tbuckley/cabot-search huggingface dataset:
Comparison of Natriuretic Peptides as Risk Markers for All-Cause Mortality and Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes
Authors: Nete Tofte, Simone Theilade, Signe A. Winther, Sørine Birkelund, Jens P. Goetze, Tine W. Hansen, Peter Rossing
Journal: Diabetes Care (2020)

OBJECTIVE Few studies have compared midregional proatrial natriuretic peptide (MR-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP). We compared their value as risk markers for all-cause mortality and cardiovascular (CV) and renal complications in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS MR-proANP and NT-proBNP were measured in 664 individuals. Hazard ratios (HRs) were assessed per doubling of NT-proBNP or MR-proANP for risk of a composite of ischemic events, heart failure (HF), a combined renal end point of end-stage kidney disease (ESKD), decline in estimated glomerular filtration rate (eGFR) ≥30%, and all-cause mortality or individual end points. Adjustments included CV risk factors and addition of MR-proANP or NT-proBNP. RESULTS Median follow-up was 5.1–6.2 years. MR-proANP was associated with higher risk of all-cause mortality (n = 57; HR 1.7, 95% CI 1.1–2.7), combined CV end point (n = 94; 1.6, 1.1–2.2), HF (n = 27; 2.8, 1.5–5.2), combined renal end point (n = 123; 1.6, 1.2–2.1), and ESKD (n = 21; 3.1, 1.2–7.8) independent of CV risk factors (P ≤ 0.02). After addition of NT-proBNP, significance for all end points was lost. A doubling of NT-proBNP was associated with higher risk of all-cause mortality (HR 1.5, 95% CI 1.2–1.8), the combined CV end point (1.3, 1.1–1.5), HF (1.7, 1.3–2.1), and the combined renal end point (1.3, 1.1–1.4) independent of CV risk factors (model 2 [P &amp;lt; 0.001]) and MR-proANP (model 3 [P ≤ 0.03]). There was no association with decline in eGFR ≥30% (n = 93). CONCLUSIONS Higher NT-proBNP was independently associated with all-cause mortality, CV disease, HF, and the combined renal end point. MR-proANP was associated with all end points but decline in eGFR, although not independent of NT-proBNP. MR-proANP may contribute to the predictive value of NT-proBNP for risk stratification in type 1 diabetes.
From biomarkers to therapeutic targets: the promise of PD-L1 in thyroid autoimmunity and cancer
Authors: Grégoire D'Andréa, Sandra Lassalle, Nicolas Guevara, Baharia Mograbi, Paul Hofman
Journal: Theranostics (2020)

The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint proteins hold promise as diagnostic, prognostic, and therapeutic targets for precision oncology. By restoring antitumor T cell surveillance, the high degree of effectiveness of the immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. However, the majority of patients (65-80 %) treated with ICIs experience significant side effects, called immune-related adverse events (irAEs), resulting in autoimmune damage to various organs. Therefore, broadening the clinical applicability of these treatments to all cancer types requires an improved understanding of the mechanisms linking cancer immune evasion and autoimmunity. The thyroid is the endocrine gland the most frequently involved in autoimmunity and cancer, the growing incidence of which is raising serious public health issues worldwide. In addition, the risk of developing thyroid cancer is increased in patients with autoimmune thyroid disease and thyroid dysfunction is one of the most common irAEs, especially with PD‑1/PD-L1 blockade. Therefore, we chose the thyroid as a model for the study of the link between autoimmunity, irAEs, and cancer. We provide an update into the current knowledge of the PD‑1/PD-L1 axis and discuss the growing interest of this axis in the diagnosis, prognosis, and management of thyroid diseases within the context of autoimmunity and cancer, while embracing personalized medicine.
LINC-38. 500 CONSECUTIVE SURGICAL CASES FROM THE PEDIATRIC ONCOLOGY NEUROSURGERY GROUP: UNDERSTANDING THE PERSPECTIVE OF A TERTIARY CENTER IN BRAZIL
Authors: Felipe Hada Sanders, Hamilton Matushita, Manoel Jacobsen Teixeira
Journal: Neuro-Oncology (2020)

Abstract With this presentation we aim to present cases submitted to surgery by the same group of surgeons since 2010, presenting the physical structure, medical assistance, scientific production and the challenges that we need to overcome in the second decade of the twenty-first century, in a developing country.
TAMI-46. TNFα SECRETED BY GLIOMA ASSOCIATED MACROPHAGES PROMOTES ENDOTHELIAL ACTIVATION AND RESISTANCE AGAINST ANTI-ANGIOGENIC THERAPY
Authors: Qingxia Wei, Olivia Singh, Can Ekinci, Jaspreet Gill, Mira Li, Mamatjan Yasin, Shirin Karimi, Severa Bunda, Sheila Mansouri, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) remains a universal fatal disease and improving survival remains a challenge. One of the most prominent features of GBM is hyper-vascularization, characterized by abnormally dilated, distorted, and leaky vessels. Bone marrow (BM)-derived macrophages are recognized to be an important host cell population that are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs). GAMs are found to associate closely with blood vessels, and thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate and promote endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not understood. To understand how GBM, GAMs and EC interacts, we designed and developed a novel GBMs-GAMs-EC co-culture system as well as a unique in vivo model in which the BM of NOD/SCID mice were reconstituted with red fluorescent protein (RFP)-BM cells to create a chimeric mouse and then using intracranial injection of GFP-U87 cells to create a GBM xenograft. Our study is the first to demonstrate that glioma cells-secreted IL8 and CCL2 which stimulate GAMs to secrete TNFα and promote EC activation. TNFα inhibition led to normalization of the tumor vasculature and significant improvement in survival in glioma mice model. More importantly, we validate these findings using clinical data showing that TNFα is a predictor of overall survival and response to AATx in GBM patients. We further demonstrated that increased macrophage recruitment and upregulation of TNFα in GAMs activating EC in response to bevacizumab treatment is one of the critical molecular mechanisms underlying the failure of AATx in GBM. Collectively, these results provide compelling evidence to further explore the clinical impact of inhibiting TNFα concurrent with AATx.
TBIO-09. <i>IN SILICO</i> ANALYSIS IDENTIFIES A PUTATIVE CELL-OF-ORIGIN FOR <i>BRAF</i> FUSION-POSITIVE CEREBELLAR PILOCYTIC ASTROCYTOMA
Authors: Subhi Talal Younes
Journal: Neuro-Oncology (2020)

Abstract Childhood cancers are increasingly recognized as disorders of cellular development. This study sought to identify the cellular and developmental origins of cerebellar pilocytic astrocytoma, the most common brain tumor of childhood. By leveraging publicly available gene expression data from such tumors and controlling for driver mutations, a set of eight known neuro-developmental genes were identified as being upregulated in cerebellar pilocytic astrocytoma. Mapping those genes onto mouse neuro-developmental atlases identified significant overlap in their expression within the ventricular zone of the cerebellar anlage. Further analysis with a single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at the division point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor cells and their progeny exhibited evidence of MAPK pathway activation, the paradigmatic oncogenic cascade known to be active in cerebellar pilocytic astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories as those found in mice. Taken together, these data suggest this population of ventricular zone progenitor cells as the cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.
Assessing Uncertainty in the Rooting of the SARS-CoV-2 Phylogeny
Authors: Lenore Pipes, Hongru Wang, John P Huelsenbeck, Rasmus Nielsen
Journal: Molecular Biology and Evolution (2020)

Abstract The rooting of the SARS-CoV-2 phylogeny is important for understanding the origin and early spread of the virus. Previously published phylogenies have used different rootings that do not always provide consistent results. We investigate several different strategies for rooting the SARS-CoV-2 tree and provide measures of statistical uncertainty for all methods. We show that methods based on the molecular clock tend to place the root in the B clade, whereas methods based on outgroup rooting tend to place the root in the A clade. The results from the two approaches are statistically incompatible, possibly as a consequence of deviations from a molecular clock or excess back-mutations. We also show that none of the methods provide strong statistical support for the placement of the root in any particular edge of the tree. These results suggest that phylogenetic evidence alone is unlikely to identify the origin of the SARS-CoV-2 virus and we caution against strong inferences regarding the early spread of the virus based solely on such evidence.
Presence of Liver Steatosis Is Associated With Greater Diabetes Remission After Gastric Bypass Surgery
Authors: Roman Vangoitsenhoven, Rickesha L. Wilson, Deepa V. Cherla, Chao Tu, Sangeeta R. Kashyap, David E. Cummings, Philip R. Schauer, Ali Aminian
Journal: Diabetes Care (2020)

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and β-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery.A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin <6.5% [48 mmol/mol] off medications).Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients compared with remission in 44 out of 112 (39%) patients without steatosis (P = 0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96 [95% CI 1.04-3.72]; P = 0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission.This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are distinct variants of T2DM in which metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.
COVD-03. IMPACT OF COVID-19 ON THERAPY PROVISION FOR CHILDREN WITH CNS TUMOURS
Authors: Helen Hartley, Barry Pizer, Ram Kumar, Joanne Owen, Helen Paisley, Amillie White
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The COVID-19 pandemic has led to widespread change in the delivery of rehabilitation. The Teenage Cancer Trust reported that 69% of young people with cancer saw their physiotherapist less than usual during the pandemic raising concerns about physiotherapy input. METHODS Retrospective analysis of all children’s therapy input managed under the Neuro Oncology Rehabilitation Team (NORT) between 1st April and 30th July 2020. Descriptive analysis of change to physiotherapy provision during this time period by Tertiary and local community services. RESULTS 49 children were managed under the NORT Therapy Team during this timeframe. 9 children were newly diagnosed with CNS tumours. There was no impact on inpatient therapy provision, 3 had delayed local therapy provision on discharge requiring increased virtual input by the Tertiary centre. 40 children were outpatients managed under the NORT therapy team. 16 children were also receiving regular local physiotherapy input prior to the COVID-19 pandemic. 13 of these children subsequently had their local physiotherapy input suspended during this time period, 8 children were offered virtual input as an alternative by the Tertiary centre, 2 children received increased face to face appointments at the Tertiary centre. 14 of the 24 children managed solely under the Tertiary NORT Therapy Team changed to virtual therapy reviews. DISCUSSION There is a clear change in therapy provision as a result of the COVID-19 pandemic. Future research should consider the effectiveness of neurorehabilitation conducted virtually and the impact on physical function of reduced local therapy provision in children with CNS tumours.
RONC-15. OUTCOMES OF BRAIN AND SKULL-BASE TUMOURS IN ADOLESCENTS AND YOUNG ADULTS TREATED WITH PENCIL BEAM SCANNING PROTON THERAPY
Authors: Pei Shuen Lim, Sébastien Tran, Stephanie G C Kroeze, Alessia Pica, Jan Hrbacek, Barbara Bachtiary, Marc Walser, Anthony J Lomax, Damien C Weber
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The use of highly conformal proton therapy in adolescents and young adults (AYAs) for management of brain/skull-base tumours is becoming increasingly common. This study aims to assess the long-term clinical outcomes, prognostic factors and employment status of AYAs (15–39 years) treated with pencil-beam-scanning proton-therapy (PT). METHODS Between 1997–2018, 176 AYAs were treated with PT at the Paul Scherrer Institute. Median age was 30 years (range, 15–39) and the male/female ratio was 0.8. RESULTS After a median follow-up of 66 months (range, 12–236), 24 (13.6%) local failures and 1 (0.6%) distant failure were observed between 6 and 152 months after PT. The most common histologies treated were chordomas/chondrosarcomas (61.4%), followed by meningiomas (14.2%) and gliomas (15.3%). The 6-year local-control (LC), distant-progression-free survival and overall-survival (OS) rate was 83.2%, 97.4% and 90.2% respectively. On univariate analysis, age ≥24 years was a negative prognostic factor for LC. Recurrent disease, infratentorial tumours and low-grade-glioma histology were poor prognostic factors for both LC and OS. The 6-year ≥G3 PT-related late toxicity-free survival was 88.5%. The moderate-high grade late toxicity crude rates were 37.8% G2, 12.2% G3, 0.6% G4 and 0.6% G5. No secondary malignancies were observed. The unemployment rate was 7.3% at PT, rising to 25.3% at survivorship. High-grade(≥G3) toxicity rate in the unemployed vs employed group was 21% vs 8.5%. CONCLUSION PT is an effective treatment for AYAs with brain/skull-base tumours with good tumour control and acceptable long-term toxicity. Despite having satisfactory clinical outcomes, around 1 in 4 AYAs surviving brain/skull base tumours are unemployed.
GCT-56. ACUTE MYELOID LEUKEMIA FOLLOWING CHEMORADIOTHERAPY FOR INTRACRANIAL GERMINOMA: A CASE REPORT
Authors: Masato Nakaya, Yuya Koda, Kentaro Yamaguchi, Kazunari Yoshida, Hikaru Sasaki
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Therapy-related acute myeloid leukemia (t-AML) is known as possible complication of chemotherapy, especially topoisomerase Ⅱ inhibitor, alkylating agents, and platinum agents. Although there are many reports of therapy-related leukemia associated with gonadal germ cell tumor, few cases have been reported on central nervous system (CNS) germ cell tumor. CASE REPORT: A 35-year old gentleman presented with diplopia. CT and MR imaging showed enhancing nodules on his right hypothalamus and around fourth ventricle, and differential diagnoses included sarcoidosis and germinoma. Biopsy for fourth ventricle lesion was performed via transvermian approach, and histopathological diagnosis was germinoma. He was treated by 3 cycles of CARE chemotherapy (carboplatin and etoposide) followed by craniospinal irradiation (CSI, 24Gy). After completion of chemoradiotherapy, he was followed up every half year by MRI, and there had been no evidence of tumor recurrence. Two years after chemoradiotherapy, however, the patient presented with bleeding tendency, which led to the diagnosis of AML. Based on the history of chemoradiotherapy and the presence of t(16;21)(q24; q22), t-AML was diagnosed. Complete remission was successfully achieved by chemotherapy consisting of idarubicin and cytarabine. DISCUSSION t-AML was diagnosed after chemoradiotherapy in a patient with CNS germinoma probably due to the administration of topoisomerase II inhibitor, etoposide. The prognosis of t-AML is known to be poorer as compared with de novo AML. Therefore, intensive therapy such as allogeneic stem cell transplantation should be considered in younger patients. CONCLUSION A possibility of t-AML should be kept in mind following chemotherapy for CNS germ cell tumors.
LGG-31. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS: ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORT WITH 101 PAIRED TUMOR SAMPLES
Authors: Margot A Lazow, Austin Schafer, Mariko D DeWire-Schottmiller, Adam Lane, Daniel R Boué, Diana S Osorio, Jonathan L Finlay, Erin Wright, Sarah Rush, Lindsey M Hoffman, Jamie Reuss, Trent R Hummel, Ralph Salloum, Peter M de Blank, Natasha Pillay Smiley, Mary E Sutton, Anthony Asher, Charles B Stevenson, Rachid Drissi, Maryam Fouladi, Christine Fuller
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries. RESULTS 101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]). CONCLUSIONS Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
Abstract P195: Reproductive History and Subsequent Stroke in Middle-aged African American Women: The Pitt County Study
Authors: Debbie Barrington, Sherman James
Journal: Circulation (2016)

Introduction: Women with a history of pregnancy loss or delivery of low birth weight (&lt; 2500 grams) and/or preterm (&lt; 37 weeks gestation) (LBW/PTB) infants have an increased subsequent risk for cardiovascular morbidity and mortality. The association between nulliparity and cardiovascular disease has been mixed; some studies reported excess risk among nulliparous women compared to women who had one or two births, while others found decreased risk. Research among African American women is limited regarding whether reproductive history influences risk for cardiovascular disease (e.g., stroke). Hypothesis: We investigated whether a history of pregnancy loss, LBW/PTB delivery and nulliparity increased risk for stroke among middle-aged African American women. Methods: Multiple logistic regression was used to determine the association between LBW/PTB delivery and hypertension among 750 African American female participants (mean baseline age = 35.4 years) in the Pitt County Study, a 13 year (1988-2001) probability-based cohort study in eastern North Carolina. Reproductive history and physician-diagnosed stroke were assessed by self-report in 2001. Statistical analyses adjusted for known and suspected confounders, including adult socioeconomic position, medical conditions, health behaviors, and psychosocial risk factors. Results: By 2001, 3% of the women, ages 37 to 63 years, reported having had a stroke. 33% reported at least one pregnancy loss and 21% had a reproductive history of LBW/PTB delivery. After adjusting for confounders, women with a history of pregnancy loss had 2.9 times the odds of stroke compared to those not experiencing a pregnancy loss; covariate-adjusted AOR = 2.94; 95%CI: (1.97, 4.37). Women with a history of LBW/PTB had a 61% greater odds of stroke compared to those who had only normal weight and at-term births, AOR = 1.61; 95%CI: (1.07, 2.44). Women who never had a pregnancy or a live birth also had increased risk for stroke, AOR = 5.09; 95%CI: (3.03, 8.54) and AOR = 2.85; 95%CI: (1.75, 4.64), respectively. Conclusions: History of pregnancy loss, LBW/PTB delivery and nulliparity were independently associated with increased risk for stroke among middle-aged African American women. These findings highlight the potential of reproductive history to be a clinically useful predictive marker of later-life stroke for African American women.