bluuebunny/crossref_metadata_2025 huggingface dataset:
MDB-87. REAL-LIFE EXPERIENCE WITH A “MEMMAT-LIKE” METRONOMIC REGIMEN FOR RELAPSED/REFRACTORY MEDULLOBLASTOMA
Authors: Cacchione Antonella , D’Antonio Federica , Ruscio Valentina Di , Megaro Giacomina , Baldo Giada Del , Liguoro Ilaria , Tornesello Assunta , Cocciolo Alessandro , Vennarini Sabina , Chiesa Silvia , Carai Andrea , Colafati Giovanna Stefania , Mastronuzzi Angela
Published: June 2024

BACKGROUND

Standard salvage regimen for medulloblastoma’s relapse is currently lacking. An evolving alternative approach is metronomic chemotherapy, which aims to interfere with tumor angiogenesis. We report our experience on a modified combinatorial metronomic chemotherapic/antiangiogenic approach, the Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial (MEMMAT) regimen. Our study aimed to test efficacy and tolerance of that approach in pediatric patients with relapsed/refractory medulloblastoma treated in outpatient unit.

METHODS

The study was conducted from January 2017 to December 2022 at Bambino Gesù Children’s Hospital in Rome. MEMMAT-like regimen consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by intravenous bevacizumab and intrathecal topotecan.

RESULTS

Fourteen patients met the eligibility criteria. At diagnosis, six patients (43%) presented a localized disease, the other eight patients (57%) metastatic one; eight patients had the first recurrence and six had multiple recurrences at the start of MEMMAT-like therapy. At relapse, all the recurrences had a metastatic pattern. Methylation profiling classification showed three subgroups 3, six subgroups 4, three with SHH subgroup, and two WNT. The median overall survival after the recurrence that prompted to the use of MEMMAT like regimen, for the whole group, was 17,9 months (range, 8-32 months), with 79% (60%,100%) at 12 months and 19% (5,7%-64%) at 24 months; the mean progression-free survival (PFS) at 12 and 24 months was 57% (36%-90%) and 26% (10%-66%). When the one-year PFS rate was evaluated according to the MEMMAT-like number of treatment lines (after the first relapse or third and beyond), we found respectively 62% (37%-100%) and 50% (22%100%).

CONCLUSIONS

The metronomic outpatient MEMMAT-like combination is feasible, well tolerated, and can lead to sustained control of relapse in medulloblastoma. The best setting seems to be after the first relapse to achieve a higher PFS.
MDB-103. THE SIGNIFICANCE OF CEREBROSPINAL FLUID CYTOLOGY IN SURVEILLANCE FOR RECURRENT MEDULLOBLASTOMA
Authors: Arja Mohammad Hatim Mohammad Abu , Okcu Fatih , Su Jack , Aldave Guillermo , Mohila Carrie , Blessing Melissa , Chintagumpala Murali M
Published: June 2024

BACKGROUND

Surveillance of patients with medulloblastoma includes magnetic resonance imaging of the brain and spine and cerebrospinal fluid (CSF) cytology evaluation. Certain protocols require frequent CSF cytology evaluations off-therapy while others perform CSF cytology only at the time of radiographic relapse. We wanted to determine the incidence of isolated CSF positivity at the time of recurrence and the outcome of these patients.

METHODS

We performed a retrospective analysis of patients with relapsed medulloblastoma treated at Texas Children’s Hospital between 1997 and 2023.

RESULTS

Out of 223 patients with medulloblastoma, 45 patients developed recurrences. Twenty-five (55.5%) patients underwent lumbar puncture for CSF cytology at the time of relapse. The radiographic distribution of recurrences was focal (n=7), focal and disseminated (n=6), disseminated (n=11), and negative imaging (n=1). Seven out of the 25 (28%) patients had positive CSF cytology for malignant cells at initial relapse. All seven patients succumbed secondary to disease progression. Among 18 patients who had negative CSF cytology at recurrence, three infant patients at initial diagnosis were disease-free following craniospinal radiation at recurrence. Only one among 25 patients had positive CSF cytology without radiographic evidence of relapse. Among ten patients with focal disease at the time of relapse, seven had negative CSF cytology for malignant cells, and three did not have CSF cytology evaluated at the time of relapse.

DISCUSSION

Frequent evaluation of CSF cytology to detect recurrence may not be necessary in addition to imaging studies. In our study, it did not influence the outcome of patients with recurrence. Prospective studies are necessary to support periodic CSF surveillance to detect ctDNA, which may allow for early interventions that may influence outcomes in patients with recurrent medulloblastoma who have poor outcomes.
MDB-109. CHARACTERIZING DISTINCT SIGNATURES OF RNA TRANSLATIONAL REGULATION UPON MYC OVEREXPRESSION IN H9 NEURAL STEM CELLS
Authors: Dasgupta Anwesha , Yanuzzi Ian , Ruiz-Orera Jorge , Prensner John R
Published: June 2024

BACKGROUND

Medulloblastoma (MB), a childhood brain tumor, emerges typically between 6-8 years, originating from cerebellar neuronal stem cells. Recurrent genetic alterations, notably MYC amplifications, are associated with poor therapy response. Subgrouped as WNT-MB, SHH-MB, Group 3 MB, and Group 4 MB, Group 3 MB is characterized by high-level MYC amplification in approximately 17% of cases. Patients with Group 3 MB and MYC activation present distinct transcriptional and proteomic signatures, including elevated levels of ribosomal proteins and ribosome assembly proteins.

METHODS

We conducted a comprehensive analysis of RNA-seq and Ribo-seq in human neural stem cells (H9 NSCs) with amplified MYC expression. H9-NSCs were cultured in tumor stem media and transduced with lentivirus for either GFP control or MYC cDNA. RNA and ribosome-protected fragments were isolated from cell lysates for RNA-seq and Ribo-seq in biological triplicates. Ribo-seq data was analyzed using ORFquant for coding sequence quantification and deltaTE for translational efficiency.

RESULTS

Overexpressing MYC in H9-NSCs led to significant differential expression of 4194 genes (p adj < 0.05) using RNA-seq and 2860 genes (p adj < 0.05) using Ribo-seq. While RNA-seq and Ribo-seq exhibited high correlation for most genes, we identified 364 differentially translated genes (p adj < 0.05) upon MYC overexpression. Genes regulated solely at the translational level were enriched for functions in cytoplasmic translation initiation, viral translation, and response to interleukin-4. Key genes highly regulated at the Ribo-seq level included CCND3, YBX1, and EEF2. Validating with proteomics data from the CPTAC medulloblastoma tissue set confirmed protein-specific upregulation of these targets in MYC-driven Group 3 medulloblastomas.

CONCLUSIONS

MYC overexpression revealed distinct behaviors in differentially expressed genes, either regulated at the level of translation alone, correlated with transcription, or independent of transcription. We anticipate that our findings will contribute to a refined understanding of the molecular landscape of MB, particularly in the context of Group 3 MB.
NFS-05. INCIDENCE OF BEVACIZUMAB ASSOCIATED TOXICITY IN CHILDREN WITH LOW GRADE GLIOMA WITH AND WITHOUT NF1
Authors: Yelak Alexander , Hamdani Gilad , Dagan Amit , Michaeli Orli , Toledano Helen
Published: June 2024

BACKGROUND

Low grade gliomas (LGG), both sporadic & Neurofibromatosis1 (NF1) associated, are the commonest pediatric brain tumors. When surgically unresectable, they may become progressive/ symptomatic and require chronic oncological treatment. Bevacizumab (BVZ; Avastin), a recombinant humanized monoclonal antibody to VEGF, has shown efficacy both as a single agent or combined with chemotherapy as second/ third line treatment of progressive LGG especially in the optic pathway. BVZ can be associated with adverse effects including hypertension (HTN) and proteinuria. Children with NF1 have known increased tendency to hypertension however there is no data comparing the frequency of side effects from BVZ in patients with or without NF1.

METHODS

Retrospective study of all LGG cases treated with BVZ diagnosed 2010-2023 in a tertiary oncology center. We graded hypertension, proteinuria, cardiac function, retinopathy & bleeding according to the CTCAE v5.0 in NF1 and non-NF1 patients.

RESULTS

16 children with LGG were treated with BVZ; 7 had NF1. 75% optic glioma, 25% other. All received BVZ as second or third line treatment in combination with chemotherapy. In the non NF1 group, 77% patients developed grade 2 HTN on BVZ treatment; none required medical intervention. 6 had grade 1 elevation of protein-creatinine ratio (median 0.38). In the NF1 group, 71% developed grade 2 or 3 HTN on BVZ treatment including a patient with aortic coarctation (CoA) who had worsening of previous HTN, 2 required antihypertensive therapy (p non-significant HTN non NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. Hypertension was reversible after cessation of BVZ in all except the patient with CoA.

CONCLUSIONS

Hypertension is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG. Blood pressure should be monitored and treated appropriately. BVZ is safe in young patients with NF1.
NFS-09.NF1 MUTATION IN OLIGODENDROCYTE PRECURSOR CELLS LEADS TO PRENEOPLASTIC LESION FORMATION IN THE BRAIN
Authors: Pan Yuan , Hysinger Jared , Yalçın Belgin , Lennon James , Byun Youkyeong Gloria , Raghavan Preethi , Schindler Nicole , Anastasaki Corina , Chatterjee Jit , Ni Lijun , Xu Haojun , Malacon Karen , Jahan Samin , Ivec Alexis , Aghoghovwia Benjamin , Mount Christopher , Nagaraja Surya , Scheaffer Suzanne , Attardi Laura , Gutmann David , Monje Michelle
Published: June 2024

Oligodendrocyte precursor cells (OPCs) are progenitor cells that give rise to central nervous system oligodendrocytes throughout life. Transcriptomic and lineage tracing studies suggest that OPCs may be the putative cell of origin for many glioma histologic subtypes. While children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to low-grade gliomas following bi-allelic NF1 loss, the cellular and molecular etiologies underlying tumorigenesis remain incompletely elucidated. Using a unique collection of genetically engineered Nf1 mouse strains, we identified discrete hyperdense lesions composed of OPCs. The OPCs within the lesions display a transient increase in proliferation and hypercellularity (hyperplasia). This phenotype was not observed following heterozygous mutation in other tumor suppressors (Trp53, Pten, or Rb1). OPC-specific heterozygous Nf1-mutant mice harbored similar lesions, suggesting an OPC-intrinsic phenotype. OPC-specific Nf1 loss resulted in increased OPC density throughout the entire brain, suggesting that the lesions in heterozygous Nf1-mutant mice represent spontaneous OPC Nf1 loss-of-heterozygosity events. Mechanistically, monoallelic KRAS hyperactivation phenocopies OPC hyperdensities in the brain of Nf1+/- mice; however, KRAS hyperactivity is not necessary for lesion formation or expansion. When the brains of mice engineered with heterozygous NF1 patient-derived Nf1 mutations were examined, the development of hyperdense OPC lesions reflected RAS-independent dysregulated PI3K-AKT signaling. Collectively, our study reveals a potential mechanism driving the development of preneoplastic lesions in the brains of individuals with NF1.
NFS-18. LOWER BODY SURFACE AREA IS ASSOCIATED WITH INCREASED LIKELIHOOD OF PLEXIFORM NEUROFIBROMA RESPONSE TO MEK INHIBITION
Authors: Kotch Chelsea , Dombi Eva , Gross Andrea , Weiss Brian , Mueller Sabine , Reddy Alyssa T , Perreault Sébastien , Alves Mélanie , Brown Symone , Li Yimei , Widemann Brigitte C , Fisher Michael J
Published: June 2024

BACKGROUND

MEK inhibitors (MEKi) are altering the management approach for plexiform neurofibroma (PN), with high rates of treatment response to multiple MEKi. Despite these successes, a subset of PN fail to respond and little is known about the clinical features associated with treatment response.

METHODS

We performed a retrospective cohort study integrating clinical trial data (NCT01362803, NCT02407405, NCT02096471, NCT03231306, NCT03363217) to identify baseline clinical features associated with response of PN to MEKi. Partial response (PR) was defined as ≥20 percent reduction in tumor volume from baseline.

RESULTS

Of 232 eligible participants, adequate clinical trial and imaging data was available for 223 participants. In the primary analysis of 184 participants with central response evaluation, the median age was 15.2 years with a median tumor volume of 488 milliliters at clinical trial enrollment. One hundred and eighteen (64%) participants achieved a PR with median time to PR of 8 cycles. Thirty-five participants (19%) required a dose reduction prior to 6 cycles of therapy due to toxicity. Younger age and lower body surface area (BSA) were significantly associated with PR in univariate analysis while female sex and typical PN appearance (versus nodular) on imaging approached significance. In multivariable analysis, only lower BSA was significantly associated with response while typical PN appearance approached significance. In the multivariable analysis of pediatric participants treated per BSA-based dosing, lower BSA was the only feature significantly associated with PR. In the expanded analysis of all 223 participants, lower BSA and typical PN appearance were significantly associated with PR.

CONCLUSION

Lower BSA and typical appearance of PN were associated with PR to MEK inhibitors. Future studies of MEK inhibitor for PN should integrate tumor pharmacokinetic-pharmacodynamic analyses to prospectively explore the impact of BSA on treatment response.
NFS-21. DEMOGRAPHIC, CLINICAL AND IMAGING CHARACTERISTICS OF NEWLY DIAGNOSED OPTIC PATHWAY GLIOMAS ASSOCIATED WITH NF1: RESULTS FROM THE INTERNATIONAL MULTICENTER NF1-OPG NATURAL HISTORY STUDY
Authors: Fisher Michael J , de Blank Peter , Listernick Robert , Liu Grant , Ferner Rosalie , Gutmann David , Lasky-Zeid Janice , Ullrich Nicole , Heidary Gena , Bornhorst Miriam , Stasheff Steven , Rosser Teena , Borcher March , Arden-Holmes Simone , Flaherty Maree , Hummel Trent , Motley Walker , Bielamowicz Kevin , Phillips Paul , Bouffet Eric , Reginald Arun , Wolf David , Peragallo Jason , El-Dairi Mays , Van Mater David , Sato Aimee , Tarczy-Hornoch Kristina , Klesse Laura , Hogan Nick , Foreman Nicholas , McCourt Emily , Allen Jeffrey , Ranka Milan , Campen Cynthia , Beres Shannon , Moertel Christopher , Areaux Ray , Stearns Duncan , Orge Faruk , Crawford John , O’Halloran Henry , Oattes Julius , Reddy Alyssa , Brodsky Michael , Esbenshade Adam , Donahue Sean , Cutter Gary , Avery Robert
Published: June 2024

BACKGROUND

Treatment and clinical management decisions for children with NF1-OPGs remain challenging as most existing data are retrospective and have not included standardized visual outcomes. In this study, we prospectively enrolled newly diagnosed NF1-OPGs and performed standardized neuro-oncology and ophthalmology assessments in order to develop evidence-based guidelines for monitoring and treatment.

METHODS

Children with NF1-OPG on MRI who were evaluated by both a study ophthalmologist and neuro-oncologist/NF1 expert within 1 month of radiologic diagnosis were eligible for enrollment. All subjects attempted quantitative visual acuity using Teller acuity cards (TAC) as well as ATS-HOTV testing. The neuro-oncologist/NF1 expert provided reasons for obtaining the MRI as well as initiating treatment, if applicable. Descriptive statistics calculated the success rate of acquiring TAC and reasons to obtain the MRI.

RESULTS

Two-hundred fifty subjects from 22 institutions were enrolled and had at least one visit beyond baseline (Median age 3.1 years, range 0.1–16.8; 53% female). TAC was successfully acquired in both eyes (N=195, 78%) and at least one eye in (N=206, 82%). ATS-HOTV was successfully acquired in both eyes (N=97, 39%) and at least one eye in (N=98, 39%). The two most common reasons to obtain an MRI were screening due to a diagnosis of NF1 (N=99, 39%) and ophthalmologic concern (N=81, 32%). At enrollment, continued observation occurred in a majority of subjects (N=221, 88%) while treatment with chemotherapy was initiated in only 11% (N=29). Twenty-nine (11%) subjects initially observed transitioned to treatment after enrollment (range: 2.5–25 months) thus far.

DISCUSSION

We present a prospective multicenter study of children with newly diagnosed NF1-OPGs. The ability to acquire quantitative visual acuity was higher than anticipated. The frequency of NF1-OPGs requiring treatment is lower than previously reported. Regression models of clinical and MRI features that prompted immediate treatment with chemotherapy versus observation will be discussed.
NFS-27. SELUMETINIB FOR SYMPTOMATIC, INOPERABLE PLEXIFORM NEUROFIBROMAS IN NEUROFIBROMATOSIS TYPE 1: A SINGLE-INSTITUTION EXPERIENCE
Authors: Vázquez-Gómez Felisa , Perez-Somarriba Marta , Castellano Serafin , Moreno José Luis , Cartas Susana , Cantarín Verónica , Duat Anna , Borrego Pedro , Solís Inés , Valls Isabel , Hernández Ángela , Torrelo Antonio , Esteso Borja , Tamariz-Martel Amalia , Egea Rosa María , Blasco Luis , Colmenero Isabel , Arce Begoña , Rivero Belén , Madero Luis , Lassaletta Álvaro
Published: June 2024

BACKGROUND

Half of patients with Neurofibromatosis type 1 (NF1) develop plexiform neurofibromas (PNs). PNs may grow during childhood causing significant complications, including pain, functional impairment, and disfigurement. Treatment options are limited, given their tendency to regrow following surgery and their propensity to transform into malignant tumors following radiation. Selumetinib is an oral selective inhibitor of RAS-mitogen activated protein kinase (MAPK) 1 and 2, which has shown efficacy for tumor shrinkage/ stabilisation and symptom improvement.

METHODS

Single-institution retrospective review of patients with NF1 treated with selumetinib for symptomatic PNs between 2020 and 2023. Clinical data were abstracted from medical records. Treatment consisted of selumetinib 25 mg/m2 BID. Patient follow-up included monthly complete physical examination, evaluation of treatment adherence, blood analysis, echocardiogram, ophthalmologic assessment every 3 months, and MRI every 6 months. Response evaluation criteria in solid tumors (RECIST) was used for assessment.

RESULTS

Ten patients were treated with selumetinib during the period indicated. Mean age 13.9 years (range 7-21). Predominant target locations were head and neck (60%), and abdomen-pelvis (30%). The most important comorbidities were disfigurement (50%) and pain (50%). The mean follow-up time was 519 days (range 45–1460). None of the patients presented grade 3-4 toxicities; all of them had associated grade 1-2 skin toxicity. None presented cardiac or ophthalmologic alterations. All the patients with pain had sustained clinical improvement in the first 35–60 days of treatment. At one year of treatment 6/8 patients showed stable disease and 2/8 partial response on MRI. In one patient, treatment was discontinued after 270 days (lack of clear benefit).Another patient has not reached one year of therapy yet.

CONCLUSIONS

In this study we expose that selumetinib for symptomatic, inoperable plexiform neurofibromas in NF1 was associated with clinical and radiological response. Our study also confirms the safety and good tolerance of this drug.
QOL-15. PAEDIATRIC LOW-GRADE GLIOMA (PLGG): A LIFELONG DISEASE THAT BEGINS IN CHILDHOOD. EVALUATION AND PROGNOSTICATION OF LONG-TERM PLGG SURVIVOR FUNCTIONAL AND QUALITY OF LIFE OUTCOMES
Authors: Green Katie L , Stone Tom J , Jacques Thomas S , Pickles Jessica C , Ridout Deborah , Aquilina Kristian , Phipps Kim , Bowman Richard , Gains Jenny , Aldridge Brownwen , Gan Hoong-Wei , Jorgensen Mette , O’Hare Patricia , Slater Olga , Depani Sarita , Syzchot Elwira , Chang Yen , Leyden Deirdre , Bluebond-Langner Myra , Hargrave Darren
Published: June 2024

BACKGROUND

For many patients, PLGG has a chronic disease course with potential for multiple and significant functional deficits and decreased Quality-of-Life (QOL). However, there have been limited large-cohort evaluations or prognostication studies of QOL & functional outcomes.

AIMS

1. Large-cohort analysis of long-term PLGG survivor functional & QOL outcomes: combining clinical follow-up assessment with survivor-reported QOL & function. 2. Evaluation of prognostic associations between PLGG variables & functional/QOL outcomes.

METHODS

Demographic, tumour & treatment factors of PLGG patients diagnosed 1980-2021 at Great Ormond Street Hospital, UK, were retrospectively collected & evaluated prognostically with functional outcomes from last clinical follow-up.Cohort long-term survivors completed prospective QOL(PedsQl Core) & function(PESAT-PT) questionnaires.PedsQL scores were evaluated prognostically with patient/tumour/treatment factors using multivariate logistic regression.PedsQL scores were compared with healthy (N=649) & chronically-ill (N=137) reference populations.

RESULTS

PLGG cohort (N=814) OS was 94.3%,PFS 76% & median treatments 1 (0-21) at median follow-up 8 years. 42% had 1 functional deficit at last clinical follow-up. Diagnostic age, tumour location, surgical resection, & receipt chemo/radiotherapy were independently associated with functional outcomes. 122 long-term survivors completed prospective questionnaires at median follow-up 21 years. 87% reported dysfunction: physical 60%,visual 50%,neurocognitive 49%,social 25%, endocrine 23%,travel 21%,employment 18%,& hearing 11%. Mean PedsQl scores:Physical 82(0-100), Psychosocial 73(13-100), Total 76(9-100). PLGG survivors had significantly lower mean Total, Physical & Psychosocial PedsQl scores than healthy controls (p0.0001,p0.0003,p0.0001), but comparable to people with chronic illness (p0.60,p0.14,p0.21). No correlation identified between PedsQl scores & number of impaired functional domains. Favourable Total PedsQl scores were associated with surgical resection(OR-5.94,p0.02) & fewer treatment interventions on multivariate analysis(OR-2.8,p0.0005). Adverse PedsQl scores were associated with NF1 (OR-11.82,p0.04), BRAF-V600E mutation(OR-18.55,p0.04), OPGs(OR-12.1,p0.01), & seizures(OR-18.93,p<0.0001).

CONCLUSIONS

Prognostication of heterogeneous PLGG survivor functional and QOL outcomes is complex but possible, without clear correlation between QOL and functional outcomes. For many, PLGG is a lifelong disease that begins in childhood.
QOL-45. SOCIAL DETERMINANTS OF HEALTH PREDICT NEUROPSYCHOLOGICAL OUTCOMES IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Gioia Anthony R , Jacobson Lisa A , Acharya Sahaja , Peterson Rachel K
Published: June 2024

BACKGROUND

Pediatric brain tumors and their treatment impact cognition including intellectual functioning (IQ), attention, working memory, and processing speed. Few studies have examined the role of social determinants of health (SDoH) on cognition in pediatric brain tumors. To date, studies have primarily focused on family-related SDoH factors such as insurance status or parental education as predictors of cognition. To our knowledge, no study has examined multiple indicators of SDoH to determine which family-based and community-based predict cognition.

METHODS

Participants included 151 pediatric brain tumor patients (M diagnosis age=8.82) seen for a clinical neuropsychological evaluation (M evaluation age=13.71). IQ, brief attention (WISC/DAS-II Digits Forward), working memory (WISC/DAS-II Digits Backwards), and processing speed (WISC Coding) were obtained from age-appropriate measures (WISC>6 years, DAS-II<6 years). Family-based SDoH indicators include insurance type (public, private) and maternal education (<high school degree, some college, ≥college degree). Community-based SDoH include the Area Deprivation Index (ADI) and Childhood Opportunity Index (COI). Multiple regressions examined variance in IQ, attention, working memory, and processing speed accounted for by the SDoH measures, after controlling for treatment exposures using the Neurological Predictor Scale.

RESULTS

Insurance accounted for 14.9% of the IQ variance [β=-.316, t(151)=-4.18; p<.001]; COI accounted for 18.3% of the IQ variance [β=.202, t(151)=2.70; p=.008]. Insurance accounted for 12% of the variance in attention [β=-.324, t(152)=-4.22; p<.001], and 17.5% of the variance in processing speed [F(2,134)=15.399, p<.001]. In the working memory model, insurance [β=-.179, t(148)=-2.19; p=.03] and ADI [β=-.171, t(148)=-2.11; p=.04], accounted for 5.3% and 7.5% of the variance, respectively.

CONCLUSIONS

Findings highlight the important contribution of both family and community factors on neuropsychological outcomes in pediatric brain tumors. Nuances of the data will be discussed as they relate to clinical care and research.
NURS-01. NOVEL TREATMENTS FOR ACNEIFORM ERUPTIONS CAUSED BY TARGETED THERAPIES IN THE PEDIATRIC POPULATION
Authors: Meyer Ashley S , Cluster Andrew , Ogle Andrea , Brossier Nicole , Beck Mary , Lampe Ashley , Rocco Abbey , Shatara Margaret , Mchugh Michele , Abdelbaki Mohamed , Coughlin Carrie C
Published: June 2024

BACKGROUND

Drugs that target the mitogen-activated protein kinase pathway can cause frequent and severe cutaneous toxicities with acneiform eruptions being one of the most common and challenging to manage. The literature is limited regarding treatment recommendations especially when this rash is refractory to first-line therapies.

METHODS

A single-institution case series regarding the treatment of acneiform eruptions with oral isotretinoin after failure of first-line therapies was performed.

RESULTS

Two female, adolescent patients who developed refractory acneiform eruptions while on trametinib were included. Their acneiform eruption emerged within the first cycle of trametinib requiring treatment with oral doxycycline plus a variety of topical medications. They remained on doxycycline for 6 and 7 months. Both patients then switched to oral isotretinoin after minimal rash response and rebound of the rash when attempting to discontinue doxycycline. The initial isotretinoin doses were 0.2-0.3 mg/kg/day rounded per pill size. Both patients required a dose reduction due to worsening xerosis. Once decreased, isotretinoin was well tolerated. No changes in baseline lipid panels or ALT were seen. No associated neurologic symptoms or pseudotumor cerebri. While on oral isotretinoin, no additional topical therapies were required to treat the acneiform eruption. The first patient’s acneiform rash improved from a CTCAE v5 grade 3 to grade 1 after only 3 weeks of isotretinoin. All locations of the rash responded to therapy. The second patient developed a grade 2 acneiform rash after starting trametinib and became ungradable with only residual pink papules to cheeks after receiving isotretinoin.

CONCLUSIONS

Both patients were successfully treated with isotretinoin after multiple prior therapies including 6 or more months of treatment with oral antibiotics. We recommend further research of treatment therapies in addition to oral antibiotics given concerns on their impact of the microbiome.
NURS-13. NEUROCOGNITIVE SIDE EFFECTS OF PEDIATRIC BRAIN TUMORS: A CONTINUING CHALLENGE
Authors: Rangan Kasey , Briamonte Courtney Baker , Higgins Micah , Hoffman Carly , Holtzclaw Susan , McHugh Michele , Meyer Ashley , Raber Shannon , Schmus Cindy , Seidl Kenny , Strachan Marylynne , Waters Kaaren , Yeh-Nayre Lanipua
Published: June 2024

BACKGROUND

Pediatric brain tumors pose a considerable challenge in clinical oncology, necessitating multimodal treatment approaches. Many of these have the potential to impact cognition on vulnerable, young brains. While advancements in therapies have improved survival rates, neurocognitive outcomes continue to be one of the most challenging late effects that affect quality of life for pediatric brain tumor survivors.

METHODS

We conducted a literature review to identify 1) current treatment approaches for pediatric brain tumors, 2) the neurocognitive effects that survivors of pediatric brain tumors experience, and 3) appropriate interventions that can be implemented to mitigate those neurocognitive effects.

RESULTS

Novel chemotherapeutic agents, such as molecularly targeted therapies, are increasingly implemented in a personalized approach to treatment. New approaches to radiation therapy, particularly proton therapy, have shown promise in minimizing cognitive decline compared to traditional photon therapy. Advances in neuroimaging techniques have enabled a more detailed understanding of structural and functional brain changes associated with treatment. While these newer treatment modalities are promising, their long-term side effects are mostly unknown and bear close monitoring over time. Because neurocognitive side effects continue to underscore the impact of pediatric brain tumor treatments, recent studies often specifically evaluate the cognitive side effects as well as attempt to personalize treatments to reduce cognitive damage.

CONCLUSIONS

Recent research findings reinforce the enduring concern of neurocognitive side effects in pediatric brain tumor survivors. The integration of advanced therapeutic modalities and targeted supportive care interventions may hold the key to optimizing treatment outcomes while minimizing cognitive morbidity. Continued research efforts are essential for refining treatment protocols and developing personalized strategies to safeguard neurocognitive function in this vulnerable population. Additionally, studies exploring the role of supportive care interventions, such as cognitive rehabilitation and neuroprotective strategies, demonstrate potential avenues for mitigating cognitive sequelae but require ongoing research.
NURS-23. THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE PAIRED NORMAL SPECIMEN PROCESS AT A TERTIARY CARE CENTER
Authors: Hemenway Molly S , Winzent-Oonk Shelby
Published: June 2024

BACKGROUND

Paired tumor - normal specimen testing is standard of care to improve the timing and knowledge of genetic variations present in the brain tumor cell and germline. A new process was developed to ensure the paired normal specimen (PNS) testing was completed.

METHODS

The Neuro-Oncology Advanced Practice Provider (APP) is integral in the process of ordering and obtaining the PNS.

RESULTS

In the last 15 months, this tertiary care center has performed more than 90 pediatric brain tumor biopsies and/or resections. APPs identify patient surgery dates via the neurosurgery calendar. On the day of surgery a PNS is ordered for the Solid Tumor panel (predetermined by pathology and neuro-oncology) and “Include germline variant resolution information if applicable?” is answered as “No”. The laboratory runs the next generation sequencing (NGS) on PNS and tumor but the findings remain blinded until a second order is placed to “unblind” the specimen. By doing so, the treating physician collaborates with a genetics counselor prior to discussing with the family. Initial difficulty included patient identification, ordering, and collecting PNS. The APPs developed a shared list with patient identifiers, surgery date, order and collection date of PNS which has ensured less than 5% of PNS have been missed. Challenges include weekend surgeries, APPs out of office, and communication to nursing to collect PNS. Updated protocol includes ordering PNS, messaging shift nurse with order explanation and request to collect. Additionally, the pathology team now messages the APPs if a PNS is not submitted and the tumor is undergoing NGS.

CONCLUSIONS

Comprehensive processes ensure that paired normal – tumor testing is completed in a timely manner and during the same admission with surgery to ensure better insurance coverage and less cost to families, as well as earlier results of somatic and germline variants.
PATH-06. AN INTEGRATIVE MULTI-MODAL DIAGNOSTIC APPROACH TO PEDIATRIC CHOROID PLEXUS TUMORS
Authors: Markowitz Alexander L , Suddock Jolee , Castaneda Everardo , Ji Jianling , Margol Ashley , Tamrazi Benita , Bluml Stefan , Cotter Jennifer A
Published: June 2024

BACKGROUND

Choroid plexus tumors (CPTs) consist of a diverse group of neoplasms, more prevalent in children. They include choroid plexus papillomas (CPPs, grade 1), atypical choroid plexus papillomas (aCPPs, grade 2), and choroid plexus carcinomas (CPCs, grade 3). Traditional grading of CPTs relies on histologic assessment, but morphologic criteria for determining tumor grade are subjective. Evidence suggests incorporation of clinical, radiologic, and molecular characteristics may increase diagnostic accuracy. Here, we investigated the multi-modal associations of CPT subtypes to develop a classification system to aid in CPT subtype diagnostics.

METHODS

We aggregated an integrative dataset that consists of digitized whole-slide images, NGS sequencing panels, methylation arrays, and magnetic resonance spectroscopy (MRS) spectra from in-house and publicly available data sources (n=110). We tested for clinically significant associations and established multi-modal profiles of CPT subtypes, as well as a machine-learning classifier to predict multi-modal based CPT subtypes.

RESULTS

CPT subtypes exhibit distinct characteristics across modalities with consistent correlations across anatomy, molecular, and metabolic datasets. Computer-vision models achieved high accuracy (89.7%) in classifying CPT subtypes using H&E images. Ki-67 immunostaining displayed increased reactivity in CPC compared to CPP and aCPP (p = 0.007, ANOVA). Methylation-based classifications confidently predicted CPP and CPC subtypes, while aCPP tumors clustered with either CPP or CPC due to the lack of a defined subtype. Molecular variants (i.e. TP53, MYCN) were significantly associated with CPC (p = 0.007, ANOVA). Metabolites such as inositol (p = 0.031) and choline (p = 0.004) were associated with CPT grade based on MRS-spectra.

CONCLUSION

Multi-modal analysis reliably separates CPTs by grade. The study underscores the significance of integrating multi-modal datasets in refining the accuracy of diagnosis and prognosis of CPTs. Continued research will focus on a multi-modal approach to improve prediction of aggressive behavior and understanding of inherent metabolic heterogeneity of CPT subtypes.
PATH-09. CNS EMBRYONAL TUMOUR WITHZNF532:NUTM1 FUSION: A RARE NEW CNS TUMOUR TYPE
Authors: Haberler Christine , Schned Hannah , Müllauer Leonhard , Schmook Maria , Sievers Philipp , Aldape Kenneth , Zied Abdullaev , von Hoff Katja , Johann Pascal , Gojo Johannes
Published: June 2024

BACKGROUND

Rare embryonal and sarcomatous CNS tumours represent a diagnostic and therapeutic challenge. In the latest WHO 2021 several new tumour types, defined by molecular alterations, have been introduced. Some of these tumours have molecular counterparts outside the CNS e.g. CNS tumour with BCOR alteration or CIC-altered sarcoma.We report a CNS tumour with unusual histological and molecular features.

METHODS/RESULTS

A 3-year-old boy presented with a 5x3 cm sized tumour in the left lateral ventricle, which was removed at an external institution. After treatment with 1 cycle carboplatin/etoposide the patient presented at our clinic with leptomeningeal dissemination across all CNS compartments. Therapy was switched to HIT-MED Guidance augmented by intraventricular therapy. Histology showed a highly cellular tumour composed of small uniform cells with round nuclei, distinct nucleoli and a scant cytoplasm. The cells were arranged sheet-like without discernible background. Mitotic figures were conspicuous. Immunohistochemically, expression of Olig2, Chromogranin A, NCAM, BCOR and EGFR was present; synaptophysin and SOX10 were positive in a fraction of cells. DNA methylation profiling using the DKFZ and the Bethesda CNS tumour classifier did not match with any methylation class. Archer FUSIONPlex panel revealed a ZNF532::NUTM1 fusion, which was confirmed by RNA sequencing, leading to the diagnosis of a CNS embryonal tumour NEC with ZNF532::NUTM1 fusion.

CONCLUSIONS

NUTM1 fusion oncogenes, including among other fusion partners ZNF532, are drivers of aggressive NUT carcinomas. Furthermore, NUTM1 can be a fusion partner in CIC-rearranged sarcoma. The present case neither qualified as carcinoma nor sarcoma. As no clear response was evident after 3 cycles of HIT-MED Guidance therapy was switched to the Scandinavian Sarcoma Protocol. A similar case showing embryonal morphology has been recently reported (PMID 37203791). In conclusion, the spectrum of NUTM1-rearranged tumours is expanding and rare unclassifiable CNS embryonal tumours should be checked for NUTM1 immunopositivity/rearrangement.
LMIC-10. GLOBAL MAPPING OF CLINICAL TRIALS FOR CHILDREN WITH CNS TUMORS
Authors: Mikkelsen Margit , Sotelo Catrian , Kelley Mackenzie , Edwards Michael , Moreira Daniel
Published: June 2024

BACKGROUND

While there has been an international call to increase access to pediatric oncology clinical trials, the current landscape of global clinical trials for pediatric central nervous system (CNS) tumors has not been described. We sought to analyze the availability of clinical trials available for children with CNS tumors worldwide.

METHODS

Clinical trials were included if they were interventional studies registered in International Clinical Trials Registry Platform (ICTRP) that included pediatric patients (≤17 years old) with a CNS tumor. PubMed and Google Scholar were used to identify peer-reviewed manuscripts describing the results of identified trials.

RESULTS

From 114,414 oncology trials, 322 studies met inclusion criteria. Geographically, 307 (95%) studies were sponsored by and conducted in high-income countries (HICs), while 15 studies (4.7%) were sponsored by and conducted in middle-income countries (MICs). No studies were registered in or accrued from low-income countries. Studies were mostly sponsored in the United States (244, 76%), United Kingdom (20, 6.2%), or France (13, 4.0%). Trials were mostly sponsored by individual institutions (168, 52%), followed by governmental organizations (100, 31%), collaborative groups (36, 11%) and pharmaceutical companies (18, 5.5%). Study characteristics differed with income status, with HICs registering mostly clinical trials for cancer-directed treatment (261, 85%) and MICs registering later phase supportive care-based or diagnostic trials (9, 60%). Of the studies included, 132 (43%) were published. There were similar rates of publishing results in HIC and MICs. Discussion: Low- and middle-income countries are under-represented in the global clinical research landscape of pediatric CNS tumors. Furthermore, these data describe the urgent needs to invest in clinical research infrastructure in LMICs and to foster collaborations that include LMICs as a critical step in achieving equity in global pediatric cancer care.
LMIC-12. INFANT-TYPE HEMISPHERIC GLIOMA: CAN IT BE EFFECTIVELY MANAGED IN AN UPPER-MIDDLE-INCOME COUNTRY?
Authors: Dassi Natália , Balsanelli Julia D , Toledo Silvia R C , Gamba Francine T , Alves Maria T S , Cavalheiro Sergio , Dastoli Patricia A , Costa Marcos D , Silva Frederico A , Silva Nasjla S , Cappellano Andrea M
Published: June 2024

BACKGROUND

Infant-type hemispheric glioma (IHGs) is a rare congenital tumor and a newly defined entity in the 2021 WHO classification for central nervous system tumors. It harbors, in mostly cases, a tyrosine kinase receptor rearrangement in NTRK family, ALK, ROS1 and MET. The aim of this study is to describe the demographic characteristics, treatment, and outcomes of a cohort of pediatric patients with IHGs in one single institution.

METHODS

A retrospective study was performed between 2012-2023. Overall survival (OS) was measured from diagnosis to date of death or last follow-up. The Kaplan–Meier method was used for survival analysis.

RESULTS

Fourteen patients were included. Median age was 4.4 months (range 0.1- 37months). All patients underwent neurosurgical resections, with a median of 2 (range 1-6). Eight patients performed molecular analyses showing three ALK, two NTRK, two ROS and one MET rearrangement. Twelve patients received chemotherapy-lines, four of them more than one schema, with a median of 3 (range 2-5). Three patients were submitted to focal radiotherapy after 3 years of age and three received target therapies (crizotinib/ alectinib, lolartinib and repotrectinib). In a median follow-up of 46.9 months (2-125months), the OS in 5/10 years was 73.9% and 55.4%, respectively. Four patients died, one due to neurosurgical complications at diagnosis, one from refractory seizure 47 months after diagnosis with no evidence of disease, and two due disease progression with eight and 74 months after initial diagnosis, the last one despite 2-lines of target therapy.

CONCLUSION

Our series reveals acceptable and encouraging survival rates, demonstrating that not only new molecular discoveries but also optimal multidisciplinary treatment makes a difference in survival of patients with IHG even in countries with limited resources. However, access to targeted therapy remains an obstacle to be overcome for the optimal management of these patients.
LMIC-19. A RETROSPECTIVE ANALYSIS OF PEDIATRIC RECURRENT PINEOBLASTOMA IN BEIJING
Authors: Li Miao , Sun Yanling , Zhang Zhen , Wu Wanshui , Sun Liming
Published: June 2024

OBJECTIVE

To explore the clinical characteristics of pediatric recurrent pineoblastoma in Beijing.

METHODS

Eighteen patients with newly diagnosed pineoblastoma were admitted to Beijing Shijitan Hospital between January 2014 and December 2022. The clinical data were retrospectively analyzed.

RESULTS

Among the 18 patients (M/F=8:1), all were treated with surgery, and both radiotherapy and chemotherapy were administered. Nine patients experienced recurrence, and 2 patients died at last follow-up. The Median follow-up time were 56 months. The 5-year progression-free survival (PFS) and 5-year overall survival (OS) were (42.0±13.1) %, and (88.1±7.9) %, respectively. Among the 9 recurrent patients, one was < 3 years, and 8 cases ≥ 3 years. One girl and 8 boys relapsed; 7 cases were M0 and 2 with metastases at diagnosis; 7 cases were GTR; Two cases experienced recurrence within one year (10 months each), and one died. The other 7 patients relapsed after one year, the median time to first relapse were 24.0 (range: 10.0~49.0)months. The sex, age group, metastases at diagnosis, GTR or not, recurrent sites were not significantly affects PFS. Although the 9 recurrent patients received both cerebral and spinal irradiation and chemotherapy followed by surgery, the different order of chemotherapy or radiotherapy first were significantly affected the duration of remission. The median time before the first relapse after surgery was longer in those who treated under the order of craniospinal irradiation followed by chemotherapy than those of the inverse order (29m vs 13m, χ2=6.528, P=0.011). In addition, one case with germline mutation of Dicer1, experienced recurrences more than 3 times although received second surgery and second radiotherapy, and multiple cycles of chemotherapy in our center, which indicates poorer outcome.

CONCLUSION

Pineoblastoma is rare and prone to relapse, the order of chemotherapy first may have shorter remission time before the first recurrence after surgery (P< 0.05).
MODL-07. BUILDING BETTER MODELS OF BRAIN TUMOURS TO ADVANCE PATIENT TREATMENT WITH MINIMAL SIDE EFFECTS
Authors: Gkotsi Danai Stella , Forder-Denham Isabelle , Ritzmann Timothy A , Ramage Judith , Kerr Ian D , Jackson Andrew , Mata Alvaro , Coyle Beth
Published: June 2024

BACKGROUND

Paediatric brain tumours pose a formidable challenge in oncology, necessitating innovative approaches to bridge the gap between molecular understanding and therapeutic efficacy. Current preclinical models lack fidelity in capturing the dynamic interplay between tumour cells and their microenvironment, hindering translation of research findings into clinical practice.

METHODS

We are developing advanced three-dimensional (3D) models of paediatric brain tumours, integrating crucial components of the tumour microenvironment. Leveraging self-assembling peptide amphiphiles (PAs), we are constructing subgroup-specific PA-ECM-Immuno models mimicking brain stiffness, ECM composition, immune cell interactions, and oxygen levels. Spatial transcriptomics and multiplex immunohistochemistry are being employed to elucidate tumour-microenvironment interactions.

RESULTS

Building upon our successes in modelling brain tumour growth and behaviour, as well as other types of tumours (the Mata lab has previously successfully established PA-ECM models of prostate and ovarian cancer), our approach demonstrates feasibi lity in incorporating immune cells and subgroup-specific ECM components into PA-ECM matrices. These models provide insight into dynamic interactions driving tumour progression, facilitating identification of key pathways and potential therapeutic targets.

CONCLUSIONS

Our approach represents a novel paradigm in paediatric neuro-oncology research, aiming to establish clinically relevant 3D models faithfully recapitulating intricate tumour-microenvironment interactions. By elucidating mechanisms of tumour progression and employing spatial transcriptomics and multiplex immunohistochemistry, our tailored models will enable the identification of precision therapies with enhanced efficacy and reduced off-target effects. Collaborative efforts through our multidisciplinary approach are poised to advance the field towards personalised treatments and improved outcomes for paediatric brain tumour patients.
MODL-14. TARGETING GL1/GL2-DNMT1-UHRF1 EPIGENETIC COMPLEX DISRUPTION VIA BET INHIBITION IMPAIRS SHH MB DEVELOPMENT
Authors: Jangde Nitish , Wynn Daniel , Egan Isabelle , Robbins David , Ayad Nagi
Published: June 2024

BACKGROUND

Sonic Hedgehog Medulloblastoma (SHH MB) shares 30% among all molecular subtypes of medulloblastomas (MBs). Constitutive activation of SHH signaling in the cerebellum’s granular cell precursors (GCPs) is critical for this MB development. When SHH receptor PATCHED-1 (PTCH1) is mutated, stimulation of this receptor by SHH ligand binding leads to derepression of heterotrimeric GTP-binding protein–coupled receptor Smoothened (SMO) eventually altering the activity, location, and stability of the three downstream glioma associated oncogene (GLI) family members: GLI1, GLI2, and GLI3. GLI1 and GLI2 mostly function as transcriptional activators, while GLI3 mainly plays a repressor role. The bromodomain and extra-terminal domain (BET) family of proteins comprises four conserved members (Brd2, Brd3, Brd4, and Brdt), which are critical regulators of GLI1 and GLI2-mediated transcription.

METHODS

In the present study, we pharmacologically inhibited BETs with a previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, discovered by our lab. We treated human SHH MB cells (ONS76 cells) in vitro and ex vivo in mouse SHH MB cells (from Ptch1 conditional knockout mice) with minimum effective concentrations of these inhibitors. We screened for GLI1/GLI2-DNMT1-UHRF1 epigenetic complex components expressions by immunoblotting and assessed the effectiveness of inhibiting their interactions by performing PLA assays.

RESULTS

In this study, we show that pharmacological inhibition of BETs leads to attenuated GLI1 and GLI2 levels. This GLI1 and GLI2 inhibition eventually disrupts the previously reported GL1/GL2, DNMT1-UHRF1 epigenetic complex, which is crucial for SHH MB development. A previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, synthesized and characterized by our lab can inhibit BETs. This could be a potential therapeutic approach targeting GLI-associated epigenetic complexes to treat SHH medulloblastoma.