bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCMP-19. RADIATION-INDUCED CRANIAL NEUROPATHY PRESENTING AS PROGRESSIVE BULBAR SYNDROME
Authors: Correia Carlos Eduardo Silva , Chen Xi 
Published: November 2021

Abstract
Neuropathy is a well-known complication of radiation, especially when administered in proximity to the brachial plexus (BC), with symptoms usually appearing years after radiation. Pain is a less prominent feature when compared to neoplastic infiltration, with numbness and weakness being a more common and disabling complaint. Radiation-induced neuropathies tend to reach clinical stabilization after several months with por response to treatment. This is a case report of a 59 year-old Malaysian man who was diagnosed with nasopharyngeal carcinoma in 2002 treated with radiation to the nasopharynx in China. He has no evidence of disease to this date. In 2016 he started to develop progressive bulbar symptoms, such as hoarseness, hypophonia, and dysphagia. Symptoms worsened over the subsequent 18 months after presentation with clinical stabilization thereafter. Following the initial bulbar symptoms, he also developed bilateral hearing loss, atrophy of bilateral sternocleidomastoid muscles, significant tongue atrophy with fasciculations and tongue deviation. His clinical picture was consistent with bulbar amyotrophic lateral sclerosis. MRI brain and total spine did not show any intraparenchymal or nerve disease. An electromyography test was performed, which showed myokymia of the tongue and trapezius consistent with radiation-induced cranial neuropathy (CN). He received steroids without any clinical improvement, followed by hyperbaric oxygen with minimal improvement of his dysphagia, hoarseness and hypophonia. On last follow up his symptoms continued to be stable. Radiation to nasopharynx can cause radiation-induced CN with similar electromyographic findings to radiation-induced brachial plexopathy, such as myokymia. Symptoms can appear more than 10 years from radiotherapy, with progression over several months followed by clinical stabilization. Treatment with steroids, bevacizumab or hyperbaric oxygen only provide minimal benefit on this population.
NCOG-10. RADIATION THERAPY CAN BE SAFELY DEFERRED IN OLIGODENDROGLIOMAS
Authors: Demopoulos Alexis , Knisely Jonathan 
Published: November 2021

Abstract
Deferring multimodal aggressive therapies in young patients to delay treatment-induced toxicity without jeopardizing long-term outcome would be of great benefit to our patients. After IRB approval, we retrospectively reviewed 80 confirmed IDH mutant and 1p19q codeleted oligodendrogliomas treated at one institution between 2005 and 2020. Median follow-up was 5 (range 1-26) years. All patients underwent maximal safe resection, followed by observation with routine imaging (n=28), chemotherapy alone (n=27), or radiation with chemotherapy (n=25) as initial upfront therapy. Median progression free survival was 36 (range 1-203), 54 (range 1-306), and 57 (range 4-281) months, respectively. Median overall survival was not reached, with 85% (67/80) alive, 8 on treatment and 59 stable off therapy. Among 35 patients who died or were followed for 10 years, median PFS was 12, 15, and 10 years for observation (n=9), chemotherapy (n=11) and chemoradiotherapy (n=15), with deaths or KPS below 50 in 3, 6, and 8, respectively. Three deaths in the observation group occurred 12, 12 and 17 years after diagnosis; one at 95 years old and another tumor-unrelated. Among 44 patients eventually receiving radiation, 15 suffered toxicity, including pathologically proven necrosis (n=6), cognitive decline with KPS&lt; 50 (n=5), memory loss with KPS &gt; 50 (n=3), and optic neuropathy (n=1). Myelosuppression from PCV was more pronounced after chemoradiation than in the upfront setting. Temozolomide after PCV chemotherapy was well tolerated. Long term follow-up of oligodendroglioma patients is challenging, but essential in determining late toxicities and treatment efficacy. Long-term results of European and North American multicenter cooperative group trials contradicted earlier publications reporting no benefit from early chemotherapy. Some management practice guidelines established a half-century ago persist (i.e., administer radiation therapy early), despite potentially crippling late effects. Deferring upfront radiation therapy is safe, less toxic, and equally efficacious in codeleted oligodendrogliomas.
NCOG-36. LONG-TERM SURVIVAL AND COGNITIVE FUNCTION FOLLOW UP OF PRIMARY CNS LYMPHOMA TREATED WITH R-MVP FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANT CONSOLIDATION
Authors: Therkelsen Kate , Grommes Christian 
Published: November 2021

Abstract

BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare central nervous system malignancy, and long-term follow up studies are uncommon. First line therapy is based on high-dose methotrexate and different consolidation therapy options. This is a long-term follow up study of PCNSL patients enrolled in a prospective trial using R-MPV chemotherapy regimen followed by high dose chemotherapy and autologous stem cell rescue to determine long-term survival and cognitive effects.

METHODS
From June 2005 to September 2011, 32 newly diagnosed immunocompentent PCNSL were enrolled. Patients received 5-7 doses of rituximab (500mg/m2), methotrexate (3.5 gm/m2), procarbazine (100mg/m2), and vincristine (1.4mg/m2) (R-MVP). Consolidation therapy consisted of high dose chemotherapy (HDC) with thiotepa (250 mg/m2), busulfan (3.2 mg/kg), and cyclophosphamide (60 mg/kg), followed by autologous stem cell rescue (ASCT) in those with partial or complete response to R-MVP. Long-term follow-up status including disease status, cognitive status (KPS, NANO score), and leukoencephalopathy (modified Fazkas Scale) were collected.

RESULTS
26 of 36 underwent HDC and ACST. Of those, 3 died due to treatment related effects; 2 died of disease progression within two years after ASCT. After a median follow-up of 10.5 years, none of the remaining 21 patients progressed. At the time of last follow up, the median KPS was 90, compared to 80 at time of ASCT. The median NANO score and leukoencephalopathy score post ASCT and at follow-up did not change. Of note, 2 of 4 patients with a partial or complete response to R-MVP that elected not to proceed with HDC-ASCT consolidation, experienced progression at a mean of 52 months.

CONCLUSION
Long-term follow up demonstrates that treatment was tolerated well with stable leukoencephalopathy on MRI and good performance status. Disease recurrence 2 years after HDC with ASCT consolidation was not observed.
NCOG-37. THE UTILITY OF NEUROPSYCHOLOGICAL SCREENING IN MULTIDISCIPLINARY CLINICS FOR PEDIATRIC NEURO-ONCOLOGY POPULATIONS
Authors: Mietchen Jonathan , Kessler-Jones Alanna , Damodharan Shawn , Puccetti Diane 
Published: November 2021

Abstract

BACKGROUND
The purpose of this project was to examine the utility of neuropsychological screening in multidisciplinary clinics for pediatric neuro-oncology populations and determine whether a brief evaluation can adequately screen children for cognitive dysfunction or psychiatric comorbidities.

METHODS
Children underwent neuropsychological screening as part of their multidisciplinary clinic visit. This screening evaluation consisted of clinical interview, neuropsychological testing, and the completion of emotional/behavioral checklists. Our neuropsychological test battery included the Kaufman Brief Intelligence Test-Second Edition (KBIT-2) and the NIH Toolbox Fluid Cognition Composite (consisting of 6 subtests).

RESULTS
Over a six-month period 40 children and adolescents with CNS tumors and/or NF1 were seen in our neuropsychology screening clinic. Females made up 37.5% of the sample. The average age was 11.1 years (range=5-25 years). The average time to complete neuropsychological testing was 56.8 minutes. On average, children in this sample met criteria for 1.8 neuropsychological diagnoses with an average of 1.2 new diagnoses that had not been given prior to their neuropsychological screening. The most common new diagnoses were major or mild neurocognitive disorder (mild=27.5%, major=20%), anxiety (27.5%), ADHD (15%), mood disorder (12.5%), and intellectual disability (10%). On average, these children performed lower than expectation on neurocognitive tests, including intellectual functioning (KBIT-2 Verbal IQ=93.1; KBIT-2 Nonverbal IQ=88.7; KBIT-2 Total IQ=90.1), attention (NIH Flanker T-Score=44.1), working memory (NIH Working Memory T-Score=42.9), processing speed (NIH Processing Speed T-Score=39.9), cognitive flexibility (NIH Card Sort T-Score=43.4), memory (NIH Picture Memory T-Score=44.5), and fluid cognition (NIH Fluid Cognition Composite T-Score=38.7). Behavioral health recommendations were needed for 72.5% of this sample. Educational recommendations were needed for 62.5%.

CONCLUSIONS
Brief neuropsychological screening completed as part of multidisciplinary clinics for pediatric neuro-oncology patients was efficient and useful in identifying neuropsychological diagnoses in children.
NCOG-41. HISTOLOGICAL ANALYSIS OF SLEEP AND CIRCADIAN BRAIN CIRCUITRY IN CRANIAL RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH) MOUSE MODEL
Authors: Shuboni-Mulligan Dorela , Young Jr. Demarrius , Minyety Julianie De La Cruz , Briceno Nicole , King Amanda , Gilbert Mark , Smart DeeDee , Armstrong Terri 
Published: November 2021

Abstract

BACKGROUND
Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving cranial radiation-induced hypersomnolence (C-RIH) remain unclear but we hypothesize this may result from damage to neural circuits controlling sleep behavior. We developed a mouse model of C-RIH to explore the impact of radiation on the brain: examining region-specific differences in acute DNA damage response and neuroanatomic structure.

METHODS
Mice received whole brain radiation then behaviors were monitored using PhenoTyper® cages to determine optimal dose and long-term effects. To test short-term neurologic effects, brains were collected 1hr post-radiation then stained for γH2AX, a signal for DNA damage. Long-term effects were quantified 1-month post-treatment using neuroimaging to determine brain volume and T1 mapping changes in regions associated with sleep, circadian rhythms, and cognition.

RESULTS
Mice displayed decreased general activity and increased daytime sleep in a dose-dependent and sustained manner. Histologic staining demonstrated that DNA damage following radiation varies across the brain, with homeostatic sleep regions and cognitive regions expressing higher levels of γH2AX than the circadian suprachiasmatic nucleus. These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes using both trypan blue (F(1,18)=235.937, p&lt; 0.001) and clonogenic assays (F(1,24)=40.796, &lt; 0.001). Brain volumes were significantly smaller in irradiated than sham animals in the hippocampus (t(4)=3.833, p=0.019) and the pontine central grey (t(4)=3.504, p=0.025). T1 maps also showed significant changes in relaxation times in many cognitive regions but not sleep or circadian areas.

CONCLUSIONS
These findings suggest that the homeostatic sleep region and cognitive circuits are vulnerable to radiation and may be relevant to the development of treatment plans in patients. We plan to introduce intracranial tumor to the model to evaluate the impact of timing of treatment and C-RIH on survival.
EXTH-03. COMBINED TOP1 AND PARP INHIBITION ENFORCES GENOMIC INSTABILITY AND CELL DEATH IN PTEN-DEFICIENT GLIOBLASTOMA
Authors: Kim Olga , Butler Madison , Pang Ying , Yu Guangyang , Merchant Mythili , Ranjan Alice , Gilbert Mark , Pommier Yves , Wu Jing 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma is an aggressive brain tumor with high mortality. The development of new therapies is critical for improving patient outcomes. LMP400, a novel topoisomerase I (TOP1) inhibitor, traps TOP1 cleavage complexes, thereby generating DNA damage. Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair responses triggered by TOP1 inhibition. Niraparib is a potent PARP inhibitor that can cross the blood-brain barrier. Loss of phosphatase and tensin homolog (PTEN) occurs in 40% of GBM patients and is known to promote DNA damage repair deficiency. Here, we hypothesize that PTEN loss presents a vulnerability to a combined induction of DNA damage and inhibition of repair mechanisms.

METHODS
Human glioblastoma cells (U251, SNB-75, SF-295, LN18) and patient-derived glioblastoma stem cells (GSC923 and GSC827) were treated with LMP400 and/or Niraparib. Cell viability and apoptosis were examined using Celigo image cytometer and Annexin V/PI assay at 72h after treatment. Single clones after PTEN knockdown using shRNA were isolated after puromycin selection. For planned studies of PTEN knockout, sgRNA plasmids targeting PTEN will be transiently transfected and GFP-positive single KO clones will be isolated. PTEN will be restored in PTEN-null cells using lentiviral transduction.

RESULTS
CRISPR-Cas9 KO screening in GSC923 cells suggests that LMP400 is unlikely a substrate for ABC transporters. LMP400 and Niraparib synergistically induced cytotoxic effects in U251, SF-295, GSC923, GSC827 cells lacking PTEN expression. Combined LMP400/Niraparib led to increased expression of gamma-H2AX, cleaved caspase 3 and PARP, indicative of enhanced DNA damage and cell death.

CONCLUSION
LMP400 and Niraparib act synergistically to target PTEN-deficient glioblastoma by inducing DNA damage and cell death. These results will be further verified in isogenic cells in vitro as well as in vivo in a mouse model driven by PTEN deletion which would strongly support a novel therapeutic strategy in a subset of glioblastoma with PTEN loss.
EXTH-09. TUMOR PHARMACOKINETICS, PHARMACODYNAMICS AND RADIATION SENSITIZATION IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA TREATED WITH THE AURORA KINASE A INHIBITOR LY3295668
Authors: Mehta Shwetal , Tovmasyan Artak , Tien An-Chi , Holter Michael , Hopkins Barbara , Margaryan Tigran , Chang Yu-Wei , Himes Sarah , Elliott Mackenna , Melendez Ernesto Luna , Pennington-Krygier Chelsea , White Connor , Molloy Jennifer , Liu Miao , Knight William , Sanai Nader 
Published: November 2021

Abstract
Cell-cycle deregulation is at the crux of all malignancies, including glioblastoma (GBM). Aurora Kinase A (AURKA) plays a central role in G2/M transition and faithful chromosome segregation. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and radiation sensitization properties of LY3295668, a highly specific AURKA inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Mice with intracranial tumors were randomized to 50 mg/kg LY3295668 PO BID x 4 days vs. placebo. LY3295668 levels in plasma and contrast-enhancing tumor tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Immunohistochemistry was performed to assess levels of pAURKA (T288), phospho-Histone H3 (pHH3), and cleaved caspase 3 (CC3). For survival studies, mice with intracranial tumors were randomized to four cohorts – vehicle, radiotherapy, LY3295668 monotherapy, and LY3295668 plus radiotherapy. The median unbound concentration of LY3295668 was 270.88 nmol/L and 22.33 nmol/kg in plasma and tumor tissue, respectively – significantly higher than the biochemical IC50 of LY3295668 for AURKA inhibition (0.8 nM). A decrease in pHH3(+) cells (0.8% vs. 6.4%, p=0.036) indicated drug-induced mitotic arrest and was accompanied by an increase in CC3(+) cells (6.4% vs. 8.0%, p=0.67). Combination of LY3295668 with radiotherapy prolonged survival compared to either therapy alone in orthotopic GBM PDX models. LY3295668 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Preclinical combination of LY3295668 with radiation therapy leads to synergistic effects and supports future clinical study of this multimodal strategy in glioblastoma patients.
EXTH-17. A FOCUSED ULTRASOUND BLOOD BRAIN BARRIER DISRUPTION MODEL TO TEST THE INFLUENCE OF TIGHT JUNCTION GENES TO TREAT BRAIN TUMORS
Authors: Iyer Jayashree , Akkad Adam , Tang Nanyun , Berens Michael , Zenhausern Frederic , Gu Jian 
Published: November 2021

Abstract
Treating primary or metastatic tumors in the brain (glioblastomas, melanoma, lung cancer, breast cancer) proves challenging by virtue of the protective function of the blood brain barrier (BBB). The tight junction proteins (TJPs) binding the specialized endothelial cells of the BBB largely contribute to the limited permeability of cancer-therapeutic drugs. In both preclinical and clinical models, low intensity focused ultrasound (LIFU) coupled with microbubbles has been proven to safely and transiently open the BBB. Despite this method being established, potential genetic influences on the durability and vulnerability of tight junctions to LIFU have not been elucidated, nor have the determinants of tight junction repair post LIFU been thoroughly investigated. We report the development of an ultrasound transparent organ-on-chip model populated by iPSC-derived endothelial cells (iPSC-EC) co-cultured with astrocytes. We aim to probe the contributions of various tight junction genes to barrier integrity along with the subsequent protein topology involved in reassembly post ultrasound. Thus, this model serves to determine parameters for ultrasound disruption for precision opening of the BBB. The BBB-On-Chip was successfully fabricated and assembled with an optimized technique that has an 80% yield of leak-free devices, with stable cavitation post nanobubble injection. Furthermore, Western blots show expression of claudin-5, a key TJP, in our iPSC-ECs. We have also demonstrated by confocal microscopy that another component of the TJP complex, ZO-1, can be visualized at iPSC-derived cell junctions. Further benchmarking of device-ultrasound interactions, successful iPSC differentiation, tight junction formation, and fabrication of nanobubbles and their assistance in ultrasound BBB disruption will be presented. Efforts are underway to characterize the contributions of tight junction genes and their variations to the integrity and disruption of the BBB.
EXTH-29. DUAL TGFB AND PD1 BLOCKADE PROMOTES GERMINAL-CENTER B-CELL IMMUNE RESPONSES AGAINST GLIOBLASTOMA
Authors: Dapash Mark , Hou David , Castro Brandyn , Rashidi Aida , Zhang Peng , Stupp Roger , Miska Jason , Lesniak Maciej , Chang Catalina 
Published: November 2021

Abstract
In contrast to other malignancies such as melanoma and sarcoma, Glioblastoma (GBM) remains difficult to treat with immunotherapies. Recent studies have shown that positive immunotherapeutic responses are mediated by the accumulation of germinal-center-like B cells which are predictive of survival in patients treated with neoadjuvant PD1 blockade. In contrast, GBM-associated B-cells are scarce and the establishment of germinal-center like cells have not been observed. This study seeks to identify how B-cells are driven towards their immunosuppressive phenotypes in GBM and how this prevents immunotherapeutic efficacy. Utilizing single-cell RNA sequencing (scRNA-seq) in a CT2A murine glioma model, TGFb receptors 1 and 3 were identified as the most highly expressed inhibitory receptors on GBM-associated B cells. Furthermore, using scRNA-seq, TGFb1 was identified as the most highly expressed immunosuppressive cytokine in the TME, which was produced principally by tumor-associated myeloid cells (TAMCs). Inhibiting the myeloid compartment using intracranial anti-Gr1 antibody in combination with PD1 blockade resulted in B-cells exhibiting greater proliferation and differentiation into memory B-cells in addition to germinal-center-like B-cells. Further demonstrating B-cell functional reprogramming, autologous T cells isolated from spleens exhibited greater proliferation and robust anti-tumor cytotoxicity when cocultured with tumor-associated B-cells from the dual treatment group. Finally, inhibiting a5b8 integrin, a key complex in releasing active TGFb, increased tumor-infiltrating proliferating B-cells and conferred a long-term survival benefit in the CT2A murine model. Our results demonstrate that the immunosuppressive TME of GBM is influenced by the vital interplay between B-cells and the TME through TGFb signaling. This study highlights the potential therapeutic benefits of targeting the TGFb signaling pathway in conjunction with the current standard of care for GBM.
EXTH-39. DUAL CHLOROTOXIN CAR AND MGMT ΓΔ T CELLS FOR DRUG RESISTANT IMMUNOTHERAPY OF GLIOBLASTOMA MULTIFORME
Authors: Ding Lei , Lamb Lawrence 
Published: November 2021

Abstract
While recent advances in immunotherapies have shown promise in extracranial tumors, Glioblastoma Multiforme (GBM) has remained challenging. We have previously developed a novel approach to the treatment of primary GBM by combining simultaneous intracranial administration of gene-modified γδ T cells expressing O-6-Methylguanine-DNA Methyltransferase (MGMT) and standard temozolomide (TMZ) chemotherapy. To further improve tumor targeting and the efficacy of the γδ T cell against GBM, we modified γδ T cells with a CAR using chlorotoxin (CLTX), a small peptide derived from scorpion venom that specifically binds the glioma-specific chloride channel, as binding domains (CLTX-CARs). MGMTp140k was co-expressed within the same CLTX-CAR vectors to confer TMZ resistance to the CAR-T cells. We optimized the CAR constructs as CLTX-CD8a-CD28TM-CD28co-CD3z-P2A-MGMT and the activation of CD69 was verified in CLTX-CAR transduced Jurkat T cells with GBM cell co-culture. We further tested dual-CLTX-CAR constructs with 2x CLTX peptide as binding domains (dCLTX-CAR) and demonstrated dCLTX-CAR-Jurkat T cells can activate T cells efficiently with improved persistence compared to the mono-CLTX-CAR-Jurkat T cells 3 weeks after transduction (84% vs 37%). In order to preserve the powerful innate-recognition properties of γδ T cells, we developed CLTX-CARs without CD3z activation domain (NoZ-CLTX-CAR) to mitigate activation induced cell death (AICD) and tonic signaling issues. NoZ-CLTX-CAR-Jurkat T cells showed no CD69 activation with GBM cells co-culture and superior CAR-T persistence compared to CLTX-CARs with a CD3z signaling domain. Furthermore, we were able to efficiently transduce (up to 70% transduction efficiency) γδ T cells with NoZ-dCLTX-CAR lentiviral which demonstrated enhanced cytotoxicity against GBM cells compare to non-transduced control γδ T cells. Our approach of combining the dCLTX-CAR and TMZ resistance will be further validated in animal model experiments and could be a potential candidate for clinical development for GBM.