tbuckley/cabot-search huggingface dataset:
DIPG-44. MOLECULAR AND CHROMOSOMAL CHARACTERIZATION OF A UNIQUE SERIES OF DIFFUSE MIDLINE GLIOMAS IN CHILDREN AND YOUNG ADULTS
Authors: Charlotte Dufour, Romain Vasseur, Romain Perbet, Pierre Leblond, Matthieu Vinchon, Nicolas Reyns, Gustavo Touzet, Claude-Alain Maurage, Escande Fabienne, Renaud Florence
Journal: Neuro-Oncology (2018)

Diffuse midline gliomas and especially diffuse intrinsic pontine gliomas are aggressive tumors with poor prognosis and no effective treatment. The identification of histone H3.3 mutations has been a large advance by defining groups with different prognoses. However, molecular and chromosomal landscape of these tumors needs to be further explored to identify key events of oncogenesis. We provide here a unique series of 55 diffuse midline gliomas with pre-treatment samples for each patient (frozen and/or FFPE samples). We performed CGH-array and next-generation sequencing, using a wide panel of genes involved in chromatin remodeling. Different immunohistochemical markers were tested. Survival and clinical data were also available. With molecular results, we reclassified every tumor according to WHO classification 2016. Within histone H3 mutant subgroup (74% of all the samples), 80% harbored a K27M H3.3 mutation and 20% a K27M H3.1 mutation. We identified additional somatic mutations in TP53 (55%), ACVR1 (20%) and PIK3CA (13%) and rarer mutations in BRAF, EGFR, PDGFRA, PPM1D, MED12, KIT, MET, ARID1B, CHEK2, FGFR1 and PIK3R1. Recurrent chromosomal alterations such as gain of 1q and 2, loss of 5q, 10q, 13, 14, 16q and 17p and amplification of PDGFRA were also identified. These data were correlated together and associated with survival in order to define different molecular subgroups. To conclude, these results allowed us to define more precisely the genomic landscape of these tumors and to identify recurrent molecular and chromosomal alterations, correlated to survival and relevant to be therapeutic targets.
Big Topics for <i>Diabetes Care</i> in 2018: Clinical Guidelines, Costs of Diabetes, and Information Technology
Authors: Matthew C. Riddle, George Bakris, Andrew J.M. Boulton, Lawrence Blonde, David D’Alessio, Eddie L. Greene, Mary de Groot, Korey Hood, Frank B. Hu, Steven E. Kahn, Sanjay Kaul, Derek LeRoith, Robert G. Moses, Stephen S. Rich, Julio Rosenstock, William V. Tamborlane, Judith Wylie-Rosett, Lyn Reynolds
Journal: Diabetes Care (2018)

Diabetes Care ’s editorial committee customarily presents a midyear report of activities and progress. At the midpoint of 2018 we can describe, in addition to a satisfying array of original scientific reports, important feature articles of current interest and a significant new initiative.

In the first half of this year, the journal published several feature articles related to our core responsibility as a journal representing the American Diabetes Association (ADA). An update to the ADA’s “Standards of Medical Care in Diabetes” (Standards of Care [SOC]) appeared as a supplement to the January issue (1). The SOC is prepared by the Professional Practice Committee of the ADA and contains guidance on various aspects of care of those with or at risk for diabetes, together with summaries of published data supporting these statements. Because scientific information is accumulating faster than ever before, the ADA announced a new policy in the March 2018 issue (2). The yearly January supplement to Diabetes Care will continue as before, but the SOC will now be updated more frequently. The ADA now uses a web annotation tool to update and revise the online version throughout the year, whenever new evidence or regulatory changes merit immediate incorporation. Already in 2018 new information has been added regarding two medications recently approved by the U.S. Food and Drug Administration (semaglutide and ertugliflozin) and an update on the definitions of hypoglycemia. Changes of this kind will be communicated by the ADA through its print, online, and social media channels.

Additional consensus statements and commentaries on new or controversial topics will continue to appear in Diabetes Care . Unlike the SOC, they are not official guidance statements but generally reflect the ADA’s thinking. For example, a joint statement by representatives of the ADA and the European Association for the Study of Diabetes …
DEV-10. OUTCOME OF INTRACRANIAL GERM CELL TUMOURS: 20-YEAR EXPERIENCE OF A SINGLE TERTIARY CENTER FROM A MIDDLE-INCOME COUNTRY
Authors: Revathi Rajagopal, Sheng Hoay Leong, Dharmendra Ganesan, Anita Zarina Bustam Mainudin, Kein Seong Mun, Jen Chun Foo, Vida Jawin, Tsiao Yi Yap, Hany Ariffin
Journal: Neuro-Oncology (2018)

To evaluate the survival outcomes in patients diagnosed with intracranial germ cell tumours (iGCT). Retrospective review of all patients with iGCT treated in a single center from July 1996 to Jun 2017. Three treatment regimens were used: MSKCC, SIOP CNS GCT 96 and SIOP CNS GCT II. Thirty patients were identified with a median follow-up of 4.04 years (range 0.17–19.10). The mean age was 10.23 years. Male: female ratio was 5:1. Visual impairment (50%), endocrinopathy (30%) and precocious puberty (20%) were the commonest presenting symptoms. Duration of symptoms prior to presentation ranged from 1 to 108 weeks. Pure germinomas (n=15) and non-germinomatous germ cell tumours (NGGCT) (n=15) were equally distributed. Tumour location was pineal in 15 (50.0%), suprasellar in 8 (26.7%), hypothalamic in 2 (6.7%) and other sites (basal ganglia, thalamus, frontal lobe) in 5 (16.7%) patients. Eight patients (26.7%) had metastatic disease at diagnosis. Four cases underwent surgical debulking, 14 were biopsied and 7 had complete resection. Fifteen patients received chemo-radiotherapy, 7 had chemotherapy only and 8 underwent radiotherapy only. Elevated levels of serum alpha-fetoprotein and beta-human chorionic gonadotropin normalised after 2 courses of chemotherapy in all NGGCT cases. The 5-year event-free survival (EFS) and overall survival (OS) were 61.3 ± 14.1% and 78.3 ± 11.1% for pure germinoma, respectively. For NGGCT, the 5-year EFS and OS were 36.0 ± 13.3% and 41.3 ± 13.7%. Eleven recurrences occurred within a median duration of 11 months following diagnosis and 8 of them died within 10 months. Compared to pure germinoma, NGGCTs have poor prognosis.
Clinical Relevance and Suppressive Capacity of Human Myeloid-Derived Suppressor Cell Subsets
Authors: Stephan Lang, Kirsten Bruderek, Cordelia Kaspar, Benedikt Höing, Oliver Kanaan, Nina Dominas, Timon Hussain, Freya Droege, Christian Eyth, Boris Hadaschik, Sven Brandau
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease, three major MDSC subpopulations can be defined as monocytic (M-MDSC), granulocytic [polymorphonuclear-MDSC (PMN-MDSC)], and early stage (e-MDSC), which lacks myeloid lineage markers of the former two subsets. The purpose of this study was to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer. Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T-cell–suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of patients with HNC. Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T-cell–suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC. Conclusions: A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance. Clin Cancer Res; 24(19); 4834–44. ©2018 AACR.
MEDU-20. HDAC AND NFκB ANTAGONISTS SYNERGISTICALLY INHIBIT GROWTH OF MYC-DRIVEN MEDULLOBLASTOMA
Authors: Viktoria Marquardt, Johanna Theruvath, David Pauck, Daniel Picard, Nan Qin, Lena Blümel, Finn K Hansen, Jörg Felsberg, Samuel Cheshier, Guido Reifenberger, Arndt Borkhardt, Thomas Kurz, Siddhartha Mitra, Marc Remke
Journal: Neuro-Oncology (2019)

Medulloblastoma is the most common malignant brain tumor in childhood and comprises four distinct molecular subgroups with further layers of intertumoral heterogeneity. Amplification of the oncogene MYC drives tumorigenesis and constitutes a hallmark feature underlying Group 3 biology. Metastatic dissemination is frequently observed at diagnosis or recurrence and confers a dismal prognosis. Employing our in-house drug screening pipeline, we evaluated a library of epigenetic inhibitors (n=78) in various brain tumor cell lines including glioblastoma (n=14), medulloblastoma (n=14) and atypical teratoid/rhabdoid tumors (n=11). By this cross-entity approach we revealed preferential activity of histone deacetylase inhibitors (HDACi) in MYC-driven medulloblastoma. In a secondary HDACi (n=20) screen, we identified the clinically established, class I selective HDACi CI-994 as the compound with the most preferential antitumoral effect in MYC-driven medulloblastoma. We confirmed that the inhibitor response was in part MYC-dependent as our lentiviral based MYC-overexpression model showed higher sensitivity towards CI-994 treatment as compared to the isogenic control with low endogenous MYC expression. Moreover, we observed significantly reduced MYC mRNA and protein expression levels, decreased cell viability and induction of apoptosis following CI-994 treatment. Notably, CI-994 showed significant antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven medulloblastoma. Additionally, a screen for synergistic drug interaction with a clinical inhibitor library of approved chemotherapeutics and clinical phase III/IV agents (n=199) revealed a favorable interaction of the NFκB inhibitor bardoxolone methyl with CI-994. In line with our synergy data, RNA sequencing profiling confirmed the functional relevance of NFκB pathway induction upon CI-994 treatment. In all, our pharmacogenomic approach suggests that the combination with NFκB inhibitors has the potential to increase the anitumoral activity of HDACi and the pronounced activity in MYC amplified medulloblastoma, where therapeutic options are limited, is particular noteworthy and warrants further clinical investigation.
Challenges in Passive Immunization Strategies to Treat Parkinson Disease
Authors: Fredric P. Manfredsson, Malú G. Tansey, Todd E. Golde
Journal: JAMA Neurology (2018)

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Abstract 12752: Left Ventricular Dysfunction After Aortic Valve Replacement in Mixed Aortic Valve Disease: Are We Operating Too Late?
Authors: Alexander Egbe, Carole Warnes
Journal: Circulation (2016)

Introduction: The fate of the left ventricle (LV) after aortic valve replacement (AVR) in mixed aortic valve disease (MAVD) is unknown. Hypothesis/objectives: To determine prevalence and predictors of early and late left ventricular dysfunction (LVD) defined as EF &lt;50% at 1 and 5 years post-AVR. Methods: Patients with moderate-severe MAVD, ejection fraction ≥50%, no documented coronary artery disease, and a minimum of 2-year follow-up after AVR were identified. Moderate-severe MAVD was defined as a combination of ≥moderate aortic stenosis and ≥moderate aortic regurgitation. EF was assessed at 1 and 5 years post-AVR. Results: Patients with MAVD (n=179); age 63±8 years, males 134 (75%); underwent AVR at Mayo Clinic from 1994-2010. Early LVD occurred in 38(21%). Predictors of early LVD were LV mass index/LV end-diastolic dimension (LVMI/LVEDD) &gt;3.1 (hazard ratio [HR] 1.83, confidence interval [CI] 1.59-1.98); relative wall thickness (RWT) &gt;0.46 (HR 2.16, CI 1.21-4.99); and older age per decade (HR 1.62, CI 1.23-3.02). Assessment of LV function was performed in 124 patients at 5 years post-AVR, and late LVD was present in 29 (23%). Predictors of late LVD were LVMI/LVEDD &gt;3.1 (HR 1.77, CI 1.24-2.01) and RWT &gt;0.46 (HR 1.65, CI 1.29-2.24). All-cause mortality occurred in 21 (12%), and was more common in patients with higher preoperative LV mass, P&lt;0.05. Patients with postoperative LVD showed less regression of LV mass after AVR even after controlling for blood pressure, P&lt;0.001. Conclusions: LVD can occur after AVR even in the setting of normal preoperative LV function and absence of coronary artery disease. Preoperative LV mass was predictive of LVD, and should be taken into consideration when determining the timing of AVR. LEGENDS Comparison of the occurrence of LVD and all-cause mortality by preoperative left ventricular mass.% of patients with early LVD (blue), late LVD (red) and death (green) between the patients with LVMI/LVEDD ratio ≤3.1 vs &gt;3.1 (A), and ≤0.46 vs &gt;0.46 (B)
Multicenter phase Ib/II study of biweekly TAS-102 with bevacizumab combination for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study) - Trial in progress
Authors: T. Kato, H. Satake, K. Oba, Y. Kagawa, H. Yasui, M. Nakamura, T. Watanabe, T. Matsumoto, K. Hirata, K. Muro, Y. Komatsu, T. Yoshino, K. Yamazaki, H. Mishima, M. Kotaka, A. Tsuji, Y. Kakeji, E. Oki, N. Nagata, J. Sakamoto
Journal: Annals of Oncology (2018)

Introduction: TAS-102 (trifluridine/tipiracil) plus bevacizumab combination therapy has shown a promising activity with manageable safety profile in patients with heavily pretreated metastatic colorectal cancer. In a previously reported study assessed this combination therapy, TAS-102 has been given orally every 4 weeks (35mg/m2 given orally twice daily on day 1-5 and 8-12 in a 28-day cycle) and bevacizumab has been administered every 2 weeks (5mg/kg, administered by intravenous infusion for 30 min every 2 weeks) (C-TASK FORCE, Kuboki et al., Lancet Oncol 2017). The aim of this phase Ib/II study was to assess the activity and safety of biweekly TAS-102 with bevacizumab combination for patients with metastatic colorectal cancer who were refractory or intolerant to standard therapies. Methods: We conducted an investigator-initiated, open-label, single-arm, multicenter, phase Ib/II study of biweekly TAS-102 with bevacizumab combination. Inclusion criteria were ≥ 20 years; histologically confirmed unresectable metastatic colorectal adenocarcinoma; refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type RAS); Eastern Cooperative Oncology Group performance status 0 or 1; evaluable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Phase Ib part is designed to evaluate the incidence of dose limiting toxicities during the first cycle and to determine the recommended phase II dose (RP2D) in the dose de-escalation design (3 + 3) with TAS-102 (35mg/m2 given orally twice daily on day 1-5 and bi-weekly bevacizumab. In phase II part, patients received the RP2D in phase Ib part were included in efficacy and safety populations. The primary endpoint in phase II part was an investigator assessed progression-free survival rate at 16 weeks (16w-PFS). Major secondary endpoints included PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. We set the threshold 16w-PFS rate at 15% and the expected 16w-PFS rate at 38.7% on the basis of the results of C-TASK FORCE study. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 patients were required using an exact single-stage binomial design. With 10% of drop-out, we set 45 patients as a target sample size in this study.
RADI-22. DIAGNOSTIC ACCURACY OF NEUROIMAGING IN PEDIATRIC OPTIC PATHWAY/SELLAR/SUPRASELLAR TUMORS
Authors: Gregory Norris, Jacquelyn Garcia, Todd Hankinson, Michael Handler, Nicholas Foreman, David Mirsky, Nicholas Stence, Kathleen Dorris, Adam Green
Journal: Neuro-Oncology (2018)

Various tumors arising in the optic pathway/sellar/suprasellar region in children necessitate different therapeutic approaches. Although surgical biopsy is the gold standard for diagnosis, not all tumors in this area require surgical intervention, and surgery here is associated with a high risk of morbidity. If an accurate diagnosis can be made by neuroimaging alone, surgery may be avoided completely for some tumors. We evaluated the ability to differentiate tumor type by neuroimaging in the optic pathway/sellar/suprasellar region. 53 patients were identified at our institution from 2007-2017 who were diagnosed with optic pathway glioma (OPG), craniopharyngioma, germ cell tumor (GCT), or Langerhans cell histiocytosis (LCH) of the optic pathway/sellar/suprasellar region by biopsy. Patients with neurofibromatosis type 1 were excluded, as their tumors in this area are presumed to be OPG. We compared the predicted diagnosis from the neuroimaging (MRI/CT) read(s) to the pathologic diagnosis. 38 of 53 tumors were correctly diagnosed by neuroimaging, for a prediction accuracy of 72%. The prediction accuracies were for 87% (20/23) for craniopharyngioma, 79% (11/14) for OPG, 64% (7/11) for GCT, and 0% (0/5) for LCH. CT to look for calcifications was helpful in diagnosing craniopharyngioma. Presence of a posterior pituitary bright spot excluded GCT and LCH. Diagnosis of pediatric tumors in the optic pathway/sellar/suprasellar region by imaging alone should be considered when biopsy is considered high-risk. CT is indicated if craniopharyngioma is in the differential. Biopsy is needed to differentiate GCT from LCH when the posterior pituitary bright spot is absent.
Time to change the primary outcome of lupus trials
Authors: Frederic A Houssiau
Journal: Annals of the Rheumatic Diseases (2018)

In ARD , a group of outstanding investigators report the results of another lupus trial missing its primary endpoint, namely the Phase III CHABLIS-SC study aimed at testing the efficacy of blisibimod,1 composed of a tetrameric BAFF/BLyS domain fused to a human IgG1 Fc region. Interestingly, blisibimod displayed unequivocal effects on biomarkers, such as reduction of circulating B cells, serum immunoglobulin titres or anti-DNA antibodies and increase in complement levels, changes in line with its mode of action and known to correlate with improved clinical outcome. Moreover, although the trial was not intended to demonstrate renal efficacy, an interesting reduction of proteinuria was noticed. This paradox raises the possibility that the failure of CHABLIS-SC stems more from the choice of the primary efficacy endpoint than from the drug itself, the more so as BAFF/BLyS was proven to be an appropriate target in four previous clinical trials, namely the belimumab BLISS-52,2 BLISS-763 and BLISS-SC4 and the tabalumab ILLUMINATE-25 studies, all showing the same effects on biomarkers and a significant, although modest, clinical efficacy. Of note, while the primary outcome (SRI-6) failed in the CHABLIS-SC trial, a trend (p=0.056) in favour of blisibimod was demonstrated when a modified endpoint was used, which takes into account, besides SRI-6, achievement of a steroid dose reduction between weeks 40 and 52 compared with day 1.

The main goal of this editorial is to propose a ‘U loop’ in …
EPID-10. EVOLVING SURVIVAL TRENDS IN INFANTS WITH BRAIN TUMORS: A LONGITUDINAL POPULATION BASED STUDY
Authors: Claire Faltermeier, Timothy Chai, Lior Elkaim, George Ibrahim, Anthony Wang, Alexander Weil, Anne Bendel, Aria Fallah, Albert Tu
Journal: Neuro-Oncology (2018)

Management of brain tumors in infants has evolved over time, however, historical prognostication does not reflect current treatment and survival trends. This study used a population-based approach to differentiate contemporary from historical survival curves to provide up-to-date prognostication. Observational cohort analysis was performed using the Surveillance, Epidemiology and End Results (SEER) database. Infants with brain tumors from 1973-2013 were divided by tumor subtype (diffuse astrocytic/oligodendroglioma, choroid plexus, embryonal, ependymal, medulloblastoma and pilocytic astrocytoma). The 1, 5 and 10 year survival was stratified by decade. Trends in management and outcomes were analyzed. Between 1973 and 2013, 2996 patients <24 months were identified. All tumor types except embryonal and choroid plexus demonstrated improved survival with time. Infants with embryonal tumors showed a decline in survival between the 1970s and 1990s (p= 0.008). Infants with choroid plexus tumors had no change in survival over time. The greatest improvement in survival was seen for infants with ependymal tumors, with 5-year survival improving from 28% (95% CI 15-42%) in the 1980s to 77% (95% CI 69-83%) the 2000s. Radiation therapy declined from 1970 to 2000 for all tumors, however, radiation treatment for embryonal and ependymal subtypes has increased since 2000. Despite improved overall survival from the 1970s onwards, certain subtypes of infant brain tumors have not matched this trend. The use of radiation has declined, although in specific tumor types, its use has been associated with better survival. Prognostication in infants with brain tumors should be updated to reflect current treatment trends.