tbuckley/cabot-search huggingface dataset:
LGG-48. PROLIFIC GROWTH OF BRAF V600E MUTANT PILOCYTIC ASTROCYTOMA WHILE ON KETOGENIC DIET: CASE REPORT
Authors: Patti Batchelder, Anandani Nellan, Charuta Joshi, Adam Green, Michael Handler, Todd C Hankinson
Journal: Neuro-Oncology (2020)

Abstract Epilepsy is a common diagnosis among pediatric patients with supratentorial tumors, particularly infiltrating gliomas. The ketogenic diet can be a successful antiepileptic therapy for patients with medically intractable epilepsy. Acetoacetate, a main ketone released during ketosis, has been shown to increase BRAFV600E binding to MEK1 and MEK1 phosphorylation in BRAFV600E mutant melanoma cells, thereby promoting proliferation and tumor growth (Kang et al, 2015, Xia et al, 2017). BRAFV600E mutation is common in pediatric low-grade gliomas. Therefore, use of a ketogenic diet to manage coincident epilepsy could, in theory, promote tumor growth. However, this has not been previously reported in a human patient. We present a 3 year-old male with a non-NF1 optic pathway BRAFV600E mutant pilocytic astrocytoma and medically intractable epilepsy. He was treated with carboplatin and bevacizumab for 1 year, with good tumor response and vision recovery. He showed stable, non-progressive disease for several months. He was placed on a ketogenic diet 9 months into treatment and became seizure free. Tumor recurrence occurred at 8 months off therapy, at which time a biopsy demonstrated BRAFV600E mutation. The tumor progressed rapidly despite treatment with Trametinib and Dabrafenib, leading to salvage therapy with carboplatin, vinblastine, bevacizumab, and XRT, without tumor control. We discuss the potential effect of the ketogenic diet on this patient’s outcome.
RADT-20. HISTOPATHOLOGIC FINDINGS IN MALIGNANT PERIPHERAL NERVE SHEATH TUMOR ARE BOTH PROGNOSTIC FOR OVERALL SURVIVAL AND PREDICTIVE FOR RESPONSE TO RADIATION THERAPY
Authors: Harish N Vasudevan, Calixto-Hope G Lucas, William Chen, Stephen Magill, Steve Braunstein, Line jacques, Sonika Dahiya, Fausto Rodriguez, Andrew Horvai, Arie Perry, Melike Pekmezci, David Raleigh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Malignant peripheral nerve sheath tumor (MPNST) is an aggressive neoplasm associated with neurofibromatosis type 1 (NF1). Despite multimodal therapy, clinical outcomes remain poor. To elucidate markers of MPNST treatment response, we retrospectively reviewed the medical records of MPNST patients at a single institution and performed histopathological and immunohistochemical (IHC) analysis for predictive and prognostic features. METHODS We identified 54 consecutive patients treated at University of California San Francisco between 1990 and 2018 that met diagnostic criteria for MPNST on pathologic review with sufficient tissue available for histology and immunohistochemistry (IHC) assays. IHC was performed for Ki-67, EGFR, p53, H3K27me3, neurofibromin, S100, p75NTR, SOX10, p16, and SOX2. Overall survival (OS), metastasis free survival (MFS), and locoregional failure free rate (LFFR), were estimated using the Kaplan-Meier method. Log-rank test, Cox Proportional Hazards regression, and hierarchical clustering were performed in R. RESULTS With a median follow up of 19.2 months, the 5-year OS, MFS, and LFFR were 58%, 68%, and 66%, respectively, with no significant differences between NF1 associated (n=32) and sporadic tumors (n=22). Radiation therapy significantly improved 5-year LFFR (80% versus 49%, p=0.05), but not OS or MFS. Tumor grade was associated with worse OS by Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) grading (p=0.02). Furthermore, elevated Ki-67 index was associated with worse 5-year OS (39% versus 73% for Ki-67 index ³ 60 and Ki-67 index &amp;lt; 60, p=0.01). Finally, hierarchical clustering of IHC data identified a predictive signature defined by elevated Ki-67 and EGFR expression associated with improved responses to radiation therapy (5-year OS 86% versus 10%, p=0.004). CONCLUSIONS Our data provide insights into the diagnosis and treatment of MPNST. Additional investigation is needed to understand the biologic mechanisms and generalizability of the signatures uncovered in our analysis.
Abstract 13715: Poor Concordance Between Respiratory Variation in Inferior Vena Cava and Surrogates of Cardiac Output Measurements for Determination of Fluid Responsiveness
Authors: Isaac Laniado, Jee Young You, Balaram Krishna J Hanumanthu, Jorge-Bleik Ataucuri-Vargas, Errold S Reid, Harmeen Goraya, Perminder Gulani
Journal: Circulation (2019)

Introduction: Fluid responsiveness in critically ill patients is paramount but often challenging to determine. Point-of-care ultrasound (POC-US) is increasingly being used as a tool to for its asse...
HGG-44. DEFECTS OF MISMATCH REPAIR PROTEINS IN PEDIATRIC HIGH GRADE GLIOMAS
Authors: Christine Haberler, Philippe Muller, Leonhard Müllauer, Andreas Peyrl, Thomas Czech, Katharina Wimmer, Irene Slavc
Journal: Neuro-Oncology (2020)

Abstract Hetero- and homozygous germline mutations of the mismatch repair genes MLH1, PMS2, MSH2 and MSH6 cause Lynch and constitutional mismatch repair (CMMRD) cancer predisposition syndrome, respectively. Affected CMMRD individuals are at risk to develop a variety of neoplasms including CNS tumors, particularly high grade gliomas (HGG), during childhood. Currently, few data exist on the prevalence of CMMRD in children with pediatric HGG. We screened a consecutive series of 79 supratentorial HGGs. Tumor tissue was available in 42 patients, 5 were reclassified as non-HGGs. Immunohistochemistry with antibodies against MLH1, PMS2, MSH2 and MSH6 was performed in 37 tumors. Four patients (3 families) with known CMMRD were included. The evaluation of the slides was performed blinded to the CMMRD status. All four patients with known CMMRD (3 patients with PMS2, one with MSH6 mutation) were identified, showing loss of PMS2 and MSH2/MSH6, respectively. Additionally, we identified 6 patients with loss of MSH2/MSH6 staining in tumor cells, but retained staining in preexisting cells, indicating a pattern like in Lynch syndrome. NGS sequencing of these tumor tissues revealed in 2 patients MSH2 mutations and in one patient a hypermutator phenotype with MSH2 and MSH6 mutations. In 3/6 patients no mutations in the MMR genes were detectable. In summary, we found a low prevalence of CMMRD among HGGs, but identified also 2 patients with probable Lynch syndrome. Immunhistochemistry is an effective tool to screen for patients with MMR defects and should be performed in HGGs to optimize treatment and offer affected families genetic counseling.
TMOD-03. PAN-CANCER ANALYSIS OF ORTHOTOPIC PATIENT DERIVED XENOGRAFTS FROM BRAIN METASTASES
Authors: Yu Zeng, Kristine Pelton, Smitha Yerrum, Pei-Lun Kao, Claire Sinai, Tony Tran, Rileen Sinha, Aniket Shetty, Michael Tolstorukov, Aliya Jaber, Dylan Freitas, William Pisano, Sigitas J Verselis, Zach T Herbert, Nancy Lin, Jean J Zhao, David M Weinstock, Ugonma Chukwueke, Ayal A Aizer, E Antonio Chiocca, Wenya Linda Bi, Patrick Wen, Eudocia Lee, Lakshmi Nayak, David Meredith, Sandro Santagata, Kin Hoe Chow, Keith Ligon
Journal: Neuro-Oncology (2020)

Abstract Brain metastases (BM) are a leading cause of cancer death and prognosis remains poor despite treatment advances at other sites. Models are central to therapeutic development, but few orthotopic patient-derived xenograft (PDX) models of BM exist. To represent diversity across BM types, we established a program to create orthotopic PDX at scale from all BM patients. To date BM were received from 100 patients and PDX attempted by direct brain injection (PDX, n=89) or injection of low passage patient-derived cell lines (PDCLX, n=11). We created 65 successful BM PDX from 13 cancers: 17 lung (55% take), 15 breast (68%), 6 melanoma (75%), 5 CNS lymphoma (83%), 3 gastrointestinal (75%), 2 esophageal (40%), 2 ovarian (67%), 1 sarcoma (100%), 1 laryngeal (100%), 1 prostate (100%), 1 pancreatic (100%), 1 uterine adenosarcoma (100%), and 1 yolk sac tumor (100%). Take rate was similar for models derived from patients with prior chemotherapy-only versus immune/targeted therapy-only (63 vs 58%). Fifteen patients had live tumor and matching PBMCs archived for modeling in vitro immunotherapy responses. Mean time to moribund among different cancer types ranged from 27 days (yolk sac tumor) to 177.5 days (ovarian). BM PDX had a favorable timeline for preclinical study (90% moribund at 180 days). All PDX retained high fidelity to the patient driver SNVs and copy aberrations, even at &amp;gt;P4. No significant differences noted by immunodeficient strain (SCID versus NSG) or injection site (orthotopic versus heterotopic). Explants from BM PDX were able to generate long-term cell lines (60%) or short-term cultures with qualitative concordance of model-to-patient responses to targeted therapy (Osimertinib, EGFRi) and immunotherapy (Pembrolizumab, PD1i). Genomic and clinical data were used to create the DFCI BM PDX cBioPortal for public release and models distribution will be available through the DFCI Center for Patient Derived Models.
Contemporary Multi-Institutional Cohort of 550 Cases of Phyllodes Tumors (2007-2017) Demonstrates a Need for More Individualized Margin Guidelines
Authors: Laura H. Rosenberger, Samantha M. Thomas, Suniti N. Nimbkar, Tina J. Hieken, Kandice K. Ludwig, Lisa K. Jacobs, Megan E. Miller, Kristalyn K. Gallagher, Jasmine Wong, Heather B. Neuman, Jennifer Tseng, Taryn E. Hassinger, Tari A. King, James W. Jakub
Journal: Journal of Clinical Oncology (2020)

Phyllodes tumors (PTs) are rare breast neoplasms, which have little granular data on margins. Current guidelines recommend ≥ 1 cm margins; however, recent data suggest narrower margins are sufficient, and for benign PT, a negative margin may not be necessary.We performed an 11-institution contemporary (2007-2017) review of PT practices. Demographics, surgical, and histopathologic data were captured. Logistic regression was used to estimate the association of select covariates with local recurrence (LR).Of 550 PT patients, the majority underwent excisional biopsy (55.3%, n = 302/546) or lumpectomy (wide excision) (38.5%, n = 210/546). Median tumor size was 30 mm, 68.9% (n = 379) were benign, 19.6% (n = 108) borderline, and 10.5% (n = 58) malignant. Surgical margins were positive in 42% (n = 231) and negative in 57.3% (n = 311). A second operation was performed in 38.0% (n = 209) of the total cohort, including 51 patients with an initial negative margin (82.4% with < 2 mm), and 157 with an initial positive margin, with residual disease only found in six (2.9%). Notably, 32.0% (n = 74) of those with an initial positive margin did not undergo a second operation, among whom only 2.7% (n = 2) recurred. Recurrence occurred in 3.3% (n = 18) of the total cohort (n = 15 LR, n = 3 distant), at median follow-up of 36.7 months. LR (all PT grades) was not reduced with wider negative margin width (≥ 2 mm v < 2 mm: odds ratio [OR] = 0.39; 95% CI, 0.07 to 2.10; P = .27) or final margin status (positive v negative: OR = 0.96; 95% CI, 0.26 to 3.52; P = .96).In current practice, many patients are managed outside of current guidelines. For the entire cohort, a wider margin width was not associated with a reduced risk of LR. We do not recommend re-excision of a negative margin for benign PT, regardless of margin width, as a progressively wider surgical margin is unlikely to reduce LR.
Getting Good Vibes: The Therapeutic Power of Microbubbles and Ultrasound⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Flordeliza S. Villanueva
Journal: JACC. Cardiovascular imaging (2012)
Systematic Assessment of GATA2 Genetic Variation Reveals the Presence of Novel Disease-Causing Synonymous Exonic Mutations
Authors: Emilia J Kozyra, Victor Pastor Loyola, Claudia Wehr, Sushree Sangita Sahoo, Rebecca Voss, Enikoe Amina Szvetnik, Shinsuke Hirabayashi, Albert Catala, Henrik Hasle, Marry M. Van den Heuvel-Eibrink, Krisztián Kallay, Riccardo Masetti, Barbara De Moerloose, Markus Schmugge, Owen Smith, Marek Ussowicz, Jan Stary, Ester Mejstrikova, Ramunė Pasaulienė, Irith Baumann, Gudrun Göhring, Brigitte Schlegelberger, Ulrich Salzer, Michael Lübbert, Eirini Trompouki, Charlotte M. Niemeyer, Marcin W. Wlodarski
Journal: Blood (2017)
DIPG-29. PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE (PI3K) INHIBITION DRIVES PROTEIN KINASE C ACTIVATION (PKC) IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Ryan J Duchatel, Abdul Mannan, Evangeline R Jackson, Dilana Staudt, David A Skerrett-Byrne, M Fairuz B Jamaluddin, Ameha S Woldu, Alicia Douglas, Esther Hulleman, Angel M Carcaboso, Michelle Monje, Frank Alvaro, Maria Tsoli, David S Ziegler, Matthew D Dun
Journal: Neuro-Oncology (2020)

Abstract Recurring somatic mutations and gene amplifications to members of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling axis are overarching contributors to the aggressive growth and survival of diffuse intrinsic pontine gliomas (DIPG). However, targeting PI3K has thus far failed to improve outcomes for patients in the clinic. To identify the mechanisms underpinning PI3K/AKT/mTOR treatment failure in DIPG, we have employed high-resolution quantitative phosphoproteomic profiling in patient-derived DIPG cell lines harboring H3K27M and PI3K mutations, +/- the blood-brain barrier permeable PI3K inhibitor, paxalisib (previously “GDC-0084”, currently in Phase I trials - NCT03696355) and rapamycin. Paxalisib was significantly more potent than rapamycin at inducing PI3K/AKT/mTOR inhibition, however, both simultaneously activated protein kinase C signaling (pT500PKCβ +8.2 and +4.5 fold, respectively). PKC lies directly upstream of myristoylated alanine-rich C-kinase substrate (MARCKs), which was phosphorylated at Ser170 by +9.4 and +4.7 fold, respectively; promoting actin cytoskeletal remodeling and cellular migration. Indeed, activation of PKC signaling using phorbol 12-myristate 13-acetate (PMA), increased DIPG cell growth and migration by &amp;gt;3 fold. Targeting PKC using midostaurin (FDA-approved for acute myeloid leukemia), and enzastaurin (blood-brain barrier penetrant inhibitor of PKCβ), in combination with paxalisib was highly synergistic (CI=&amp;lt;0.9), reducing proliferation and driving apoptosis. Mechanistically, compensatory activation of PKC signaling following PI3K inhibition was regulated by the accumulation of Ca+2 ions, as chelation using BAPTA-AM significantly reduced PKC activity following PI3K inhibition. These data highlight the power of phosphoproteomic profiling for the rational design of drug combination strategies, which need to be tested in vivo prior to clinical trials for DIPG.
NCOG-48. TRANSFORMATION FROM LOW GRADE MENINGIOMA AND PROGNOSTIC FACTORS FOR SHORTER TIME TO RECURRENCE OF WHO GRADE III MENINGIOMA DIAGNOSIS
Authors: Jessica Chew, William Chen, Matthew S Susko, Harish N Vasudevan, Steve Braunstein, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND WHO grade III meningiomas are rare, and clinical outcomes data are limited. To address this problem, we analyzed a single institution retrospective cohort of patients with WHO grade III meningiomas. METHODS Patients who underwent resection of WHO grade III meningiomas between 1983 and 2019 with available follow-up data were included. Treatment, local recurrence, and overall survival rates were obtained. Kaplan-Meier analysis, log rank tests, and Student’s t tests were used for statistical analyses. RESULTS Ninety consecutive patients met inclusion criteria. Median follow-up was 3.2 years (IQR: 1.2-7.9), median age was 58 years (IQR: 46-67). Twenty-three patients (26%) underwent resection alone, and 58 (64%) underwent resection with adjuvant radiotherapy. Fifty-one patients developed local recurrences, with median time to recurrence of 1.0 year (IQR: 0.6-2.9) and higher MIB-1 labeling index for tumors that recurred within 1 year (25% versus 17%, p=0.04). There was a median of 2 recurrences per patient (IQR: 1-3), with a median of 2 resections and 2 radiotherapy courses for initial and salvage treatments. Thirty-nine patients with recurrences died, with median overall survival of 3.7 years (IQR: 1.8-8.8). Thirty-seven patients (41%) had prior low grade meningioma diagnoses with subsequent transformation to grade III, including 6 (7%) with grade I, 16 (18%) with grade II, and 15 (17%) with unknown grade. There was a median of 1 low grade recurrence per patient (IQR: 0-3) before transformation to grade III, which occurred a median of 4.3 years (IQR: 2.4-9.9) after initial diagnosis. Prior low grade diagnosis was associated with shorter time to recurrence of WHO grade III meningioma (p=0.01), and worse overall survival (p=0.03). CONCLUSION Patients with WHO grade III meningioma have poor outcomes despite aggressive multimodal therapy, and there is an urgent, unmet need for new high grade meningioma treatments.
CD4 <sup>+</sup> T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis
Authors: Qing Zhao, Lennard W. Duck, Fengyuan Huang, Katie L. Alexander, Craig L. Maynard, Peter J. Mannon, Charles O. Elson
Journal: Science Immunology (2020)

Activation by multi-epitope peptide plus mTOR inhibition depletes flagellin-reactive CD4 + T cells and prevents intestinal inflammation.
Abstract 10209: The Impact Of Sepckle Tracting Echocardiography In Patient With Lymphoma Receiving Chemotherapy
Authors: Hsien-Yuan Chang, Chun-Hui Lee, Yen-Wen Liu
Journal: Circulation (2019)

Background: Owing to the recent enormous advances in cancer therapies, the survival rates of cancer patients significantly increased. However, there are more antineoplastic therapy related cardiova...
The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease
Authors: Erica Jennison, Christopher D. Byrne
Journal: Clinical and Molecular Hepatology (2020)

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with a prevalence that is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. The pathogenesis of NAFLD is complex and multifactorial, involving environmental, genetic and metabolic factors. The role of the diet and the gut microbiome is gaining interest as a significant factor in NAFLD pathogenesis. Dietary factors induce alterations in the composition of the gut microbiome (dysbiosis), commonly reflected by a reduction of the beneficial species and an increase in pathogenic microbiota. Due to the close relationship between the gut and liver, altering the gut microbiome can affect liver functions; promoting hepatic steatosis and inflammation. This review summarises the current evidence supporting an association between NAFLD and the gut microbiome and dietary factors. The review also explores potential underlying mechanisms underpinning these associations and whether manipulation of the gut microbiome is a potential therapeutic strategy to prevent or treat NAFLD.
Enterococcus faeciumの片利共生株におけるボツリヌス神経毒素様毒素の同定【Powered by NICT】
Authors: Zhang Sicai, Lebreton Francois, J Mansfield Michael, Miyashita Shin-Ichiro, Zhang Jie, A Schwartzman Julia, Tao Liang, Masuyer Geoffrey, Martinez-Carranza Markel, Stenmark Pal, S Gilmore Michael, C Doxey Andrew, Dong Min
Journal: Cell Host & Microbe (2018)
Abstract 406: Dantrolene, a Ryanodine Receptor Stabilizer, Can Significantly Attenuate Atrial Fibrillation Inducibility in a Rat Myocardial Infarction-Heart Failure Model Under Sympathetic Stimulation
Authors: Colleen Nofi, Ada Wong, Ying Li, Youhua Zhang
Journal: Circulation Research (2017)

Background: Compared to sympathetic stimulation (SS), normal hearts are more sensitive to vagal stimulation induced atrial fibrillation (AF). In contrast, we have recently demonstrated that failing hearts are less sensitive to vagal stimulation induced AF and more sensitive to SS induced AF. The exact mechanism underlying this SS enhanced AF in heart failure (HF) remains to be investigated. We now hypothesize that SS can worsen ryanodine receptor dysfunction already present in HF, leading to enhanced AF vulnerability. Consequently dantrolene, by stabilizing ryanodine receptors, can decrease SS enhanced AF inducibility in HF. Methods and Results: A rat myocardial infarction (MI)-HF model was used. MI was produced in rats by coronary artery ligation. HF was confirmed in 17 rats 2 months after the surgery. These animals were randomized into control (vehicle treated, n=9) and dantrolene (10mg/kg, IP, n=8) groups. In vivo atrial electrophysiology and AF inducibility tests under SS were studied using a catheter approach in all animals 30 minutes after the respective treatments. SS was mimicked by intravenous isoproterenol (0.1ug/min) infusion. Compared with the control group, dantrolene treatment significantly reduced AF inducibility and AF duration under SS (figure). Conclusion: The ryanodine receptor stabilizer dantrolene can significantly attenuate SS enhanced AF inducibility in a rat MI-HF model, suggesting that ryanodine receptor dysfunction may play a critical role in enhancing AF inducibility under SS in HF. The ryanodine receptor stabilizer dantrolene may be a new treatment option in reducing AF in HF.
Abstract P500: 24-Month Follow-Up of the <i>‘Stand and Move at Work’</i> Sedentary Behavior Intervention: Effects on Cardiometabolic Risk in Those With Dysglycemia
Authors: Mark A Pereira, Sarah L Mullane, Meynard J Toledo, Sarah A Rydell, Miranda Larouche, Brenna Vuong, Linda H Feltes, Nathan R Mitchell, Junia N de Brito, Kristina Hasanaj, Neil Carlson, Glenn A Gaesser, Noe C Crespo, J. M Oakes, Matthew P Buman
Journal: Circulation (2020)

Long-term effects of workplace sedentary behavior interventions on cardiometabolic risk are poorly understood. Stand and Move at Work was a multi-site group randomized trial in 24 worksites (N=630, 74% female, 45±11 years of age) of office-based employees in Phoenix, AZ and Minneapolis/St. Paul, MN. Worksites in the STAND+ study arm received 12 months of a multilevel (i.e., worksite policy, environmental, and individual-level strategies) intervention to increase light-intensity physical activity along with a sit-stand workstation (SSW) to increase standing time. Worksites in the MOVE+ study arm received the same multilevel intervention but were not provided the SSW until after the intervention ended at 12 months. The STAND+ arm, but not the MOVE+ arm, had significant reductions in sedentary time over the 12-month intervention. However, 12-month improvements in cardiometabolic risk factors were only observed among a subgroup with dysglycemia (prediabetes or diabetes). Here we report the long-term follow-up of these changes, 12 months after the end of the trial (24 months). Results are shown in the Table. The effects at 12 months were largely sustained at 24 months. Although limited by the small sample size in this subgroup, long-term meaningful and sustained improvement in blood glucose, triglycerides, systolic blood pressure, and weight may be observed from a multilevel workplace sedentary behavior intervention that includes sit-stand workstations.