tbuckley/cabot-search huggingface dataset:
LMIC-26. DEVELOPMENT OF THE ST. JUDE GLOBAL VIRTUAL PEDIATRIC NEURO-ONCOLOGY FELLOWSHIP (VPNOF): INCREASING PEDIATRIC NEURO-ONCOLOGY CAPACITY IN LOW- AND MIDDLE- INCOME COUNTRIES (LMIC)
Authors: Zeena Salman, Daniel Moreira, Alma Benito Resendiz, Julieta Hoveyan, Ludi Rahmartani, Rahat Ul Ain, Anan Zhang, Nisreen Amayiri, Simon Bailey, Eric Bouffet, Godfrey Chi-Fung Chan, Anthony P Y Liu, Andres Morales La Madrid, Naureen Mushtaq, Karen Tsui, Vasudeva Bhat, Ramona Cirt, Thandeka Ngcana, Mauricio Sanchez Salazar, Mahendra Somathilaka, Peiyi Yang, Girish Chinnaswamy, Girish Dhall, Tejpal Gupta, Rakesh Jalali, Alvaro Lassaletta, Diana S Osorio, Margaret Shatara, Santhosh Upadhyaya, Ramya Uppuluri, Carlos Rodriguez-Galindo, Ibrahim Qaddoumi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Most children with central nervous system (CNS) tumors reside in LMICs, yet their complex management is limited by the availability of trained pediatric neuro-oncologists (PNO). The St. Jude Global VPNOF was designed to train pediatric oncologists (PO) in LMICs as CNS tumor experts while remaining in their home countries. METHODS The VPNOF structure was initially developed through semi-structured interviews of physicians who had served as global mentors or mentees in pediatric oncology. Employing a modified Delphi method, we identified the key components necessary to virtually train POs in LMICs to become PNOs. RESULTS A two-year fellowship program was designed with a curriculum tailored for POs in LMICs. Two main components were identified as critical to the objective of building PNO capacity: mentorship and clinical training. Mentorship involves a triad with one global and one loco-regional mentor per fellow, aiding in the fellow’s career and institutional goal setting to advance PNO care. Clinical training includes regularly scheduled virtual tumor boards and didactics, and ad-hoc case discussions with mentors while managing patients at their home institution. Additionally, fellows travel to their mentors’ institution twice for a four-week clinical rotation. In 2022, five fellows from Armenia, China, Indonesia, Mexico, and Pakistan were selected. In 2023, an additional six fellows were selected from China, Costa Rica, India, Romania, South Africa, and Sri Lanka. To date, 18 months of the two-year fellowship have resulted in the establishment of multi-disciplinary approaches, increased patient volume, increased evidence-based practices, and publication by the first cohort of 21 abstracts and two journal publications to date. CONCLUSIONS The VPNOF is an innovative approach to leveraging global mentorship to train PO in resource-limited settings to become PNOs. Virtual mentorship and training have led to implementation of new practices aimed at improving quality of care for children with CNS tumors in LMICs.
NURS-02. THE DEVELOPMENT AND IMPLEMENTATION OF SKINCARE TREATMENT PLANS AND PRODUCT KITS FOR PEDIATRIC PATIENTS RECEIVING TARGETED THERAPIES THAT CAUSE SKIN TOXICITY
Authors: Ashley S Meyer, Andrea Ogle, Michele Mchugh, Mary Beck, Ashley Lampe, Andrew Cluster, Nicole M Brossier, Margaret Shatara, Abbey Rocco, Mohamed S Abdelbaki, Carrie C Coughlin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Mitogen-activated protein kinase (MAPK) pathway inhibitors are incorporated into the treatment regimens for several pediatric cancers. However, they commonly trigger dermatologic side effects, which can be challenging to manage and may have a significant impact on the quality of life. METHODS We previously performed a prospective study looking at the satisfaction and utilization of skincare kits and patient education regarding basic skincare practices. Based on these data, we developed revised skincare product kits and treatment plans that can be individualized for patients who are at risk of developing dermatologic side effects from targeted therapies. RESULTS Based on our prior study, 77% of patients thought the skincare kits and instructions were helpful. Seventy-seven percent of patients also recommended that they be distributed at the initiation of therapy. Through this study, we discovered that the patient reported medical history questions were inconsistent when compared with medical chart reviews. The most common discrepancies included information regarding patient’s diagnosis, prescribed medications, skin-related problems, and past medical history. From this data, we have developed a new skincare product kit and patient skincare plans which we distribute to every patient prior to starting their targeted therapy. The skincare kits consist of a cleanser, emollient, oral care products, sunscreen, pyrithione zinc containing shampoo, and facial moisturizers for adolescent patients. Our patient skincare plans consist of patient-specific information including diagnosis, medications, and their targeted agent. The plan provides details on how and when to use each product, application time, and order in which to apply products and topical medications. CONCLUSION Our project has highlighted the importance of patient education regarding dermatologic side effects in those starting targeted therapies. We have successfully implemented this by providing our patients with both skincare products and patient-specific care plans.
Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms
Authors: Amandeep Kaur, Alexandra E. Rojek, Emily Symes, Mariam T. Nawas, Anand A. Patel, Jay L. Patel, Payal Sojitra, Barina Aqil, Madina Sukhanova, Megan E. McNerney, Leo P. Wu, Aibek Akmatbekov, Jeremy Segal, Melissa Y. Tjota, Sandeep Gurbuxani, Jason X. Cheng, Su-Yeon Yeon, Harini V. Ravisankar, Carrie Fitzpatrick, Angela Lager, Michael W. Drazer, Caner Saygin, Pankhuri Wanjari, Panagiotis Katsonis, Olivier Lichtarge, Jane E. Churpek, Sharmila B. Ghosh, Ami B. Patel, Madhu P. Menon, Daniel A. Arber, Peng Wang, Girish Venkataraman
Journal: Blood Cancer Journal (2024)

Abstract Current therapies for high-grade TP53 -mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53 -mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 &amp; 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender ( P = 0.026), ≥2 autosomal monosomies ( P &lt; 0.001), −17/17p ( P = 0.011), multi-hit TP53 allelic state ( P &lt; 0.001) and CUX1 co-alterations ( P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies ( P = 0.004), TP53 VAF &gt; 25% ( P = 0.002), TP53 splice junction mutations ( P = 0.007) and antecedent treated myeloid neoplasm ( P = 0.001). In addition, mutations/deletions in CUX1 , U2AF1 , EZH2 , TET2 , CBL , or KRAS (‘ EPI6 ’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8]; P &lt; 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals ( N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival ( P &lt; 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.
SURG-06. FRAMELESS STEREOTACTIC INTRACRANIAL CATHETER PLACEMENT FOR DELIVERY OF INTRATUMORAL CELLULAR THERAPIES
Authors: Rakesh A Murugesan, Alexander Tucker, Cassie Kline, Jessica Foster, Peter Madsen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND As the leading disease-related cause of death in children, pediatric brain tumors, and in particular diffuse midline glioma, require novel treatment approaches. Cellular-based therapies offer promise, but challenges still exist in defining their optimal delivery route. Emerging data from our group suggest there may be a role for intratumoral injection in treatment algorithms. We here describe a surgical workflow for intratumoral injection of cellular therapies that utilizes existing and widely used neurosurgical technologies that can be incorporated into future clinical trials. METHODS Infusion target and catheter trajectory was planned using standard pre-operative MRI. Components from an FDA-approved frameless stereotactic intracranial biopsy system were chosen such that they would accept and guide an FDA-approved rigid intracranial catheter system intended for MR-guided procedures. Following catheter insertion, an intraoperative CT was used to determine accuracy of catheter placement by merging the image with the pre-operative MRI. RESULTS The proposed system was tested in a simulated fashion using a phantom cranial model registered to an accompanying brain MRI. The stereotactic biopsy mount was affixed to the skull at the planned entry site for a posterior fossa approach to the pons. Catheter insertion depth was determined using the stereotactic system and the catheter was inserted to this depth through the biopsy mount. Intraoperative CT confirmed the catheter tip location which correlated with the planned infusion target with sub-millimetric accuracy. CONCLUSION Our proposed intratumoral delivery method using frameless stereotaxy shows promise for use in future clinical trials that require intratumoral delivery of cellular therapies. Utilizing FDA-approved devices allows for quick integration into protocols and their wide-spread use makes the approach generalizable. This approach also eliminates the need for MR-guided procedures which can increase cost and require significant hospital resources to perform. Future work will be aimed at streamlining the intraoperative workflow.
NURS-01. NOVEL TREATMENTS FOR ACNEIFORM ERUPTIONS CAUSED BY TARGETED THERAPIES IN THE PEDIATRIC POPULATION
Authors: Ashley S Meyer, Andrew Cluster, Andrea Ogle, Nicole Brossier, Mary Beck, Ashley Lampe, Abbey Rocco, Margaret Shatara, Michele Mchugh, Mohamed Abdelbaki, Carrie C Coughlin
Journal: Neuro-Oncology (2024)

Abstract 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.
LMIC-27. MEK INHIBITORS IN PEDIATRIC LOW-GRADE GLIOMAS (PLGG)- EARLY EXPERIENCE IN A RESOURCE LIMITED SETTING
Authors: Girish Chinnaswamy, Venkata Rama Mohan Gollamudi, Amit Choudhari, Maya Prasad, Archya Dasgupta, Abhishek Chatterji, Aekta Shah, Arpita Sahu, Kajari Bhattacharya, Vikas Singh, Ayushi Sahay, Prakash Shetty, Aliashgar Moiyadi, Tejpal Gupta, Epari Sridhar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric Low-Grade Gliomas (PLGG), encompass a heterogenous set of tumours, with upregulation of RAS/MAPK pathway, making them amenable to therapeutic targeting. MEK inhibitors are emerging as a promising alternative to conventional chemotherapy strategies which have modest efficacy with significant toxicity/hospitalisation and hence long periods of stay away from home (&amp; school). Recently, we transitioned to use of MEK inhibitors, where feasible, in children with PLGG. METHODOLOGY Retrospective analysis of children(&amp;lt;15 years) with newly diagnosed, recurrent/progressive PLGG who received Trametinib at Tata Memorial Hospital, India between September’2021-October’2023. Diagnosis of PLGG was by histopathology/radiology. Molecular testing was performed by qualitative real-time PCR for BRAFV600E and KIAA1549:BRAF fusion. Decision to start MEK inhibitors was taken at the Neuro-oncology MDT meeting. Financial support for therapy was provided through the childhood cancer foundation (ImPaCCT) and other agencies. RESULTS Twenty four children were treated with Trametinib, of which 22 were evaluable for response (&amp;gt;3 months therapy). Median age at start of Trametinib was 6.4 years(2.3–14.5years). Histopathological confirmation of PLGG was done in 19 patients and 5 had a clinico-radiological diagnosis. 13/18(72%) had KIAA1549:BRAF fusion, and 5 were BRAF-Wild type. While 12/22 children received Trametinib as salvage therapy, 10 children received it upfront. 2 received Trametinib due to chemotherapy intolerance. At a median therapy duration of 18 months(3-28 months), 17/22(77%) showed stable disease and 3/22 showed response(2 Partial and 1 minor) as per RANO criteria. Two patients had disease progression [BRAF status included unavailable (n=1), wild-type (n=1)]. Toxicities noted were skin rash(n=8), paronychia(n=3), oral ulcers(n=2) &amp; thrombocytopenia(n=1). Dose reduction due to toxicity was done in one child. School attendance increased and frequency of hospital visits significantly decreased in this cohort. CONCLUSIONS Early experience with Trametinib as an effective/well tolerated alternative to chemotherapy in PLGG is encouraging. Long-term treatment related toxicities and disease control after Trametinib withdrawal are yet unanswered questions.
NURS-06. MUSIC THERAPY: AN INTEGRAL PART OF REHABILITATION FOR CEREBELLAR MUTISM SYNDROME
Authors: Kathryn Matson, Gwendolyn Corr
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cerebellar mutism syndrome (CMS) also known as posterior fossa syndrome (PFS), can occur in up to 25% of pediatric patients following surgical resection of posterior fossa brain tumors, particularly medulloblastoma. It is well recognized that intensive rehabilitation with physical therapy, occupational therapy and speech therapy are essential to recovery. Music therapy can be immensely helpful during rehabilitation to stimulate brain functions involved in movement, cognition, speech, emotions, and sensory perceptions. This case-based review aims at analyzing the available evidence to support our recommendation to include music therapy in the rehabilitation plan for all patients. METHODS We report on the case of a 4-year-old male with medulloblastoma and cerebellar mutism syndrome who began talking after just a few sessions with music therapy. We include an extensive review of the literature where multiple papers were found describing the positive effects of music therapy for management of neurologic diseases. RESULTS The pathophysiology of CMS is still poorly understood however, the most likely mechanism is injury along proximal components of the efferent cerebellar pathway. Intensive inpatient rehabilitation remains the standard of care. Music therapy uses and activates many different parts of the brain at the same time, promoting neuron repair and regeneration. Some of the advantages of music therapy are: it promotes plasticity in the brain and facilitates processing of sensory information and motor function; improves stress and helps patients adapt to stressful environments; facilitates more normative speech production for patients with dysarthria. CONCLUSIONS Despite efforts to identify preventative measures for CMS, it still occurs. Intensive rehabilitation remains the cornerstone of treatment. The case study as well as the review of the literature support our recommendation to include music therapy in the rehabilitation plan for patients with CMS. More studies are necessary to explore the therapeutic efficacy of music on patients with CMS.
MDB-08. MYC AND TGFΒ PROMOTE GROUP 3 MEDULLOBLASTOMA TUMOR RESISTANCE THROUGH DEREGULATION OF POLYCOMB TARGETS
Authors: Zulekha A Qadeer, Samantha Westelman, Mackenzie O Johnson, Elise Hou, Shane Grele, Kyle Smith, Liam Hendrikse, Dara Siegel, Linyu Wang, Mary Clare Beytagh, Christin Schmidt, Miller Huang, Michael D Taylor, Paul Northcott, William A Weiss
Journal: Neuro-Oncology (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 &amp;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&amp;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.
SURG-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS
Authors: Luca Szalontay, Travis CreveCoeur, Justin Neira, Zachary Englander, Eleonora Spinazzi, Peter Canoll, James Garvin, Jessica Fino, Dmitry Zamoryakhin, Alexis Maddocks, Neil Feldstein, Jeffrey Bruce, Cheng-Chia Wu, Stergios Zacharoulis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Histone deacetylase inhibitors have been found preclinically to be among the most active agents against Diffuse Midline Gliomas (DMGs), however, they are clinically ineffective with systemic delivery due to low blood brain barrier penetration and systemic toxicity. Using an implantable subcutaneous pump connected with a catheter directly implanted into the pons we have conducted a phase I, 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Biodexa Ltd), a water-soluble formulation of panobinostat, via CED. METHODS Eligible patents were between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without evidence of hemorrhage or cyst in the tumor, and having normal organ function. First, patients underwent tumor biopsy and device implantation, then received two 48-hour-infusion pulses 7 days apart. Three dose levels of MTX110 infusions (30, 60, 90 mcM) were studied. The infusion pump was prefilled with MTX110 (and gadolinium for co-infusion as a contrast agent), which was then administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. RESULTS Nine patients were treated in the study (30 mcM group, n=3; 60 mcM group, n=4; 90 mcM group, n=2). All patients had an H3K27M mutated tumor. All but one patient had adequate tumor coverage with the infusate. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) or infusion (n=3). We observed one objective response. Median PFS was 10 months from diagnosis (range 8 to 20 months) while median OS was 16.5 months (range 12 to 35 months). CONCLUSIONS The study has demonstrated safety and feasibility of repeated infusions of MTX110 via CED in DMG patients with a favorable trend in overall survival warranting further trials with higher number of infusion pulses.