bluuebunny/crossref_metadata_2025_split huggingface dataset:
QOL-25. IMPACTS OF IMPLEMENTING A PROSPECTIVE TREATMENT AND SURVEILLANCE PROTOCOL FOR THE MANAGEMENT OF NF2-ASSOCIATED VESTIBULAR SCHWANNOMAS ON TUMOR GROWTH, HEARING OUTCOMES, AND QUALITY OF LIFE
Authors: Rousseau Julien , Dahoud Andrea , Labidi Moujahed , El Haffaf Zaki , Florescu Marie , Saliba Issam , Gosselin Marie-Hélène , Lapointe Sarah 
Published: November 2022

Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant neurocutaneous syndrome associated with the development of nervous system tumors, including vestibular schwannomas (VS), meningiomas, and ependymomas. Although considered a rare illness, it is a source of significant morbidity, mainly due to early hearing loss leading to decreased autonomy and productivity among young adults. Bevacizumab, a monoclonal antibody against VEGF, has been shown to improve audition and tumor size in observational studies on NF2-associated VS. The most common limitations in the literature include the lack of reliable control groups, the paucity of data on quality of life, and the lack of detailed audiology testing guidelines. Moreover, the cost of bevacizumab is a limiting factor in access to care. In our Canadian tertiary care center, bevacizumab has been offered to NF2 patients with VS complications without specific indications on optimal treatment initiation time or duration. We present a hybrid cohort study protocol with retrospective and prospective arms aimed at measuring the impacts of introducing a standardized treatment and surveillance protocol on tumor growth, hearing outcomes, and quality of life. Patients from the multidisciplinary neurofibromatosis clinic at the University of Montreal Health Center, Canada, will be evaluated for inclusion in the prospective arm through regular audiological evaluations and imaging. Eligible individuals will receive bevacizumab at an initial dose of 5 mg/kg every 2 weeks for a year while participating in serial audiological, radiological, and quality of life assessments. The results will be compared to those of our historical cohort. Our primary outcomes will be tumor growth rate (% per year) for vestibular schwannomas, meningiomas and ependymomas, audiological test results, and quality of life and subjective hearing estimated through standardized questionnaires (SF-36, SSQ). We hypothesize that patients enrolled in the prospective arm will show improved clinical response compared to our historical cohort.
RBIO-02. ACTIVATION OF GABAA RECEPTORS WITH A NON-TOXIC, BRAIN PENETRANT SMALL MOLECULE SENSITIZES LUNG ADENOCARCINOMA PRIMARY AND BRAIN METASTATIC TUMOR CELLS TO RADIATION VIA AUTOPHAGY INDUCTION
Authors: Bhattacharya Debanjan , Barille Riccardo , Toukam Donatien Kamdem , Gawali Vaibhavkumar , Kallay Laura , Ahmed Taukir , Cook James , Karve Aniruddha , Desai Pankaj , Medvedovic Mario , Krummel Daniel Pomeranz , Sengupta Soma 
Published: November 2022

Abstract
Most advanced-stage non-small cell lung cancer (NSCLC) patients have brain metastases that render a dismal prognosis. Treatment of metastatic brain lesions from NSCLC and other tumor types include radiation as part of a multimodal treatment regimen. Challenges in the application of radiotherapy include overcoming radiation resistance and reducing associated co-morbidities. Non-toxic therapeutics capable of sensitizing tumors to radiation are needed to improve survival and mitigate radiation side-effects. Many CNS and solid systemic tumors express ligand-gated ion channels, which may contribute to tumor growth. Leveraging ion channels is therefore a potential way of diminishing the spread of cancer. We find that NSCLC and its brain metastases express subunits of the type-A GABA-gated chloride channel or GABAA receptor. Importantly, patient-derived NSCLC cells have functional GABAA receptors. We identified a brain penetrant, small molecule activator of GABAA receptors (AMLAL-101), which alone impairs the viability of both primary NSCLC cells and brain metastatic cells. In addition, AMLAL-101 combined with radiation is a highly potent inducer of NSCLC cell death and clonogenic arrest. Using a human ex vivo model of NSCLC-on-chip, we assessed the efficacy and toxicity of AMLAL-101 relative to Docetaxel, an antimicrotubular agent used in treating advanced NSCLC. AMLAL-101 is as potent as Docetaxel but does not exhibit its toxic side effects. AMLAL-101 also potentiates radiation in vivo, significantly reducing lung adenocarcinoma xenograft tumor growth in mice, equivalent to docetaxel plus radiation. Mechanistically, AMLAL-101 activates GABAA receptors in NSCLC and synergizes with radiation by inducing an autophagic response that includes: (i) stabilization of Beclin-1, BNIP3L/NIX, and GABARAP; (ii) ATG7 upregulation; and (iii) utilization of ubiquitin-binding protein p62. Activating GABAA receptors in NSCLC and other tumor types may improve radiation efficacy and mitigate its toxic side effects in treating brain metastases.
RBIO-05. QUANTIFICATION OF TSPO EXPRESSION AND TSPO RADIOLIGAND UPTAKE IN PET IN HUMAN AND MURINE GLIOBLASTOMA ON CELLULAR LEVEL
Authors: Kirchleitner Sabrina , Bartos Laura , Tonn Joerg-Christian , Albert Nathalie , Glass Rainer , Kaelin Roland , Quach Stefanie , Binter Fabian , Holzgreve Adrien , Brendel Matthias 
Published: November 2022

Abstract

OBJECTIVE
Translocator protein (TSPO) PET imaging is used in different neurological diseases and emerges as new tool for the diagnosis and therapy planning of glioma patients. Various signal sources of the TSPO-PET signal, however, hamper image interpretation and biological understanding. Here we assess the TSPO expression and ligand uptake in a murine model and human tissue derived from glioma patients.

METHODS
Mice with implanted GFP+ glioblastoma (n=20) or after sham implantation (n=14) were injected with the TSPO tracer [18F]GE-180 and received PET imaging. Tumors were harvested and processed to single cell suspension. Subsequently, tumors were either stained for TSPO, CD11b, ACSA2, GFAP and analyzed by flowcytometry or else magnetic cell sorting was performed to isolate tumor and CD11b+ cells that were measured by gamma counter. Multiple regression was used to determine contributions of GFP, CD11b, ACSA2 and GFAP positive cells to the total uptake. In TSPO PET-scans of glioma patients, regions with different GE-180 uptake were defined. Tumor samples (n=12) of these predefined areas were collected during surgery and analyzed by FACS as described above.

RESULTS
The expression of TSPO and PET signal in mice was increased in the tumor compared to tumor-free brain (SUVRGBM: 2.06 / SUVRSHAM: 0.92). FACS detected TSPO in tumor cells, microglia/macrophages and astrocytes. Tumor cells showed higher tracer uptake per cell when compared to CD11b+ cells (+31%). The contribution to the whole TSPO tracer uptake was high for tumor (β=0.41, P=0.018) and microglia/macrophages (β=0.35, P=0.042), and lowest for astrocytes (β=0.28, P=0.011). Patients with high-grade glioma indicated higher TSPO tracer uptake in GFAP+ cells when compared to CD11b+ cells and single cell uptake correlated with PET signal.

CONCLUSION
In experimental orthotopic glioblastoma, we could detect TSPO tracer signal at cellular resolution level. TSPO-PET can provide information about tumor and tumor-associated myeloid cells.
RBIO-06. CLINICAL AND MOLECULAR PREDICTORS OF RADIATION RESPONSIVENESS IN MENINGIOMAS: A MULTICENTER RETROSPECTIVE COHORT STUDY
Authors: Wang Justin , Nassiri Farshad , Patil Vikas , Liu Jeff , Lee Grace , Rogers Lauren , Tsang Derek , Laperriere Normand , Zadeh Gelareh 
Published: November 2022

Abstract

BACKGROUND
Aside from surgery, radiotherapy (RT) remains the only standard of care treatment for meningiomas. However, few studies have identified clinical/molecular biomarkers associated with responsiveness to RT and the optimal timing of RT after surgery remains controversial. We aimed to assess outcomes in a large multi-institutional cohort of RT-treated meningiomas to identify clinical factors and DNA methylation and RNA expression markers associated with progression-free survival (PFS) post-RT.

METHODS
Patients with intracranial meningiomas who underwent treatment with fractionated RT between 1997-2018 were included. DNA-methylation using the Illumina 850K EPICArray and RNA-sequencing were performed on tumours with sufficient tissue. Primary endpoints were radiographic recurrence of progression and time to progression from the time of RT completion.

RESULTS
404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-RT, usually within 5-years of RT. Previous RT to the meningioma, having a WHO grade 3 meningioma, and older age at diagnosis were independently associated with poorer PFS post-RT. Following propensity score matching, patients that received adjuvant RT had significantly better PFS post-RT compared to those that received salvage RT after recurrence (p=0.04). DNA methylation on 220 of these meningiomas segregated tumours into two distinct methylation groups (RT-resistant and RT-sensitive) based on unsupervised consensus clustering. DNA methylation were able to independently predict PFS post-RT better than all clinical factors. Differential RNA-expression analysis of these groups showed up-regulation of pathways involved in chromosome segregation and mitotic cell cycle and down-regulation of fatty acid metabolism pathways in RT-resistant meningiomas.

CONCLUSION
While there are a paucity of clinical factors that can reliably predict a meningioma’s response to RT, DNA methylation and RNA expression biomarkers may aid in differentiating RT-resistant meningiomas from RT-sensitive tumours. Patients that receive adjuvant RT may have prolonged PFS post-RT compared to those that receive salvage RT only after recurrence has already occurred.
RBIO-08. MEMANTINE INCREASES DENDRITIC ARBORIZATION OF IMMATURE NEURONS AFTER IRRADIATION WITH NO EVIDENCE OF DISRUPTION IN THE NORMAL BRAIN FUNCTION
Authors: Zisiadis Georgios Alkis , Rodrigues Carlos , Pizzirusso Giussy , Arroyo-García Luis , Osman Ahmed , Blomgren Klas 
Published: November 2022

Abstract
Cranial irradiation (IR) is a cornerstone in the treatment of high-grade pediatric brain tumors. While lifesaving, it is associated with severe sequalae in 50-90 % of the survivors, as they often show disabling cognitive dysfunction, declined IQ, impaired processing speed, anxiety and posttraumatic stress symptoms, resulting in poorer academic accomplishments and social isolation. Memantine (Mem) is a non-competitive NMDA receptor antagonist and a potent enhancer of neural plasticity. While an improvement in cognition in post-IR cancer survivors and in synaptic plasticity in association to hippocampal neurogenesis have been documented, the exact mechanisms underlying Mem’s actions are poorly understood. The goal of this project is to further dissect the actions of Mem and identify factors that contribute to hippocampal neurogenesis. To this end, 20-day-old C57BL6/J mice were subjected to a single dose of 7 Gy whole brain irradiation and then supplied with Mem in the drinking water (10 mg/kg/day) to obtain a steady-state plasma concentration of the drug. Two weeks after IR, Sholl analysis of the morphology of the newborn neurons of Mem treated animals showed a statistically significant increase in coverage area (500 µm2 vs. 250 µm2, p &lt; 0,0001) and number of dendrites (15 vs. 5, p &lt; 0,0001) compared to non-treated individuals. Bulk-RNA sequencing analysis revealed 9 differentially expressed genes (alpha=0.1) between the hippocampal cell populations of Mem and vehicle-treated IR mice, which are related to protein folding and the programmed cell death machinery. At six weeks after IR, Mem treatment maintains the gamma oscillatory dynamics in the hippocampal CA3 region (~2x10-9 V2 in non-IR, ~1x109 V2 in IR), but with no apparent recovery to the sham levels. These results emphasize the strong neurogenic effect that Mem exerts on the surviving newborn neurons, while also highlighting Mem’s low toxicity and impact on the normal function of the brain.
RTID-04. CLINICAL POTENTIAL OF TARGETING TRANSFORMING GROWTH FACTOR BETA 2 WITH OT-101 FOR POST-RADIATION CONSOLIDATION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Uckun Fatih , Trieu Vuong 
Published: November 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) in children has a dismal prognosis with a median overall survival (OS) of 10 months and a 2-year overall survival rate of &lt; 10% after standard radiation therapy. Chemotherapy does offer clinically meaningful benefits. Therefore, there is an urgent need for therapeutic innovations for treatment of pediatric DIPG. High-grade glioma cells, including pediatric glioblastoma and DIPG cells have been shown to produce transforming growth factor beta 2 (TGFB2) which has been implicated both as promoter of glioma cells and as a key contributor to the T-cell hyporesponsiveness of the tumor microenvironment (TME) towards glioma cells. OT-101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive and tumor promoting actions of TGF-B2. At low micromolar concentrations, OT-101 reduces the TGFB2 secretion by human glioma cells, blocks their proliferation as well as migration, and restores the anti-glioma cytolytic function of patient-derived T-cells. In a Phase 2 clinical study, intracerebrally applied OT-101 administered via convection-enhanced delivery showed promising single agent activity in Recurrent/Refractory (R/R) high-grade glioma (HGG) (Uckun et al., Cancers. 2019 28;11(12):1892). The intrathecal administration of antineoplastic drugs directly in the CSF allows to bypass the selective filter of BBB, achieving significant concentrations of the antineoplastic agents in CSF, while reducing the likelihood of systemic toxicity. Informed by favorable safety pharmacology studies of intrathecally delivered OT-101 in rabbits and primates and encouraged by its single agent activity in adult patients with HGG, we decided to embark upon a multi-center, two-part, randomized Phase 1-2 study of OT-101 in pediatric patients with DIPG. Multiple doses of OT-101 will be administered after completion of radiation therapy as intrathecal bolus injections. The study is designed to determine: 1) the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of OT-101, and 2) its efficacy in children with DIPG.
SURG-11. AKT1 E17K AND NF2 MUTATIONS DOMINATE SPINAL MENINGIOMAS WHO GRADE 1 AND PRESENT DISTINCT TUMOR FEATURES
Authors: Hua Lingyang , Alkhatib Majd , Meinhardt Matthias , Cahill Daniel , Brastianos Priscilla , Clark Victoria , Shankar Ganesh , Wakimoto Hiroaki , Schackert Gabriele , Juratli Tareq 
Published: November 2022

Abstract

INTRODUCTION
While the mutational landscape of intracranial meningiomas has been extensively studied, our understanding of the molecular profile of spinal meningiomas (SM) remains incomplete. In this study, we correlate the molecular status with tumor features in a clinically well-characterized cohort.

METHODS
Samples from 50 patients (38 females and 12 males) with WHO grade 1 SM were collected. We performed next-generation sequencing (NGS) using an assay covering frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA, POLR2A, SMARCB1, SMARCE1, SMO, SUFU, and TRAF7. We correlated clinical and imaging data with the molecular tumor status.

RESULTS
AKT1 E17K mutations were detected in 15 (30%) and NF2 mutations in 32 (64%) patients. Both mutations were mutually exclusive. In contrast to AKT1-mutant intracranial meningiomas, AKT1-mutant SM only harbored a TRAF7 co-mutation in a single case. NF2-mutant meningiomas had a significant female predominance (n= 30/32, 94%) when compared to the balanced incidence of AKT1-mutant tumors (n= 7/15, 46.7%, p= 0.0006). The two groups demonstrated stark differences in the location: a thoracic localization was significantly more common in NF2-mutant meningiomas (n= 25/32, 78.1%, p= 0.0012), while meningiomas harboring an AKT1 mutation were predominantly located in the cervical spine (n= 11/15, 73.3%). Moreover, while a substantial proportion of NF2-mutant meningiomas developed in the dorsal location (n= 19/32, 59.3%), the vast majority of AKT1-mutant meningiomas (n= 13/15, 87%) arose ventral to the spinal cord. The histologic subtype of NF2-mutant meningiomas was variable, while all but one AKT1-mutant meningioma showed meningothelial histology (93.3%, p= 0.0001). All calcified meningiomas (n= 17) were NF2-mutant (p= 0.0002), whereas none of the AKT1-mutant meningiomas showed intratumoral calcifications.

CONCLUSIONS
Our findings support the central role of AKT1 and NF2 mutations in the molecular pathogenesis of WHO grade 1 SM. These mutations are mutually exclusive and are associated with distinct tumor and clinical features.
SURG-27. THERAPEUTIC OPTIONS FOR RECURRENT GLIOBLASTOMA-EFFICACY AND SAFETY OF TALAPORFIN SODIUM MEDIATED PHOTODYNAMIC THERAPY WITH MAXIMAL RESECTION
Authors: Muragaki Yoshihiro , Kobayashi Tatsuya , NItta Masayuki , Shimizu Kazuhide , Kawamata Takakazu 
Published: November 2022

Abstract

INTRODUCTION
Recurrent glioblastoma (GBM) remains one of the most challenging clinical issues, with no standard treatment and effective treatment options.

METHODS
To evaluate the efficacy of talaporfin sodium (TS) mediated photodynamic therapy (PDT) as a new treatment for this condition, we retrospectively analyzed 70 patients who underwent surgery of maximal resection with PDT (PDT group) for recurrent GBM and 38 patients who underwent surgery of maximal resection alone (control group).

RESULTS
The median progression-free survival (PFS) in the PDT and control groups after second surgery was 5.7 and 2.2 months, respectively (p = 0.0043). The median overall survival (OS) after the second surgery was 16.0 and 12.8 months, respectively (p = 0.031). Both univariate and multivariate analyses indicated that surgery with PDT and a preoperative Karnofsky Performance Scale were significant independent prognostic factors for PFS and OS. In the PDT group, there was no significant difference regarding PFS and OS between patients whose previous pathology before recurrence was already GBM and those who had malignant transformation to GBM from lower grade glioma. PDT was well tolerated by all patients and in no case did treatment-related severe adverse effects. There was also no significant difference in TS accumulation in the tumor between these two groups.

CONCLUSION
According to these results, additional PDT treatment for recurrent GBM could have potential survival benefits and its efficacy is independent of the pre-recurrence pathology.
Comparison of Indirect Fungal Diagnostic Tests in Patients With Proven Histoplasmosis
Authors: Krishnan Gayathri , Power Margaret , Bariola J Ryan , Dare Ryan 
Published: November 2022

Abstract

Background
Histoplasmosis is a common cause of invasive fungal infection in endemic regions and accurate diagnosis is difficult without direct tissue culture or pathology. Indirect fungal antigen testing for various fungal pathogens are typically performed to assist with diagnostic workup, though cross-reaction can lead to difficulty in interpreting results. We aimed to compare indirect fungal diagnostic tests and evaluate prevalence of positive antigen testing for non-Histoplasma fungal pathogens in patients with proven histoplasmosis.

Methods
We performed a single-center retrospective review of adult patients with proven histoplasmosis diagnosed by fungal culture and/or cytology from January 2010 to March 2018. Patient demographics, clinical characteristics, and results of fungal antigen testing for Histoplasma, Blastomyces, Aspergillus, Cryptococcus, and (1→3)-β-D-glucan were evaluated. Two different urine Histoplasma antigen assays were used during the study period.

Results
Fifty-seven of 182 (31.3%) patients reviewed had proven histoplasmosis and presented with acute pulmonary (n = 10), chronic pulmonary (n = 7), and disseminated (n = 40) disease. Forty-one (72%) of these patients were immunosuppressed. Urine Blastomyces antigen (93%) and serum (1→3)-β-D-glucan (88%) were commonly positive in patients with histoplasmosis, whereas Aspergillus antigen was detected in 50% of patients and Cryptococcus antigenemia was rare (5%). In patients with disseminated disease, the MiraVista urine Histoplasma antigen assay had higher sensitivity than the Viracor urine Histoplasma antigen assay (86% vs 50%, respectively; P = .019).

Conclusions
Noninvasive fungal antigen assays are helpful diagnostic tools; however, given their low specificity, clinicians must be aware of the various clinical presentations of invasive fungal infections and be aware of the limitations of these tests.
Biobehavioral Assessments in BACPAC: Recommendations, Rationale, and Methods
Authors: Greco Carol M , Wasan Ajay D , Schneider Michael J , Mehling Wolf , Williams David A , Darwin Jessa , Harte Steven E 
Published: November 2022

Abstract
The Biobehavioral Working Group of BACPAC was charged to evaluate a range of psychosocial, psychophysical, and behavioral domains relevant to chronic low back pain, and recommend specific assessment tools and procedures to harmonize biobehavioral data collection across the consortium. Primary references and sources for measure selection were the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, the Minimum Data Set from the National Institutes of Health (NIH) Research Task Force on Standards for Chronic Low Back Pain, the Patient-Reported Outcomes Measurement Information System, and NeuroQOL. The questionnaire’s recommendations supplemented the NIH HEAL Common Data Elements and BACPAC Minimum Data Set. Five domains were identified for inclusion: Pain Characteristics and Qualities; Pain-Related Psychosocial/Behavioral Factors; General Psychosocial Factors; Lifestyle Choices; and Social Determinants of Health/Social Factors. The Working Group identified best practices for required and optional Quantitative Sensory Testing of psychophysical pain processing for use in BACPAC projects.
No Work for Fundamental Facts
Authors: Oberle Thomas 
Published: November 2022

Abstract
Metaphysical foundationalists argue that without fundamental facts, we cannot explain why there exist any dependent facts at all. Thus, metaphysical infinitism, the view that chains of ground can descend indefinitely without ever terminating in a level of fundamental facts, allegedly exhibits a kind of explanatory failure. I examine this argument and conclude that foundationalists have failed to show that infinitism exhibits explanatory failure. I argue that explaining the existence of dependent facts in terms of further dependent facts ad infinitum is unproblematic by arguing for the plausibility of a ground-theoretic version of the Hume-Edwards Principle, which states that if each fact in a plurality of facts has a ground, then the plurality itself has a ground.