bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-09. REBOUND GROWTH AFTER MAPKI WITHDRAWAL INVOLVES RAPID MAPK REACTIVATION AND CYTOKINE-MEDIATED MICROGLIA RECRUITMENT IN PEDIATRIC LOW-GRADE GLIOMA MODEL
Authors: Kocher Daniela , Cao Lei , Guiho Romain , Langhammer Melanie , Lai Yun-Lu , Becker Pauline , Friedel Dennis , Selt Florian , Vonhören David , Zaman Julia , Valinciute Gintvile , Herter Sonja , Rettenmeier Johanna , Maass Kendra K , Pajtler Kristian W , von Deimling Andreas , Pusch Stefan , Pfister Stefan M , Oehme Ina , Jones David T W , Halbach Sebastian , Brummer Tilman , Martinez-Barbera Juan Pedro , Witt Olaf , Milde Till , Sigaud Romain 
Published: June 2024

Abstract
Patients with pediatric low-grade gliomas (pLGG), the most common primary brain tumor in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Four patient-derived pLGG models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset of the rebound model encompassing different MAPKi withdrawal timepoints was generated using RNA sequencing and LC-MS/MS based phospho-/proteomics to investigate possible driving mechanisms of rebound growth. Following in vitro validation, putative rebound driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. Of the tested models, BT-40 (BRAFV600E, CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal, characterized by faster cell regrowth after MAPKi withdrawal compared to standard-of-care chemotherapy. Using this model, we observed MAPK pathway reactivation within hours after withdrawal, associated with a transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels. Additionally, we observed increased expression and secretion of cytokines (in particular CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal (at least until 24 h). While increased cytokine expression did not affect response to MAPKi or rebound growth upon withdrawal in an autocrine manner, increased attraction of microglia cells mediated by these cytokines was observed. MAPK pathway reactivation during rebound growth and increased expression of CX3CL1 and CXCL10 induced by MAPKi treatment could further be confirmed in vivo. Taken together, these data indicate a rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound driving mechanism. Furthermore, increased microglia recruitment during MAPKi treatment and withdrawal, mediated by cytokines, may play a role in response to MAPKi treatment and rebound growth upon withdrawal, warranting further evaluation.
LGG-25. ADVANCING RESPONSE ASSESSMENT OF LOW-GRADE GLIOMAS: IDENTIFYING VOLUME CORRELATIONS OF BI-PERPENDICULAR DIAMETER CHANGES WITH MACHINE LEARNING
Authors: Dumbrille Gabe , Zhang Silu , Robinson Giles W , Merchant Thomas E , Bag Asim K 
Published: June 2024

Abstract

BACKGROUND
Assessing brain tumor response is key for effective management and clinical trial benchmarks. Traditionally, bi-perpendicular diameter (BPD) measurements have been used to estimate tumor size. However, recent studies suggest volumetric assessment yields a more accurate measure of response and estimate of tumor burden. Advances in technology enable rapid volume assessments. Integrating volumetric analysis into clinical settings is challenged by the absence of volume-based standards aligned with traditional RAPNO bi-dimensional criteria. Our goal was to correlate volume change percentages with bi-perpendicular diameter changes using machine learning.

METHODS
In this project, we compared 2 machine learning models to establish a correlation between percentage change of sum of products of BPD and percent change in volume using a generalized linear model (GLM) and an artificial neural network (ANN). We analyzed 49 patients with low grade glioma, treated with focal irradiation (NCT04065776) (n=27) or mirdametinib (NCT04923126) (n=22). We trained and validated the models at train-test split ratios of 80/20, 75/25, and 70/30, incorporating a proportionate split of tumors from each group. The models were compared on the validation data set using mean-squared error (MSE).

RESULTS
At percentage changes of +25%, -25%, -50%, and -75% in the sum of BPDs, the GLM predicts changes in volume to be +33%, -31%, -59%, and -83%, respectively. For the ANN, the predicted changes are +20%, -29%, -53%, and -78%. The ANN demonstrated a lower MSE compared to the GLM. The two models showed higher concordance in their volume predictions at negative percentage changes in the sum of BPDs: -25% (p=0.15), -50% (p=0.03), and 75% (p=.08)

CONCLUSION
We identified volume percentage changes matching BPD changes per RAPNO criteria using two machine learning methods, both agreeing on negative values. Further testing with a larger dataset is needed to reliably correlate percentage changes.
LGG-28. THE ROLE OF REOPERATION IN PEDIATRIC CEREBELLAR PILOCYTIC ASTROCYTOMA
Authors: Kameda-Smith Michelle Masayo , Green Katherine , Hutton Dana Louise , Jeelani Owase , Thompson Dominic , Hargrave Darren , Aquilina Kristian 
Published: June 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.
LGG-54. PEDIATRIC LOW-GRADE GLIOMAS TREATED WITH MEK INHIBITORS
Authors: Fraustro Milena , Maddox Breyonna , Valdes Lilibet Fernandez , Lopez Elizabeth , Niazi Toba , Maher Ossama , Khatib Ziad 
Published: June 2024

Abstract

BACKGROUND
Low-grade gliomas (LGG) represent the most common brain tumor in children. It is well known that these tumors present mutations involving the BRAF gene, causing activation of the MAPK/ERK pathway. MEK inhibitors have now become an important treatment option over the recent years, slowing the growth of cancer cells.

METHODS
Retrospective analysis of 23 patients with LGG that were treated with MEK inhibitors at Nicklaus Children’s Hospital between 2015-2022.

RESULTS
Of the 23 patients; 6 were males and 17 were females, with a median age at diagnosis of 9.5 years of age. BRAF V600E mutation was present in 52% of patients (9/17). Other mutations found were: BRAF, BRAF KIAA1549, p.Q61K, and FGFR. Six patients had known associations with NF1. 7 of 23 patients had not received any prior treatment before MEK therapy, 8 underwent partial or total resection only prior, 4 had previous chemotherapy treatment, 3 underwent resection with chemotherapy, and 1 patient had both chemotherapy and proton radiation prior to MEK therapy. Targeted therapies included Trametinib (17/23), Dabrafenib (9/23), Selumetinib (5/23), and Binimetinib (1/23). Of the 9 patients with BRAF V600E mutation, 7/9 were given dual targeted therapies whereas only two were treated with only one inhibitor. The average length of therapy was one year. Most reported side effects were dermatologic manifestations such as dry skin or acne (9/23). Five patients showed objective improvement, 16 patients had stable residual disease, one had local recurrence, and one patient expired. Currently 12 patients are off therapy and 10 remain on treatment. Of the patients with BRAF V600E mutation, 4 had clinical and/or radiologic response, 1 patient expired due to disease progression and 1 has stable disease.

CONCLUSION
MEK inhibitors as a treatment of pediatric low-grade gliomas demonstrated promise as a therapeutic approach, so far proving to slow progression of disease in some cases. However, long-term side effects and toxicity remain unknown. Further large-scale prospective analysis would be helpful in future studies.
LGG-59. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR; MOLECULAR IMPLICATIONS ON PROGNOSIS
Authors: Munir Faryal , He Jiasen , Stitzlein Lea M , Chen Melissa , McAleer Mary F , McGovern Susan , Paulino Arnold , Friedman Gregory K , Sandberg David , Zaky Wafik 
Published: June 2024

Abstract

BACKGROUND
Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are extremely rare tumors that were first described in the WHO Classification in 2016. While usually considered low-grade tumors, DLGNTs currently lack a standard of care as well as literature on molecular profiling and treatment responses.

METHODS
Retrospective review of pediatric DLGNTs seen at MD Anderson Cancer Center with Institutional Board Review approval.

RESULTS
Twelve patients with a histopathological and neuroradiological diagnosis of DLGNT were identified with a median age at diagnosis of 7.5 years (range 4 months – 21 years). Histologically, 10/12 (83%) tumors were low-grade while 2 were reported as high-grade. BRAF gene alterations were reported in 50% (6/12; 4 fusions and 2 mutations). Other reported genetic alterations were mutations [PTPN11 (n=2), PIK3CA (n=1), FGFR1 (n=1), ALK (n=1)], amplifications [NOTCH1 (n=1) and STK11(n=1)], and fusion [NTRK (n=1)]. Upfront, 9 patients received chemotherapy including temozolomide (n=5), carboplatin (n=4), and vincristine (n=4) or vinblastine (n=1). Nine patients (88%) received proton radiation, including 5 upfront and 4 upon progression. Targeted therapy [NTRK (n=1), BRAF (n=1) or MEK inhibitors (n=6)] was initiated upon progression in 8 patients, and at diagnosis in one. The median progression-free survival (PFS) in the group receiving upfront chemoradiation (n=3) is 57 months versus chemotherapy alone (n=6) of 30.5 months, and 26.7 months for radiotherapy alone (n=3). The PFS at 2 years and 5 years were 58.3% and 17% respectively; OS was 100% at both time intervals. BRAF genetic alterations and younger age trended toward a worse outcome, hence upfront targeted therapy may be warranted when radiation needs to be avoided.

CONCLUSION
In our experience, DLGNTs are more commonly low-grade with frequent BRAF gene alterations; upfront chemoradiation provided the longest PFS compared to chemotherapy or radiation alone. In the absence of established standard of care, our case series emphasizes the potential role of targeted therapy upfront for younger patients and progressive disease post-chemoradiation. Larger prospective, collaborative studies are greatly needed for DLGNTs.
MDB-02. RECURRNET SPINAL DESMOID FIBROMATOSIS IN A CHILD WITH APC GERMLINE MUTATION-RELATED MEDULLOBLASTOMA
Authors: Mobarak Nahla Aly , Balbaid Ali Abdullah O , Alotabi Fahad , AlMalki Salman A , Alyamna Basma , Alharbi Musa 
Published: June 2024

Abstract

BACKGROUND
Familial adenomatous polyposis (FAP) is an autosomal-dominant dominant Familial Cancer Syndrome FCs Caused by Germline inactivation of adenomatous polyposis coli (APC) tumor suppressor gene, results in up-regulation of the WNT signaling pathway which increases the risk of colorectal cancer CRC, colon polyposis and extracolonic tumors like gastric and duodenal carcinomas WNT-activated Medulloblastoma MBL and Desmoid fibromatosis (DF) DF are locally aggressive soft tissue tumors with high local recurrence rates after Surgical excision role of adjuvant chemotherapy or Radiotherapy is still unclear.

METHODS
A 6-year-old boy product of non-consanguineous marriage with positive family HX brain tumor Diagnosed with Non-Metastatic Average Risk MBL WHO grade IV classic histology, he had craniotomy and Gross tumor resection followed by craniospinal irradiation at 23.4 Gy, plus a boost to posterior fossa/tumor bed up to 54 Gy, followed by 8 maintenance chemotherapy cycles as HIT-MED protocol Cisplatin/VCR/CCNU total. 3 years post end of therapy the pateint was in complete remission from MBL when routing MRI surveillance showed a new left paravertebral muscle lesion within the irradiation field from T1 to T4 levels which progressed gradually over a short follow-up time he had surgical resection of the tumor with Pathological diagnosis of Desmoid fibromatosis. after six months he had a second recurrence of the spinal tumor that needed a second surgical resection. Result: positive Genetic testing for Germline pathogenic mutation of APC gene exons 7 to 16 confirmed the diagnosis of autosomal familial adenomatous polyposis type 1(FAP1). Up to date, he is stable on endoscopic and MRI surveillance with radiological evidence of slow progression of the paraspinal tumor

CONCLUSION
Medulloblastomas associated with APC germline mutation have favorable outcomes that may need de-escalating therapeutic protocol with reduced intensity craniospinal irradiation aiming to reduce the incidence of secondary tumors after adjuvant treatment for MBL
MDB-03. MEDULLOBLASTOMA AT RELAPSE: FOR WHICH PATIENTS AND WHICH TUMORS REIRRADIATION IS THE BETTER CHOICE
Authors: Massimino Maura , Vennarini Sabina , Buttarelli Francesca Romana , Antonelli Manila , Minasi Simone , Pecori Emilia , Giussani Carlo , Trezza Andrea , Schiavello Elisabetta , Biassoni Veronica , Erbetta Alessandra , Chiapparini Luisa , Nigro Olga , Gianno Francesca , Miele Evelina , Modena Piergiorgio , Dossena Chiara , De Cecco Loris , Pollo Bianca , Barretta Francesco 
Published: June 2024

Abstract

BACKGROUND
First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not yet standardized. We report the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups.

METHODS
Patient’s staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported.

RESULTS
Between 2002 and 2019, relapsing patients were 25, median age at diagnosis 11.4 years, 8 had metastases, three LC/A histotype. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors (6 TP53 mutated,1 + MYC and 1 + NMYC amplification), 11 non-WNT/non-SHH (2 with MYC/MYCN amplification). Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in 9, distant-DR in 14, LR+DR in two) was 26 months. Fourteen patients were re-operated, in 5 excising single DR-sites, thereafter 3 received CT, two after re-RT; out of 11 not re-operated patients, 4 had re-RT as first treatment and 7 after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, CSI in 5, never resulting in radionecrosis. Median post-relapse-PFS/after re-RT were 16.7/8.2 months, while overall survival-OS were 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. MYC,MYCN,P53 status and molecular subgroups, RT extension/fractionation, gender and age were not statistically prognostic; in the multivariable model, OSs were positively influenced by longer intervals before re-RT, re-surgery and not-SHH subgroups (P=0.019 from recurrence and 0.004 from second RT).

CONCLUSIONS
Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belonged to SHH-subgroup.
MDB-08. MYC AND TGFΒ PROMOTE GROUP 3 MEDULLOBLASTOMA TUMOR RESISTANCE THROUGH DEREGULATION OF POLYCOMB TARGETS
Authors: Qadeer Zulekha A , Westelman Samantha , Johnson Mackenzie O , Hou Elise , Grele Shane , Smith Kyle , Hendrikse Liam , Siegel Dara , Wang Linyu , Beytagh Mary Clare , Schmidt Christin , Huang Miller , Taylor Michael D , Northcott Paul , Weiss William A 
Published: June 2024

Abstract
Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at &lt;50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated new humanized models for G3MB by transforming neuroepithelial stem cells (NESC) derived from human induced pluripotent stem cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. Excitingly, both MYC and TGFβ effectors drove tumor formation in vivo with the combination of TGFβ effectors and MYC leading to more aggressive tumors. Moreover, NESC-derived tumors clustered with human G3/G4MB samples, indicating our models recapitulates human disease. We next found that NESCs expressing MYC with either TGFβR1 or TGFβ1 showed resistance to clinical TGFβR1 inhibitors, compared to cells driven by either TGFβR1 or TGFβ1 alone. To decipher mechanisms of resistance, we integrated CUT&RUN to probe for MYC genomic localization and relevant histone PTMs with RNA-seq analysis and discovered a subset of genes upregulated in MYC and TGFβ-driven lines that are targets of the histone demethylase KDM2B and Polycomb Repressive Complex 2 (PRC2) member SUZ12. Moreover, we found that MYC is bound to regions normally regulated by PRC interactors. We postulate that chromatin remodeling via MYC and recruitment of other MYC-interacting cofactors to PRC targets culminates in transcriptional changes that lead to aggressive disease. Work from others suggests that PRC-mediated chromatin regulation is critical in many adult and pediatric brain tumors, underscoring its significance in MB. Our studies provide important insight on identifying new therapeutic avenues with a focus on the epigenetic landscape for patients with MYC and TGFβ driven G3MB.
MDB-09. WNT AND GROUP 4 MEDULLOBLASTOMAS OF EARLY CHILDHOOD TREATED WITH HIGH DOSE CHEMOTHERAPY AND CRANIOSPINAL IRRADIATION SPARING APPROACH
Authors: Cansanay Rose Daynielle , Erker Craig , Ratterman Erin , Schlosser Mary Pat , Ronsley Rebecca , Cacciotti Chantel , Hukin Juliette , Cheng Sylvia , Pillay-Smiley Natasha , Magimairajan Vanan , Cluster Andrew , Abdelbaki Mohamed S , Margol Ashley , Michael George , Chi Susan , Salloum Ralph , Ramaswamy Vijay , Zapotocky Michal , Lopez Vicente Santa Maria , Toledano Helene , Dorris Kathleen , Mynarek Martin , Rutkowski Stefan , Lassaletta Alvaro , Bouffet Eric , Lafay-Cousin Lucie 
Published: June 2024

Abstract

BACKGROUND
WNT and group 4 medulloblastoma (MB) are rare in young children and their outcome when treated with radiation avoidance infant strategies is unknown.

METHOD
This retrospective international cohort included children less than 7 years of age, with molecularly characterized group 4 or WNT MB, treated with high-dose chemotherapy(HDC) and CSI sparing approach.

RESULTS
The current cohort includes 29 patients (19M/10F). For the 26 patients with group 4 MB (median age at diagnosis 45.9 months), 16 (61.5%) were M0 and 17 (65.3%) underwent initial gross total resection (GTR). The most common consolidation regimen used was three cycles of high dose carboplatin and thiotepa (65.5%) or a single cycle of high dose of carboplatin, etoposide and thiotepa (31%).Two received adjuvant focal radiotherapy. Sixteen patients (61.5%) relapsed at a median time of 21.4 months from diagnosis (median age of 5.2 years). Relapse was local for 50% of the patients. One patient underwent palliative management and 15 received radiation-based salvage therapy (2 focal, 13 CSI+/- boost).The median dose of CSI was 36Gy (18-36). Five of the 15 died of disease. Overall, at a median follow-up of 37.9 months from diagnosis, 17/26 (65.3%) patients were alive, six had died of disease and two of toxicity. All 3 WNT patients (median age at diagnosis 57.8 months) underwent GTR and two were M0. Two received sequential high dose carboplatin and thiotepa. One patient with initial partial response, progressed 2 months after treatment completion and received salvaged CSI (18Gy). All of them were alive at a median follow up of 88 months from diagnosis.

CONCLUSIONS
HDC and CSI sparing approaches led to a high rate of relapse for young patient with group 4 (61.5%). However, 2/3 were salvaged with radiation-based therapy given at a median age 5.2 yrs. Additional WNT patients are needed to better describe their management.