tbuckley/cabot-search huggingface dataset:
Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials
Authors: Ignace Vergote, Corneel Coens, Matthew Nankivell, Gunnar B Kristensen, Mahesh K B Parmar, Tom Ehlen, Gordon C Jayson, Nick Johnson, Ann Marie Swart, René Verheijen, W Glenn McCluggage, Tim Perren, Pierluigi Benedetti Panici, Gemma Kenter, Antonio Casado, Cesar Mendiola, Gavin Stuart, Nick S Reed, Sean Kehoe, Claes Tropé G., Stephen Dobbs, Sharadah Essapen, P. Hoskins, John Green, E. Gilby, M. Van Baal, Jeremy Twigg, Maria E.L. Van Der Burg, Keith Godfrey, Angel J. Lacave, R. Angioli, Rahul Nath, Kirk Chin, Charles Redman, R. Lotocki, Adeola Olaitan, B. Mosgaard, G. Rustin, Thomas Ind, Mojca Persic, Martin Hogg, J. Van Der Velden, J. Ledermann, Peter Sykes Peter Sykes, Krishnawam Madhavan, P. Kannisto, Vicky Hird, A. Evans, R. Sandvei R., P. Gauthier, D.J. Cruickshank, P.B. Ottevanger, Sheila Pearson, Henry Kitchener, Marcia Hall, P. Bessette, S. Pecorelli, E. Gerdin, Tito Lopes, Andrew Fish, Clare Barlow., K. Van Eygen, A. Floquet, B. Tholander, N. Gul, Robert Gornall, David Luesley, Philip Kirwan, Paul Symonds, Richard Henry, David Poole, Ian McNeish, Mark Hocking, Al Sammaraie, P. Speiser, E. Leblanc, J.A. Green, C.F. De Oliveira, R. Grimshaw, P. Zola, David Parkin, David Luesley, Martin Lamb, Anne Hong, Alan Gillespie, Abdel Hamid, Ahmed Ahmed, M. Plante, B. De Valk, A. Nordin, Andrew Clamp, David Perez, Graham Dark Graham Dark, Michelle Ferguson, Carol MacGregor, Geraldine Skailes, Rachel Jones, Alan Gillespie, G. Cawdell, Simon Leeson, L. Elit, C. Dittrich, W. Gotlieb, David Poole, John Cullimore, Barbara Crosse, Paul Ridley, Anthony Head, Joaquin Nieto, Saif Awwad, Dirk Brinkmann, Damian Eustace, Andrew Hindley, D. Katsaros, C. Popadiuk, Tome Kristeller, C. Redman, S. Chan, C. Marth, Dennis Yiannakis, Kate Lankaster, Gareth Beynon, Anwar Suhail, Fernando Indrajit, Anne Hong, Mary Quigley, Olu Adeyemi, Mojca Persic, Fiona Lofts, Orla McNally, Amanda Tristam, Martin Lee, R. Counsell, N. Gleeson, A. Papadopoulos, T. Maggino, A. Honkoop, P. Ghatage, J.B. Vermorken, J. De Greve, K. Boman, E Petru, F. Amant
Journal: The Lancet Oncology (2018)
Pulmonary Vascular Disease in Premature Infants. Early Predictive Models of Late Respiratory Morbidity
Authors: Philip T. Levy, Roberta L. Keller
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Pulmonary vascular disease (PVD) and established pulmonary hypertension (PH) are common associations of bronchopulmonary dysplasia (BPD) (1).Although the reported incidence of PH is 14-44% in infants with recognized BPD (2, 3), recent evidence indicates that up to 20% of extremely low gestational age neonates without BPD will develop some degree of PVD during the neonatal period (2, 3).The mechanistic interrelation of both pathologies in more prematurely born infants is informed by the tandem development of the alveoli and microvasculature (4).BPD and PH share similar risk factors and overlapping symptoms, with some pointing to early PVD as an essential causative factor in the pathobiology of BPD (2) and others suggesting that PVD could be a distinct feature of prematurity, rather than a manifestation of BPD (5-7).Regardless of its association with BPD, it is more likely that PVD is just one of many factors leading to impaired respiratory function after preterm birth.It is not surprising that early identification of PVD, independent of the diagnosis BPD, may predict later pulmonary dysfunction, especially because preterm birth is associated with an increased risk of PH in childhood, adolescence, and adulthood (8).Improved echocardiographic assessment of PVD has led to increased recognition that disrupted pulmonary vascular growth in preterm infants may contribute to the pathogenesis of late respiratory disease (LRD) (2, 7).The diagnosis of PVD and the true prevalence of PH in preterm infants has been difficult to discern because of the paucity of reliable noninvasive measures to evaluate pulmonary hemodynamics (1) and an underappreciation for the practice of screening for PVD in extremely low gestational age neonates, with a focus primarily on infants with BPD (9).However, preterm infants without a diagnosis of BPD also remain at risk for respiratory morbidities and abnormal lung function into childhood, emphasizing the need to focus on alternate measures that explore differing mechanisms of disrupted pulmonary vascular and airway growth after prematurity (10).In this issue of the Journal, Mourani and colleagues (pp.1020-1027) leveraged a multicenter cohort of preterm infants to demonstrate that echocardiographic evidence of PVD at 7 days of age was associated with a higher incidence of LRD in early childhood (11).This builds on their previous report demonstrating that early
Immunotherapy and Hyperprogression: Unwanted Outcomes, Unclear Mechanism
Authors: David A. Knorr, Jeffrey V. Ravetch
Journal: Clinical Cancer Research (2018)

Hyperprogression (HP) is a recently defined clinical phenomenon in which patients treated with immunotherapy paradoxically exhibit rapid tumor growth. The mechanisms of hyperprogression remain ill-defined, although recent studies in this issue point to a possible role for Fc receptors in this process.See related article by Lo Russo et al., p. 989.
DRES-13. VEGF BLOCKADE ENHANCES T REGULATORY CELL FUNCTION BY DYSREGULATING GLUTAMATE TRANSPORT IN GBM
Authors: Yu Long, Aida Karachi, Adam Grippin, Haipeng Tao, Wang Zhang, Elias Sayour, Loic Deleyrolle, Duane Mitchell, Zhiguo Lin, Jianping Huang
Journal: Neuro-Oncology (2018)

In treating patients with cancer, inhibition of the VEGF pathway has been shown to prolong recurrence-free survival (RFS). However, anti-VEGF therapy has failed to improve overall survival in patients in randomized clinical trials. To help patients who are undergoing anti-angiogenic treatment, we attempted to tackle the obstacles of the treatment, using glioma animal models. In contrast to most literature reports focusing on the immediate post-treatment effect, we mainly investigated the animals that had failed the treatment. We found that tumor immunosuppression plays a critical role in treatment failure. Higher-doses of anti-VEGF treatment resulted in an over-representation of Tregs in tumor-infiltrating lymphocytes (TILs) and elevated expression of checkpoint molecules on TILs. The therapy mediates overexpression of xCT (a glutamate/cystine antiporter), which leads to excessive glutamate (a neurotoxin) production by glioma cells. The glutamate is responsible for the enhanced Treg suppressive function, which is signaling through upregulation of glutamate receptor 1(mGluR1) on the Tregs. Depleting CD25+ T cells prior to anti-VEGF therapy restores T cell production of IFN-g, enhancing the antitumor response. Collectively, VEGF blockade exacerbates Treg suppressive function by dysregulating glutamate antiport, and co-administration of Treg depletion with VEGF blockade can provide a synergetic antitumor effect for treating GBM.
Abstract 18216: Essential Role of Platelet Glycoprotein Ibα Dependent Thrombin-FXI Feedback Loop in Arterial Hypertension, Vascular Dysfunction and Inflammation
Authors: Sabine Kossmann, Sven Jäckel, Kerstin Jurk, Moritz Ehlken, Jérémy Lagrange, Tanja Schönfelder, Maike Knorr, Moritz Brandt, Susanne H Karbach, Andreas Daiber, Matthias Oelze, Ulrich Walter, Thomas Renné, Wolfram Ruf, Thomas Münzel, Philip Wenzel
Journal: Circulation (2015)

Interactions of platelets, leukocytes and the vessel wall play pivotal roles in activating coagulation and precipitating thrombosis. High levels of angiotensin II (ATII) cause arterial hypertension by a complex inflammatory pathway requiring leukocyte recruitment and reactive oxygen species production within the vessel wall coupled to vascular dysfunction. Here we report an upregulation of tissue factor, thrombin-dependent endothelial cell VCAM-1 expression and integrin α4- and platelet-dependent leukocyte adhesion to arterial conductance vessels by ATII in vivo (1mg/kg/d for 7d). ATII-induced vascular dysfunction and Ccl2, VCAM-1 and Ly6C mRNA expression were ameliorated by thrombin inhibition, platelet-depletion as well as in hIL-4R/Ibα mice missing the extracellular ligand binding domains of GPIbα. Blockade of TF during ATII administration also attenuated vascular dysfunction and reduced vascular oxidative stress. Platelet rich plasma (PRP) of ATII-treated mice showed an increased thrombin evoked endogenous thrombin potential (ETP), whereas PRP from mice with pharmacological inhibition of FXI production or of hIL-4R/Ibα mice failed to amplify ETP following chronic ATII exposure. These data show that a FXI-dependent thrombin generation feedback loop requires GPIbα on platelets and suggest that TF-initiated coagulation promotes additional thrombin formation on platelets to cause vascular inflammation. The therapeutic potential of blocking FXI synthesis via antisense oligonucleotides was generalized by experiments with 5/6 nephrectomized (5/6 Nx) rats. 5/6 Nx rats showed after 4 wk of surgery an endothelial dysfunction, increased blood pressure, vascular inflammation and oxidative stress, as well as a elevated ETP compared to sham whereas pharmacological inhibition of FXI synthesis attenuated these effects. Our results reveal a critical role of platelet GPIbα to promote localized thrombin amplification and supporting a FXI-thrombin feedback loop in ATII-induced vascular inflammation. By using a FXI targeted approach, we propose a novel therapeutic possibility to interrupt this heterotypic cellular coagulation-inflammatory circuit.
ATIM-32. PERSONALIZED NEOANTIGEN-TARGETING VACCINE GENERATES ROBUST SYSTEMIC AND INTRATUMORAL T CELL RESPONSES IN GLIOBLASTOMA (GBM) PATIENTS
Authors: David Reardon, Derin Keskin, Itay Tirosh, Annabelle Anandappa, Nathan Mathewson, Jing Sun, Sachet Shukla, Evisa Gjini, Shuqiang Li, Anita Giobbie-Hurder, Christine McCluskey, E Antonio Chiocca, Donna Neuberg, Kai Wucherpfennig, Mario Suva, Edward Fritsch, Scott Rodig, Keith Ligon, Patrick Wen, Kenneth Livak, Aviv Regev, Nir Hacohen, Catherine Wu, Patrick Ott
Journal: Neuro-Oncology (2018)

The impact of individualized neoepitope vaccination targeting neoantigens arising from tumor-specific mutations for GBM, a low mutation burden tumor with an immunologically cold tumor microenvironment, as well as that of concurrently administered dexamethasone (dex), are unknown. Individualized vaccination of up to 20 synthetic, long neoepitope peptides with high predicted HLA binding affinity admixed with poly-ICLC, were administered subcutaneously using a prime-boost schedule after RT to newly diagnosed, MGMT unmethylated, at least partially resected, GBM patients without progression after radiation (RT) in our phase 1b study. 9 of 10 screened patients had sufficient (10) identified neoepitope peptides. 8 patients without progression after RT received vaccine consisting of a median of 12 peptides (range, 7–20) beginning a median of 19.9 wks (range 17.1–24.7) after surgery. Adverse events were limited to infrequent grade 1/2 local reactions and fatigue. Median PFS and OS were 7.5 mths (90% CI: 6.2, 9.7) and 16.8 mths (90% CI: 9.6, 21.3). Evaluation of neoepitope-specific immune responses and tumor immune infiltrate analyses were performed on five patients with pre- and post-vaccination samples. Three patients on dex for post-RT edema during vaccine had no immune responses and no change in tumor infiltrating effector cells. In contrast 2 patients not on dex had robust, de novo immune responses against multiple predicted personal neoantigens including polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched for memory and activated phenotypes as well as increased numbers of tumor-infiltrating CD4+ and CD8+ T cells. T cell receptor analysis from one patient identified identical clonotypes isolated from post-vaccination tumor tissue and peripheral blood including two clonotypes specific for ARHGAP35, a neoantigen targeted by vaccination. Individualized, multi-neoepitope vaccines are feasible, safe and capable of generating systemic and intra-tumoral immune responses in GBM patients that appear to be abrogated by dex.
TMOD-36. PRECISE INVESTIGATION OF CANCER STEM CELLS IN A MOUSE GLIOBLASTOMA MODEL
Authors: Xuanhua Xie, Dan Laks, Daochun Sun, Asaf Poran, Ashley Laughney, German Belenguer, Joan Massague, Xiuping Zhou, Isabel Farinas, Olivier Elemento, Luis Parada
Journal: Neuro-Oncology (2018)

Cancer stem cells (CSCs) have been shown to play a critical role in glioblastoma (GBM) pathogenesis. However, a precise and thorough understanding of these cells is still lacking. Here we design a novel mouse model to label, purify, and study cancer stem cells in vivo. Firstly we generate and characterize a new transgene to label neural stem/progenitor cells in the subventricular zone (SVZ) with GFP, and drive expression of CreERT2 and human diphtheria toxin receptor in the same cells (CGD: nestin-CreERT2-H2BeGFP-hDTR). Following analysis with both bulk and single cell RNA sequencing of the SVZ tissue demonstrate its faithful expression in the stem/progenitor cell compartment. We then crossed the transgene with floxed alleles of the top three mutated tumor suppressor genes in GBM patients. This genetic configuration (CGD-M4: CGD; Nf1fl/+;p53fl/+; Ptenfl/+) efficiently promotes brain tumors initiated from wild-type neural stem/progenitor cells. Investigation of the tumors showed the CGD-GFP+ cells are quiescent in vivo, yet form more spheres in vitro than the GFP- cells. Further analysis with serial transplantation assays demonstrated the GFP+ cells are more competent to develop tumors and continuously maintain a quiescent population in the transplanted tumors. Diphtheria toxin treatment eliminates the CGD-GFP+ cells through the hDTR receptor in the transgene and greatly reduces the tumor bulk. The conventional chemotherapeutic drug, temozolomide, benefits only GFP- cell transplanted mice but not GFP+ cells. These cells are collected for RNA sequencing to identify genes associated with the CGD-GFP+ cells. Following CRISPR candidate screen reveals genes essential for the CGD-GFP+ cells. This study provides an unprecedented mouse model to study CSCs, which demonstrates their essential role in GBM initiation, recurrence, and drug resistance.
Abstract 15862: Discovering and Validating Disease Subtypes for Heart Failure using Unsupervised Machine Learning Methods
Authors: Ghazaleh Fatemifar, R T Lumbers, Daniel I Swerdlow, Spiros Denaxas
Journal: Circulation (2017)

Background: Heart failure (HF) is a complex syndrome that arises when abnormalities of cardiac structure or function lead to inadequate cardiac output. Clinical classifiers of HF subtype, such as b...
Scottish health secretary orders independent inquiry into bullying culture at NHS Highland
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The Scottish government has ordered an independent inquiry into alleged bullying at NHS Highland after doctors blew the whistle on what they described as a “culture of fear and intimidation” at the health board for the past decade.

Scottish health secretary Jeane Freeman said an independent external investigation would take place following the allegations that surfaced in September 2018 when a group of clinicians including Inverness GP Iain Kennedy wrote to The Herald newspaper1 warning that “bullying” and “intimidation” of whistleblowers was rife at NHS Highland and …
ATIM-24. INTERIM RESULTS OF A PHASE II MULTICENTER STUDY OF THE CONDITIONALLY REPLICATIVE ONCOLYTIC ADENOVIRUS DNX-2401 WITH PEMBROLIZUMAB (KEYTRUDA) FOR RECURRENT GLIOBLASTOMA; CAPTIVE STUDY (KEYNOTE-192)
Authors: Gelareh Zadeh, Frederick Lang, Mariza Daras, Timothy Cloughesy, Howard Colman, Shirley Ong, Rohan Ramakrishna, Michael Vogelbaum, Morris Groves, Farshad Nassiri, L Sue Frederick, Karen Gammon, Sheila Fulling, Kari Anne Rowland, Erin Mitchell, Brett Ewald, Frank Tufaro, Joanna Peterkin
Journal: Neuro-Oncology (2018)

BACKGROUND
DNX-2401 (tasadenoturev) is a replication-competent, tumor-selective, oncolytic adenovirus. A dose-escalating, Phase II study of a single intratumoral injection of DNX-2401 with pembrolizumab to determine optimal dose, safety and efficacy is ongoing and enrolling up to 48 patients with recurrent glioblastoma. Key inclusion criteria include patients with a single lesion at first or second recurrence for which resection is not possible or planned.
Role Models, Allies, and Diversity—Global Issues for Female Cardiology Trainees
Authors: Sonya N. Burgess, Elizabeth Shaw, Sarah J. Zaman
Journal: JAMA Cardiology (2018)

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NCMP-29. CEREBRAL EDEMA FROM RAPIDLY PROGRESSIVE METASTATIC CNS ATRT AND CHEMOTHERAPY INDUCED TUMOR LYSIS
Authors: Pournima Navalkele, Thomas Geller, Miguel Guzman, Philippe Mercier
Journal: Neuro-Oncology (2018)

Young pediatric patients with Central Nervous System (CNS) Atypical Teratoid Rhabdoid Tumor (ATRT) often present with metastasis and have extremely poor prognosis with the 2-year event-free survival of 11% or less. We report a case of metastatic CNS ATRT with literature review. A 22-month-old girl presented with subacute onset ataxia, vomiting, weight loss, headaches, motor and speech regression followed by acute onset seizures. MRI brain revealed a heterogeneously enhancing solid-cystic pineal mass causing hydrocephalus. Tumor biopsy confirmed ATRT, WHO grade IV, SMARCB1/ INI1 loss CSF cytology revealed M3 disease. Germline rhabdoid predisposition syndrome was ruled out. The primary tumor was resected. Immediate postoperative MRI was concerning for further metastasis of the tumor. Chemotherapy based on Medical University of Vienna (MUV) protocol was begun but within 36 hours of doxorubicin, the patient succumbed to acute respiratory failure, hyponatremia, seizures and cardiac arrhythmia. CT head showed diffuse cerebral edema and early transtentorial herniation. A limited autopsy showed brain tissue studded with tumor cells. DISCUSSION: In our patient, the primary tumor was resected based on the reports of improved event-free survival in the setting of reduced tumor burden. MUV chemotherapy was started given its best-reported outcomes so far with the 5-year event-free survival of 89% in patients with M1-M3 CNS ATRT. Our patient may have suffered from doxorubicin-induced acute arrhythmia, rare but a known complication. In the light of rapidly metastasizing tumor, the possibility of doxorubicin-induced tumor lysis leading to acute cerebral edema cannot be excluded. Thus a combination of rapidly progressive metastatic tumor and rare chemotherapy complications may have led to the fatal outcome.
DRES-09. IN VIVO FUNCTIONAL GENOMICS IDENTIFIES DRIVERS OF CHEMORESISTANCE IN MEDULLOBLASTOMA
Authors: Ana Guerreiro Stücklin, Livia Garzia, Patryk Skowron, Pasqualino De Antonellis, Carolina Nör, Xiaochong Wu, Michael Taylor
Journal: Neuro-Oncology (2018)

Brain tumours are the main cause of cancer-related death during childhood and medulloblastoma an aggressive embryonal tumour that arises in the posterior fossa – is the most common malignant tumour in this age group. Chemotherapy is a cornerstone of the postsurgical treatment, particularly in younger children in whom craniospinal irradiation is omitted due to the devastating side effects in the developing brain. Medulloblastoma often progresses or recurs after chemotherapy with a dismal prognosis. We used the Sleeping Beauty (SB) transposon-driven Ptch+/−/Math1-SB11/T2Onc sonic hedgehog (SHH) medulloblastoma murine model as a functional genomic tool to perform a genome-wide screen and identify genes and pathways that promote resistance to chemotherapy. After sub-total resection of the primary tumours, the mice were treated with repeated cycles of chemotherapy (cisplatin 5 mg/kg IP once on day 1 followed by cyclophosphamide 150 mg/kg IP daily from day 2 – 5) every 2 weeks for up to 3 cycles and monitored for tumour recurrence. The primary tumours (pre-treatment) and the tumours and metastasis that regrew after chemotherapy were deep sequenced to determine the transposon insertion sites. We identified recurrence-specific clonally selected insertions that promoted tumour growth despite therapy, including p53 (recurrently mutated in human tumours at relapse) and several other genes involved in DNA repair. Using cerebellar orthotopic models of p53-mutated SHH medulloblastoma, we observed a significant improvement in survival when the ATM inhibitor AZ32 was added to the chemotherapy backbone. This provides a rationale for developing therapeutic approaches targeting DNA repair in combination with conventional chemotherapy to prevent chemoresistance and medulloblastoma recurrence.
TMOD-27. HUMANIZED MICROBIOME MOUSE MODELS TO ENHANCE IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Braden McFarland, Kory Dees, Rebecca Little, William Van, Der Pol, Etty Benveniste, Casey Morrow, L Burt Nabors
Journal: Neuro-Oncology (2018)

Cancer immunotherapies, including the checkpoint inhibitors, demonstrate remarkable success in patients with melanoma, but have not shown a similar efficacy in patients with glioblastoma (GBM). Recently, the composition of the gut microbiome has been shown to promote resistance to immune checkpoint inhibitors in melanoma and other cancers suggesting a favorable composition of the gut microbiome is needed to produce an optimal response to checkpoint inhibitors and subsequent anti-tumor immune responses. We propose that the gut microbiome of GBM patients promotes resistance to immunotherapies. To investigate this, we have collected and analyzed the gut microbiome from GBM patients (short-term and long-term survivors) and healthy controls by microbial 16S and metagenomic sequencing. These results will determine microbiome differences between GBM patients and controls, as well as differences within each patient as the disease progressed. Furthermore, all GBM pre-clinical studies to date have been performed in mouse models using mouse gut microbiota. We have previously found that human fecal samples can be transplanted into gnotobiotic (germ-free) mice to successfully colonize the mouse GI tract with human microbes. Herein, we have established humanized microbiome mice utilizing human GBM donor fecal samples previously obtained and analyzed. This model is critical because it allows us to study the relationship between the human microbiome among different GBM patients, and the responsiveness to therapies using the syngeneic GL261 intracranial model. We are currently using these humanized microbiome mouse models to analyze pre-clinical testing of anti-PD-1 in GBM, and endpoints to assess efficacy will include survival times, tumor growth, and examining the periphery and tumor environment for phenotype(s) of infiltrating immune cells. These studies will enhance our understanding of the mechanism of GBM patient’s microbiome in the resistance to immunotherapies and lead to new therapeutic strategies to alter the microbiome composition to enhance immunotherapy for GBM.