tbuckley/cabot-search huggingface dataset:
LGG-29. BEYOND MAPK SIGNALING - GENOME-SCALE CRISPR/CAS9 SCREENS REVEAL NEW TARGETS FOR TREATMENT OF KIAA1549::BRAF-DRIVEN PEDIATRIC LOW-GRADE GLIOMA
Authors: Anna Borgenvik, Sean Misek, Alexander Zhang, Ruth Fekade, Timothy Ragnoni, Aaron Fultineer, Kevin Zhou, Daniel Bondeson, Dana Novikov, Sher Bahadur, Seung (Riley) H Choi, Amy Goodale, Alexandra L Condurat, Carolina Ortiz Cordero, Nicole Persky, Laura Kiessling, David Root, Michael Eck, Jesse Boehm, David Jones, Rameen Beroukhim, Pratiti (Mimi) Bandopadahayay
Journal: Neuro-Oncology (2024)

Abstract Since the KIAA1549::BRAF fusion was discovered as the most common driver of pediatric low-grade glioma (pLGG), it has been hypothesized that the fusion induces oncogenicity through BRAF activation as a result of KIAA1549 replacing the BRAF negative regulatory N-terminus. This led to the rapid translation of MAPK pathway inhibitors into the clinical setting. Despite most tumors exhibiting promising initial responses, some tumors are not sensitive and about half of responsive tumors grow back after treatment cessation. Therefore, strategies that result in sustained tumor responses are desperately needed. We have recently performed genome-scale CRISPR/Cas9 screens across isogenic neural stem cell models transduced to express pLGG-associated oncogenes (KIAA1549::BRAF, BRAFV600E, and multiple FGFR1 and MYB family alterations) to generate a dependency map of genetic vulnerabilities associated with expression of these oncogenes. We also included normal neural stem cells to allow identification of genetic dependencies specifically induced by the expression of each oncogene. Surprisingly, through these efforts, we have discovered KIAA1549::BRAF expressing cells to harbor striking and specific dependency on multiple members of an enzymatic complex that exerts its activity outside of the MAPK signaling axis*. Interestingly, this enzymatic complex has been described to modify only a few substrates, including KIAA1549, suggesting specificity. We have now validated this dependency across other isogenic models of KIAA1549::BRAF-expressing cells. Finally, our KIAA1549::BRAF-expressing models exhibit preferential sensitivity to a tool compound that targets our novel enzyme, suggesting novel therapeutic potential for KIAA1549::BRAF. These findings highlight a MAPK pathway-independent avenue for therapeutically targeting the most frequent genomic alterations in pediatric brain tumors. Consequently, we also propose that the fusion partner KIAA1549 is instrumental for the aberrant BRAF signaling driving pLGGs. (* we are currently in the process of working with our IP offices to ensure that we can disclose the names of the genes and proteins at the ISPNO meeting)
NFS-14. INTERCEPTION TREATMENT STRATEGY FOR INCIDENTAL LESIONS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS (AYA) USING LASER INTERSTITIAL THERMAL THERAPY (LITT)
Authors: Rita H Nguyen, Sergio Guadix, Maria Donzelli, Colleen Sanders, Marc K Rosenblum, Tejus A Bale, Jeffrey P Greenfield, Mark M Souweidane
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Due to widespread availability and lower threshold for neuroimaging, incidental brain lesions have increased. When a high index of suspicion exists for a neoplastic process, early treatment might be beneficial. This is appealing in cases of tumor predilection such as cancer predisposition syndromes or history of therapeutic irradiation. LITT may provide a means for total tumor extirpation in these otherwise surgically inaccessible lesions and intercept eventual anatomic or pathologic evolution. The aim of this study is to evaluate our evolving experience based on an early and minimally invasive strategy using LITT. METHODS Prospective review of pediatric and AYA patients in whom incidentally discovered lesions were treated with simultaneous stereotactic biopsy and LITT. Demographic data, presenting symptoms, adverse events and outcomes are reviewed. RESULTS Mean age for 9 patients is 11.8 years. 4 patients had tumor predilection: 2 with familial tumor predisposition syndrome and 2 history of cranial-sirradiation. In 4 patients imaging was performed for surveillance of other brain tumor or focal cortical dysplasia. 3 patients had imaging for headache. Mean time from initial finding to treatment was 29.7 months. Recommendation to proceed with treatment was due to interval growth, concerning features (contrast-enhancement), or high potential for malignant transformation. 1 patient had facial weakness and 1 patient had visual field deficit that resolved. Pathological diagnoses revealed low-grade tumor in 4 patients and non-diagnostic pathology in 5. No patients received additional tumor-directed therapy during a mean follow-up of 14.7 months. There was no evidence of tumor recurrence in any patient. CONCLUSION An early therapeutic strategy aimed at tumor interception is feasible in pediatric and AYA patients for incidental lesions. Early results might influence the design of future strategies for simultaneous or sequential diagnostic and thermal therapy. Evolving tumor control rates support the therapeutic potential of LITT in central, surgically-inaccessible incidental tumors.
HGG-44. BRAINSTEM HIGH-GRADE ASTROCYTOMA WITH PILOID FEATURES (HGAP) WITH AN NTRK FUSION: A HISTOLOGICAL MIMICKER AND RARE PEDIATRIC BRAIN TUMOR
Authors: Lame Balikani, Yasin Yilmaz, Emily Mattera, Jeffrey R Leonard, Marco Leung, Karen Tsuchiya, Kathleen M Schieffer, Yassmine Akkari, Allison McEnroe, Aaron McAllister, Catherine Cottrell, Elaine Mardis, Maryam Fouladi, Sara Khan, Daniel R Boue
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND HGAP is a recently defined rare glial neoplasm, whose classification requires pathognomonic epigenetic signatures. HGAP can arise anywhere within the central nervous system but most have been reported in the cerebellum (74%). Rarely seen in children, the diagnosis of HGAP can be challenging due to morphologic overlap with other glial neoplasms, especially pilocytic astrocytoma (PA). CASE We present an 11-year male with history of poor weight gain and bilateral sensorineural hearing loss detected on routine screening. Examination showed ataxia, with nystagmus on lateral gaze. MRI brain showed a solid/cystic, dorsally exophytic, cervicomedullary tumor with extension into the 4th ventricle, and hydrocephalus. The tumor showed heterogeneous enhancement with no restricted diffusion, nor intracranial or spinal metastases. Histologic sections from the biopsy suggested classic biphasic PA, with abundant Rosenthal fibers, vascular sclerosis, and no obvious mitoses. Ki67 index was low (&amp;lt;5%; hotspots up to 5-10%+). ATRX mostly retained, even within the most atypical nuclei. The histological impression was classic PA. Comprehensive molecular analysis with DNA methylation showed a high confidence match (0.9883) for HGAP. Paired exome sequencing revealed CDKN2A/2B biallelic loss, missense variant and copy number loss involving NF1, loss of function splice variant in ATRX with no germline alterations detected. Interestingly, fusion panel revealed a BCR::NTRK2 fusion. He received focal photon radiation (54Gy) and adjuvant therapy with Larotrectinib. He remains well with stable disease (EFS 7months). CONCLUSION A comprehensive 2023 review of literature revealed only 14 pediatric cases (range 4-18yo) out of 144 reported cases. Including our patient, 9 were male; 8 posterior fossa, 4 supratentorial, 1 spinal cord, and 2 of unknown location. Molecular analysis of the previously reported 14 pediatric cases showed only one case with a different NTRK fusion. We herein present a unique pediatric HGAP, with entirely classic biphasic and benign PA-like features, brainstem location, and targetable NTRK2 fusion.
LGG-28. THE ROLE OF REOPERATION IN PEDIATRIC CEREBELLAR PILOCYTIC ASTROCYTOMA
Authors: Michelle Masayo Kameda-Smith, Katherine Green, Dana Louise Hutton, Owase Jeelani, Dominic Thompson, Darren Hargrave, Kristian Aquilina
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cerebellar pilocytic astrocytomas (cPAs) in childhood have long been recognized to have a good prognosis after total resection but the outcome after incomplete resective surgery remains largely unpredictable with the incidence of radiological progressive disease ranging from 18-100%. Traditionally thought that GTR was required for long-term survival, small residuals were classically resected in a subsequent operation. METHODS We analyzed our Pediatric Low-Grade Glioma (PLGG) database, between 1985 and 2020, and filtered for intracranial pilocytic astrocytomas to determine what clinical or radiological factors precipitated revisional resective surgery in our single quaternary center cohort. RESULTS Using our Pediatric Low-Grade Glioma (PLGG) database, 283 patients were identified to have a histopathological diagnosis of intracranial pilocytic astrocytoma between 1985-2020 of which 202 were within the cerebellum (68.2%). The majority of patients with cerebellar PA were between 1-10 years of age (n=147, 73.5%) without gender predominance (M:F=99:101), usually presenting with 1 lesion (n=197, 98.5%). Gross total resection (GTR) was achieved in 74.5% (n=149) of initial surgeries for cerebellar PA. In patients with NTR or STR, the mean largest diameter of the post-operative residual was 1.1cm (0.2-3.7cm). Seven patients with STR did not require a second resective intervention. In 31 patients the neuro-oncology multidisciplinary team (MDT) recommended a second surgical resection at a mean time interval of 22.9 months (0.13-81.6 months) from the initial surgery. Proportionally, the children who underwent multiple resections were also more likely to receive adjuvant chemo/radiotherapy. Functionally, the children in the multiple operation cohort experienced more complications of therapy including ongoing endocrinopathy, treatment-associated hearing deficit, and neurocognitive deficits. CONCLUSION Residual disease in cPA should be maintained under clinocoradiological surveillance post-operatively with adoption of a more conservative approach when residual disease is not significantly changing over time.
HGG-45. HIGH GRADE GLIOMA PRESENTING AS A SYNCHRONOUS CANCER IN A PATIENT WITH DIFFUSE LARGE B CELL LYMPHOMA: A UNIQUE TREATMENT DILEMMA
Authors: Nicole Kendel, Yelena Wilson, Erin N Wright
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with synchronous tumors pose significant treatment dilemmas. We present a pediatric patient found to have concomitant Diffuse Large B-cell Lymphoma (DLBCL) and a High Grade Glioma (HGG). His unique presentation and family history uncovered a familial diagnosis of Lynch Syndrome. CASE A 7-year-old male presented with acute appendiceal rupture. Surgical resection identified an appendiceal mass consistent with localized DLBCL. While undergoing staging evaluations, the patient complained of new onset blurry vision with normal neurologic and ophthalmologic exams. Subsequent imaging was concerning for a high-grade lesion. Biopsy confirmed HGG and he underwent gross total resection. Family history included a brother with relapsed leukemia status post bone marrow transplant and multiple first cousins with lymphoma and gastrointestinal cancers. RESULTS While awaiting genetics and mutational analysis, we initiated treatment. The HGG was treated with focal radiation to the tumor bed starting 2 weeks after resection. Lymphoma therapy was initiated concurrently per the REBOOT regimen with the goal of decreasing doxorubicin dosing during radiation. Lumbar punctures and intrathecal chemotherapy were deferred until completion of radiation. Biopsy of residual abdominal masses following consolidation 1 showed &amp;lt;5% viable cells and therapy was intensified to ANHL1331, Group C1. Evaluation of both lesions identified hypermutation (mutational burden &amp;gt; 150mutations/Mb). Two unique germline mutations of PMS2 were also identified, consistent with Lynch syndrome. After completion of above therapy, the patient received maintenance therapy with nivolumab checkpoint inhibition. The patient developed severe neutropenia leading to cessation of nivolumab and quick progression of his HGG. CONCLUSION Synchronous tumors pose significant treatment dilemmas given the need to treat multiple lesions while balancing side effects. While checkpoint inhibitors may provide a way to address multiple lesions, our patient had unacceptable side effects limiting the utility of this therapy.
HGG-43. DIFFUSE PEDIATRIC HIGH GRADE GLIOMA SUCCESSFULLY TREATED WITH MULTIMODAL THERAPY
Authors: Vibhuti Agarwal, Ramamoorthy Nagasubramanian, Rochelle Maxwell, Dorothea Douglas-Lindsay, Catherine Mercado, Laura Hayes, Tushar Chandra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high grade glioma (HGG) have a dismal prognosis despite aggressive treatment. In this report, we discuss a patient with HGG successfully treated with combination of resection, radiotherapy, chemotherapy, and biologic therapy. RESULTS An 8-year-old male presented with intermittent headaches, vomiting and fatigue. Imaging demonstrated four solid/cystic enhancing intra-axial lesions within the left cerebral hemisphere- two within the left frontotemporal region, one in the superior parietal region, and one in the temporal lobe, all with perilesional edema and resultant subfalcine herniation with midline shift. The patient underwent subtotal resection of the frontotemporal and parietal lesions. Histopathology was consistent with glioblastoma. Whole exome sequencing revealed alterations in TP53, ATRX, PTEN, TSC2 as well as subclonal mutation in NF1. The tumor was unable to be further classified by DNA methylation. However histopathologic and molecular findings support the diagnosis of diffuse pediatric-high grade glioma, H3-wildtype and IDH-wildtype. The patient received adjuvant 59.4 Gy focal proton therapy with concurrent temozolomide and maintenance chemotherapy with temozolomide and lomustine for 6 cycles. End of therapy imaging demonstrated complete resolution of all sites of disease. Due to high likelihood of recurrence, the patient was subsequently started on targeted therapy with everolimus and ribociclib which continue to be well tolerated without dose adjustments. The patient remains stable and without recurrence 2.5 years since diagnosis, and 15 months since initiation of biologic therapy. Additionally, the patient underwent testing for cancer predisposition which revealed presence of TP53 heterozygous mutation consistent with Li-Fraumeni syndrome. The patient remains without other malignancies on surveillance imaging per LFS guidelines. CONCLUSION Our case report illustrates the value of both chemotherapy and biologic therapy in treatment of HGG. In addition to this, it emphasizes the importance of germline testing for cancer predisposition in patients with high grade tumors.
LGG-33. NETWORK ANALYSIS INTEGRATING MICRORNAS AND CLINICAL DATA TO DETERMINE PROGNOSTIC OUTCOME IN PEDIATRIC LOW-GRADE GLIOMA PATIENTS
Authors: Giuseppina Catanzaro, Federica Conte, Zein Mersini Besharat, Federica D’Antonio, Zaira Spinello, Andrea Carai, Luca Massimi, Marco Gessi, Dominique Figarella-Branger, Paola Paci, Franco Locatelli, Angela Mastronuzzi, Elisabetta Ferretti
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low-grade pediatric gliomas (pLGGs) are the most common pediatric brain tumors. Surgical resection, when feasible, represents the standard of care. If complete resection cannot be achieved, disease progression occurs in about 30% of the cases, and these patients receive adjuvant therapy. The identification of predictive biomarkers to predict tumors that will progress after partial resection, requiring systemic treatment (Chemotherapy or target therapy), could support clinicians in the decision-making strategy. MicroRNAs have been related to tumorigenesis and tumor maintenance and can be used as important biomarkers. This study aims to develop a predictive model able to determine prognostic outcomes and to better stratify pLGG patients according to disease progression. METHODS MicroRNAs levels have been assessed in 76 human tumor tissue samples. Clinical data have been collected for statistical and network-based analyses. Using a network-based approach, we integrated clinical data and tissue microRNA expression to identify a microRNA signature able to predict disease progression. RESULTS Our preliminary microRNA expression analysis displayed new promising signatures correlating with prognostic features, such as disease progression and embryological origin of the tumor. CONCLUSION The predictive model we developed integrating biomarkers and clinical data could be crucial to support clinicians in the decision-making strategy and in advancing personalized medicine.
NFS-13. UNUSUAL NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PILOCYTIC ASTROCYTOMAWITH MALIGNANT TRANSFORMATION IN A 7-YEAR-OLD GIRL
Authors: Nahla Aly Mobark, Fahad Alotabi, Ali Abdullah O Balbaid, Azhar Alshoumer, Sadeq Al-Dandan
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Neurofibromatosis type 1(NF1) is a tumor predisposition syndrome with germline NF 1 gene aberrations with overactivation of the RAS–MAPK signaling pathway. NF1-associated gliomas in children are usually low-grade Glioma with indolent course. Malignant transformation in NF1 associated LGG is predominated in adults is scarce in children METHOD A 7-year-old girl diagnosed as NF1-based on diagnostic criteria and germline NF1 gene mutation, presented with progressive RT side hemiplegia, Brain MRI showed a large left thalamic cystic and solid mass and obstructive hydrocephalus she had VPS insertion and stereotactic biopsy.pathological examination revealed aggressive High-grade Glioma HGG features diffuse brain infiltration, endothelial hyperplasia, increased mitotic activity necrosis, and High Ki67. Immunohistochemically and molecular analysis showed NF1 mutation in addition to TP53 mutation, retained ATRX, negative CDKN2A/B, and high tumor mutational burden (6 Muts/Mb). Tumor methylation profiling (DKFZ CNS v12.5) classified as Supratentorial midline pilocytic astrocytoma (score 0.6878). debulking of the tumor and ommaya reservoir insertion was done with recurrent aspiration of the cystic component. The second biopsy demonstrated low-grade pilocytic astrocytoma, confirmed by methylation profiling (score 0.9377). Immunohistochemically and molecular analysis showed NF1 mutation, negative TP53, and Retained ATRX RESULT She was treated with low-grade glioma chemotherapy carboplatin/ vincristine, with improved clinical and neurological condition and stable MRI evaluation. One year after diagnosis while on maintenance LGG chemotherapy MRI imaging showed tumor progression Subtotal resection of the mass was performed, morphology and molecular studies confirmed HGG, and she received focal radiation therapy. Up till now, the patient is currently stable clinically and by imaging surveillance. CONCLUSION Our case characterized a transformed glioma in a child with NF1 illustrating the intratumoral heterogeneity and presence of transformed/anaplastic clone within NF1-associated pilocytic astrocytoma and demonstrate the complexity of molecular genetics of gliomas in children with NF1.
LGG-30. CLINICAL CHARACTERIZATION OF PEDIATRIC LOW-GRADE GLIOMAS REQUIRING MULTIPLE ANTI-TUMOR TREATMENTS
Authors: Tiago P J Rijsdijk, Julie A S Lammers, Mariëtte E G Kranendonk, Lisethe Meijer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In pediatric low-grade gliomas (pLGG), central nervous system World Health Organization grade 1-2 tumors, the majority of patients achieve favorable outcomes. However, a significant minority requires multiple anti-tumor treatments. The objective of this study is to identify the clinical characteristics of patients requiring multiple anti-tumor treatments, enabling early detection and the subsequent adjustment of treatment strategies METHODS Data was retrieved on tumor location, age at diagnosis, gender, NF1 status, extent of resection, and number and type of anti-tumor treatments of 282 patients from our institution. Patients were categorized into a single (STG) and multi-treatment group (MTG). Multi-treatment was defined as tumor progression after initial anti-tumor treatment requiring additional treatment, including more than a 3-month waiting period between initial surgery and subsequent treatment. RESULTS The median follow-up was 3 years. Optic pathway glioma was more prevalent in the MTG vs the STG, 62% vs 22%, respectively. Patients in the MTG were younger at diagnosis vs the STG (4.9 vs 8.5 yrs, P &amp;lt; 0.001). There was no significant difference in NF1 prevalence or gender between both groups. The predominant characteristic of patients in the MTG was carboplatin and vincristine as initial treatment, with a tumor in the optic pathway and a mean age at diagnosis of 4.9 yrs. In addition, the patients in the MTG mostly underwent partial resection (PR) and never gross total resection (GTR). CONCLUSIONS Our results indicate that a younger age at diagnosis, a tumor in the optic pathways and not undergoing GTR are prognostic factors for multi-treatment. The goal of anti-tumor treatment is to achieve senescence. Our results show that in the MTG, this is not attainable with the current treatment strategies. Therefore, exploring alternative treatment strategies is essential to diminish morbidity and mortality and enhance the quality of life for these patients.
LGG-32. MALIGNANT TRANSFORMATION OF PEDIATRIC LOW-GRADE GLIOMA TO SECONDARY HIGH-GRADE GLIOMA - REPORT FROM THE GERMAN BRAIN TUMOR STUDIES
Authors: Thomas Perwein, Gerrit H Gielen, Daniela Kandels, Brigitte Bison, Michael Karremann, Alexander Kühn, Dominik Sturm, Claudia Spix, Monika Warmuth-Metz, Annika Stock, Miriam van Buiren, Camelia M Monoranu, Christian Hartmann, Lea L Friker, Matthias Eyrich, André O von Bueren, Pablo Hernáiz Driever, Olaf Witt, Arend Koch, Torsten Pietsch, Martin Benesch, Christof M Kramm, Astrid K Gnekow
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Malignant transformation (MT) of pediatric low-grade glioma (pLGG) to secondary high-grade glioma (sHGG) is a rare but momentous event. We explored its clinical, epidemiologic, and molecular characteristics and risk factors. METHODS Forty-eight pediatric patients with histology-based or radiological (n=4) diagnosis of primary LGG (median age 10.2 years [range, 0.7–16.9]) and subsequent sHGG were identified within registries of the HIT-network from 1996-2019. For 29 patients, tumor specimens of both pLGG and corresponding sHGG were available for neuropathological review and studied genetically. RESULTS MT occurred after median 4 years (range, 0.5-14) following LGG diagnosis. Its 15-year cumulative incidence was 1.6±0.4% (23/1586 SIOP-LGG-2004 patients), but 11.7±4.1% (9/100) for diffuse pLGG WHO-grade 2 (DG2). Clinical risk factors for MT were spinal location and prior dissemination. MT was accompanied by an increment of nuclear p53 accumulation (20/29 tumors), cytogenetic and molecular alterations. CDKN2A/B homozygous deletions (7/12 tumors), 1p/1q alterations (4/12) and ATRX loss (3/12) were the most common acquired alterations detected in sHGG. 8/16 tumors were unclassifiable by methylation profiling. DG2s (n=19), harboring IDH-1 mutation in 3/9 cases, progressed to diffuse WHO-grade 3 (n=8) or grade 4 HGG (n=9), two developed gliomatosis cerebri. Circumscribed LGG (PA, n=13; GG, n=7; PXA, n=4; DNET, n=1) typically harbored MAPK/ERK pathway alterations (BRAF-/NTRK-/FGFR-fusions, n=5/9; BRAFV600E mutation, n=4/12) and transformed to non-diffuse HGG (n=14), but also to diffuse grade 4 HGG. H3 K27M-/BRAFV600E co-mutation in two of these patients eventually resulted in MT to fatal diffuse midline glioma. Thirty-five sHGG patients received radio-chemotherapy. Overall survival at 5 and 10 years following MT was 49±8% and 31±8%. CONCLUSIONS Our findings underline the importance of careful long-term follow-up of patients with pLGG. Repeated resection/biopsy of recurrent/progressing or “atypical” tumors should be pursued and include molecular typing to identify patients at risk for MT and initiate appropriate treatment.