tbuckley/cabot-search huggingface dataset:
CLINICALLY DELIVERABLE OPTUNE AND DEEP BRAIN STIMULATOR GENERATED ELECTRICAL FIELDS HAVE VARIABLE EFFICACY ON DIFFERENT TYPES OF BRAIN TUMOUR
Authors: Joshua Branter, Maria de los Angeles Estevez-Cebrero, Richard Grundy, Surajit Basu, Stuart Smith
Journal: Neuro-Oncology (2018)

Phase III trials of Tumour Treating Fields (TTFields) (Optune) have shown potentially positive results in both primary and recurrent adult Glioblastoma multiforme (GBM) patients. These results have given credence to electromagnetic fields, presenting a new treatment paradigm for brain tumour patients. Here we present investigations into repurposing deep brain stimulation (DBS) electrodes as a novel delivery method of therapeutic electric fields to high grade brain tumours and compare to TTFields treated cell lines. Medtronic DBS electrodes were inserted into cell culture flasks and delivered electric fields over a range of frequencies and intensities to a panel of GBM, Medulloblastoma and Ependymoma cell lines. Inovitro is the laboratory based TTFields delivery system. Inovitro was used to deliver TTFields over a range of clinically relevant frequencies (100-400kHz) to a panel of paediatric GBM, Medulloblastoma and Ependymoma cell lines. Differences in the effects of both treatments on cell viability, cell cycling, long-term effects of treatment, as well as genome-wide expression were analysed. RESULTS Both DBS electric fields and TTFields negatively affect cell proliferation and viability of brain tumour cell lines. The magnitude of these effects were dependent upon frequency and intensity. Cells treated with either modality were re-seeded and growth rates were compared to non-treated cells. The treated cells experienced significantly slower growth rates following treatment. Cell cycle analysis revealed that DBS treated cells have significant levels of G0 phase accumulation relative to control flasks, while TTFields treated cells demonstrated greater levels of G2M phase accumulation across all panels of cell lines tested. The effects of electrotreatment on gene expression will be discussed. Both treatment modalities have demonstrated efficacy against our array of brain tumour cell lines. The treatments likely have differing mechanisms of action at the cellular level and this is reflected in the differences that have been observed.
A Prospective Study of the Association between Physical Activity and Risk of Prostate Cancer Defined by Clinical Features and TMPRSS2:ERG
Authors: Claire H. Pernar, Ericka M. Ebot, Andreas Pettersson, Rebecca E. Graff, Francesca Giunchi, Thomas U. Ahearn, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Konrad H. Stopsack, Elizaveta Gazeeva, Rosina T. Lis, Giovanni Parmigiani, Eric B. Rimm, Stephen P. Finn, Edward L. Giovannucci, Michelangelo Fiorentino, Lorelei A. Mucci
Journal: European Urology (2018)
Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients
Authors: Bryce A. Manso, Henan Zhang, Molly G. Mikkelson, Kimberly A. Gwin, Charla R. Secreto, Wei Ding, Sameer A. Parikh, Neil E. Kay, Kay L. Medina
Journal: Leukemia (2018)
In vitro and in vivo metabolism of sunitinib in nonclinical species and humans
Authors: William Speed, Carlo Bello, Geoffrey Peng, Shem Patyna, Ellen Wu
Journal: Cancer Research (2008)

1285  Sunitinib malate (SU11248) is an oral, multitargeted, tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. We report here the results of preclinical studies investigating the in vitro and in vivo metabolism of sunitinib, which guided the design and conduct of human drug-drug interaction (DDI) and radiolabeled mass balance studies.  Sunitinib was metabolized in vitro by liver microsomes from mice (M), rats (R), dogs (D), monkeys (Mo), and humans (H). SU12662 (N-desethyl, active metabolite) was the major metabolite in M, Mo, and H liver microsomes, while SU12487 (an N-oxide metabolite) was the major metabolite in D liver microsomes. In R liver microsomes, SU12487 was the major metabolite at a low concentration (2 μM) of sunitinib, but SU12662 predominated at a higher substrate concentration (25 μM).  Pharmacokinetic and metabolism studies with sunitinib in M, R, rabbits (Rb), and Mo demonstrated high systemic levels of the parent drug, while SU12662 was the only quantifiable metabolite in plasma in M, R, Rb, and Mo; in D, SU12487 was also found. The predominant drug-related compounds found in bile were sunitinib and SU12662 and, in urine, sunitinib, SU12662, and SU12487. Monohydroxylation on the aromatic ring system and aliphatic moieties occurred and their sulfate and glucuronide conjugates were found in bile and urine as minor metabolites. Across studies (M, R, Mo), sunitinib and SU12662 were the only major drug-related compounds found in plasma. SU12487 was only found in M and D plasma.  CYP3A-mediated N-deethylation to form SU12662 was the major pathway of sunitinib metabolism in R, Mo and H liver microsomes. In H liver microsomes, sunitinib N-deethylation was correlated only with testosterone 6β-hydroxylase (CYP3A4) activity (r2 = 0.56). N-deethylation of SU12662 in human hepatic microsomes was also mediated by CYP3A4 as shown by its metabolic inhibition by ketoconazole (93% inhibition at 1 μM), but not by furafylline (CYP1A inhibitor). In human liver microsomes and hepatocytes, sunitinib or SU12662 did not induce or inhibit major CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) and are unlikely to have any clinically relevant DDIs with drugs that may be metabolized by these enzymes.  In summary, sunitinib was moderately metabolized in all species evaluated. The N-desethyl metabolite, SU12662, was the primary metabolite identified in the majority of species with minor quantities of the N-oxide metabolite, SU12487. CYP3A4 was the primary route of metabolism, but neither sunitinib nor SU12662 are likely inhibitors or inducers of this or any other CYP450-mediated metabolism. Only sunitinib and SU12662 are measured in clinical trials and clinical recommendations are given only for coadministration of potent CYP3A4 inhibitors and inducers.
Abstract 14221: MicroRNA-145-loaded Poly Lactic-co-glycolic Acid Nanoparticles Attenuate Venous Intimal Hyperplasia: A Basic Study for Preventing Vein Graft Diseases
Authors: Hiroomi Nishio, Hidetoshi Masumoto, Hideo Kanemitsu, Koji Ueyama, Kazuhiro Yamazaki, Tadashi Ikeda, Kenji Minatoya
Journal: Circulation (2017)

Background: Vein grafts implanted under arterial pressure are susceptible to atherosclerosis, which is defined as vein graft disease. A key mechanism is intimal hyperplasia caused by a phenotypic s...
The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL
Authors: Ian W. Flinn, Peter Hillmen, Marco Montillo, Zsolt Nagy, Árpád Illés, Gabriel Etienne, Julio Delgado, Bryone J. Kuss, Constantine S. Tam, Zoltán Gasztonyi, Fritz Offner, Scott Lunin, Francesco Bosch, Matthew S. Davids, Nicole Lamanna, Ulrich Jaeger, Paolo Ghia, Florence Cymbalista, Craig A. Portell, Alan P. Skarbnik, Amanda F. Cashen, David T. Weaver, Virginia M. Kelly, Barry Turnbull, Stephan Stilgenbauer
Journal: Blood (2018)
Screening for neurocysticercosis in internationally adopted children: yield, cost and performance of serological tests, Italy, 2001 to 2016
Authors: Lorenzo Zammarchi, Andrea Angheben, Teresa Fantoni, Elena Chiappini, Antonia Mantella, Luisa Galli, Valentina Marchese, Giorgio Zavarise, Zeno Bisoffi, Alessandro Bartoloni
Journal: Eurosurveillance (2018)

IntroductionNeurocysticercosis (NCC) is one of the leading causes of epilepsy worldwide. The majority of cases in Europe are diagnosed in immigrants. Currently in Italy, routine serological screening for cysticercosis is recommended for internationally adopted children (IAC) coming from endemic countries. Methods: We retrospectively analyse the results of the serological screening for cysticercosis in IAC 16 years old or younger, attending two Italian third level paediatric clinics in 2001-16. Results: Of 2,973 children included in the study, 2,437 (82.0%) were screened by enzyme-linked immune electro transfer blot (EITB), 1,534 (51.6%) by ELISA, and 998 (33.6%) by both tests. The seroprevalence of cysticercosis ranged between 1.7% and 8.9% according to EITB and ELISA, respectively. Overall, 13 children were diagnosed with NCC accounting for a NCC frequency of 0.4% (95% confidence interval (CI): 0.2-0.6%). Among the 168 seropositive children, only seven (4.2%) were diagnosed with NCC. Of these children, three were asymptomatic and four presented epilepsy. Among seronegative children (n = 2,805), seven presented with neurological symptoms that lead to the diagnosis of NCC in six cases. The sensitivity, specificity, positive and negative predictive value for the diagnosis of NCC were 54.5%, 98.6%, 14.6%, 99.8% for EITB and 22.2%, 91.1%, 1.4%, 99.5% for ELISA. The yield of the screening programme was 437 NCC cases per 100,000. The number needed to screen to detect one NCC case was 228. The cost per NCC case detected was EUR 10,372. Conclusion: On the base of our findings we suggest the ongoing serological screening for cysticercosis to be discontinued, at least in Italy, until further evidence in support will be available.
Combining Oral Anticoagulants With Platelet Inhibitors in Patients With Atrial Fibrillation and Coronary Disease
Authors: Caroline Sindet-Pedersen, Morten Lamberts, Laila Staerk, Anders Nissen Bonde, Jeffrey S. Berger, Jannik Langtved Pallisgaard, Morten Lock Hansen, Christian Torp-Pedersen, Gunnar H. Gislason, Jonas Bjerring Olesen
Journal: Journal of the American College of Cardiology (2018)
A PHASE I EXPANSION STUDY OF PEGARGIMINASE, CISPLATIN AND PEMETREXED IN ARGININOSUCCINATE SYNTHETASE 1-NEGATIVE RECURRENT HIGH GRADE GLIOMAS (HGGS)
Authors: Peter Hall, Rachel Lewis, Nelofer Syed, Richard Shaffer, Jane Evanson, Stephen Ellis, Matthew Williams, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Fiona Harris, Raj Jena, Sarah Jefferies, Ramsay Khadeir, Bor-Wen Wu, John Bomalaski, Timothy Crook, Michael Sheaff, Simon Pacey, Nick Plowman, Peter Szlosarek
Journal: Neuro-Oncology (2018)

Patients (pts) with recurrent HGGs are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains poor with an overall survival (OS) of 7–9 months. Preclinically, we showed that HGGs are a target for arginine depletion with Pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-ve HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. We expanded a phase 1 trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS), which noted activity in aggressive thoracic cancers, to pts with relapsed HGGs (clinicaltrials.gov NCT02029690). Pts with ASS1-ve recurrent HGGs were enrolled (01/16 – 06/17) to receive ADI-PEG20 weekly at the maximum tolerated dose of 36 mg/m2 i.m. plus PEM 500 mg/m2 and CIS 75 mg/m2 i.v. every 3 weeks for up to 6 cycles. Pts with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability and preliminary estimates of activity. Additional endpoints included pharmacodynamics, immunogenicity, OS, and ASS1/ASL epimutations. 10/19 ASS1-ve heavily pre-treated pts were enrolled onto ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events (AEs) being CTCAE v4.03 grade 1–2; 7 pts (70%) had at least one grade 3 or 4 AE with neutropenia (40%) and thrombocytopenia (30%). The best response was stable disease by RECIST 1.1 and partial response (n=1; 10%) by RANO criteria. The median (95% CI) OS was 6.5 (1.8, 9.7) months. Two pts are alive and one continues 16 months on ADI-PEG20 as 3rd-line therapy for a de novo IDH-wildtype glioblastoma multiforme. Epimutations in ASS1 and/or ASL were detectable in pts’ tumours consistent with prior studies. ADIPEMCIS was well tolerated and compares favourably to historical controls in recurrent HGG. A randomised, phase II trial comparing ADIPEMCIS with alkylating drugs at first relapse is planned (ATOMIC-G).
A State-of-the-Science Review of Mercury Biomarkers in Human Populations Worldwide between 2000 and 2018
Authors: Niladri Basu, Milena Horvat, David C. Evers, Irina Zastenskaya, Pál Weihe, Joanna Tempowski
Journal: Environmental Health Perspectives (2018)

The Minamata Convention on Mercury provided a mandate for action against global mercury pollution. However, our knowledge of mercury exposures is limited because there are many regions and subpopulations with little or no data.
DIFFUSION KURTOSIS IMAGING IDENTIFIES THE IDH MUTATION STATUS OF GLIOMAS
Authors: Gehad Abdalla, Laura Mancini, S Eser Sanverdi, Tarek Yousry, Sotirios Bisdas
Journal: Neuro-Oncology (2018)

Since the 2016 WHO classification, the mutation status of the encoding gene of Isocitrate-dehydrogenase enzyme (IDH) is an important element in the integrated diagnosis of gliomas. Diffusion Kurtosis imaging (DKI) has been used to assess the microstructure of brain tissue as well as gliomas by quantifying the water molecules’ non-Gaussian distribution. We therefore hypothesize that DKI can determine the IDH status of gliomas. MATERIALS / 20 patients (F/ 12/8, mean age: 39 ± 14.6 years) with histopathologically proven gliomas were included in this prospective study. Diffusion images were obtained on a 3T system with 10/ 30/ 60 diffusion gradient directions with b-value of 300–2500 sec/mm2. Kurtosis analysis was performed using the Diffusional Kurtosis Estimator software, and segmentation was manually drawn on the co-registered FLAIR-DWI images. The mean value of the “mean kurtosis (MK)” and “mean diffusivity (MD)” were extracted from the solid tumour component and from the contralateral normal-appearing white matter. We then correlated MK and MD with the 2016 CNS WHO tumor grades using statistical software STATA,V15. 7 patients had IDH-wild type (wt) gliomas and 13 IDH-mutant gliomas. Normalized MK (MKn) significantly differed between IDH-mutant and IDH-wt gliomas (p=0.04), while MDn didn’t reach the statistical significance level (p=0.059). In those patients with a lack of 1p/19q co-deletion all MKn, MK, MDn, MD significantly differed (p< 0.007). DKI enables the differentiation of gliomas according to the WHO 2016 integrated diagnosis. Further studies with a larger patients’ number are required to confirm these findings.
Doing research using apps in the NHS is harder than it should be
Authors: Dr Alasdair G Rooney, Mr Will Hewins, Dr Robin Grant, Prof Anthony J Chalmers, Dr Catherine Mcbain
Journal: Neuro-Oncology (2018)

The use of smartphone apps is an increasing theme for researchers worldwide. MyFitnessPal is a lifestyle app used by c.100 million people. BT-LIFE is a UK Randomised Controlled Trial of lifestyle interventions for fatigue after primary brain tumour, which has been in set-up. We wished to offer patients the option of using MyFitnessPal in BT-LIFE. We prospectively surveyed The Brain Tumour Charity’s Research Involvement Network of patients and carers. We studied the acceptability of using apps to record lifestyle information in BT-LIFE. Results are summarised descriptively and combined with a frontline narrative of our subsequent experience of sponsorship review. Survey: There were 19 respondents (mean age=49 years [range 31–75]). Of these, 18/19 had a smartphone or tablet which could use apps. Most respondents (16/19) expressed a willingness or preference to use apps, and apps were highly acceptable overall (mean acceptability [n=19] = 8.0 / 10, where 10 is ‘very acceptable’). Narrative: However, the study sponsor was obliged by protocol to query the data protection procedures of the U.S. (non-EU) company that runs MyFitnessPal. That patients would give informed consent, and also have an option not to use the app, were considered irrelevant. The automatic query triggered multiple reviews, in series, that delayed ethical submission by months. This delay jeopardised the study opening date. Accordingly, we removed the app from the protocol. BT-LIFE subsequently opened on-time and is currently recruiting. Given the acceptability of apps and their ubiquitous use in real life, doing research using apps in the NHS is harder than it should be. Automatically objecting to an app used by millions in daily life may divert governance resources from higher-risk studies, and makes it difficult to do technologically savvy research. We should lobby for ‘common sense’ and streamlined research governance policies that befit modern life.
Collaboration between academics and industry in clinical trials: cross sectional study of publications and survey of lead academic authors
Authors: Kristine Rasmussen, Lisa Bero, Rita Redberg, Peter C Gøtzsche, Andreas Lundh
Journal: BMJ (2018)

To determine the role of academic authors, funders, and contract research organisations in industry funded trials of vaccines, drugs, and devices and to determine lead academic authors' experiences with industry funder collaborations.Cross sectional analysis of trial publications and survey of lead academic authors.The most recent 200 phase III and IV trials of vaccines, drugs, and devices with full industry funding, at least one academic author, published in one of the top seven high impact general medical journals (New England Journal of Medicine, Lancet, JAMA, BMJ, Annals of Internal Medicine, JAMA Internal Medicine, and PLoS Medicine).Employees of industry funders co-authored 173 (87%) of publications; 183 (92%) trials reported involvement of funders in design, and 167 (84%) reported involvement of academic authors. Data analysis involved the funder in 146 (73%) trials and the academic authors in 79 (40%). Trial reporting involved the funder in 173 (87%) trials and academic authors in 197 (99%). Contract research organisations were involved in the reporting of 123 (62%) trials.Eighty (40%) of 200 lead academic authors responded to the survey. Twenty nine (33%) of the 80 responders reported that academics had final say on the design. Ten responders described involvement of an unnamed funder and/or contract research organisation employee in the data analysis and/or reporting. Most academic authors found the collaboration with industry funder beneficial, but 3 (4%) experienced delay in publication due to the industry funder and 9 (11%) reported disagreements with the industry funder, mostly concerning trial design and reporting.Industry employees and academic authors are involved in the design, conduct, and reporting of most industry funded trials in high impact journals. However, data analysis is often conducted without academic involvement. Academics view the collaboration as beneficial, but some report loss of academic freedom.
PTH-052 Oesophagogastroduodenoscopy (ogd) after abnormal radiology findings. how often do we diagnose an upper gastrointestinal malignancy?
Authors: AS Bancil, P Youd, AG Lim, P Patel, SJ Moodie
Journal: Gut (2017)

Introduction  Computed Tomography (CT) is often an initial investigation when investigating someone for malignancy. Other malignancies can be identified via incidental findings from other modalities such as Magnetic Resonance Imaging (MRI) or Barium studies. There is anecdotally a perception that CT is not reliable in the diagnosis of upper gastrointestinal malignancies. Despite this, when there are findings suggestive of malignancy such as thickening of gastric tissue, an OGD is indicated.  Method  We analysed all OGDs performed in Epsom & St Helier NHS Trust from February 2016 to February 2017 due to abnormal radiology. We searched for these using the Endoscopy program HICSS database.  Results  We identified 30 OGDs performed in the above period. Initial indications for imaging included dysphagia (8 patients), weight loss and anaemia (4 patients), abdominal pain (1 patient), raised ALP (2 patients), staging CT for other malignancies (6 patients), imaging for another disorder (1 patient), haemetemesis or malaena (3 patients), evaluation of obstructive lung disease (1 patient), duplication cyst on Barium swallow (1 patient), MRI for spinal disease (1 patient), and decompensated liver disease surveillance for malignancy (2 patients).  After OGD, 5 new malignancies were identified (2 known malignancies) (Positive Predictive Value of 16.67%, 95% CI 13.16% to 20.88%) with 7 OGDs showing no abnormality, 6 showing oesophagitis or a hiatus hernia, 2 with food residue, 2 benign polyps, 2 ulcers, 2 benign strictures, 1 oesophageal candidiasis and 1 Barrett’s oesophagus.  Conclusion  The above results confirm that OGDs completed due to suspicious imaging (mainly CT) are appropriately performed and are able to diagnose a significant amount of upper gastrointestinal malignancies.  Disclosure of Interest  None Declared
RAPID GENETIC CLASSIFICATION OF GLIOMAS USING RAMAN SPECTROSCOPY
Authors: Laurent James Livermore, Martin Isabelle, Ian Bell, Puneet Plaha, Claire Vallance, Olaf Ansorge
Journal: Neuro-Oncology (2018)

Raman spectroscopy probes the unique molecular vibrations of a sample to accurately characterise its molecular composition. No sample processing is required allowing for rapid analysis of fresh tissue. The genetic classification of gliomas, particularly isocitrate dehydrogenase (IDH) mutations, is critical for clinical decision-making. With the development of new drugs targeting specific glioma genetic subtypes it will become increasingly important for surgeons to be aware of the genetics of the tumour at the time of operation to inform their surgical strategy. The aim of this study was to use Raman spectroscopy on fresh samples taken straight from the operating theatre and to classify gliomas according to their genetic subtypes. Similar classification models were built using cryosections and formalin-fix paraffin embedded (FFPE) sections. Raman spectra were collected using a Renishaw benchtop RA800 series spectrometer. Parallel sections underwent immunohistochemistry with targeted genetic sequencing when required to confirm the following five glioma subtypes: glioblastoma, IDH-mutated; glioblastoma, IDH-wildtype; astrocytoma, IDH-mutated; astrocytoma, IDH-wildtype; oligodendroglioma. Fresh tissue samples from 62 patients were collected (9 glioblastoma, IDH-mutated; 35 glioblastoma, IDH-wildtype; 10 astrocytoma, IDH-mutated; 2 astrocytoma, IDH-wildtype; 5 oligodendroglioma, 1 excluded). A principal component-linear discriminant analysis (PCA-LDA) model demonstrated 80%-95% sensitivity and specificity for predicting the five glioma genetic subtypes. For prediction of IDH mutation alone the model gave a 92% sensitivity and 91% specificity. 86 cryosection and 117 FFPE samples underwent Raman with models demonstrating 87–94% sensitivity and 77–80% specificity for predicting IDH mutations. In the fresh tissue samples, the mean time for spectra collection was 9.5 minutes with the whole process from tumour biopsy to genetic classification taking under 30 minutes. These results demonstrate proof of concept that Raman spectroscopy can be used for rapid, intraoperative glioma genetic classification. Further work is being done to refine model building to increase classification performance.