tbuckley/cabot-search huggingface dataset:
Right ventricular dysfunction and impaired right ventricular–pulmonary arterial coupling in paradoxical low‐flow, low‐gradient aortic stenosis
Authors: Richard J. Nies, Felix S. Nettersheim, Simon Braumann, Svenja Ney, Laurin Ochs, Johannes Dohr, Jasper F. Nies, Hendrik Wienemann, Matti Adam, Victor Mauri, Stephan Baldus, Stephan Rosenkranz
Journal: European Journal of Heart Failure (2024)

Aims Paradoxical low‐flow, low‐gradient aortic stenosis (pLFLG AS) may represent a diagnostic challenge, and its pathophysiology is complex. While left ventricular (LV) systolic function is preserved, right ventricular dysfunction (RVD) and consecutive LV underfilling may contribute to low‐flow and reduced stroke volume index, and to adverse outcomes following transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the potential role of RVD in pLFLG AS, and to assess the impact of pre‐procedural RVD on clinical outcomes after TAVI in patients with pLFLG AS. Methods and results Out of 2739 native AS patients, who received TAVI at the University of Cologne Heart Center between March 2013 and June 2021, 114 patients displayed pLFLG AS and were included in this study. Right ventricular (RV) function was assessed by transthoracic echocardiography, and a fractional area change (FAC) ≤35% and/or a tricuspid annular plane systolic excursion (TAPSE) &lt;18 mm determined RVD. In addition, the TAPSE/systolic pulmonary artery pressure ratio (TAPSE/sPAP) was monitored as a measure of RV–pulmonary arterial (PA) coupling. An impaired FAC and TAPSE was present in 21.9% and 45.6% of patients, respectively, identifying RVD in 50.0%. RVD ( p = 0.016), reduced FAC ( p = 0.049), reduced TAPSE ( p = 0.035) and impaired RV–PA coupling (TAPSE/sPAP ratio &lt;0.31 mm/mmHg; p = 0.009) were associated with significantly higher all‐cause mortality compared to patients with normal RV function. After adjustment for sex, age, body mass index, EuroSCORE II, previous myocardial infarction and mitral regurgitation, independent predictors for all‐cause mortality were FAC, sPAP, TAPSE/sPAP ratio, right atrial area, RV diameter and tricuspid regurgitation. Conclusions Adverse RV remodelling, RVD and impaired RV–PA coupling provide an explanation for low‐flow and reduced stroke volume index in a subset of patients with pLFLG AS, and are associated with excess mortality after TAVI.
LGG-53. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA
Authors: Giles W Robinson, Anna Vinitsky, Asim K Bag, Jason Chiang, QIan Li, Tong Lin, Mary Ellen Hoehn, Angela Edwards, Diana Storment, Anjali Singh, Jennifer Larkin, Jana Freeman, Johanna Pranica, Kelsey Bertrand, Aditi Bagchi, Todd Baughman, Thuy Hoang, Todd Shearer, Daniel Moreira
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS Phase 1 required patients to be &amp;gt;2 and &amp;lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort planned to evaluate the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), MYB (n=1;4%). The median time of follow-up was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on therapy; 4 (17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior exposure to MEKi.
TRLS-09. CONNECT1903: A PILOT AND SURGICAL STUDY OF LAROTRECTINIB FOR TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED HGG WITH NTRK FUSION (NCT04655404)
Authors: Susan N Chi, Margot Lazow, Ralph Salloum, Adam Lane, Darren Hargrave, Olaf Witt, Peter de Blank, Sarah E S Leary, Hamza Gorsi, Christopher Pierson, John Breneman, Jeremy Jones, Edward Yang, Leonie Mikael, David T W Jones, Maryam Fouladi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recurrent fusions in neurotrophic tropomyosin-receptor kinase genes NTRK 1-3 are found in variety of cancers, including pediatric HGG: DIPG (~4%) and non-brainstem HGG (~10%). For non-brainstem HGG seen in children &amp;lt;3 years of age, approximately 40% harbor NTRK alterations. NTRK fusions provide a promising target for gliomas and to that end, Larotrectinib, a globally approved, highly potent, small molecule inhibitor of TRKA/B/C, has previously been investigated and has shown tolerability and efficacy in children with recurrent solid tumors. Compassionate use in a case of infantile GBM showed proof-of-concept with blood-brain penetrance and efficacy. Further evidence of efficacy in two earlier clinical trials has also been previously demonstrated in children with recurrent TRK-fusion primary intracranial tumors (NCT02637687, NCT02576431). METHODS This international trial conducted through the CONNECT consortium, supported in part by Bayer, investigates larotrectinib monotherapy; its feasibility and tolerability in combination with standard systemic chemotherapy (Baby POG or HIT-SKK) or radiation therapy whereby treatment plan determination is response-based. Objectives include: to assess disease control rate (CR, CCR, PR and SD) after two cycles of larotrectinib monotherapy (28-day cycles); to assess feasibility and to describe toxicities of larotrectinib in combination with standard chemotherapy; to assess objective response rate (CR and PR); to assess OS and PFS as compared to historical data from Baby POG, HIT-SKK and radiotherapy. A phase 0 surgical cohort will be explored whereby patients who are planned to undergo a definitive resection will receive pre-surgery larotrectinib, and target inhibition, intratumoral and plasma pharmacokinetics will be investigated. Radiographic responses will also be quantitated. This trial is currently open to accrual at ten CONNECT sites across North America and Australia and has enrolled five patients to date. Sites in UK, Germany and Netherlands are pending activation. A total of 15 patients are anticipated to be enrolled and evaluable.
TRLS-12. EFFICACY AND SAFETY OF ENTRECTINIB IN CHILDREN WITH<i>NTRK</i> OR<i>ROS1</i> FUSION-POSITIVE (FP) PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Aditi Bagchi, Giles W Robinson, Ami V Desai, Yeming Wu, Huanmin Wang, Ellen M Basu, Michela Casanova, Cornelis M van Tilburg, Quentin Campbell-Hewson, Amy E Armstrong, Nicolas André, Clare Devlin, Jade Wulff, Alison Cardenas, Katherine E Hutchinson, Qinshu Lian, Carolina Ryklansky, Vesna Sneller Harmach, Elizabeth Fox, Amar Gajjar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Entrectinib (CNS-penetrant, TRK/ROS1 inhibitor) has shown efficacy and safety in children with NTRK/ROS1-fp CNS tumors. We present updated data from an integrated analysis of children with NTRK/ROS1-fp CNS tumors enrolled in three early-phase trials: STARTRK-NG (NCT02650401), TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267). METHODS TRK/ROS1 inhibitor-naïve patients &amp;lt;18 years old (YO) with NTRK/ROS1-fp CNS tumors with measurable/evaluable-only disease, who received ≥1 entrectinib dose before disease progression, unacceptable toxicity, or consent withdrawal, and with ≥6 months’ follow-up were efficacy evaluable. Any &amp;lt;18 YO on study who received ≥1 entrectinib dose, regardless of genetic alteration and follow-up duration, was evaluable for safety. Primary endpoint: blinded independent central review (BICR)-assessed confirmed objective response rate (ORR). Key secondary endpoints: BICR-assessed confirmed ORR in patients with measurable disease; duration of confirmed response (DoR); time to confirmed response (TtR); progression-free survival (PFS); safety. RESULTS On 16 July 2023 (cut-off for analysis), 27 patients were efficacy evaluable (NTRK-fp: n=20; ROS1-fp: n=7). Median age at enrolment: 4.0 Y (NTRK-fp) and 6.0 Y (ROS1-fp); 45.0% (NTRK-fp) and 42.9% (ROS1-fp) of patients received ≥2 prior therapy lines. Median survival follow-up: 26.2 months (NTRK-fp); 36.1 months (ROS1-fp). ORR: 50.0% (NTRK-fp) and 71.4% (ROS1-fp) in efficacy-evaluable patients, and 58.8% (n=10/17; NTRK-fp) and 83.3% (n=5/6; ROS1-fp) in patients with measurable disease. Median DoR: 25.4 months, TtR: 1.9 months, PFS: 23.1 months in NTRK-fp patients. DoR and PFS were not evaluable in ROS1-fp patients; median TtR was 1.9 months. In the safety-evaluable population (N=34), the most common adverse events were weight increase (50.0%), blood creatinine increase and anemia (each 41.2%). Bone fractures were reported in 26.5% of patients. Most fractures occurred in children 2–12 YO (n=7/9). CONCLUSIONS Our analysis confirms the rapid and durable activity of entrectinib in children with NTRK/ROS1-fp primary CNS tumors. The safety profile described was in line with previous reports.
DIPG-52. CEREBROSPINAL FLUID DIVERSION DOES NOT PROLONG OVERALL SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Neevika Manoharan, Tab Cooney, Mariko DeWire-Schottmiller, Adam Lane, Anandani Nellan, Sarah Leary, Sonia Partap, Lindsay Kilburn, Karen D Wright, Trent Hummel, David S Ziegler, Maryam Fouladi, Lindsey M Hoffman, Katherine E Warren
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The role of permanent cerebrospinal fluid (CSF) diversion in the management of patients with diffuse intrinsic pontine glioma (DIPG) is poorly elucidated. There are no standard practice guidelines regarding the role of these neurosurgical interventions in patients with DIPG or large studies regarding the impact of CSF diversion on overall survival (OS) or palliation in this disease. METHODS Data were extracted from subjects registered in the International DIPG registry (IDIPGR). Univariable analyses were performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. RESULTS Of n=1104 evaluable patients with DIPG registered in the IDIPGR, n=303 (27.4%) had permanent CSF diversion. Median time from diagnosis to CSF diversion was 1 month (range 0-4 months). There were no significant differences in age, gender or race in subjects with CSF diversion versus no CSF diversion. Patients with CSF diversion had a higher incidence of hydrocephalus at diagnosis (64.1% vs 11.3%, p&amp;lt;0.001). There was no significant difference in OS or post-progression survival (PPS) at 1,2 and 3 years between subjects with permanent CSF diversion compared to those without (p=0.5 and p=0.8, respectively). Median OS was 11 months in both. Median PPS was 7 months (no CSF diversion) and 6 months (CSF diversion). Patients reported less headache and vomiting after permanent CSF diversion compared to pre-diversion (p&amp;lt;0.0001), however steroid use was also significantly higher after CSF diversion (p&amp;lt;0.001). CONCLUSIONS In this, the largest reported international cohort of patients with DIPG with permanent CSF diversion, we show that permanent CSF diversion was not associated with an improvement in OS or PPS. CSF diversion improved headache and vomiting but was also associated with increased rates of steroid use. This highlights the need for consensus guidelines regarding the use of these diversion strategies in patients with DIPG.
DEI-03. COMPASSIONATE USE OF NOVEL AND TARGETED THERAPIES IN RELAPSED AND PROGRESSIVE MALIGNAT PEDIATRIC BRAIN TUMORS: EXPERIENCE OF A SINGLE INSTITUTION
Authors: Palma Solano-Páez, Gloria Moreno-Madueño, Eduardo Quiroga-Cantero, Mónica Rivero -Garvia, Concepción Alvarez-Vayo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Off-label use of targeted therapy in pediatric Neuro Oncology is often offered to patients in the absence of available Clinical Trials specifically designed to this population. We present here six pediatric patients diagnosed with a malignant brain tumor who received compassionate treatment with targeted/novel therapy, alone or in combination, at disease progression or relapse, in a palliative setting. METHODS Retrospective chart review of patients diagnosed with a malignant brain tumor harboring a targeted molecular alteration, who received compassionate prescription of novel therapies not approved for the specific indication, and that were no eligible for a clinical trial. Patient demographics, dose of treatment delivered, tolerance, adverse effects, length of treatment, reason to discontinue the drug and survival rates were analyzed. RESULTS Four girls and two boys were identified; Median age at initiation of off-label drug: 4 years (3-17). Tumor type and targeted therapy delivered: DIPG H3 mutant (2), Diffuse Midline Glioma H3 and FGFR mutant (1), SHH-Medulloblastoma (1), ATRT (1), Diffusse Glioma EGFR and MET mutant (1). Off label drugs prescribed were ONC201, Erdafinitib, Sonidegib, Tazemetostat, and combination of crizotinib and erlotinib, respectively. Adverse events were mainly grade 1 and 2, however, 2/6 patients required hospital admission to manage adverse effects related to the experimental drug. One patient discontinued the drug due to side effects. All patients died of disease progression at a median of six months. CONCLUSIONS The anecdotical use of compassionate use of experimental drugs do not allow to gather clinical experience or to demonstrate a clinical benefit or impact in survival. Although the tolerance was generally good, the potential side effects caused by off-label drugs in a palliative population deserves a thorough individual assessment for its indication. Urgent need of targeted and novel therapies is warranted for pediatric children with malignant brain tumors.
EPEN-04. OVERWHELMING ZFTA-RELA NUCLEAR LOCALIZATION AS A THERAPEUTIC STRATEGY AGAINST EPENDYMOMA
Authors: Amir Arabzade, Siri Ippagunta, Alisha Kardian, Erik Emanus, Srinidhi Varadharajan, Hazheen Shirnecki, Monica Venere, Richard Kriwacki, Benjamin Deneen, Stephen C Mack, Kelsey C Bertrand
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric ependymoma is a malignant brain tumor without targeted therapies. The 10-year survival is close to 50%, as this relentless tumor often relapses years following initial diagnosis. Over two thirds of supratentorial ependymomas harbor a gene fusion between ZFTA and RELA (ZFTA-RELA). Despite evidence that ZFTA-RELA drives tumorigenicity, mechanistic details remain elusive, hindering efforts to uncover therapeutic vulnerabilities. Since direct targeting of ZFTA-RELA is not currently possible, we hypothesized that ZFTA-RELA fusion binding partners would represent vulnerabilities amenable to therapeutic targeting. METHODS We investigated the biochemical basis of ZFTA-RELA, with the goal of identifying key members of the protein interaction landscape. This was performed in our in utero electroporation mouse model of ZFTA-RELA ependymoma. A series of sucrose gradient and immuno-precipitation experiments were performed, coupled with mass spectrometry. ZFTA-RELA interaction proteins were functionalized using focused CRIPSR-Cas9 library screens in cell cultures. Critically, these revealed novel dependencies and druggable targets, with XPO1 emerging as a lead candidate. In vitro and in vivo studies were conducted to evaluate targeting XPO1 in ZFTA-RELA ependymoma. RESULTS ZFTA-RELA regulates XPO1 gene transcription, and elevated gene expression is associated with poor survival in these patients. While expression of ZFTA-RELA is necessary for oncogenic transcription, extremely elevated nuclear localization is associated with reduced growth. This suggests a ‘goldilocks’ model in which XPO1 titrates precise levels of nuclear ZFTA-RELA protein. We reveal that a potential therapeutic vulnerability emerges through modulation of ZFTA-RELA nuclear localization. Supporting this, chemical inhibition of XPO1 using Selinexor, has a direct effect on ZFTA-RELA cellular localization patterns. Critically, in patient derived orthotopic xenograft models, XPO1 inhibition exerts anti-tumor effects both in vitro and in vivo. CONCLUSION Our findings reveal a novel therapeutic strategy in ependymoma, and provide the mechanistic and pre-clinical data needed to develop a clinical trial for patients with ZFTA-RELA ependymoma.
EPEN-08. MULTI-OMICS PROFILES REVEAL UNIQUE DEFINING MOLECULAR FEATURES OF POSTERIOR FOSSA EPENDYMOMA SUBTYPE A FROM INFANTS
Authors: Anbarasu Lourdusamy, Rebecca J Chapman, Timothy A Ritzmann, Richard G Grundy, Robert A Dineen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymoma is a heterogeneous brain cancer with multiple subgroups based on locations and molecular profiles. Tumours of the methylation class, posterior fossa group A (PF-EPN-A) represent the most common and aggressive neoplasms and have a poor outcome. PF-EPN-A tumours in infants (under three years of age) are understudied; this project aimed to characterise these infant tumours. METHODS We collected DNA methylation (n=570) and gene expression (n=56) profiles of PF-EPN-A tumours, and single-cell RNA sequencing data of human fetal cerebellum from published studies. RESULTS Analysis of copy number profiles derived from DNA methylation arrays showed that infants with PF-EPN-A have relatively quiescent genomes when compared to children aged four to eighteen years (mean fraction of changes in infants (n=300) = 0.018 and children (n=270) = 0.055; p-value &amp;lt; 2.2 × 10-16). No recurrent focal amplifications or losses were detected, however, copy number loss involving chromosome arms, 12q (12%), 7q (9.7%), 5p (8.3%), and 16p (6%) were relatively common in infants, while 1q gain, 6q loss, and 22q loss were more frequent in children. When we stratified PF-EPN-A based on copy number alterations, infants with altered genomes were associated with poor outcomes compared to infants with stable genomes (fraction of changes = 0), which in turn showed poor overall survival compared to children with stable genomes. Gene set enrichment analysis using data from microarrays showed that infant tumours were specifically enriched with genes involved in the extracellular matrix organization, interferon gamma signaling, neuronal system, autophagy, and signaling by Interleukins, VEGF and PDGF. Integration with single-cell data from the human fetal cerebellum revealed that infants in PF-EPN-A had significantly higher proportions of glial progenitor cells and decreased granule cell progenitor subpopulations. CONCLUSIONS Together, our study identifies distinct genetic and transcriptional programs among infants in PF-EPN-A tumours, representing opportunities to refine future treatment.
STEM-08. ANGIOGENESIS IN PEDIATRIC CHOROID PLEXUS PAPILLOMAS
Authors: Nurfarhanah Bte Syed Sulaiman, Khurshid Z Merchant, Wan Tew Seow, Lee Ping Ng, Sharon Y Y Low
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid plexus papillomas (CPP) are rare brain tumors that tend to occur in very young children. Although most of them are curative with surgical resection, a subset of them has propensity for tumor recurrence, progression, and metastasis. Moreover, surgery can be technically difficult due to their deep locations and high vascularity. In-depth mechanisms of their biology remain poorly understood. Separately, the process of angiogenesis has been implicated in several cancers. To date, there has been no previous study focused on CPP and angiogenesis. This study aims to explore and ascertain the existence of angiogenesis in CPP. METHODS This is a study approved by the hospital ethics review board. Cerebrospinal fluid (CSF) and CPP tumor samples are collected at the time of surgery. A multiplex immunoassay panel is used to measure cytokine concentrations in the CSF samples. Identified cytokines of interest are input into online platforms to assess for protein-protein interaction pathways. Concurrently, patient-derived primary cell cultures and their supernatants are derived from CPP samples. A targeted proteome blot array and HUVEC tubule formation assays are used to validate clinical and in silico findings. RESULT CSF profiling showed higher expression of MCP-1, MMP-1, IL-2, TNF-ɑ, TRAIL and CD40-L in CPP patient samples versus non-tumor controls. Next, in silico assessment via STRING and BioGRID platforms report that these cytokines are associated with endothelial cell regulation. This is clinically relevant as we are aware that the endothelium has important functions in the regulation of angiogenesis. Using an angiogenesis-focused approach, CPP-derived cell lines and supernatants showed congruently higher expression of MCP-1, MMP-1 and TNF-ɑ. Next, tubule formation was observed in HUVEC cultures where conditioned CPP cell culture media was added. CONCLUSIONS Based on our preliminary findings, this proof-of-concept study demonstrates potential to explore the role of angiogenesis in CPP for better disease understanding.