tbuckley/cabot-search huggingface dataset:
Retention of Interstitial Genes between <i>TMPRSS2</i> and <i>ERG</i> Is Associated with Low-Risk Prostate Cancer
Authors: Stephen J. Murphy, Farhad Kosari, R. Jeffrey Karnes, Aqsa Nasir, Sarah H. Johnson, Athanasios G. Gaitatzes, James B. Smadbeck, Laureano J. Rangel, George Vasmatzis, John C. Cheville
Journal: Cancer Research (2017)

TMPRSS2-ERG gene fusions occur in over 50% of prostate cancers, but their impact on clinical outcomes is not well understood. Retention of interstitial genes between TMPRSS2 and ERG has been reported to influence tumor progression in an animal model. In this study, we analyzed the status of TMPRSS2-ERG fusion genes and interstitial genes in tumors from a large cohort of men treated surgically for prostate cancer, associating alterations with biochemical progression. Through whole-genome mate pair sequencing, we mapped and classified rearrangements driving ETS family gene fusions in 133 cases of very low-, low-, intermediate-, and high-risk prostate cancer from radical prostatectomy specimens. TMPRSS2-ERG gene fusions were observed in 44% of cases, and over 90% of these fusions occurred in ERG exons 3 or 4. ERG fusions retaining interstitial sequences occurred more frequently in very low-risk tumors. These tumors also frequently displayed ERG gene fusions involving alternative 5'-partners to TMPRSS2, specifically SLC45A3 and NDRG1 and other ETS family genes, which retained interstitial TMPRSS2/ERG sequences. Lastly, tumors displaying TMPRSS2-ERG fusions that retained interstitial genes were less likely to be associated with biochemical recurrence (P = 0.028). Our results point to more favorable clinical outcomes in patients with ETS family fusion-positive prostate cancers, which retain potential tumor-suppressor genes in the interstitial regions between TMPRSS2 and ERG Identifying these patients at biopsy might improve patient management, particularly with regard to active surveillance. Cancer Res; 77(22); 6157-67. ©2017 AACR.
PDTM-47. CHARACTERIZATION OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE IN PILOCYTIC ASTROCYTOMA AND ITS ROLE IN ONCOGENE-INDUCED SENESCENCE
Authors: Juliane Hohloch, Florian Selt, Thomas Hielscher, Felix Sahm, David Capper, Diren Usta, Jonas Ecker, Ina Oehme, Cornelis M van Tilburg, Andreas von Deimling, Martin U Schuhmann, Andrey Korshunov, David Jones, Tilman Brummer, Stefan M Pfister, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2017)

Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. This single-pathway disease exhibits aberrant activation of the MAPK pathway driving the tumor into oncogene-induced senescence (OIS). OIS is proposed to be the source of the unstable however benign growth observed in PA patients. Senescence is thought to be regulated by the senescence-associated secretory phenotype (SASP) which comprises a variety of cytokines, growth factors and proteases. Markers of senescence have been detected in PA, but the functional relevance of the SASP and its relation to OIS in PA is unknown. The first patient-derived PA cell culture model DKFZ-BT66 was utilized for the characterization of OIS and the role of the SASP in PA. The model allows experimental switching between senescent and proliferating states by modulation of the p53/RB pathway. Both conditions were analyzed by gene-expression profiling (GEP), Western Blot, real-time qPCR, ELISA, cell counts and viability by automated trypan blue exclusion staining. A significant increase of the SASP could be detected by GEP in the OIS state of the PA cell line. Moreover, the OIS expression signature was associated with improved progression free survival in a cohort of n=112 PA patients. Upregulation of IL-6 and IL-1B, two representative SASP factors, could be demonstrated on mRNA and protein level in DKFZ-BT66 during OIS. Both cytokine receptors are expressed and activation of the respective pathways was confirmed. Activation of the IL-1 pathway led to decreased growth of proliferating PA cells. Overall, the novel primary PA tumor model provides functional evidence of the presence of OIS in PA and exhibits increased activity of the SASP during the senescent state. In order to find an explanation for the clinically observed spontaneous on/off growth behavior, current studies aim to investigate the disruption of the OIS-characteristic growth arrest by inhibition of inflammatory signaling pathways.
Abstract 20145: Multiple Novel Plasma Biomarkers are Associated With Aortic Stenosis
Authors: Aeron Small, Daniel Kiss, Julio Chirinos, Scott Damrauer, Jay Giri, Marie Guerraty, Giovanni Ferrari, Daniel Rader
Journal: Circulation (2016)

Introduction:  Calcific aortic valve disease (CAVD) can progress to aortic stenosis (AS) when the remodeling of valve tissue is sufficiently severe to result in hemodynamic changes. The discovery of biomarkers represents a complementary approach to echocardiography in stratifying risk and timing of intervention in CAVD, and has the advantage of providing insight into potential causal factors for the disease. Only a limited number of circulating plasma biomarkers have been reported to be associated with AS and there are no medical therapies to prevent or slow the progression of CAVD.   Objective:  We leveraged an academic biobank linked to electronic health record data to generate a large AS case/control sample. We then utilized a multiplexed biomarker approach to novel biomarker discovery.   Methods/Results:  We applied natural language processing algorithms to cardiac ECHO reports and intersected results with the Penn Medicine Biobank to generate a sample of 1,071 patients with a range of AS (mild to severe), and age and sex matched controls (n=1,026). As expected, plasma levels of lipoprotein(a) [Lp(a)] were significantly higher in subjects with AS (54.0 +/- 2.4 mg/dl) compared with controls (42.8 +/- 1.9 mg/dl, p=3.0E-04). Banked plasma samples were screened against a panel of 50 candidate biomarkers using Luminex Bead Assays. Using multivariable modeling to control for clinical covariates and after correcting for multiple testing, 11 proteins were found to be significantly different in AS subjects with a Bonferroni corrected p-value of 1E-3. We confirmed previous reports of increased pro-BNP (p=7.4E-09), and FGF-23 (p=7.7E-06) in subjects with AS and identified 9 novel circulating proteins that are significantly different in AS, including syndecan-4 (p=1.1E-10) and GDF-15 (p=4.6E-09).   Conclusions:  Biomarker discovery for CAVD and AS represents a new approach to diagnosis and can shed light on disease pathogenesis. We report 9 novel biomarkers significantly different in AS patients compared with matched controls using a large case-control study.
PUB076 Programmed Cell Death Ligand 1 and Neutrophil to Lymphocyte Ratio to Predict Response to Nivolumab in Non-Small Cell Lung Cancer
Authors: C. Bennati, M. D'Arcangelo, G. Minuti, S. Vecchiarelli, L. Landi, V. Mazza, A. Gili, M. Puccetti, F. Cappuzzo
Journal: Journal of Thoracic Oncology (2017)
P2.01-050 Predicting Risk of Hospitalization in Patients with NSCLC Receiving Chemotherapy Using the LCSS 3-Item Global Index (3-IGI)
Authors: R. Gralla, P. Hollen, N. Gaspe, R. Hall, R. Genzler, H. Cordero, H. Cheng, J. Gildersleeve, J. Crawford, L. Rosen, M. Lesser
Journal: Journal of Thoracic Oncology (2017)
P1.02-002 Diagnostic Utility of MUC4 Expression to Differentiate Epithelioid Mesothelioma from Lung Adenocarcinoma and Squamous Cell Carcinoma
Authors: V. Amatya, A. Mawas, K. Kushitani, Y. Kai, Y. Miyata, M. Okada, Y. Takeshima
Journal: Journal of Thoracic Oncology (2017)
MNGI-18. BEVACIZUMAB IN THE TREATMENT OF ATYPICAL AND ANAPLASTIC MENINGIOMAS. A CASE SERIES AND REVIEW OF THE LITERATURE
Authors: Divya Mella, Edward Pan
Journal: Neuro-Oncology (2017)

To report 8 cases of atypical and anaplastic meningiomas treated with Bevacizumab and review the available literature. Meningiomas account for 30% of all brain tumors with multiple meningiomas occurring in 5-15% of patients. Atypical meningiomas (WHO Grade II) account for 5-15% of all meningiomas. Anaplastic meningiomas (WHO Grade III) account for 1-2% of all meningiomas. Meningiomas are treated with surgical resection, radiation and stereotactic radiosurgery. Recurrent and refractory meningiomas that have failed these therapies can be treated with Bevacizumab. This is a retrospective review of WHO Grade II and III meningiomas treated between 2008 and 2017 at University of Texas Southwestern (UTSW) selecting patients who received Bevacizumab. 8 patients with WHO Grade II and III meningiomas who had progressed through standard surgical and radiation therapies received intravenous Bevacizumab at UTSW. Age at diagnosis ranged from 21-74 years. 3 out of the 8 patients were female. One patient had NF-2. 6 out of 8 patients had atypical or WHO Grade II meningiomas, one had anaplastic or WHO Grade III meningioma, pathology was not available for one patient who had NF-2. 7 out of 8 patients had failed prior treatment with surgical resection, radiosurgery and/or radiation. Bevacizumab was given at a dose of 10 mg/kg every 2 weeks. Mean duration of treatment was 9 months (18 doses). Patients were followed every 2 months with neurologic exams, brain MRIs with contrast and urine protein levels. All 8 patients demonstrated improvement in symptoms as well as radiographic stability in tumor size. 7 out of 8 patients developed hypertension. 2 patients developed proteinuria requiring increase in dosage interval. One patient developed non-fatal intracranial hemorrhage requiring discontinuation of Bevacizumab. Bevacizumab may slow the growth of meningiomas. It is well tolerated and is a potentially effective treatment for atypical and anaplastic meningiomas.
Doctors are less likely to be struck off for dishonesty than other health workers
Authors: Clare Dyer
Journal: BMJ (2017)

The stresses of work and the influence of a malfunctioning workplace are important factors when doctors and other healthcare professionals are charged with professional misconduct, research has concluded.1

An analysis of 6714 cases of professional misconduct brought by three healthcare regulators, including the General Medical Council (GMC), identified three types of perpetrators. These are described as: the self serving “bad apple”; the individual who is corrupted by falling standards in the workplace; and the depleted perpetrator struggling to cope with the pressures of life.

The study, led by Rosalind Searle, professor of organisational behaviour and psychology at the University of Coventry, looked at professional misconduct cases from 2014 to 2016 seen …
P2.01-023 Reasons for Withholding Systemic Therapy in Stage IV NSCLC: Comparison of Years 2004 to 2007 and 2010 to 2013
Authors: G.S. Bhattacharyya, H. Malhotra, K. Govindbabu, G. Biswas, A. Vora, T. Shahid
Journal: Journal of Thoracic Oncology (2017)
Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia
Authors: Samantha Le Sommer, Nicola Morrice, Martina Pesaresi, Dawn Thompson, Mark A. Vickers, Graeme I. Murray, Nimesh Mody, Benjamin G. Neel, Kendra K. Bence, Heather M. Wilson, Mirela Delibegović
Journal: Cancer Research (2017)

Abstract Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B−/− mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Significance: This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Cancer Res; 78(1); 75–87. ©2017 AACR.
NIMG-90. TEXTURE ANALYSIS OF MR FINGERPRINTING IN ADULT BRAIN TUMORS
Authors: Chaitra Badve, Sara Dastmalchian, Ozden Kilinc, Debra McGivney, Dan Ma, Mark Griswold, Jeffrey Sunshine, Vikas Gulani, Jill Barnholtz-Sloan, Andrew Sloan
Journal: Neuro-Oncology (2017)

Magnetic resonance fingerprinting (MRF) is a non-invasive quantitative imaging technique, which allows rapid, simultaneous quantification of T1 and T2 relaxometry. We have demonstrated the ability of 2D single-slice MRF-based relaxometry to differentiate between various intraaxial brain tumors using first order statistics. In this study, we assess the utility of texture analysis on MRF quantitative maps to differentiate common intra-axial adult brain tumors. Single slice 2D-MRF acquisition was performed in 31 untreated brain tumors including 17 glioblastomas (GBM), 6 lower grade gliomas (LGG) and 8 metastases (METs). Regions of interest (ROI) for the solid tumor (ST) and peri-tumoral white matter (PW) (range: 0.32-12 and 0.25-2.5 cm2 respectively) were drawn on quantitative T1 and T2 maps. Second-order texture features were calculated from gray level co-occurrence matrices (GLCM). Pearson correlation coefficients were applied for removal of redundant features. Five features including correlation, homogeneity, cluster-shade, information measure of correlation-1 and sum-average were compared across tumor types using the unpaired Student’s t-test and receiver operating characteristic (ROC) analysis. In ST analysis, T1 correlation and T2 homogeneity of LGGs were higher compared to GBMs (p=0.009 and p=0.002 respectively). In PW analysis, T1 cluster-shade values of METs and LGGs were different (p= 0.004). There was difference in T2 correlation values between GBMs and METs (p=0.034). The ROC analysis revealed that T2 homogeneity of ST regions offers best separation between GBMs and LGGs with AUC of 0.91 (p=0.003) and between METs and LGGs with AUC of 0.94 (p=0.007). Texture analysis of MRF data improves characterization of tumoral and peri-tumoral regions and captures tissue heterogeneity above and beyond the first order features. MRF based texture analysis may offer a unique method for distinguishing various types of intra-axial adult brain tumors.
P2.01-007 Molecular Characterization of Non-Small Cell Lung Cancers (NSCLC) in Young Patients from an Argentine Population
Authors: V. Denninghoff, G. Recondo, M. Cuello, M.M. García Falcone, V. Romano, M. Greco, V. Wainsztein, F. Galanternik, M. De La Vega, E. Rojas Bilbao, M.A. Avagnina, G. Recondo
Journal: Journal of Thoracic Oncology (2017)
An oncolytic measles virus–sensitive Group 3 medulloblastoma model in immune-competent mice
Authors: Sangeet Lal, Diego Carrera, Joanna J Phillips, William A Weiss, Corey Raffel
Journal: Neuro-Oncology (2018)

Oncolytic measles virus (MV) is effective in xenograft models of many tumor types in immune-compromised mice. However, no murine cell line exists that is tumorigenic, grows in immune-competent mice, and is killed by MV. The lack of such a model prevents an examination of the effect of the immune system on MV oncotherapy.Cerebellar stem cells from human CD46-transgenic immunocompetent mice were transduced to express Sendai virus C-protein, murine C-Myc, and Gfi1b proteins. The resultant cells were injected into the brain of NSG mice, and a cell line, called CSCG, was prepared from the resulting tumor.CSCG cells are highly proliferative, and express stem cell markers. These cells are permissive for replication of MV and are killed by the virus in a dose- and time-dependent manner. CSCG cells form aggressive tumors that morphologically resemble medulloblastoma when injected into the brains of immune-competent mice. On the molecular level, CSCG tumors overexpress natriuretic peptide receptor 3 and gamma-aminobutyric acid type A receptor alpha 5, markers of Group 3 medulloblastoma. A single intratumoral injection of MV‒green fluorescent protein resulted in complete tumor regression and prolonged survival of animals compared with treatments with phosphate buffered saline (P = 0.0018) or heat-inactivated MV (P = 0.0027).This immune-competent model provides the first platform to test therapeutic regimens of oncolytic MV for Group 3 medulloblastoma in the presence of anti-measles immunity. The strategy presented here can be used to make MV-sensitive murine models of any human tumor for which the driving mutations are known.
QLIF-32. MEETING THE PATIENTS - MEETING THE NEEDS: PLATFORMS FOR PATIENTS USING OPTUNE® TO EXCHANGE EXPERTISE
Authors: Almuth F Kessler, Elisabeth Jentschke, Vera Dufner, Thomas Linsenmann, Thomas Westermaier, Wanja Wolber, Ralf-Ingo Ernestus, Carsten Hagemann, Mario Löhr
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) patients and their relatives (PaR) face tremendous distress and psychological burden due to limited survival and neurological/neuropsychological deficits. Tumor Treating Fields (Optune®, TTFields 200 KHz) are a novel therapy for patients with newly diagnosed and recurrent GBM. TTFields being a new therapy, provide means for PaR to actively contribute to therapy, but require concerted attention. Additionally, PaR may have to adapt to social exposure. Our clinical experience in Germany shows an urgent need for personal exchange; especially expressed by female patients. Establishing patient-driven support groups is limited mainly due to the rapid clinical course alongside with neurological/neuropsychological deficits. The aim of this study is to systematically evaluate PaR`s needs, to implement a platform for personal exchange, and to analyze PaR`s benefit. Questionnaires to evaluate PaR`s needs regarding meeting other PaR included: preferences for time, frequency, and maximal travel distance. In addition, type/frequency of the desired professional support was queried. Quality of life and emotional function were determined 2 weeks before and after implementing this program by the questionnaires PHQ-2 and GAD-2. We assessed 9 PaR using Optune® at our department. 7/9 PaR expressed a strong demand to interact frequently with other PaR using Optune®, especially during the first months after start of treatment. Therefore, we established a meeting in a stimulating surrounding, accompanied and supported by the treating physician and psychologist. Additionally, an internet platform will be established allowing PaR exchanging contact data, but with access only for PaR using Optune®. According to the assessed needs, this pilot project established a communication platform for GBM-PaR using Optune®. Furthermore, we have implemented this concept into our clinical routine. Every PaR will be offered access to the internet platform and we encourage other centers to consider a guided PaR meeting.
NCOG-08. NEUROCOGNITIVE FUNCTIONING IN EORTC BRAIN TUMOR GROUP RANDOMIZED PHASE II TAVAREC TRIAL (EORTC 26091, NCT01164189) ON TEMOZOLOMIDE WITH OR WITHOUT BEVACIZUMAB in 1p/19q INTACT RECURRENT GRADE II AND III GLIOMAS
Authors: Martin Klein, Jaap C Reijneveld, Ahmed Idbaih, Walter Taal, Paul M Clement, Filip de Vos, Antje Wick, Paul Mulholland, Martin J B Taphoorn, Joanne Lewis, Michael Weller, Tina Verschuere, Vassilis Golfinopoulos, Thierry Gorlia, Martin van den Bent
Journal: Neuro-Oncology (2017)

EORTC study 26091 showed that addition of bevacizumab (BEV) to temozolomide (TMZ) does not improve overall survival (OS) or progression-free survival (PFS) in recurrent grade II and III 1p/19q intact gliomas; regardless of isocitrate dehydrogenase (IDH) mutational status. This abstract reports the neurocognitive functioning (NCF) outcomes. NCF was evaluated before randomization and at every 12 weeks during treatment using Hopkins Verbal Learning Test (Free Recall, Delayed Recall, and Delayed Recognition), Trail Making Test (TMT A/B); and Controlled Oral Word Association Test (COWA). 148/155 patients had at least one NCF assessment. Compliance was 91.5% at baseline and dropped to 61.9% at week 60. Primary analysis (at 5% significance level) compared NCF at the last disease assessment before or at week 60 in patients who had at least one NCF assessment after baseline. Patients in the temozolomide+bevacizumab arm did not differ from patients in the temozolomide only arm. Except for Delayed Recognition, all NCF outcomes were positively associated with WHO performance status. TMT A (p=0.03), TMT B (p=0.006) and COWA (p<0.0001) were significantly worse in patients receiving steroids at study entry. Furthermore, delayed recognition was worse in patients with larger tumors (>26.5 vs <=26.5 mm; p=0.04). Memory performance was poorer in patients with tumors in the left hemisphere (Free Recall; p=0.0002), Delayed Recall; p<0.0001, Delayed Recognition; p=0.004). Except for Free Recall and Delayed Recognition, all other baseline raw scores were associated with OS in univariate analyses. In a multivariate Cox regression model, TMT B and tumor size were identified as independent OS prognostic factors while baseline WHO performance status and steroids use were not included. At the group level patients in the temozolomide+bevacizumab arm do not differ from patients with temozolomide only, individual patients’ verbal memory capacity might negatively be affected by tumor volume and tumor location.
Generating new evidence, improving clinical practice and developing research capacity: the benefits of recruiting to the U.K. Dermatology Clinical Trials Network's <scp>STOP GAP</scp> and <scp>BLISTER</scp> trials
Authors: J.M. Batchelor, A. Chapman, F.E. Craig, K.E. Harman, G. Kirtschig, A. Martin‐Clavijo, A.D. Ormerod, S. Walton, H.C. Williams
Journal: British Journal of Dermatology (2017)

Clinical trials may benefit clinical practice in three ways: firstly, clinicians may change their practice according to the new trial evidence; secondly, clinical processes can improve when working on a trial; and thirdly, research capacity is increased. We held a meeting to present and discuss the results of two large multicentre randomized controlled trials delivered through the U.K. Dermatology Clinical Trials Network. Investigators gave reflections on how the trials had changed their clinical practice. The STOP GAP trial showed that prednisolone and ciclosporin are equally effective as first‐line systemic treatment for pyoderma gangrenosum. The final decision of which treatment to use should be based on the different adverse event profiles of the two drugs in relation to comorbidities, along with age, disease severity and patient preference. The BLISTER trial showed that starting people with pemphigoid on doxycycline produces acceptable short‐term effectiveness and a superior safety profile to oral corticosteroids. Recruiting to these trials has led to the development of new specialist clinics with improved documentation. It has increased the profile of participating departments and embedded research in the department's activities. Helping to design and run these trials has also allowed trial staff to develop new skills in research design, which has been beneficial for career development. These and other benefits of recruiting to the trials are summarized here. We hope that these reflections will inspire wider involvement in clinical research.
P2.02-015 Mutation Patterns in a Swedish Non-Small Cell Lung Cancer Cohort
Authors: L. La Fleur, E. Falk-Sörqvist, P. Smeds, J. Mattsson, M. Sundström, E. Branden, H. Koyi, J. Isaksson, H. Brunnström, M. Nilsson, P. Micke, L. Moens, J. Botling
Journal: Journal of Thoracic Oncology (2017)