tbuckley/cabot-search huggingface dataset:
PATH-01. ACCURATE AND RAPID PAEDIATRIC BRAIN TUMOR CLASSIFICATION (PBT) BY METHYLATION PROFILING USING NOVEL NATIVE REAL TIME OXFORD NANOPORE TECHNOLOGY SEQUENCING TECHNOLOGY
Authors: Galina Feinberg, Assaf Grunwald, Nurit Gal Mark, Lena Shinderman Maman, Keren Shihrur, Michal Hameiri-Grossman, Helen Toledano, Orly Michaeli, Suzanna Fichman, Shai Izraeli, Yehudit Birger
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumors (PBTs) pose a significant challenge being the leading cause of cancer related mortality in children. The existing classification process is time-consuming and fails to capture the heterogeneity of PBTs. Urgent advancements in diagnostic and therapeutic approaches are needed. The WHO classification 5th edition for CNS tumors introduced DNA methylation analysis into the diagnostic process, especially for difficult-to-diagnose cases. However, the currently available DNA methylation array-based methods are laborious, costly, &amp;require large amounts of DNA METHODS Nanopore methylation analysis is rapid, accurate, and inexpensive &amp; requires minimal tissue. We applied this technology on 24 PBT samples that were classified into ten molecular subgroups. RESULTS Our results were compatible with those obtained through Heidelberg methylation analysis, standard histopathological examination, and molecular tests and were in concordance with the final neuro-pathological diagnosis. Moreover, for five prospective cases, that would have challenged standard methods, Nanopore yielded same-day results, guiding additional tests and providing a significant diagnostic advantage. In one case, a 2.2-year-old male, with a large left parieto-temporal tumor and a suprasellar lesioninitially treated elsewhere with upfront chemotherapy without biopsy, developed clinical deterioration. We resected the temporal lesion and frozen tissue diagnosis suggested low-grade glioma. However, same day Nanopore sequencing analysis indicated a high score for ‘Meningioma’. Final pathology examination 10 days later confirmed ‘‘Atypical meningioma, WHO grade 2” – an extremely rare diagnosis in this age group. Visual deterioration prompted immediate resection of the second lesion before final pathological confirmation. Thus, early Nanopore classification played a vital role in diagnosis and management. CONCLUSIONS Our preliminary results underscore the potential of Nanopore potential for accurate and rapid PBT classification from small brain biopsies, with DNA input as low as 100 nanograms. This cutting-edge technology promises to substantially reduce time to diagnosis, shaping future neurosurgical strategies for individualized PBT patient management.
TRLS-07. PNOC016: INTRATUMORAL PHARMACOKINETICS AND PHARMACODYNAMIC (PK/PD) RESULTS FROM A TARGET VALIDATION STUDY OF A NOVEL PAN-HDAC AND PI3K INHIBITOR, FIMEPINOSTAT, IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG), RECURRENT MEDULLOBLASTOMA (MB), AND RECURRENT HIGH-GRADE GLIOMA (HGG)
Authors: Cassie Kline, John R Crawford, Alyssa T Reddy, Nicolas Gerber, Ana Guerreiro Stucklin, Lindsay Kilburn, Roger Packer, Ashley Margol, Erin Crotty, Elias Sayour, Andrea Franson, Joanna Phillips, Shefali Singh, Erin Hamanishi, Christopher Lee, Aashim Bhatia, Elizabeth George, Andreas Rauschecker, Annette Molinaro, Michael Prados, Javad Nazarian, Sriram Venneti, Robert Wechsler-Reya, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND An intact blood-brain barrier is a limitation to effective therapies for pediatric brain tumors. PNOC016 investigated the tumor penetration of an orally available, promising pan-HDAC and PI3K-inhibitor, fimepinostat, in high-risk pediatric brain tumors, including DIPG, MB, and HGG. Fimepinostat is active as a primary drug and via its metabolite, M2, which exhibits PI3K inhibition. METHODS Patients between 3 and 39 years old with newly diagnosed DIPG (stratum A), recurrent MB (stratum B), or recurrent HGG (stratum C) were eligible. Disease-based strata enrolled independently up to 10. Patients received 3 neoadjuvant doses before standard-of-care resection/biopsy and underwent tissue collection for PK/PD analysis. Patients continued single-agent maintenance therapy for up to 12 months with ongoing collection of circulating tumor DNA (ctDNA) from blood, quality of life (QOL) measures, survival, and response outcomes. RESULTS Thirty-one patients enrolled between August 2019 and August 2022 (n=1 replaced due to disease progression before treatment started). All patients with completed PK analysis had detectable fimepinostat (n=18), metabolite M1 (n=23), or metabolite M2 (n=24) in tumor. Median intratumoral levels of fimepinostat, M1, and M2 (nM) by stratum were as follows: stratum A-2.6, 4.9, 28.3; stratum B-9.5, 6.5, 32.4; stratum C-9.9, 10.7, 15.9. The lowest intratumoral levels were seen in stratum A. Pre-surgical blood PK positively trended with intratumoral PK. Phosphorylation and acetylation PD analyses are underway. The most common grade 3 or above related adverse events were hematologic, with platelet decrease being the most frequent (n=9). Median OS from the diagnosis for stratum A was 13 months. PFS from surgery for stratum B and C was 3 and 3 months. CONCLUSION Fimepinostat crossed the blood-brain barrier in newly diagnosed DIPG and recurrent MB and HGG. PD assessment is underway to correlate PK with biological effects. PD correlation, survival analyses, ctDNA, and QOL will be presented.
CP-12. PHASE 0 AND FEASIBILITY SINGLE-INSTITUTION CLINICAL TRIAL OF INTRAVENOUS TOCILIZUMAB FOR ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Kathleen Dorris, Ashley Mettetal, Molly Hemenway, Shelby Winzent-Oonk, Nathan Dahl, Jean Mulcahy Levy, Eric Prince, Jennifer McWilliams, Kimberly R Jordan, David Mirsky, Lindsey Hoffman, Todd Hankinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. ACP lacks medical antitumor therapies. Current standard therapy with surgery and radiation is associated with poor quality of life. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control. METHODS Children aged 2–21 years with newly diagnosed or previously treated ACP with measurable disease are eligible for the Phase 0/feasibility single-institution clinical trial (NCT03970226) of intravenous (IV) tocilizumab at Children’s Hospital Colorado (Aurora, CO, USA). The phase 0 stratum is completed and involved a single IV tocilizumab dose prior to a standard-of-care surgical resection. The feasibility portion of the trial involves IV tocilizumab every two weeks for up to 13 28-day cycles. Tocilizumab is administered at the established weight-based pediatric dosage of 8 mg/kg for patients who weigh ≥30kg or 12 mg/kg for patients who weigh &amp;lt;30kg. RESULTS Six patients (4 female; median age—10 years, range—6-15 years; 4 who had progressive disease after radiation prior to enrollment) have been treated on the feasibility stratum. The subjects have received a median of 6 cycles (range 0.5-13 cycles). The best response to date is minor response. One dose reduction for myelosuppression has been required. One patient discontinued therapy due to anaphylaxis related to tocilizumab on the first dose. CONCLUSION Systemic delivery of tocilizumab at the established pediatric dosage is promising for treatment of ACP based on preclinical work and its demonstrated penetration into cystic and solid portions of ACP tumors. The therapy to date has been well tolerated overall. Further study is underway through a CONNECT consortium international Phase II trial (NCT05233397) to explore clinical efficacy.
HGG-14. COMPARING THE RADIOSENSITIZATION POTENTIAL OF VARIOUS COMPOUND CLASSES IN PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA
Authors: Alessia Cais, Szymon Lipiec, Kenneth Chun-Ho Chan, Nina Hofmann, Clara Gade, Laura von Soosten, Roland Imle, Mareike Roscher, Rosemarie Euler-Lange, Tuyu Zheng, Frederik Manz, Lena M Kutscher, Kristian W Pajtler, Heike Peterziel, Ina Oehme, Olaf Witt, Ina Kurth, David T W Jones, Stefan M Pfister, Marc Zuckermann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The 5-year survival rate of patients suffering from pediatric-type diffuse high-grade glioma (pHGG) remains at only ~20%. Often resection and/or X-ray radiation therapy (RT) are the only treatment options for these patients, though only providing palliative benefits. To date, the concomitant combination of RT and targeted agents is largely unexplored, especially as first line treatment. METHODS AND RESULTS To identify drugs and compound classes that radiosensitize pHGGs, we performed a series of high-throughput drug screens in combination with RT. Using a custom library of ~90 FDA-approved compounds, we analyzed combinatorial efficacies in 10 pHGG cell cultures. We identified a variety of drugs demonstrating increased efficacy with RT that have not been described as radiosensitizers yet. Of these, we prioritized compounds that presumably cross the blood-brain-barrier (BBB) and are clinically relevant, yielding a selection of 6 drugs comprising HDAC-, Proteasome-, MEK- and BCL-inhibitors. Next, we analyzed whether these compounds act tumor-specifically by screening two non-cancer cell cultures: Neural stem cells and HEK293T cells. While 3 of those compounds also demonstrated efficacy in one of the control cell lines, the 3 remaining drugs potentiated RT specifically in pHGG. We then successfully validated the radiosensitization of selected compounds using cell viability and apoptosis assays, and are currently performing clonogenic assays to prioritize the most effective drug-RT combinations for in vivo trials. OUTLOOK AND CONCLUSION We will evaluate the most promising treatment combinations preclinically using established PDX-mouse models. We are also planning to perform pharmacokinetic analyses of selected compounds to validate BBB permeability. Ultimately, mechanisms of radiosensitization will be functionally investigated. Our comparative results will generate a comprehensive overview of the radiosensitization potential of different compound classes in a variety of pHGG models, allow mechanistic insights into the interplay of both modalities, and provide a basis for future clinical trials.
GCT-15. CLINICAL AND MOLECULAR CHARACTERIZATION OF INFANTILE CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
Authors: Kohei Fukuoka, Hirokazu Takami, Kaishi Satomi, Yoshiko Nakano, Yohei Inoue, Akira Miyahara, Yuko Matsushita, Yuko Hibiya, Miho Kato, Tetsuya Takimoto, Atsuko Nakazawa, Takako Yoshioka, Junko Hirato, Yoichi Nakazato, Junji Shibahara, Hidehiro Oka, Jun Kurihara, Katsuyoshi Koh, Masao Matsutani, Ryo Nishikawa, Motoo Nagane, Koichi Ichimura
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The management of infantile central nervous system germ cell tumors (CNS-GCTs) presents unique challenges, including variable clinical presentations such as tumor size and propensity for hemorrhage. Moreover, data on the clinical and molecular features remain limited. METHODS We conducted a clinical and molecular analysis of CNS-GCTs in children aged 6 years or younger, registered with the Japan Children’s Cancer Group and the iGCT consortium. DNA methylation analysis was performed using the Illumina Methylation EPIC array to identify potential molecular prognostic indicators. RESULTS The cohort comprised 43 patients, with a median age at onset of 6.5 months (0–68 months). Notably, 23 patients (54%) were diagnosed before 1 year of age. The male-female ratio was 27:15. Most common tumor location was cerebellum (13 cases). The median AFP level was 538 ng/ml (0–206460). Pathologically, the tumors were predominantly diagnosed as teratomas and yolk sac tumors. Teratomas were more common in patients diagnosed before 1 year of age, while mixed GCTs were more frequent in those diagnosed after 3 years. Molecular analysis identified four cases as embryonal tumors, including three AT/RTs and one DICER1-mutant intracranial sarcoma. The 3-year overall survival rates varied significantly by diagnosis: mixed GCTs at 100%, teratomas at 90.6%, yolk sac tumors at 30.0%, and embryonal tumors at 0%. Notably, two patients with teratomas developed metachronous tumors more than 10 years post-diagnosis, with both secondary tumors exhibiting mutations in the MAPK pathway absent in the primary tumors. CONCLUSION Infantile CNS-GCTs exhibit distinct clinical and molecular profiles compared to those in older children and adults. Not all tumors classified as GCTs based on molecular characterization were GCTs; some were embryonal tumors, potentially impacting treatment strategy. The genetic analysis suggests that some metachronous GCTs may represent second primary tumors rather than recurrences.
NFS-01. EXTREMELY RARE CASE OF CHILDREN WITH NIJMEGEN BREAKAGE SYNDROME AND MEDULLOBLASTOMA – A THERAPEUTIC CHALLENGE
Authors: Malgorzata A Krawczyk, Ewa Bien, Marta Perek-Polnik, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Nijmegen Breakage Syndrome (NBS) is an autosomal recessive inherited disorder characterized by DNA repair abnormalities. It manifests with heightened sensitivity to radiotherapy (RT) and predisposes individuals to neoplastic diseases. Antineoplastic treatment in NBS patients is particularly challenging due to concurrent immune disorders, intense toxicities, and contraindications for RT. Hematologic disorders, especially lymphomas, are among the most prevalent malignancies in NBS patients. Solid tumors in NBS are extremely rare, with only two pediatric cases documented in the literature, both succumbing due to severe complications of treatment. METHODS A review and analysis of the medical documentation of a child with NBS and MB treated at the Department of Pediatrics, Hematology, and Oncology, Gdansk, Poland, were conducted. RESULTS A genetically confirmed NBS girl displaying typical phenotypic features presents symptoms at the age of 2 years, such as headaches, reluctance to walk, and drowsiness. Imaging confirmed a tumor in the left cerebellar hemisphere, measuring 40x33x30mm, displaying radiological features consistent with Medulloblastoma (MB). The patient underwent gross total resection of the tumor. The pathology revealed a desmoplastic type of MB with SHH activation, TP53 wild type, and ongoing molecular analysis. Postoperative imaging confirmed clinical remission, and cerebrospinal fluid examination was negative. Considering the substantial toxicities of chemotherapy in NBS patients and the contraindications for RT, the patient received chemotherapy with reduced cytostatic doses. Treatment was complicated by profound and prolonged myelosuppression and infections. Currently, after completing six cycles of chemotherapy, the patient is still in remission. To maintain remission and address NBS, the patient will receive allogeneic bone marrow transplantation from a 9/10 HLA-matched unrelated donor. CONCLUSIONS Managing patients with NBS, complicated by neoplastic diseases, is exceptionally demanding and necessitates an individualized multidisciplinary approach. Modern diagnostic and therapeutic methods enhance the prospects of reducing the toxicity of oncologic treatment, improving quality of life, and extending overall survival.
ATRT-15. COMBINING THE PI3K INHIBITOR PAXALISIB WITH NUCLEOSIDE ANALOG GEMCITABINE TO IMPROVE SURVIVAL OF ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Charles Eberhart, Jeffrey Rubens, Eric Raabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) have a dismal overall survival. Targeting the mTORC1/2 pathway kills ATRT tumor cells and increases the survival of mice bearing orthotopic xenografts. Paxalisib is a brain penetrant PI3K inhibitor that is in pediatric clinical trials for diffuse midline glioma. Paxalisib activates the integrated stress response (ISR) in ATRT. Consistent high-level activation of the ISR leads to cell death. We hypothesize paxalisib will synergize with the DNA-damaging agent gemcitabine, which also triggers the ISR, to over-activate this pathway and drive ATRT apoptosis. METHODS We analyzed ISR gene expression following mTOR inhibition via RNA-seq. Children’s Brain Tumor Network (CBTN) provided comparative data on ISR genes in ATRT and other pediatric brain tumors. Paxalisib/gemcitabine effects were evaluated through cell-based assays, western blot for ISR markers, and survival in three murine models. RESULTS ATRT have high baseline expression of ISR genes (CBTN: ATF4, eIF2α), and mTOR inhibition leads to activation of ISR genes (ATF4, CHOP, PPP1R15A, p&amp;lt;0.05). Paxalisib monotherapy significantly extends median survival in murine models compared to vehicle controls (CHLA-06: 40 to 54 days, p=0.001; BT-12: 21 to 35 days, p=0.05). Paxalisib/gemcitabine therapy synergized to slow cell growth and induce cell death (SynergyFinder BLISS score in five ATRT cell lines). Combination therapy leads to ISR activation (western blot: p-eIF2α, ATF4, CHOP). Combination slowed tumor growth (bioluminescent imaging) and led to significant extension of survival in orthotopic xenograft models (CHLA-06: 22 to 82.5 days; BT-37 56-day vehicle median survival while undefined combination survival). A third model is ongoing and showing similar results. CONCLUSIONS Paxalisib/gemcitabine therapy shows potential for targeting ATRT by over-activating the ISR. Our findings prompted the Pediatric Neuro-Oncology Consortium to consider this combination for inclusion in an upcoming clinical trial targeting relapsed/refractory ATRT, offering a novel approach to treat this aggressive tumor.
GCT-18. GERMINOMAS OF THE CENTRAL NERVOUS SYSTEM (CNS): 20 YEARS EXPERIENCE WITH WHOLE VENTRICULAR IRRADIATION (WVI) AT FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI, MILAN
Authors: Veronica Biassoni, Paolo Raimondo, Elisabetta Schiavello, Monica Terenziani, Olga Nigro, Giovanna Gattuso, Filippo Spreafico, Cristina Meazza, Marta Podda, Stefano Chiaravalli, Roberto Luksch, Nadia Puma, Andrea Ferrari, Michela Casanova, Luca Bergamaschi, Giovanna Sironi, Sabina Vennarini, Maura Massimino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intracranial germ cell tumors account for 1-3% of pediatric CNS tumors, with germinomas constituting up to 65%, their prognosis being favourable compared to the non-germinomatous counterpart. METHODS After an unsuccessful experience with focal irradiation, from 2001 to 2021 we treated 68 patients (51 males/17 females, median age at diagnosis 16 years) with 4 PEB cycles (cisplatin 25 mg/sqm days 1-4, etoposide125 mg/sqm days 1-4, bleomycin 18 mg/sqm day 2, cycles every 21 days) followed by whole ventricular irradiation (WVI) 30,6 Gy/36Gy if CR/PR-SD. Patients with metastatic disease received craniospinal irradiation only (CSI 24 Gy+16Gy TB-tumor bed/WVI). RESULTS Fifty-nine patients had localized disease: 23 pineal, 22 suprasellar, 13 bifocal, 1 in the basal ganglia and 9 were metastatic. Suprasellar localization was associated with longer diagnostic delay. Five, 10 and 20 years OS and EFS were 100%, 97.5%, 97.5% and 95.3%, 92.8%.92.8% respectively. There was no statistical difference according to age at diagnosis, site and metastatic/bifocal disease. During follow-up 13/59 patients (22%) revealed moderate (2)/slight (11) impairment of the pulmonary function at spirometry assessment. Audiometric tests were available for 59 patients: 42 were normal (71%), 11 had a slight deficit, 4 moderate and 2 severe. Neurocognitive homogeneous evaluations were available only for 9 patients, so no clear correlation can be done, except observing the lowest scores in the patient with basal ganglia involvement. New endocrine deficits appeared in 9 patients after the treatment. CONCLUSIONS WVI tailored on response to chemotherapy proved effective in curing children CNS germinoma. Cisplatin and bleomycin-containing regimens induce high-response rates with known but in our experience limited sides effects. New collaborative protocols will investigate the reduction of the doses of irradiation and the use of less toxic drugs in order to achieve the same cure rates with less side effects.
TRLS-13. MULTI-OMICS AND FUNCTIONAL PRECISION MEDICINE FOR NEWLY DIAGNOSED AND RECURRENT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: John R Crawford, Yan Yuen Lo, Meghana S Pagadala, Owen S Chapman, Sunita Sridhar, Edwin F Juarez, Theophilos Tzaridis, Lianne Q Chau, Jun Wang, Tanja Eisemann, Meher Beigi Masihi, Kendall R Chambers, Deobrat Dixit, Daphne Koubourli, Jon D Larson, Lucia Guidugli, Monia Hammer, Terence Wong, Zied Abdullaev, Martha Quezado, Timothy J Martins, Michael Reich, Timothy Sears, Charlotte Hobbs, Stephen F Kingsmore, Michael L Levy, David Gonda, Denise M Malicki, Matija Snuderl, Pamela S Becker, Pablo Tamayo, Jennifer D Elster, Kenneth Aldape, Hannah Carter, Megan R Paul, Jill P Mesirov, Lukas Chavez, Robert J Wechsler-Reya
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Comprehensive molecular characterization of pediatric brain tumors has led to a more refined diagnosis. However, the feasibility of performing multi-omic and functional precision medicine approaches using ex-vivo drug screening in the clinical setting is unknown. METHODS Patients with newly diagnosed or recurrent central nervous system tumors were enrolled in a feasibility study of multi-omic analysis including whole genome trio germline sequencing, tumor whole exome/RNA sequencing, RNA-based DiSCoVER analysis, methylation profiling, immunogenic potential analysis, and ex-vivo drug screening utilizing a customized panel of 175 FDA approved/investigational drugs. Findings were presented at a multidisciplinary molecular neuro-oncology tumor board. RESULTS Eighteen patients (9 female; average age 9.4 years; 12 newly diagnosed, 6 with recurrent disease; 5 high grade gliomas, 4 ependymomas, 4 embryonal tumors, 3 low grade gliomas, 2 others) were enrolled between 2020-2022. Whole genome germline testing (N=18) was normal in half of patients (pathogenic germline mutations in 3 patients, variants of unknown significance in 6 patients). Ex-vivo drug screening results (N=14) varied among patients, however sub-micromolar efficacy was commonly observed for proteosome inhibitors, HDAC inhibitors, and topoisomerase II inhibitors. Average time from surgery to receipt of finalized results varied across platforms (drug screening 5.7 days, whole exome/RNA sequencing 14.8 days, whole genome germline 10.6 days, methylation 21 days). Fifteen patients had a modification in diagnosis and 4 patients had a change in tumor classification. Multi-omic and functional precision medicine results alone or in combination led to changes in management in 50% of patients (Tumor Molecular Sequencing 6/18, Ex-Vivo Drug Screening 4/14, RNA DiSCoVER Analysis 2/15, Methylation 1/14). CONCLUSION Our studies demonstrate the feasibility of timely ex-vivo drug screening and multi-omic analysis and show that these data may lead to changes in patient diagnosis/management. These findings are the basis of an ongoing trial for recurrent medulloblastoma (NCT05057702).