tbuckley/cabot-search huggingface dataset:
QOLP-23. PHASE II RANDOMISED PLACEBO-CONTROLLED DOUBLE-BLIND STUDY OF ACETAZOLAMIDE VERSUS PLACEBO FOR CEREBRAL OEDEMA IN RECURRENT AND/OR PROGRESSIVE HIGH-GRADE GLIOMA REQUIRING TREATMENT WITH DEXAMETHASONE
Authors: Meera Agar, Anna Nowak, Elizabeth Hovey, Elizabeth Barnes, John Simes, Janette Vardy, Helen Wheeler, Robyn Leonard, Merryn Hall, Evonne Tim, Desma Spyridopoulos, Hao-Wen Sim, Zarnie Lwin, Anthony Dowling, Rosemary Harrup, Ross Jennens, Ganessan Kichenadasse, Tracey Dunlop, Cecelia Gzell, Eng-Siew Koh
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Symptoms of raised intracranial pressure (ICP) in recurrent or progressive high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on reversing ICP symptoms. Acetazolamide reduces ICP in other clinical settings including case series in glioma. AIM To explore whether addition of oral acetazolamide enables safe dexamethasone dose reduction in management of raised ICP in recurrent and/or progressive HGG. METHODS Participants had recurrent, progressive and/or persistent residual HGG requiring recommencement of dexamethasone, dose increase or dexamethasone dependency; prior/current bevacizumab was an exclusion. Eligible participants were randomised 1:1 to acetazolamide 250mg twice daily or placebo for 8 weeks. Standardised protocols were used for dexamethasone dose changes in both arms, with planned dose decrease from day 5 once ICP symptoms were stable. The primary endpoint was a composite of dexamethasone dose reduction and stability of performance status. Secondary endpoints included toxicity and feasibility (accrual and compliance). RESULTS Thirty participants of a planned sample of 84 were enrolled (mean age 58 y (32-89)) from 7 Australian sites. The mean baseline dexamethasone dose was 6.2mg (4-16mg). Mean duration on treatment was 38 days (4-57) in placebo group and 31 days (3-60) in acetazolamide group, with 9 participants (30%) completing all study treatment (6 placebo, 3 acetazolamide). Study withdrawal was due to adverse events (n=6 (1 placebo, 5 acetazolamide)) and disease progression (n=6 (3 per arm)). Four participants (13%) (2 per arm) were stable responders meeting the primary endpoint criteria (≥50% corticosteroid dose reduction from baseline by 28 days maintained for 7 days, and no deterioration in performance status). Ten participants experienced a total of 13 serious adverse events (acetazolamide arm: 5 participants (33%), 6 events, 2 related). DISCUSSION The addition of acetazolamide did not facilitate dexamethasone reduction. The study closed early due to poor accrual and increasing availability of bevacizumab.
SURG-36. THE EVALUATION OF POSTOPERATIVE MOTOR FUNCTION DEFICITS AFTER SUPRATENTORIAL BRAIN TUMOR SURGERY THROUGH THE ANALYSIS OF INTRAOPERATIVE MEP AND ISCHEMIC LESION ON POSTOPERATIVE DWI
Authors: Seung Ho Yang, Yong Kil Hong, Young Il Kim
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The authors investigated the incidence of ischemic lesions on immediate postoperative diffusion-weighted imaging (DWI) according to the findings of intraoperative motor evoked potential (MEP) and the correlation with postoperative motor function deficits. METHODS From January 2016 to June 2018, total 127 supratentorial brain tumor patients were enrolled in this study. The intraoperative MEP results were analyzed in the following three groups: no decline below 50 % of baseline (A), transient decline below 50 % of baseline (B), no recovery until end stage of surgery (C). Postoperative magnetic resonance imaging was performed within 48 hours after surgery. RESULTS Of the total 127 patients, MEP changes (group B&amp;C) were observed in 25 patients (25/127, 19.7%), DWI positive findings were identified in 31 patients (31/127, 24.4%) and motor function deficits were observed in 19 patients (19/127, 15%), respectively. DWI positive finding rate was higher in gliomas (14/43, 32.6%) than meningiomas (8/51, 15.7%) or other tumors including metastasis (6/32, 18.8%), however, there was no statistical significance. In MEP changes, group B&amp;C (16/25, 64%) showed higher DWI positive rate than group A (13/102, 12.7%). In DWI findings, the DWI positive cases (16/31, 51.6%) showed a higher motor function deficit rates than the DWI negative cases (3/96, 3%). These two results were all statistically significant (P&amp;lt;0.01). In group A, motor function deficits were presented in 3 of 13 DWI positive case, all of which were transient. In group B, motor function deficits were presented in 9 out of 13 DWI positive cases with permanent 4 and transient 5. In group C, motor function deficits were presented in 4 out of 5 DWI positive cases with permanent 3 and transient 1. CONCLUSIONS Both intraoperative MEP changes and postoperative DWI positive findings in supratentorial brain tumor surgery were significant related with postoperative motor function deficits. Even if intraoperative MEP changes occur during supratentorial brain tumor surgery, active and appropriate efforts to prevent irreversible MEP changes may reduce the occurrence of permanent postoperative motor function deficits.
BIOM-01. TYROSINE KINASE INHIBITORS AS A TREATMENT OF SYMPTOMATIC CNS METASTASES IN ONCOGENE-DRIVEN NSCLC
Authors: Alexandra Benouaich-Amiel, Omer Gal, Elizabeth Dudnik, Ofer Rotem, Inbar Finket, Idit Peretz, Alona Zer, Jacob Mandel, Tali Siegal, Jair Bar, Shlomit Yust-Katz
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment (i.e surgery, whole brain radiation therapy or stereotactic radiosurgery) approaches can potentially delay systemic treatment and/or result in neurocognitive impairment. Recently, next generation tyrosine kinase inhibitors (TKIs) have demonstrated a remarkable intracranial activity. However, most clinical trials did not enroll patients with neurological symptoms. Our study aims to assess the CNS activity of targeted therapy in this patient population. METHOD We present a case series of nine NSCLC patients with either EGFR mutation of ALK rearrangement and symptomatic CNS metastases that were treated with TKIs, without radiation therapy or surgery. Clinicopathological characteristics, treatment and outcome were analyzed. RESULTS Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9 patients). Additionally, the majority of patients had leptomingeal disease (6/9 patients) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache and confusion. Five patients were treated with Osimertinib. One patient with ALK rearrangement was treated with Lorlatinib. The remaining 3 patients received either Gefitinib or Afatinib. Most patients (6/9 patients) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. CONCLUSION Upfront use of next generation TKIs in patients with oncogene-driver NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.
CBIO-14. ELUCIDATING THE MECHANISM OF TEMOZOLOMIDE-INDUCED ATR ACTIVATION IN MGMT-METHYLATED GLIOBLASTOMA MULTIFORME
Authors: Sachita Ganesa, Amrita Sule, Ranjini Sundaram, Ranjit Bindra
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM) is an aggressive, malignant brain tumor in adults. The current standard of care for GBM is surgical resection, radiation therapy and chemotherapy with temozolomide (TMZ). It is well established that GBM patients with a methylated MGMT promoter (MGMT-) who are treated with TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ GBM cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. It is known that MMR proteins are involved in ATR activation, however, this project aims to unravel the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions. To accomplish this, we treated an shMSH2 MGMT- GBM cell line with TMZ and an ATR inhibitor (ATRi) compared to treatment in an MSH2-proficient MGMT- GBM cell line. We observed decreased cell death in the shMSH2 setting compared to the MSH2-proficient cells, suggesting that MSH2 is integral in the activation of ATR upon TMZ treatment in the MGMT- setting. This study elucidates a potential role for MSH2 in ATR activation. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain in the treatment of patients with GBM.
QOL-15. NEURAL NETWORK INTEGRITY FOR FACIAL AFFECT RECOGNITION IN SURVIVORS OF MEDULLOBLASTOMA
Authors: Tara Brinkman, Kevin Krull, Matthew Scoggins, Zhenghong Li, John Glass, Ping Zou, Kirsten Ness, Noah Sabin, Amar Gajjar, Gregory Armstrong, Leslie Robison, Melissa Hudson, Wilburn Reddick
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Medulloblastoma survivors are at risk for social deficits, yet underlying mechanisms are poorly understood. METHODS Facial affect recognition was assessed in 50 medulloblastoma survivors treated with craniospinal radiation (median[range] 21.4[12.5–30.9] years old, 11.0[5.7–22.6] years since diagnosis) and 56 non-cancer age-, sex-, and race-matched controls. Brain activation and connectivity in core regions/nodes of the face perception network (fusiform gyri, occipital gyri, superior temporal sulcus) were examined using structural and functional neuroimaging. Structural networks were constructed from diffusion tensor imaging (DTI) data and individual node strength and efficiency were assessed. Functional MRI (fMRI) was conducted using a 1-back facial affect recognition task with assessment of regional differences in task-related cerebral blood flow (BOLD). Standardized neurocognitive testing was completed with 24 hours of brain imaging. RESULTS Medulloblastoma survivors performed worse on a behavioral measure of facial affect recognition (P=0.003) compared to matched controls. During the facial affect recognition task, controls demonstrated greater BOLD activation of the left and right fusiform gyri and the left and right middle occipital gyri compared to survivors (P’s&amp;lt;0.05, corrected for multiple comparisons). DTI indicated weaker core node strength in survivors in the right lateral occipital gyri (P=0.02) and efficiency was lower in the left (P=0.01) and right (P=0.03) occipital gyri compared to controls. CONCLUSIONS Medulloblastoma survivors have deficits in facial affect recognition and reduced activation and efficiency in brain regions comprising the face perception network compared to matched controls. Interventions targeting this specific skill and neural network may improve social functioning in survivors.
TAMI-32. TEMPOROSPATIAL INVASION AND GENETIC EVOLUTION FROM INFRATENTORIAL TO SUPRATENTORIAL COMPARTMENT IN DIFFUSE MIDLINE GLIOMA
Authors: Maria-Magdalena Georgescu
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMGs) are very aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 tumor foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3 K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of K27 tri-methylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-Myc, SOX2, p65/p50 NF-kB and STAT3 transcription factors, EGFR, FGFR2, PDGFRa/b and MET receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-Src in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis allowed spatiotemporal modeling of tumor progression and identified two general pathways of supratentorial invasion, and a multitude of migratory subpopulations within the infratentorial compartment. It also delineated common signaling pathways and potential therapeutic targets, revealing an unsuspected activation of a multitude of oncogenic pathways that may explain the resistance of DMG to current therapies.
NCOG-26. IMPACT OF GENDER ON TUMOR TREATING FIELDS COMPLIANCE IN PATIENTS WITH GLIOBLASTOMA
Authors: Lauren Karpf, Sanjeev Chawla, Lisa Desiderio, Suyash Mohan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumor treating fields (TTFields) has emerged as a novel antimitotic modality to treat glioblastoma (GBM). Recently, a positive association was reported between TTFields dose at the tumor bed and survival outcomes in GBM patients. Dose density depends upon power density and compliance rate (cumulative amount of time TTFields therapy is delivered to the patient). Increased compliance with TTFields has been proposed as an independent prognostic factor for improved clinical benefits. There is evidence that females tend to respond better than males to standard therapy. However, the impact of gender and age on TTFields compliance is not fully understood in GBM patients. OBJECTIVE To investigate potential interactions amongst age, gender and TTFields compliance in GBM patients. METHODS A cohort of 16 patients (males =9; females=7; mean-age=60.8±7.6years) with newly diagnosed and recurrent GBM receiving TTFields were analyzed retrospectively. Device usage time was collected from internal log files in each case. The mean duration of TTFields therapy in patients was 4 months. Chi-square and independent sample T-tests were performed to evaluate differences in compliance rates based on patient age and gender and to examine gender-age relationships. Additionally, Pearson correlation analyses were performed to determine associations between gender and compliance rates. The probability (p) value of 0.05 was considered significant. RESULTS A trend (p=0.067) towards greater TTFields compliance was observed in females (80.1±0.11%) versus males (63.0±0.22%). Additionally, there was a strong positive correlation (R=0.73; p=0.058) between age and compliance rates for female patients. There were 6 patients ≥ 65 years and 10 patients &amp;lt; 65 years. However, we did not find significant differences in compliance rate and gender variables between patients ≥ 65 years and &amp;lt; 65 years of age. CONCLUSIONS Our results demonstrate gender influences TTFields compliance amongst GBM patients. However, future studies with larger cohorts are warranted to validate these findings.
Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death
Authors: Vicente Fresquet, Maria J. Garcia-Barchino, Marta Larrayoz, Jon Celay, Carmen Vicente, Marta Fernandez-Galilea, Maria J. Larrayoz, Maria J. Calasanz, Carlos Panizo, Alexandra Junza, Jiahuai Han, Celia Prior, Puri Fortes, Ruben Pio, Julen Oyarzabal, Alvaro Martinez-Baztan, Bruno Paiva, Maria J. Moreno-Aliaga, Maria D. Odero, Xabier Agirre, Oscar Yanes, Felipe Prosper, Jose A. Martinez-Climent
Journal: Cancer Discovery (2020)

For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE: The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.This article is highlighted in the In This Issue feature, p. 995.
Co‐Delivery of <sup>131</sup>I and Prima‐1 by Self‐Assembled CD44‐Targeted Nanoparticles for Anaplastic Thyroid Carcinoma Theranostics
Authors: Shuo Huang, Linlin Zhang, Miaomiao Xu, Chao Li, Hongliang Fu, Jie Huang, Xin Jin, Sheng Liang, Hui Wang
Journal: Advanced Healthcare Materials (2020)

Abstract New radionuclide‐labeled targeting nanocarrier systems have generated new opportunities for tumor treatment and imaging. Nevertheless, such therapeutic strategy is clinically unfeasible on anaplastic thyroid carcinoma (ATC) patients, because of lacking suitable targets and resistance to radiation. In order to figure out a potential treatment, immuno‐histochemical staining is performed in human ATC tissue species and high expression of cluster determinant 44 (CD44) is found. Therefore, a CD44‐targeted delivery system is designed and constructed by self‐assembly of tyrosine (Tyr)–hyaluronic acid (HA)–polyethyleneimine (PEI), which can radiolabel 131/125 I and load a p53 mutant restoring regent, Prima‐1. The 125 I‐labeled nanocomposites display an impressive tumor imaging as well as a long radiation treatment cycle. The 131 I‐labeled nanoparticles show remarkable anti ATC‐tumor effects in vitro and in vivo, due to radiosensitization of Prima‐1 by reactivation of the p53 mutants.
GCT-30. TREATMENT OF PRIMARY INTRACRANIAL GERM CELL TUMORS: SINGLE INSTITUTION EXPERIENCE OF 74 CASES WITHOUT HISTOLOGICAL CONFIRMATION
Authors: Chengcheng Guo, Qunying Yang, Jian Wang, Yonggao Mou, Zhongping Chen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND AND OBJECTIVE Primary intracranial germ cell tumors (PIGCTs) are a group of heterogeneous tumors. It is very difficult to treat those patients without pathological diagnosis. This study retrospectively analyzed the clinical data and outcomes of patients with clinically diagnosed (without histologically confirmed) PIGCTs in SunYat-sen University Cancer Center. METHODS Patients who were clinically diagnosed as PIGCTs without histological diagnosis through surgical resection or biopsy were included in this study. Patients were analyzed for clinical characteristics, treatment patterns, outcomes and adverse effects. RESULTS From May 2002 to July 2014, 74 patients clinically diagnosed with PIGCTs received chemotherapy and/or radiotherapy at the Sun Yat-sen University Cancer Center. The median age was 16.5 years old (4–45 years old, majority was teenagers). The most of tumors were found in male, and located in the pineal and suprasellar regions. When the patients were grouped into diagnostic chemotherapy group (57 cases), diagnostic radiotherapy group (5 cases) and gamma knife radiosurgery group (12 cases) based on their initial anti-tumor therapy. The 5-year survival rates were 84.3%, 75.0% and 75.0%, respectively. There was a trend that the chemotherapy group got a better survival. Patients were allocated to secretory tumor group (49 cases) and non-secretory tumor group (25 cases) based on their levels of tumor makers (α-FP and β-hCG). The 5- year survival rates were 80% and 77.8% (P value = 0.966), respectively. CONCLUSION Clinical diagnosed PIGCT (without histological confirmation) patients may obtain good responses when receiving comprehensive treatments of chemotherapy combined with radiotherapy.
SWK-02. WEAVING COMFORT AND SUPPORT FOR CHILDREN WITH BRAIN TUMORS AND THEIR FAMILIES IN AN OUTPATIENT CLINIC
Authors: Ria Hawks, Jane Bloom, Maurine Packard, Sonia Lugo, Nadine Ulysses, Stergios Zacharoulis
Journal: Neuro-Oncology (2020)

Abstract Parents of children diagnosed with brain tumors report high levels of stress at diagnosis and feelings of “being lost” on transition to outpatient follow-up care (Jackson AC, et al, 2007). Ssori is a Japanese form of free-style weaving that encourages people facing life-limiting challenges to discover inner strengths. We report our experience with Saori weaving with brain tumor patients and their families in a pediatric oncology outpatient clinic at a major university medical center. During 2019, we offered weaving sessions twice a week. We had a total of 151 encounters with hematology/oncology patients (age 5–18 years), siblings, or parents. Among these patients there were 20 with primary brain tumor diagnoses. Weaving was offered in the art therapy area of the clinic. After creating a fabric, the weavers had the opportunity to have their work sewn into functional objects, such as pillows, bags, purses, or healing pouches filled with beans that can be heated or cooled for comfort. Brain tumor patients readily engaged in weaving, despite various degrees of neurologic disability including hemiparesis or low vision. In the words of an 8 y/o weaver. “This is so cool. Daddy, can we always come when the weavers are here, so I can weave?” And from a mother: “This is great. She’s focused and busy!” Case studies, including a presentation of Legacy work, will be reported. In conclusion, Saori weaving can be an impactful intervention for childhood brain tumor patients and their families in an outpatient clinic setting.