tbuckley/cabot-search huggingface dataset:
NCOG-75. ESTIMATED PHYSICIAN COST OF A NEURO-ONCOLOGY MULTIDISCIPLINARY TEAM (MDT) TUMOR BOARD MEETING AT A SINGLE ACADEMIC CENTER
Authors: Brett Schroeder, Jerome Graber, Emmanuel Cuevas
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Multidisciplinary teams (MDTs) to improve coordination across disciplines have become commonplace in oncology. Quantifying the impact of MDTs is challenging, and they carry significant costs. Weekly neuro-oncology tumor boards are attended by neuro-oncologists, neurosurgeons, radiation-oncologists, neuro-radiologists, neuro-pathologists, and support staff including mid-level practitioners, research coordinators, social workers, nurses and trainees. Our aim was to estimate costs associated with neuro-oncology MDTs. METHODS The estimated physician cost of MDT meetings were calculated from reported salaries of each physician specialty. Annual salaries from the Doximity 2019 Physician Compensation Report (PCR) included data for 4 neurosurgeons, 4 radiation-oncologists, 2 radiologists, 2 oncologists, and 2 neurologists. Medscape 2019 PCR data was compiled for 4 general surgeons, 2 radiologists, 2 oncologists, 2 pathologists, and 2 neurologists. The Physician Wages Across Specialties by Leigh in 2011 (JAMA) was utilized for 4 neurosurgeons, 4 radiation oncologists, 2 oncologists, and 2 neurologists. Annual salary data was divided by annual hours per specialty as reported by the Annual Work Hours Across Specialties, 2011. These values were then applied to an MDT for one patient, one hour, weekly, and annually. RESULTS The Doximity 2019 PCR yielded a per meeting cost of $2,520.84, and an annual cost of $131,083.68. The Medscape 2019 PCR produced a cost of $1,570.60 weekly, and $81,671.20 annually. JAMA data estimated a per meeting cost of $1,448.06, and $75.299.12. The mean per meeting and annual costs were $1846.50, and $96,018.00, respectively. With 6-10 cases per MDT, the mean costs per patient were $184.65 to $307.75. CONCLUSIONS Costs of MDT are not negligible. The impact of MDTs on patient outcomes are harder to quantify, but evidence exists that organized MDTs improve patient prognosis, and unorganized MDTs may negatively affect prognosis. Processes to streamline MDTs could help answer outcomes research questions, improve efficiency, and generate clinically relevant performance metrics.
Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19
Authors: Zhao Zhang, Liyan Guo, Xiaoxia Lu, Che Zhang, Li Huang, Xianfeng Wang, Fuyu Duan, Huiying Liang, Peikai Chen, Liang Zeng, Jianbo Shao, Hui Li, Le Li, Li Liu, Cheng Li, Jinqiu Zhang, Chui Yan Ma, Ka Yi Kwan, Wei Liu, Yi Xu, Xiaoqiong Gu, Hua Jiang, Hui Du, Ting Zhang, Yanheng Wu, Guangyin Yu, Junhui Chen, Ruibang Luo, Can Liao, Hung-fat Tse, Zhiwei Chen, Huanhuan Joyce Chen, Huimin Xia, Qizhou Lian
Journal: Theranostics (2020)

Introduction: An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow.Methods: We analysed clinical features in a cohort of 173 children with between January 22, 2020 and March 15, 2020.We systematically examined the expression and distribution of ACE2 in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and ex vivo SARS-CoV-2 pseudoviral infections.Results: It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury.The expression levels of ACE2 however do not vary by age in children's lung.ACE2 is notably expressed Ivyspring International Publisher not only in Alveolar Type II (AT II) cells, but also in SOX9 positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs.The ACE2 + SOX9 + cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children.Conclusions: Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries.ACE2 expression in multiple types of lung cells including SOX9 positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19.There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection.
Assessment of Tau Tangles and Amyloid-β Plaques Among Super Agers Using PET Imaging
Authors: Merle C. Hoenig, Niclas Willscheid, Gérard N. Bischof, Thilo van Eimeren, Alexander Drzezga
Journal: JAMA Network Open (2020)

This cross-sectional study examines positron emission tomography (PET) imaging to investigate the burden of tau tangles and amyloid β plaques in super agers, normal agers, and patients with mild cognitive impairment vs younger amyloid-negative controls.
HGG-40. EXCEPTIONAL SYNCHRONOUS OCCURENCE OF A BRAF V600E MUTANT GLIOBLASTOMA AND A H3.3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA: A CASE REPORT
Authors: Emilie De Carli, Blandine Boisselier, Luc Le Fournier, Stéphane Supiot, Coralie Mallebranche, Stéphanie Proust-Houdemont, Mylène Duplan, Isabelle Pellier, Audrey Rousseau
Journal: Neuro-Oncology (2020)

Abstract We report herein the case of a 17-year-old female who presented with intracranial hypertension and diplopia. Magnetic resonance imaging showed a large left cystic and solid temporoparietal lesion, associated with an infiltrating lesion of the brainstem, hypointense in T1 and hyperintense in FLAIR sequences, without enhancement after injection of gadolinium. Complete resection of the parietal mass and biopsy of the brainstem lesion were performed. Histopathological analysis of the parietal mass showed glioblastoma (WHO grade IV) with no IDH1/2 or H3.3/H3.1 gene mutation detected by Sanger sequencing. Immunohistochemistry found the expression of the proteins of mismatch repair system. Whole exome and RNA sequencing identified a BRAF-V600E mutation. The brainstem lesion was a diffuse midline glioma, H3K27M-mutant (grade IV) according to the 2016 WHO classification. Pan-genomic SNP arrays of the 2 tumors showed distinct genetic alterations. The parietal glioblastoma displayed complex genomic alterations whereas the brainstem glioma harbored chromosome 7q gain, chromosome 9p and 10 losses, and RB, TP53 and CDKN2A homozygous deletions. The patient was treated by concomitant radiochemotherapy (according to Stupp protocol). After 12 cycles of temozolomide, there was complete remission persistant in the parietal lobe. The brainstem tumor was stable but progressed after 3 months of temozolomide discontinuation. Treatment with mTOR inhibitors was initiated. At 21-month follow-up, the patient remains with few symptoms. No predisposition syndrome was identified in the patient or her family. Concurrent glioblastomas with distinct driver gene mutations are exceptional.
EPCO-24. COMPUTATIONAL APPROACH TO IDENTIFYING NEUROINFLAMMATION IN GLIOBLASTOMA MULTIFORME (GBM)
Authors: Wendy Sherman, Katie Martin, Larissa Rossell, Kelly Nguyen, Pamela Grady, Cynthia Zimmermann, David Chesla, Jeffrey Mackeigan
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is an aggressive brain cancer with dismal prognosis, despite aggressive surgery, radiation and chemotherapy. Therapies directed to the immune system are an exciting prospect in oncology and require an understanding of the interaction between tumors and immune cells. Our objective was to use computational tools to estimate immune infiltration in GBM and determine whether specific immune cell types are associated with clinical outcomes. METHODS RNA sequencing and targeted DNA sequencing (to 981 oncology genes) was performed from 37 surgically-resected GBM tumors. Tumor mutations were identified, and gene-level transcript counts were used to estimate tumor-associated cell types using bioinformatics tools. Clinical variables, including survival from surgery and diagnosis, were collected and tested for associations with molecular data. RESULTS We detected leukocyte fractions (i.e., immune infiltration) ranging from 2% to 50% in GBMs, with an average of 10.2%. Specifically, we found a statistically significant association between high Th2 cell estimates and reduced overall survival (from both surgery and diagnosis). Nine patients with high Th2 tumors had a median OS from surgery of 187 days, compared with a median of 454 days for 28 patients with low Th2 tumors (log-rank Matel-Cox test; p = 0.0023, HR = 3.1). We also found an association between NF1 mutant tumors, which were enriched for a KRAS signaling signature, and high immune infiltration (p &amp;lt; 0.05). CONCLUSION Our computationally-driven approach predicted significant immune infiltration in GBM and a potential association between poor prognosis and Th2 cells. The specific class of CD4+ helper T-cells is generally associated with poor anti-tumor immunity and a Th2-bias has been reported in gliomas. Our data adds to the collective understanding of the molecular landscape of GBM, as well as the complex immune environment, which will have important implications in tumor treatment and prognosis.
Exploring the mythical abscopal effect: Radiation and programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma
Authors: Jun Won Kim, Ik Jae Lee
Journal: Clinical and Molecular Hepatology (2020)

See the Original "Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study" on page 144.
EXTH-03. IODINE NANOPARTICLE RADIOTHERAPY OF HUMAN BREAST CANCER GROWING IN THE BRAINS OF ATHYMIC MICE
Authors: James Hainfeld, Sharif M Ridwan, Yaroslav Stanishevsky, Henry Smilowitz
Journal: Neuro-Oncology (2020)

Abstract About 30% of breast cancers metastasize to brain; those widely disseminated are fatal typically in 3–4 months, even with the best available surgery, drugs, and radiotherapy. To address this dire situation, we have developed iodine nanoparticles (INPs) that target brain tumors after intravenous (IV) injection. The iodine then absorbs X-rays during radiotherapy (RT), creating free radicals and local tumor damage, effectively boosting the local RT dose at the tumor. Efficacy was tested using the very aggressive human triple negative breast cancer (TNBC, MDA-MB-231 cells) growing in the brains of athymic nude mice. With a well-tolerated non-toxic IV dose of the INPs (7 g iodine/kg body weight), tumors showed a heavily iodinated rim surrounding the tumor having an average uptake of 2.9% iodine by weight (peaks at 4.5%), calculated to provide dose enhancement factors of ~5.5 (peaks at 8.0) -- the highest ever reported for any radio-sensitizing agents. With 15 Gy, single dose RT, all animals died by 72 days; INP pretreatment resulted in longer-term remissions with 40% of mice surviving 150 days and 30% surviving &amp;gt; 280 days. Fluorescence confocal microscopy revealed most INP staining co-localized with CD31in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+blood-vessels. The significant radiation dose enhancement to the prolific INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new NP, particularly INP, tumor-homing target.
SURG-24. REPEAT CONVECTION-ENHANCED DELIVERY FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Evan Bander, Alexander Ramos, Eva Wembacher-Schroeder, Iryna Ivasyk, Rowena Thomson, Peter Morgenstern, Mark Souweidane
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single dose drug infusions, agents for oncologic therapy require repeated or chronic infusions to maintain therapeutic concentrations. Repeat/chronic CED infusions have rarely been described for oncologic purposes. We report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma (DIPG). METHODS Patients were enrolled in a phase I single center clinical trial using 124I-8H9 monoclonal antibody (124I-Omburtamab, Y-mAbs Therapeutics) administered by CED (NCT01502917). Retrospective chart review was used to assess demographic data, CED infusion data, and post-operative neurologic and surgical outcomes. MRI scans were analyzed using iPlan® Flow software (Brainlab AG, Munich, Germany) for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the Clearpoint imaging software (Clearpoint®, MRI Interventions Inc. Irvine, USA). RESULTS Seven patients underwent two or more sequential CED infusions. No patients experienced deficits Clinical Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater. One patient had persistent grade 2 cranial nerve deficit after a second infusion. No patients experienced hemorrhage or stroke post-operatively. There was a statistically significant decrease in radial error (p= 0.005) and absolute tip error (p=0.008) for infusion two compared to the initial infusion. Sequential infusions did not result in significantly different distribution capacity between the first and second infusion (Vd:Vi ratio: 2.66 ± 0.35 versus 2.42 ± 0.75; p=0.45). CONCLUSIONS This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural work flow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncologic purposes.
NURS-03. DEVELOPMENT OF A PATIENT-HELD TREATMENT SUMMARY FOR PAEDIATRIC CNS TUMOUR PATIENTS
Authors: Rachel McAndrew, Bernadine Wilkie, Mark Brougham, Jo Phillips
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Following the Scottish Government Cancer Plan 2012–15(1) ‘End of Treatment’ summaries for paediatric oncology patients treated in SE Scotland have been successfully implemented. However, it became evident that the particular needs of patients with CNS tumours were not adequately captured on the standardised documentation. METHODS In view of these difficulties an alternative document was prepared specifically for this patient cohort by the multi-disciplinary team, including Nurse Specialists, Paediatric Neuro-oncology and Neuro-psychology. This was designed to be a flexible, fluid summary to be used for all such patients regardless of tumour grade or treatment modality and included those undergoing surveillance only. OUTCOMES: The document is primarily completed by the Neuro-Oncology Nurse Specialist alongside the patient and family, usually following initial treatment and is used alongside their holistic needs assessment. The document is circulated to all involved professionals, including Primary Care, and a copy is retained by the patient. This then provides a concise source of information detailing diagnosis and treatment, any specific ongoing sequelae and details of red flag symptoms to alert patients and health professionals to the potential of relapse or other associated significant health problems. These treatment summaries are currently being piloted and have been well received thus far. They will be formally audited in due course with the aim to use nationally throughout Scotland in future.
EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Muhammad Baig, Jason Johnson, Sumit Gupta, Zsila Sadighi, Wafik Zaky, Soumen Khatua
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG. METHODS After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible. RESULTS Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.
Abstract P402: Aortic Stiffness and 5-year Cognitive Decline Among Community-dwelling Older Adults: The Atherosclerosis Risk in Communities Neurocognitive Study (aric-ncs)
Authors: Jingkai Wei, Priya Palta, Aozhou Wu, Michelle Meyer, A. Richey Sharret, Hirofumi Tanaka, David Knopman, Anna Kucharska-newton, Timothy Hughes, Kunihiro Matsushita, Thomas Mosley, Gerardo M HEISS
Journal: Circulation (2020)

Background: Vascular aging is associated with cognitive decline. Aortic stiffness is a hallmark of vascular aging. We tested the hypothesis that greater aortic stiffness is associated with a faster rate of cognitive decline over 5 years among older adults. Methods: A prospective cohort study at the 5th (2011-2013) and 6th (2016-2017) examinations of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) was conducted to quantify the association between baseline aortic stiffness and cognitive decline over 5 years. A total of 4639 participants (mean age: 75 years, 41% men, 22% Black) with baseline measures of aortic stiffness and cognitive function were included in the analysis. Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using the Omron VP-1000 Plus device and analyzed continuously per 1 standard deviation meter/second (3.20 m/s). Elevated aortic stiffness was defined as the upper 25th percentile of cfPWV (13.39 m/s). Cognitive function was based on ten neuropsychological tests across multiple domains of cognition, including memory, executive function/processing speed, and language. A global cognitive performance factor score was estimated based on all cognitive tests at both visits. Multivariable linear regression was used to examine the associations of each standard deviation (SD) increment in cfPWV and elevated cfPWV with annual cognitive decline over 5 years. Interactions with baseline cognitive status were assessed. To account for attrition (35% over 5 years), multiple imputation by chained equations was used to impute missing global cognitive performance factor scores at visit 6. Results: Each 1 SD increase in cfPWV was associated with 0.008 SD (Beta (β)=-0.008, 95% confidence interval (CI): -0.010, -0.003) annual rate of decline in cognitive function after adjustment for age, sex, education, race-center and ApoE4. With additional adjustment for ever smoking, total weekly physical activity time, mean arterial pressure, diabetes, and body mass index, each SD higher cfPWV was associated with 0.005 SD (β=-0.005, 95% CI: -0.010, -0.001) annual rate of decline in cognitive function. Elevated cfPWV was associated with 0.015 SD (β=-0.015, 95% CI: -0.024, -0.005) annual decline in cognitive function, and with 0.010 SD (β=-0.010, 95% CI: -0.020, 0.0001) annual decline after additional adjustment. Conclusion: Higher aortic stiffness is associated with the rate of decline in global cognitive function among community-dwelling older adults. The hemodynamic sequelae of aortic stiffening may contribute to cognitive decline among older adults.
Inhibiting protein phosphatase 2A increases the antitumor effect of protein arginine methyltransferase 5 inhibition in models of glioblastoma
Authors: Yoshihiro Otani, Hannah P Sur, Guruprasad Rachaiah, Sriya Namagiri, Ashis Chowdhury, Cole T Lewis, Toshihiko Shimizu, Arunakumar Gangaplara, Xiang Wang, Amélie Vézina, Dragan Maric, Sadhana Jackson, Yuanqing Yan, Zhuang Zhengping, Abhik Ray-Chaudhury, Sachin Kumar, Leomar Y Ballester, Prashant Chittiboina, Ji Young Yoo, John Heiss, Balveen Kaur, Yeshavanth Kumar Banasavadi-Siddegowda
Journal: Neuro-Oncology (2021)

Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, the median survival of glioblastoma (GBM) patients is less than 15 months. Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric dimethylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. LB100, a first-in-class small molecular inhibitor of protein phosphatase 2A (PP2A), can sensitize therapy-resistant tumor cells. Here, we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition.Patient-derived primary GBM neurospheres (GBMNS), transfected with PRMT5 target-specific siRNA, were treated with LB100 and subjected to in vitro assays including PP2A activity and western blot. The intracranial mouse xenograft model was used to test the in vivo antitumor efficacy of combination treatment.We found that PRMT5 depletion increased PP2A activity in GBMNS. LB100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5-intact GBMNS. LB100 enhanced G1 cell cycle arrest induced by PRMT5 depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged survival, while LB100 treatment alone had no survival benefit.Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone.