). Patient underwent a second STRw/CF and fractionated RT(50.4Gy). Both pathologies were consistent with(c/w) papillary craniopharyngioma. Eight-years from first RT, progression occurred again within the RTfield; pathology revealed an (adeno)squamous carcinoma. The second patient, a 5-year-old female, presented with vision loss, underwent partial resection and received 54Gy focal proton therapy for adamantinonatous craniopharyngioma. Almost 5-years later, an unresectable right basal ganglia/globus pallidus mass was noted in the 30-54Gy field. Pathology was c/w anaplastic astrocytoma(AA). The third, a 9-year-old female was treated with 54Gy photon radiation and 7 years later had evidence of increasing mass. Pathology revealed high-grade-diffuse-glioma(HGDG). Molecular analysis of AA/HGDG both revealed PDGFRA amplification and CDKN2A/B homozygous loss. DISCUSSION/CONCLUSION: Malignant CNS tumors are reported following radiotherapy for a variety of primary CNS lesions. While radiation is a valuable therapy in achieving long-term disease control of pediatric craniopharyngiomas, it is important to understand the risk of developing secondary malignant neoplasms. Our report adds to the body of literature describing secondary malignancies post radiation therapy for the treatment of pediatric craniopharyngioma.
DIPG-01. Targeting p300: A master regulator of childhood diffuse intrinsic pontine glioma (DIPG)
Authors: Chowdhury Pinki , Lober Robert 
Published: June 2022

Abstract
Diffuse intrinsic pontine gliomas (DIPG) are heterogeneous, highly aggressive, accounting for ~10% of all childhood central nervous system tumors that are poorly understood. The heterogeneity of the cell populations could contribute to major variability in tumor growth and chemoresistance followed by inadequate treatment responses. Approximately 80% of DIPG patients harbor mutations on lysine-27 of histone-3 (H3K27M), which forms heterotypic nucleosomes with normal, acetylated-H3K27 (H3K27ac), and colocalizes with bromodomain proteins to sites of active transcription. p300 (or EP300) bromodomain has recently been exploited as a potential therapeutic target in other cancer, with a small molecule inhibitor showing antiproliferative activity. Bromodomain inhibitors (BrDi) have been suggested as a potential therapeutic target for DIPG too which showed antiproliferative activity in vitro. We therefore hypothesize that p300 bromodomain inhibition is a potential therapeutic strategy that must be urgently explored in DIPG. p300 is a multi-domain enhancer protein, expressed in 80% of gliomas, responsible for H3K27ac mark and localizes to sites of H3K27ac enrichment, where it serves as an essential binding partner of histones to various transcription factors. p300 interacts with BMI-1, a polycomb repressive complex 1 (PRC1) group of transcription factor, through an intermediate protein NANOG, which promotes cell proliferation in head-neck squamous cell carcinoma. However, immunohistochemical study demonstrated that there is no NANOG expression found in DIPG patient samples. Therefore, we propose that p300 and BMI-1 interact with each other directly or through an intermediate molecule, essential for tumor growth and thus can be considered as a possible therapeutic target for DIPG. The overall outcome of this research will reveal the unexplored mechanisms of DIPG cell proliferation to overcome chemoresistance in sick children and develop drug/combination against this deadly malignancy, which can be used for future clinical trials.
DIPG-05. How do potassium channels contribute to the growth and invasion of highly-aggressive brain cancers?
Authors: Boyle Yasmin , Fletcher Emily , Johns Terrance 
Published: June 2022

Abstract
Glioblastoma (GBM) is a lethal form of high-grade glioma with a dismal median survival time of just 15 months. Characterised by its’ highly diffuse and intrinsic growth pattern, GBM invades the healthy brain at an alarming rate. While diffuse midline glioma (DMG) is a much rarer disease, it is even more lethal, with a 5-year survival rate of just 2%. Though GBM is largely diagnosed in adults, DMG primarily affects young children aged 5-9 years and accounts for 10% of all childhood CNS cancers. Thus, while rare, DMG is highly aggressive and currently has no effective treatments to extend survival times beyond the median of 9 months. There is a pressing need for the development of novel and improved targeted therapies for each of these devastating diseases. Ion channels have long been implicated in the progression of numerous cancer types, due to their integral roles in proliferation, cell cycle transition, apoptosis, migration, and cellular plasticity. Voltage-gated potassium channels (VGKCs), in particular, have strong links to the key processes of proliferation, migration and invasion in GBM tumours. Given that the majority of GBM-related deaths are attributed to secondary tumours and metastasis, targeting proteins that are integral to these processes could result in reduced recurrence. Preliminary evidence suggests a potential role for the VGKC subtypes Kv5.1, Kv7.2, and the Kv4 subfamily in GBM and DMG, due to observed upregulation of these genes in both patient-derived cell lines and tumour samples. These particular VGKC subtypes are highly novel with regards to these cancers, while their significant upregulation suggests they may be associated with tumour progression. Thus, we aim to further explore the relationship between ion channel function and tumourigenesis in GBM and DMG, with a specific focus on VGKC subtypes and their potential therapeutic value.
DIPG-06. Uncovering the FACTs in Diffuse Midline Glioma (DMG)
Authors: Holliday Holly , Ehteda Anahid , Khan Aaminah , Krug Brian , Rouaen Jourdin R C , Jayatilleke Nisitha , Mayoh Chelsea , Vittorio Orazio , Jabado Nada , Tsoli Maria , Ziegler David S 
Published: June 2022

Abstract
Effective treatments are urgently needed for the incurable paediatric brainstem tumour Diffuse Midline Glioma (DMG). Most DMGs contain Histone H3 mutations (H3K27M), which produce extensive epigenetic dysregulation by inhibiting EZH2-mediated trimethylation of H3K27 (H3K27me3). Global depletion of the repressive H3K27me3 modification results in aberrantly open chromatin and is central to DMG tumorigenesis. Thus, targeting the epigenome is a promising avenue of treatment for DMG. We found that targeting the histone chaperone complex Facilitates Chromatin Transcription (FACT) with the curaxin drug CBL0137 to have potent pre-clinical efficacy against DMG, leading to a paediatric Phase I/II clinical trial for CBL0137 which includes a DMG/DIPG cohort (NCT04870944). In this project we aim to elucidate CBL0137’s molecular mechanism in DMG. FACT is critical for maintaining chromatin homeostasis during DNA replication, transcription, and repair. We therefore hypothesised that FACT maintains the aberrant epigenetic landscape resulting from H3K27M. Consistently, we found CBL0137 to be more cytotoxic against H3K27M-mutant, compared to H3-WT or isogenic DMG cells lacking the mutation. Furthermore, FACT directly interacts with H3K27M, and FACT inhibition increases both EZH2 catalytic activity and global H3K27me3 levels. We are now using ChIP-seq to discover the genome-wide distribution of FACT and H3K27M, and will interrogate the consequence of CBL0137 treatment on the epigenome and transcriptome. Preliminary results suggest that FACT is located at certain genes co-occupied by H3K27M, the active histone mark H3K27ac, and the BET protein BRD4. This implies that FACT is involved in maintaining open chromatin and perhaps transcription at these regions. Combining CBL0137 with other epigenetic drugs, such as BET inhibitors, could therefore represent a rational therapeutic opportunity for DMG. This work will ultimately inform mechanism-based targeted therapies to combine with CBL0137 to improve its efficacy and uncover valuable new insights into DMG epigenetics and pathobiology.
DIPG-09. Diffuse Midline Glioma-Adaptive Combinatory Trial (DMG-ACT): A biology-driven platform trial in pediatric and young adult patients with diffuse midline glioma
Authors: Franson Andrea , Kline Cassie , Molinaro Annette , Zhang Yalan , Hitchner Kelly , Koschmann Carl , Nazarian Javad , Mueller Sabine 
Published: June 2022

Abstract
BACKGROUND: Despite advances in our understanding of the biology of diffuse midline gliomas (DMGs), little progress has been made in improving outcomes. Therapy development is limited by lack of preclinical data across multiple model systems and laboratories; limited knowledge about blood-brain barrier penetrance; and lack of multi-agent therapies. We aim to address these issues through DMG-ACT, where we translate robust preclinical data using ONC201 as the therapy backbone in a multi-arm, combination strategy within an innovative trial design. DESIGN: DMG-ACT is an open-label, multi-institutional trial of combination therapy for patients with DMG between 2 and 39 years of age. The trial utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows ongoing assessment of therapy efficacy with borrowing of data across different arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. ONC201 is the backbone therapy in each arm and given in combination with other agents that show additive or synergistic benefit in preclinical testing. Patients enter into one of three cohorts: newly diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). The cohorts offer a target validation option to assess intratumoral pharmacokinetics and pharmacodynamics of drug given prior to tumor biopsy. Cohort 1 and 3 offer radiation or re-irradiation with concomitant single agent therapy followed by maintenance combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohort 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentration, toxicity profile of combination therapy during radiation therapy, toxicity profile and efficacy of combination therapy, CSF and ctDNA analysis, and health related quality of life, cognitive, and patient/proxy-reported outcome measures. This trial was successfully launched in November 2021 with updates to be presented at the meeting.
DIPG-10. A Phase I trial of panobinostat following radiation therapy in children with diffuse intrinsic pontine glioma (DIPG) or H3K27M-mutated thalamic diffuse midline glioma (DMG): Report from the Pediatric Brain Tumor Consortium (PBTC-047)
Authors: Monje Michelle , Cooney Tabitha , Glod John , Huang Jie , Baxter Patricia , Vinitsky Anna , Kilburn Lindsay , Robison Nathan J , Peer Cody J , Figg William D , Fouladi Maryam , Fangusaro Jason , Onar-Thomas Arzu , Dunkel Ira J , Warren Katherine E 
Published: June 2022

Abstract
INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children with progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving children with non-progressive DIPG/DMG using an alternative schedule. Primary objectives were to describe the toxicity profile and define the MTD; secondary objectives were to describe progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with non-progressive DIPG or H3K27M-mutated thalamic DMG were eligible &gt;14 days following standard radiation therapy only. Panobinostat was given every other day, 3x/week, on alternate weeks. Patients who received at least one dose of panobinostat were evaluable for toxicity. Four dose levels (DL) were evaluated: DL1 (16mg/m2/dose), DL2 (22 mg/m2/dose), DL3 (28 mg/m2/dose) and DL4 (36 mg/m2/dose). Dose escalation was determined by a continuous reassessment method. Correlative studies included pharmacokinetics obtained on course 1, day 1, and day 3 prior to subsequent dosing. RESULTS: Thirty-four eligible patients (median age, 7.6 [3-16] years) were enrolled with 29 evaluable for dose finding; DL1, n=3; DL2, n=10; DL3, n=11; DL4, n=5. The primary toxicities were myelosuppression and gastrointestinal. Eight DLTs occurred: DL2, Grade 3 thrombocytopenia (n=1); DL3, Grade 4 neutropenia (n=3), Grade 4 neutropenia and Grade 4 thrombocytopenia, (n=1); DL4, Grade 2 nausea (n=1), Grade 3 increased ALT (n=1), Grade 4 thrombocytopenia (n=1). Median PFS from drug initiation was 4.4 (1-11.2) months; median OS from diagnosis was 11.7 (4.5-25) months. These did not significantly differ from the PBTC historical cohort (PFS, p-value 0.4967; OS, p-value 0.6457). CONCLUSION: The MTD of panobinostat administered on this schedule to children with non-progressive DIPG/DMG is 22 mg/m2/dose. The primary DLT was myelosuppression. There was no significant improvement in PFS or OS in this cohort.