bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-76. ONC201 INHIBITS THE CHARACTERISTICS OF CANCER STEM CELLS IN GROUP 3 MEDULLOBLASTOMA
Authors: Abballe Luana , Antonacci Celeste , Gianesello Matteo , Lago Chiara , Mastronuzzi Angela , Catanzaro Giuseppina , Giannatale Angela Di , Tiberi Luca , Locatelli Franco , Miele Evelina 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB), the most frequent childhood brain tumor, originates in the cerebellum. Despite treatment advances, recurrence affects 40%, with a mortality rate of 30%. Cancer stem cells drive tumor initiation, maintenance, and therapy resistance, in several tumors including MB (MBSC). In response to stress, stem cells activate mechanisms like the unfolded protein response (UPR) to maintain homeostasis and survive adverse conditions. The UPR restores endoplasmic reticulum balance, supporting cell function and survival. Recent studies have shown that the UPR plays an important role in tumorigenesis, however, its function in MBSC remains unknown.

METHODS
To understand the involvement of the UPR in stem cell maintenance, we have investigated the biological effects of its pharmacological inhibition on Group 3 (G3) MBSC. We selected three G3 MB cell lines (D283-Med, D341-Med and Med411), for in vitro studies. Cell line selection was based on their fidelity to the expected methylation class, corresponding to the subgroup of the parental tumors, and were grown in “stem-like” conditions as neurospheres. We evaluated drugs targeting the UPR stress program, identifying ONC201 as the most effective against MBSC. ONC201 is an imipridone compound that activates p53-independent apoptosis causing changes in gene expression similar to those caused by UPR.

RESULTS
Our findings revealed that ONC201 modulates protein synthesis via ATF4, a pivotal UPR molecule, with stronger induction observed in MB cells cultured under “stem-like” conditions. This ATF4 upregulation triggers the activation of pro-apoptotic programs. Additionaly, ONC201 was effective on reducing the stem-like features of MBSC, including self-renewal, stem cell markers expression, migration, and invasion potential. Notably, ONC201 demonstrates synergy with vincristine and methotrexate chemotherapy.

CONCLUSIONS
These results propose ONC201 as a promising agent for targeting G3 medulloblastoma by compromising the stem cell compartment. Further investigation is warranted to confirm its efficacy and potential clinical application.
MDB-92. EFFECT OF REDUCED-DOSE CRANIOSPINAL IRRADIATION AND REDUCED-DOSE ADJUVANT CHEMOTHERAPY ON CHILDREN AND ADOLESCENTS WITH WNT MEDULLOBLASTOMA WITHOUT RESIDUAL OR METASTATIC DISEASE: RESULTS FROM THE SJMB12 CLINICAL TRIAL
Authors: Robinson Giles W , Merchant Thomas E , Orr Brent A , Bass Johnnie K , Conklin Heather M , Bag Asim , Dhanda Sandeep K , Pinto Soniya , Delaney Angela , Mikkelsen Margit , Reddick Wilburn , Huang Jie , Ashford Jason , Edwards Angela , Christy Leigh Ann , Soans Eroica , Clarke Molly , Strother Doug , Fisher Michael J , Bendel Anne , Hwang Eugene I , Zhao Sibo , Smith Amy , Gottardo Nicholas G , Hassall Timothy E G , Elster Jennifer , Perreault Sebastien , Ramaswamy Vijay , Partap Sonia , Laughton Stephen , Cohn Richard , Chintagumpala Murali , McCowage Geoffrey , Sullivan Michael , Sayour Elias , Bowers Daniel , Marks Asher , Lucas John , Tinkle Christopher , Sabin Noah D , Klimo Paul , Ellison David W , Northcott Paul A , Onar-Thomas Arzu , Gajjar Amar 
Published: June 2024

Abstract

BACKGROUND
In response to studies showing medulloblastoma (MB) survival is not only contingent on clinical factors (e.g. metastases, residual disease) but also on molecular factors (e.g. molecular group, gene aberrations), we launched the SJMB12 (NCT01878617) trial to stratify treatment using both clinical and molecular risk factors. Specifically, we sought to evaluate if patients with WNT-group MB, without metastatic (M0) or residual disease (R0), treated with reduced-dose craniospinal irradiation (CSI) and reduced-dose cyclophosphamide-based chemotherapy could maintain a high survival with fewer treatment-related side effects.

METHODS
Tumors were molecularly stratified via immunohistochemistry and fluorescence in-situ hybridization. Patients with WNT tumors were grouped into 3 strata: W1 (M0, R0, classic histology, monosomy of chromosome 6); W2 (M0, R0, without monosomy 6 or classic histology); W3 [metastatic (M+), residual disease (R+), or MYC/MYCN amplification]. Treatment of W1 consisted of 15-Gy CSI/51-Gy primary site (0.5cm CTV margin) followed by 4 cycles of chemotherapy resulting in cumulative doses of 8 mg/m2 vincristine, 300 mg/m2 cisplatin, 12 gm/m2 cyclophosphamide. Serial audiology, neurocognitive, and endocrine evaluations were conducted over a six-year follow-up period.

RESULTS
From 2013-2022, 72 patients enrolled onto the W1 stratum: median age was 10.3 years (4.9-22.0); 62.5% female; median time of follow-up was 4.5 years (1.1-10.1). 5-year progression-free survival (PFS) and overall survival were 90.4 ± 5.1% and 98.6 ± 2.1%, respectively. Five patients had PFS events: 4 relapses and 1 accidental death. Relapsed disease was local in 2, distant in 1, and mixed in 1. Time to relapse was &gt; 2 years from enrollment for 3 patients. Severe ototoxicity (SIOP grade ≥ 3) at the end of therapy occurred in 14.4 ± 4.5%. Neurocognitive, endocrine, and detailed molecular data are forthcoming.

CONCLUSIONS
Patients with low-risk WNT-MB maintained a high PFS (&gt;90%) when treated with reduced-dose CSI and reduced-dose cyclophosphamide-based chemotherapy. Preliminary data suggests fewer treatment-related side effects.
NFS-03. MEDULLOBLASTOMA IN CHILDREN WITH FANCONI ANEMIA: ASSOCIATION WITH FA-D1/FA-N, SHH TYPE AND POOR SURVIVAL INDEPENDENT OF TREATMENT STRATEGIES
Authors: Sönksen Marthe , Obrecht-Sturm Denise , Driever Pablo Hernáiz , Sauerbrey Axel , Graf Norbert , Kontny Udo , Reimann Christian , Kordes Uwe , Schwarz Rudolf , Obser Tobias , Boschann Felix , Schüller Ulrich , Altendorf Lea , Goschzik Tobias , Pietsch Torsten , Mynarek Martin , Rutkowski Stefan 
Published: June 2024

Abstract

BACKGROUND
Outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not systematically been described. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study provides a comprehensive overview about clinical and molecular characteristics of pediatric FA MB patients.

METHODS
Clinical data including detailed information on treatment and toxicities of six previously unreported FA MB patients were supplemented with data of 16 published cases.

RESULTS
We identified 22 cases of children with FA and MB with clinical data available. Biological subgroup was SHH in all cases with data available (n=9), confirmed by methylation profiling in five patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n=16) or FA-N (n=3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT)±chemotherapy (27%). 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. 14 patients (63.6%) developed 20 other malignancies, of which ten occurred before, five simultaneously with and five after MB diagnosis. Median overall survival (OS) was 1 year (95%CI 0.3-1.9). 1-year-progression-free-survival (PFS) was 26.3±10.1% and 1-year-OS was 42.1±11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3±12.9%/33.3±12.2% with adjuvant therapy, p=0.006/p=0.086), with no difference whether the patient had received chemotherapy only or RT±chemotherapy.

CONCLUSIONS
MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may improve survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Unlike in standard MB protocols, focal RT may be considered in FA MB patients. Curative therapy for FA MB-SHH remains an unmet medical need.
NFS-06. MANAGEMENT TRENDS OF MEK INHIBITOR DERMATOLOGIC ADVERSE EVENTS FOR NEUROFIBROMATOSIS PATIENTS
Authors: Parisi Rose , Dhulipalla Sanjana , Widemann Brigitte , Pichard Dominique C , Gross Andrea , Weintraub Lauren 
Published: June 2024

Abstract

BACKGROUND
Selumetinib, a MEK inhibitor (MEKi), is approved for the treatment of plexiform neurofibromas (PN) in pediatric neurofibromatosis (NF) patients. In pivotal trials, nearly 70% of participants had PN shrinkage; however, 93% experienced a rash. This is the first study to characterize management trends of MEKi induced dermatologic adverse events (DAEs).

METHODS
Physicians treating NF patients were surveyed to assess MEKi DAE frequency, treatment, and effect on MEKi therapy. The survey was distributed using the Children’s Tumor Foundation listserv.

RESULTS
The survey was completed by MD/DOs (n=15) who were pediatric hematologists/oncologists (n=13) and pediatric neurologists (n=2). Physicians treated pediatric patients (n=8), adult patients (n=2), or both (n=5). Common DAEs included folliculitis (range:10-50% of treated patients; n=11), xerosis (range:1-80%;n=8), acneiform eruptions (range: 20-80%;n=10), eczematous dermatitis (range: 10-80%;n=12), paronychia (range: 10-80%;n=12), and seborrheic dermatitis (range:1-60%;n=8). Approximately half of physicians (n=8) used prophylactic DAE treatment. Prophylaxis for pre-pubertal patients included emollients (n=4), bleach baths (n=2), topical clindamycin (n=1), and doxycycline (n=1). Post-pubertal prophylaxis included emollients (n=5), doxycycline (n=5), topical clindamycin (n=4), bleach baths (n=1), and topical hydrocortisone (n=1). Almost all physicians modified MEKi treatment at least once because of a DAE (n=14), including dose hold (range: 1-25%;n=10), dose reduction (range:1-25%;n=10), and MEKi discontinuation (range:1-25%;n=8). Of the 10 physicians who reported dose holds, 6 were from physicians utilizing prophylactic therapy. Of the 8 physicians who reported MEKi discontinuations, only 3 were reported by physicians utilizing prophylactic therapy.

CONCLUSIONS
Most physicians modified MEKi treatment for DAEs, and many started prophylactic DAE therapy. The benefit of prophylactic treatment cannot yet be determined. Given the low response rate, future research will be aimed at collecting more data. There is a need for more studies to establish standardized treatment guidelines to reduce the frequency of MEKi modifications secondary to DAEs.
NFS-20. DECIPHERING CELLULAR CROSSTALK IN PERIPHERAL NERVOUS SYSTEM TUMORS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1 THROUGH SINGLE-CELL RNA SEQUENCING
Authors: Freund Julia , Robl Bernhard , Gabler Lisa , Machreich Sarah , Madlener Sibylle , Baumgartner Alicia , Lötsch-Gojo Daniela , Azizi Amedeo , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by mutations and dysfunctional expression of neurofibromin 1 gene, a critical tumor-suppressor gene. NF1’s complex pathophysiology involves dysregulation of the RAS-MAPK signaling pathway, resulting in sustained MAPK signaling. Among others, the spectrum of clinical features includes low-grade tumors (e.g. plexiform neurofibromas (pNFs)) and malignant peripheral nerve sheath tumors (MPNST). While surgical removal of peripheral nerve tumors is common, total resection is often unattainable. Additionally, approved therapies comprising MEK inhibitors fail to prevent malignization, highlighting the urgent need for novel targets for effective therapies.

METHODS
To explore novel potential targets across a broad spectrum, we analyzed published scRNA-seq datasets (Kershner et al. 2021, Wu et al. 2022) from human patients, including pNFs and MPNSTs. We further investigated key pathways in vitro with patient-derived cell culture models.

RESULTS
ScRNA-seq provides insight into complex networks of cell-to-cell interactions that drive the malignant phenotype of cancerous tissues. Due to the rich presence of ECM in NF1 tumors we aimed to investigate cell types contributing to key extracellular matrix (ECM) components and associated signaling pathways. Analysis of 19 NF1 tumor samples revealed consistent presence of Schwann cells (SCs), fibroblasts, endothelial cells, and immune cells. Proliferating cells were found in MPNSTs, while pericytes were exclusive to pNFs. We compared secreted and ECM signaling between the cell types of both tumors. Our analysis discovered, among other findings, collagen signaling, highlighting fibroblasts as emitters and SCs as receivers. We further confirmed these findings through culturing of NF1-derived cells in vitro with and without collagen, observing increased cell proliferation in the presence of collagen. Further experiments and analyses are ongoing.

CONCLUSIONS
The emphasis on ECM and signaling adds depth to our understanding of NF1 pathogenesis and suggests potential therapeutic targets.
NFS-29. DEVELOPMENTAL SCREENING AND MONITORING IN NEUROFIBROMATOSIS-1
Authors: Janke Kelly , Lawler Danielle , Kearns Zoe 
Published: June 2024

Abstract

BACKGROUND
Pilot data showed developmental screening at Neurofibromatosis-1 (NF1) appointments is feasible to identify those needing neuropsychology or other referrals. Outcomes for this larger sample, many re-screened and/or seen for a neuropsychology visit, allow us to describe evolving clinical management.

METHODS
Screenings are offered annually (ages 2-17) at NF1 clinic appointments by the psychosocial team. Forty-eight early childhood patients (ages 2-5) were screened (54% male, 66.7% White,) while 35 were ineligible (e.g., recent neuropsychology visit) or experienced logistical barriers to screening. These groups did not differ in race/ethnicity, sex, glioma status, or childhood opportunity index. Parents completed well-validated measures including the PEDS: Developmental Milestones – Assessment Level (PEDS:DM), Modified Checklist for Autism in Toddlers, and/or an ADHD Rating for preschoolers.

RESULTS
On initial screens, 73.9% showed a delay of 25% or more on at least one PEDS:DM domain. Measures often aligned with clinical impressions (81.3%); however, when findings were contextualized with record review, there were false positives (8.3%) and negatives (10.4%). Screening identified emerging concerns in attention, fine-motor, and academic skills. Nearly half (47.9%) of patients had services at the time of screening, and new/modified recommendations were offered for 70.8%. One third were referred to our Education Coordinator or Social Worker for educational advocacy, support through Early Intervention/school evaluation, or outpatient referrals. Twenty-two (45.8%) were referred to Neuropsychology and 18 have now been seen (consultation, targeted testing, or comprehensive evaluation) to confirm or rule-out neurodevelopmental diagnoses (e.g., autism, ADHD, language or global delay) and further guide educational or intervention management. Follow-up screens (N = 21) have monitored developmental progress, previously subclinical symptoms rising to a significant level, and need for re-evaluation or additional services.

CONCLUSIONS
Multipronged systematic screening results in referrals for diagnostic clarity, guides transition from Early Intervention to school services, and supports dynamic management of changing concerns.
QOL-02. PREDICTING NEUROCOGNITIVE OUTCOMES AMONG CHILDREN EXPERIENCING VARYING DEGREES OF POSTOPERATIVE POSTERIOR FOSSA SYNDROME
Authors: Conklin Heather M , Raches Darcy , Khan Raja B , Ashford Jason M , Lin Tong , Onar-Thomas Arzu , Potter Brian S , Klimo, Jr Paul , Gajjar Amar , Robinson Giles W 
Published: June 2024

Abstract

BACKGROUND
Postoperative posterior fossa syndrome (PFS) has historically been diagnosed as present vs. absent despite a continuum of severity in presentations. We recently demonstrated categorizing children into PFS1 (complete mutism) and PFS2 (diminished speech) has prognostic utility for neurological recovery. Given children who experience PFS are also at increased risk for neurocognitive impairments, we investigated whether these PFS variants predict neurocognitive outcomes while considering well-established risk factors (i.e., age and treatment intensity).

METHODS
Children treated for medulloblastoma at St. Jude on a prospective, risk-stratified protocol (SJMB12; NCT 01878617) were study eligible if they had at least two neurocognitive evaluations. SJMB12 participants received neurological and neurocognitive evaluations prior to irradiation and annually for 5 years. Neurocognitive outcomes included intellectual functioning (Wechsler Intelligence Scale for Children [WISC-IV] estimated IQ [EIQ]), processing speed (WISC-IV Processing Speed Index [PSI]), working memory (WISC-IV Working Memory Index [WMI]), and adaptive functioning (Behavior Assessment System for Children [BASC2] Activities of Daily Living [ADL]).

RESULTS
149 patients (age at diagnosis= 10.7±5.6; 64% male; 9% 15Gy, 40% 23.4Gy, 51% ≥36Gy) were included. No significant differences between PFS1 (n=34) or PFS2 (n=16) compared to NonPFS (n=99) were identified in age, sex, or irradiation dose (ps&gt;.05). Multivariable linear mixed models indicate NonPFS have better EIQ than PFS1 and PFS2 (p&lt;.03), with EIQ improving over time (p=.01). NonPFS have better PSI than PFS1 and PFS2 (p&lt;.001). PSI declines over time irrespective of age (p&gt;.05); however, PSI declines for those receiving 36Gy while improving for those receiving 15Gy (p&lt;.001). NonPFS have better WMI than PFS1 and PFS2 (p&lt;.05); older age at diagnosis is associated with improvement in WMI over time (p&lt;.0005). ADL declines only in PFS1 patients (p&lt;.05).

CONCLUSIONS
PFS variants add value beyond established risk factors in predicting neurocognition. Severity of PFS, in addition to treatment intensity, predicts worse outcomes.
QOL-38. PSYCHOSOCIAL OUTCOMES OF CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG) –PROSPECTIVE, LONGITUDINAL PROMIS ASSESSMENTS OF PATIENTS ENROLLED ON CONNECT PHASE I CLINICAL TRIALS
Authors: Wright-Nadkarni Mariah L , Moscato Emily L , Stanek Joseph R , Schaefer Megan R , Gerhardt Cynthia A , Ashley David M , Baxter Patricia A , Chi Susan N , Dorris Kathleen , Fisher Michael J , Hummel Trent R , Hwang Eugene I , Gass David , Leary Sarah E S , Pillay-Smiley Natasha , Plant Ashley S , Murala Mythili , Mikael Leonie , Fouladi Maryam , Lazow Margot A 
Published: June 2024

Abstract

INTRODUCTION
Given poor prognoses, children with DIPG/HGG may experience psychosocial sequelae throughout their illness journey, negatively impacting quality of life (QOL). We prospectively assessed caregiver-proxy and patient-reported psychosocial outcomes of children with DIPG/HGG enrolled on two early-phase CONNECT trials.

METHODS
Patient-Reported Outcomes Measurement Information System (PROMIS) short forms were administered monthly to patients ≥8 years and caregivers of patients aged 5-17 years while enrolled on two phase I clinical trials for newly-diagnosed DIPG/HGG involving upfront radiotherapy (RT) and concurrent and/or adjuvant oral agents. T-scores (M=50, SD=10) were calculated relative to the general population for emotional distress (Anxiety and Depression) and relationship quality (Peer Relationships and Family Relationships). Linear mixed modeling compared scores at pre-RT, post-RT, 1 month pre-progression, and end of therapy (EOT). Spearman’s correlations were calculated.

RESULTS
Twenty-eight patients (median age=10 years; DIPG [n=23]; HGG [n=17]) and 40 caregivers participated. Patient and caregiver-proxy reports demonstrated comparable levels of emotional distress and relationship quality to norms and were stable over time. The proportion of patients endorsing mild or greater impairment in emotional distress (T-score &gt;55) was relatively comparable at pre-RT (Anxiety & Depression=26%), post-RT (Anxiety=36%, Depression=23%), and 1 month pre-progression (Anxiety=23%, Depression=36%), with more patients endorsing impairment (Anxiety=58%, Depression=67%) at EOT, often corresponding to disease progression; though differences were not statistically significant. Caregiver-proxy and patient-reported scores were similar across all timepoints and domains, with a pattern of higher caregiver-reported versus patient-reported emotional distress (Spearman’s Rho range: 0.62-0.67;p&lt;0.0001).

CONCLUSIONS
Children with DIPG/HGG and their caregivers reported comparable emotional functioning and relationship quality to the general population. Caregivers slightly overestimated psychological distress compared to youth self-reports. Findings may reflect resilience of this population when faced with adversity, while highlighting benefit of psychosocial supports and low therapy toxicity on QOL. Future analyses will compare psychosocial, physical, and functional symptoms.
QOL-41. FEASIBILITY OF PREOPERATIVE NEUROPSYCHOLOGICAL EVALUATION IN PEDIATRIC BRAIN TUMOR PATIENTS: IS IT POSSIBLE TO ASSESS BEFORE SURGERY?
Authors: Esteso-Orduña Borja , Vázquez-Gómez Felisa , Moreno-Carrasco José Luis , Pérez-Somarriba Marta , Castellano Serafín , Cartas-Carrión Susana , Cantarín Verónica , Cámara-Barrio Silvia , Galas Sebastián , Mingarro-Mezquita Roser Mingarro Mezquita , Alonso-García Isis , Castillo Concepción Fournier-Del , Lassaletta Álvaro 
Published: June 2024

Abstract

BACKGROUND
We aim to evaluate the feasibility of pre-surgical neuropsychological assessment in pediatric brain tumor patients and to examine the impact of various factors on cognitive changes during follow-up.

METHODS
Between 2021 and 2023, we analyzed the timing of pre-surgery neuropsychological evaluations, completion rates, referral sources, non-referral rates, as well as general cognitive ability, executive and socioemotional functioning in relation to clinical variables.

RESULTS
There were 11 preoperative evaluations (mean referral time=2.45 days) and 12 postoperative but pre-oncologic evaluations, reflecting the timing of referrals (M=13.92 days). Referrals came mainly from oncology (17 patients) and rehabilitation (6 patients) teams. Ten patients lacked preoperative or pretreatment neuropsychological referral, 7 discontinued follow-up, and 7 died. 10 patients showed full cooperation, 4 families didn’t complete questionnaires, 3 assessments were adapted due to clinical conditions, 1 patient did not cooperate and 7 were developmental assessments. Six patients’ IQ or Development Quotient (DQ) was below normal at preoperative assessment, despite a group mean of z=0.22. Only three patients had a developmental delay diagnosed at time of presurgery evaluation, 2 of whom had comorbid AED. The remaining patients had no previous diagnosis. At post-treatment evaluation, 15 patients experienced a significant decline in IQ/DQ (t=5.157; p=0.000) and worsened in executive functioning (t=-2.462; p=0.042), while 8 patients improved IQ/DQ scores (t=3.672; p=0.008) with no significant changes in executive (t=1.462; p=0.203) or socioemotional (t=-0.218; p=0.836) functioning.

CONCLUSIONS
Early neuropsychological assessment is paramount in pediatric patients with a brain tumor. However, it is not always feasible and presents significant challenges: requiring adaptation to the patient’s clinical status, coordination across departments, and managing the family’s emotional response to potential diagnoses. Incorporating preoperative neuropsychological assessment into care protocols is essential to analyze premorbid cognitive and behavioral functioning and to improve patient management and guide targeted interventions.