tbuckley/cabot-search huggingface dataset:
GENT-19. INSULATOR DYSFUNCTION AS AN ONCOGENIC DRIVER IN GLIOMA
Authors: William Flavahan, Yotam Drier, Daniel Tarjan, Brian Liau, Shawn Gillespie, Andrew Venteicher, Anat Stemmer-Rachamimov, Mario Suva, Bradley Bernstein
Journal: Neuro-Oncology (2016)

Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5’-methylcytosine hydroxylases. TET enzymes catalyze a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. We show that IDH mutant gliomas exhibit hyper-methylation at CTCF binding sites, compromising binding of this methylation-sensitive insulator protein. CTCF is a critical factor for the control of the topological structure of the genome and the control of activating elements in the genome known as enhancers. Reduced CTCF ­binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive housekeeping enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wildtype gliomaspheres up-regulates PDGFRA and increases proliferation. We also demonstrate that directed epigenetic editing can affect CTCF binding and insulator function in glioma. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
PDTB-26. TARGETED ONCOGENE SEQUENCING IN DESMOPLASTIC GANGLIOGLIOMA/ASTROCYTOMA
Authors: Anthony Wang, I. Josh Abecassis, Bonnie Cole, Sarah Leary, Christina Lockwood, James Olson, Chibawanye Ene, J. Russ Geyer, Richard Ellenbogen, Eric Holland, Jeffrey Ojemann
Journal: Neuro-Oncology (2016)

Little in the way of genetic and molecular characterization of desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) has been reported over the past 25 years. While scattered non-clonal aberrations have been reported, no specific locus has consistently appeared. We aimed to more precisely understand the genetic underpinnings of DIG and DIA, their natural histories, and their relationships to other low-grade glial-neuronal CNS tumors. Targeted next-generation DNA sequencing was performed on specimens obtained from 15 separate surgical operations from 10 patients diagnosed with DIG/DIA by histopathology. Among the 10 native tumor samples, we found no genetic aberrations in five (50%). Within the other five native tumors, we discovered four (40%) non-synonymous single nucleotide variant substitutions at the 600 position on the BRAF gene (with an FGFR3 mutation in one of these patients), and one ALK-EML4 fusion (with a CREBBP mutation in this patient). Two of these BRAF mutations were of the canonical V600E valine-to-glutamic acid variety, found in 2 of the 3 DIAs. The other two were rare V600D valine-to-aspartic acid mutations, which account for less than 1% of all V600 BRAF mutations. These V600D BRAF mutations occurred in DIG patients, both diagnosed at less than one year of age—both went on to undergo gross total resection, and neither has experienced recurrence. Three patients experienced malignant transformation of their WHO grade 1 DIG/DIA. One such patient’s tumor gained a TP53 mutation, and subsequently transformed to glioblastoma. Another patient’s tumor gained a frameshift deletion involving ATRX (as well as a BCORL1 mutation) upon malignant transformation. The patient with ALK-EML4 fusion gene in the native tumor experienced malignant transformation as well, with no new oncogenic mutation found in the malignant tumor. Through targeted DNA sequencing, we found that 50% of DIG/DIA harbored a mutation potentially treatable using targeted molecular therapies.
Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial
Authors: Jorien Werumeus Buning, Daan J. Touw, Pauline Brummelman, Robin P.F. Dullaart, Gerrit van den Berg, Melanie M. van der Klauw, Jasper Kamp, Bruce H.R. Wolffenbuttel, André P. van Beek
Journal: Metabolism (2017)
Phase I dose of oral quisinostat, in combination with gemcitabine (G) and cisplatin (Cis) or paclitaxel (P) and carboplatin (Carbo) in patients (pts) with non-small cell lung cancer or ovarian cancer (OC)
Authors: M. Fedyanin, S. Tjulandin, S. Cheporov, V. Vladimirov, V. Moiseenko, S. Orlov, G. Manikhas, A. Cakana, V. Azarova, O. Karavaeva, N. Vostokova, S. Baranovskiy
Journal: Annals of Oncology (2016)
A multi-institutional dose-finding and efficacy confirmation trial of superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for patients with locally advanced maxillary sinus cancer (JCOG1212, RADPLAT-MSC): Results of dose-finding phase
Authors: T. Sakashita, A. Homma, R. Onimaru, K. Matsuura, H. Shinomiya, R. Hayashi, K. Shiga, H. Tachibana, K. Nakamura, J. Mizusawa, M. Fujii
Journal: Annals of Oncology (2016)
NIMG-64. NOVEL METHODS FOR GENOTYPE-PHENOTYPE CORRELATION IN SCHWANNOMATOSIS
Authors: Justin Jordan, Miriam Smith, Vanessa Merker, Wenli Cai, Gordon Harris, Miriam Bredella, Serkan Erdin, James Gusella, Scott Plotkin
Journal: Neuro-Oncology (2016)

Schwannomatosis has been linked to mutations in both the SMARCB1 and LZTR1 genes, though the majority of cases have no known genetic association. We used a novel gene capturing technique with next-generation sequencing (NGS) and whole body MRI (WBMRI) to search for genotype-phenotype correlation within a cohort of patients with schwannomatosis. WBMRI and three-dimensional computerized volumetry were used to determine the number and volume of internal nerve sheath tumors. Custom biotinylated cRNA baits were used to capture the entire gene regions of SMARCB1, LZTR1, and NF2 genes from patient blood samples, and next generation sequencing was performed. Genotype-phenotype correlation was evaluated using Wilcoxon and Spearman testing in SAS 9.4. Thirty-three patients with clinically diagnosed schwannomatosis were included in the study. Gene capture was excellent (approximately 72% efficient), and NGS median coverage was 938-fold. A predicted disease-causing mutation was identified in LZTR1 in 5 patients (median age 42, 0 familial), SMARCB1 mutation in 9 patients (median age 43, 3 familial), and neither gene in 17 patients (median age 42, 2 familial). No pathogenic NF2 mutations were identified. Average tumor number was 2.2 in the LZTR1 group (median total body tumor volume 20.3cc) and 5.8 in the SMARCB1 group (median volume 130.6cc), (p=0.4569 for tumor number and p=0.2775 for volume). Median pain score was 3.6 in the LZTR1 group and 1.6 in the SMARCB1 group (p=0.0392). In conclusion, we used a highly efficient method for deep, targeted germline sequencing in patients with schwannomatosis. While numbers were small, pain was significantly higher in LZTR1-mutant patients than SMARCB1-mutant patients, which should be considered for development of disease models and targeted therapies. The anatomic limitations of WBMRI will be addressed in future studies by the addition of dedicated neuraxis imaging. Larger studies of schwannomatosis patients are needed to refine these preliminary observations.
NHS staff are key to meeting productivity challenges, says former health secretary
Authors: Abi Rimmer
Journal: BMJ (2017)

Productivity in the NHS will not improve unless staff are given support to change the way they work, former health secretary Stephen Dorrell has said.

Speaking at a Westminster health conference in London on 9 February, Dorrell said that people were key to improving productivity in the NHS because “health and care services are a people business.”

Dorrell, who is now the chairman of the NHS Confederation, said that productivity could be delivered in other sectors through the use of technology, but that this wasn’t possible in the same way in the NHS.

“It is about how we enable people to …
PALL-05. PEDIATRIC BRAINSTEM GLIOMA: IMPACT OF SURGERY AND RADIOTHERAPY ON SURVIVAL OUTCOMES
Authors: Kailin Yang, Leo Kim, Violette Recinos, John Suh, Samuel Chao, Erin Murphy
Journal: Neuro-Oncology (2016)

Pediatric brainstem glioma (BSG) comprises ~10% of all pediatric brain tumors, and is associated with poor prognosis. Recent genomic studies have revealed the molecular mechanism of its aggressive behavior. We analyzed 1961 patients of age 18 or younger with the diagnosis of BSG identified from the Surveillance, Epidemiology, and End Results registry (1973-2012). Log-rank test and multivariate Cox proportional hazard modeling were used to assess the impact of treatment on overall survival (OS). Median age was 7.7 years. Radiotherapy (RT) was delivered to 60.3% of patients. Given the critical location of these tumors, surgery was only performed in a small subset of patients with 9.7% receiving sub-total resection (STR) and 7.5% receiving gross total resection (GTR). 20.3%, 10.1%, 5.3%, and 7.6% received a diagnosis of WHO grade I, II, III, and IV glioma respectively, with the rest of unknown grade status. OS at 10 years was 41.1%, with a median follow-up time of 8.9 years. WHO tumor grade was an independent predictor of OS, with 90.7%, 60.8%, 25.0%, and 12.7% for grade I, II, III, and IV at 10 years respectively. There was no significant OS benefit with RT for grade III (23.5% with RT vs. 30.3% without RT, p=0.46) and IV (12.6% with RT vs. 13.6% without RT, p=0.92) BSG, but worse OS was observed with RT for grade I and II. Surgery was associated with improved OS for both STR (HR 0.387, 95% CI 0.285-0.514, p<0.01) and GTR (HR 0.321, 95% CI 0.205-0.478, p<0.01) as assessed by multivariate analysis. The outcome of high-grade pediatric BSG remains poor regardless the delivery of radiation therapy. Surgery in the format of STR or GTR provides survival benefit to a selected patient population. Out results further demonstrate an urgent need for effective therapeutics to treat this aggressive type of pediatric brain tumor.
Evaluation of the Toxicity of Total Body Irradation As a Separate Treatment in Preparation for Hematopoietic Cell Transplantation
Authors: Sebastian Giebel, Tomasz Kruzel, Maria Sadus-Wojciechowska, Jacek Najda, Tomasz Czerw, Leszek Miszczyk, Jerzy Holowiecki
Journal: Blood (2011)
A New Subtype of T-Cell Acute Leukemia in Very Young Children Is Defined by a Translocation Targeting the C-MYB Oncogene, and a Specific Gene Expression Signature.
Authors: Emmanuelle Clappier, Wendy Cuccuini, Anna Kalota, Antoine Crinquette, Jean-Michel Cayuela, Willem A. Dik, Anton W. Langerak, Bertrand Montpellier, Bertrand Nadel, Pierre Walrafen, Alain Aurias, Thierry Leblanc, Herve Dombret, Alan M. Gewirtz, Andre Baruchel, Francois Sigaux, Jean Soulier
Journal: Blood (2007)
NTOX-04. THE PERILS OF INTRATHECAL CHEMOTHERAPY: A TALE OF TWO PATIENTS
Authors: Ahmad Daher, Sudhakar Tummala
Journal: Neuro-Oncology (2016)

The use of intrathecal chemotherapy in hematological malignancies for CNS disease prophylaxis or treatment is challenging for multiple reasons. There is consensus to avoid prophylactic IT chemotherapy in low-grade lymphomas/leukemias and use it in high-grade ones. However, its indications in intermediate-grade lymphomas/leukemias are controversial and dependent on variable risk factors. On the other hand, treatment indications are clear but there are no standardized regimens and IT chemotherapy can injure the nervous system which radiographically may resemble disease spread findings. Here, we present 2 cases that emphasize such challenges. The first is a patient with blastic plasmacytoid dendritic cell neoplasm who developed CSF disease that cleared with systemic and IT chemotherapy but later developed paraparesis and urinary incontinence. Initial cytology and imaging studies were unremarkable but CSF disease recurrence was suspected. However, his condition deteriorated despite steroid use; he developed radiographic signs of spinal cord myelopathy consistent with IT chemotoxicity, and expired shortly after. Prior to that CSF myelin basic protein level was found to be elevated. Second patient presented with diffuse large B-cell lymphoma, was treated with systemic plus prophylactic IT chemotherapy, and achieved remission after 6 cycles. He subsequently developed cranial neuropathies and brainstem lesions on MRI that improved with steroids, had normal CSF studies; hence his presentation appeared to be consistent with IT chemotoxicity. However, he had recurrence of neurological symptoms and clinical deterioration necessitating intubation. Repeat imaging showed spread of the brainstem lesions, and CSF cytology revealed lymphoma cells. The patient eventually became unresponsive and expired. These cases highlight the diagnostic uncertainties and neurologic complications encountered in managing hematologic malignancies, especially when disease spread to the nervous system is present or suspected. Additionally, we address the need to better identify CSF biomarkers of CNS/PNS injury.
Brain Perfusion Before and After Surgical Treatment of Moyamoya Disease
Authors: Clément Drouet, Olivier Morel, Laurent Thines, Clémence Porot, Hatem Boulahdour
Journal: Clinical Nuclear Medicine (2017)

Moyamoya disease is characterized by bilateral progressive terminal internal carotid arteries steno-occlusion. In this patient, the disease affected middle cerebral arteries and was disclosed after a left frontal cerebral infarction. Brain HMPAO perfusion scintigraphy with acetazolamide challenge, obtained before surgical treatment, demonstrates an extended bilateral frontal hypoperfusion with a vascular steal phenomenon. The same examination obtained after surgical treatment demonstrates a frank improvement in basal brain vascularization, with nearly complete correction of vascular steal phenomenon. HMPAO brain scintigraphy is a very useful tool in the assessment of moyamoya disease severity before surgery and for the evaluation of treatment efficiency.
Genetic Manipulation of <i>Helicobacter pylori</i> Virulence Function by Host Carcinogenic Phenotypes
Authors: Giovanni Suarez, Judith Romero-Gallo, Johanna C. Sierra, M. Blanca Piazuelo, Uma S. Krishna, Martin A. Gomez, Keith T. Wilson, Richard M. Peek
Journal: Cancer Research (2017)

Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the cag type 4 secretion system (cagT4SS), which translocates an oncoprotein into host cells. A structural component of the cagT4SS is CagY, which becomes rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cagT4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the H. pylori cag+ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. We now use this model, in conjunction with samples from patients with premalignant lesions, to define the effects of a carcinogenic host environment on the virulence phenotype of H. pylori to understand how only a subset of infected individuals develop cancer. H. pylori cagY sequence differences and cagT4SS function were directly related to the severity of inflammation in human gastric mucosa in either a synchronous or metachronous manner. Serial infections of Mongolian gerbils with H. pylori strain 7.13 identified an oscillating pattern of cagT4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust cagT4SS function could be restored upon infection of new hosts. Changes in the genetic composition of cagY mirrored cagT4SS function, although the mechanisms of cagY alterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modify cagT4SS function via altering cagY, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche. Cancer Res; 77(9); 2401-12. ©2017 AACR.
Adjuvant endocrine therapy in elderly patient in early Breast Cancer, a less toxic therapy, is it really true? A single institution, “real life” experience
Authors: C. De Angelis, I. Bertolini, I. Ferrarini, L. Diodati, I. Montagnani, A. Fontana, B. Salvadori, A. Michelotti, E. Landucci, F. Paola, E. Pfanner, M. Lo Russo, M. Roncella, A. Falcone
Journal: Annals of Oncology (2016)
P04.09 Tumor infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression in diffuse and anaplastic gliomas
Authors: A. S. Berghoff, B. Kiesel, G. Widhalm, D. Wilhelm, O. Rajky, S. Kurscheid, M. Hegi, A. Wöhrer, C. Marosi, M. Preusser
Journal: Neuro-Oncology (2016)

AbstractBackground:Immune modulatory therapies have shown impressive and durable responses in various extracranial malignancies. An immunologically active tumor microenvironment as defined by presence of tumor infiltrating lymphocytes (TILs) or expression of PD-L1 have been proposed as predictive for response to immune checkpoint inhibitors.Methods:TILs and PD-L1 expression were analyzed with immunohistochemical methods in a retrospective cohort from Vienna (Vienna cohort: 25 diffuse low-grade gliomas (LGG; WHO grade 2) and 20 anaplastic gliomas (AG, WHO grade 3)). Histology encompassed 21/45 (46.7%) astrocytoma, 11/45 (24.4) mixed oligoastrocytomas and 13/45 (28.9%) oligodendroglioma. 36/44 (81.8%) specimens presented with IDH-R132H mutation (per immunohistochemistry) and 17/42 (40.5%) with 1p19q co-deletion (per FISH). PD-L1 gene expression was further analyzed in 205 WHO grade II and 225 WHO grade III cases from the Cancer Genome Atlas (TCGA).Results:In the Vienna cohort, CD3+ TIL infiltration was found in 13/25 (52.0%) LGG and 11/20 (55.0%) AG, CD8+ in 9/25 (26.0%) and 10/20 (50.0%), CD45RO+ in 1/25 (4.0%) and 5/20 (25.0%), FOXP3+ in 1/25 (4.0%) and 6/20 (30.0%) and PD-1+ TILs in 0/25 (0%) LGG and 0/20 (0%) AG. CD45RO+ TILs (p=0.039) and FOXP3+ TILs (p=0.0317) were more frequently observed among AG compared to LGG. PDL1 expression of tumor cells was found in 13/25 (52.0%) LGG and 11/20 (55.0%) AG. 6/25 (24.0%) LGG and 4/20 (20.0%) AG presented with PD-L1 expression in > 25% of viable tumor cells. IDH-R132H wild type specimens presented more frequently with CD8+ TIL infiltration compared to IDH-R132H mutated specimens (p=0.030). No correlation of other TIL subtypes and PD-L1 expression with IDH mutation status or 1p19q co-deletion was present (p>0.05). In the TCGA cohort, PD-L1 gene expression levels were higher in WHO grade III tumors compared to WHO grade II tumors (p= 3.966e-6). Further, PD-L1 expression levels were higher in IDH wild type specimens compared to IDH mutated specimens (p= 3.086e-6).Conclusion:Sparse TIL infiltrates and PD-L1 expression are commonly found in diffuse gliomas and seem to show some association with histological grade and molecular status.
Virus-Associated Hemophagocytic Syndrome Contributes to Fatal Outcome In Critical Ill Patients with 2009 Influenza A (H1N1) Infection.
Authors: Gernot Beutel, Olaf Wiesner, Matthias Eder, Jan T. Kielstein, Carsten Hafer, Andrea S. Schneider, Tina Ganzenmueller, Christian Kuehn, Axel Haverich, Albert Heim, Tobias Welte, Marius M. Hoeper, Arnold Ganser
Journal: Blood (2010)
P08.14 Primary solitary leptomeningeal glioma with atypical invasion to the normal cortex
Authors: T. Katsuhara, N. Moro, T. Ohta, T. Homma, A. Yoshino
Journal: Neuro-Oncology (2016)

Pending the results of the 26062 EORTC trial, no standard of care exists for elderly patients with glioblastoma.Randomized controlled trials have provided evidence of a slight survival benefit for radiotherapy versus best supportive care (Keime-Guibert) and of lack of substantial benefit from single post-surgical treatment over each other.Treatment is still largely variable according to local practice.In this study we investigated the pattern of care and outcome in patients older than 65 diagnosed with glioblatoma in 3 hospitals in Lombardia and analyzed factors with impact on survival.151 patients were included in this study, enrolled in Lecco Hospital, Niguarda Hospital and Neurooncology Unit of Fondazione IRCCS Istituto Neurologico Besta and undergoing surgery from 2004 to 2014.91 were male, 60 female.Age range was 65 to 83, with a median value of 72.Concerning clinical variables, KPS was 70 or higher in 109 patients and lower in 42.19 patients underwent biopsy, 14 partial resection and 118 total/subtotal resection as evaluated by the neurosurgeon.114 patients were treated with radiotherapy and 97 with chemotherapy (all these 97 also received radiotherapy).32 patients displayed seizures at disease onset.22 patients did not receive antiepileptic treatment, while 129 were treated with antiepileptic drugs despite absence of seizures in 48.40% of patients treated with antiepileptic drugs received enzyme-inducing drugs, 60% were treated with either VPA or levetiracetam.At disease progression, 22 patients received further treatment, including repeat surgery and/or second-line chemotherapy.In only 36 patients were molecular biology tests performed (IDH1 mutation).At univariate analysis, survival was longer in patients with higher KPS (p=0.02),those receiving partial/total surgery vs biopsy (p=0.03),those receiving total resection (p=0.003),those treated with radiotherapy (p<0.0001),chemotherapy (p<0.0001),those being treated at Istituto Besta (p=0.003).No signficant differences were detected in survival according to presence of seizures at onset or type of antiepipeptic treatment.At multivariate analysis, radiotherapy, surgery other than biopsy, and lack of antiepileptic treatment emerged as factors associated with longer survival, while age classes were not and KPS showed just a trend to prognostic value.Older patients with glioblastoma continue to be undertreated; fit elderly patients can receive multimodal therapy with benefit.Undue treatment with antiepileptic drugs (especially EIADS) may negatively impact on survival in this age group. P08.
Effectiveness of Various Dosage Regimens of Azacitidine In Patients with Myelodysplastic Syndromes: Safety and Efficacy Final Data From the Spanish Azacitidine Compassionate Use Registry
Authors: Regina García, Dunia De Miguel, Joan Bargay, Teresa Bernal, José Ramón Gonzalez, Mar Tormo, Fernando Ramos, Andreu Lapiedra, Jose Falantes, Blanca Xicoy, Guillermo F Sanz, Benet Mondedeu, Salut Brunet, Joaquín Sanchez, Grupo Andaluz Smd
Journal: Blood (2010)
Patients with Unexplained Thrombosis Require a Prompt Investigation to Search a Chronic Myeloproliferative Neoplasm (MPN), Even If Platelet Count Is &lt;600x109/L. Analysis on 129 Patients from Registro Italiano Trombocitemie (RIT)
Authors: Giulia Benevolo, Alessandra Iurlo, Gabriele Gugliotta, Alessia Tieghi, Gianluca Gaidano, Giuseppe Tagariello, Bruno Martino, Mauro Di Ianni, Potito Rosario Scalzulli, Vincenzo Martinelli, Umberto Santoro, Eloise Beggiato, Maria Luigia Randi, Giorgina Specchia, Francesco Passamonti, Alessandro M. Vannucchi, Umberto Vitolo, Luigi Gugliotta
Journal: Blood (2015)
NEJ026: Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations
Authors: M. Maemondo, T. Fukuhara, S. Sugawara, Y. Takiguchi, A. Inoue, S. Oizumi, Y. Ishii, H. Yoshizawa, T. Isobe, A. Gemma, S. Morita, K. Hagiwara, K. Kobayashi, T. Nukiwa
Journal: Annals of Oncology (2016)
Efficacy of 90Y-Ibritumomab Tiuxetan (Zevalin) in Refractory or Relapsed MALT Gastric Non Hodgkin’s Lymphoma.
Authors: Anna Vanazzi, Pier F. Ferrucci, Chiara Grana, Giancarlo Pruneri, Cristiano Crosta, Antonello Pinto, Marco Chinol, Giovanni Paganelli, Giovanni Martinelli
Journal: Blood (2006)