tbuckley/cabot-search huggingface dataset:
A sensitive method for detection of EGFR gene mutations in plasma
Authors: H. R. Sanders, K. Z. Qu, A. D. Sferruzza, C. M. Strom, R. A. Bender
Journal: Journal of Clinical Oncology (2007)

18027 Background: Somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene are associated with clinical response to TK inhibitors in patients with non-small cell lung cancer. An assay that detects such mutations in the plasma would provide a noninvasive technique to assess suitability for TK inhibitor therapy. Here we describe: 1) the development of a sensitive assay to detect the E746-A750 deletion in the TK domain of EGFR in plasma; and 2) optimization of the method for plasma DNA extraction. Methods: Our assay uses Mse I to specifically digest wild-type (WT) genomic DNA (gDNA) to reduce non-specific amplification. After digestion, samples are PCR- amplified using 1 unlabeled primer and 1 FAM-labeled primer spanning the E746-A750 deletion region and fluorescence detected with an automated analyzer. Serial dilution studies were conducted using H1650 gDNA (del E746-A750 cell line) diluted in WT gDNA after Mse I digestion. To assess detection of the deletion in plasma, 3–4 mL whole blood was spiked with 1–37 ng H1650 gDNA; gDNA from the separated plasma was then extracted (silica column/2-propanol precipitation), digested with Mse I, and amplified as above. Several extraction methods were evaluated using pooled plasma samples and PBS spiked with 10–350 ng gDNA: silica column, magnetic bead, phenol:chloroform, and 2-propanol precipitation. Results: Digestion of the WT EGFR allele followed by deletion-specific fluorescent PCR allowed detection of caof ca. 1 copy of the del E746-A750 EGFR gene (10 pg gDNA) diluted to 0.001%. Furthermore, del E746-A750 was successfully detected in 1/5 the final DNA volume (5 μl) in all spiked blood samples. Magnetic bead-based DNA extraction yielded the highest percent recovery of gDNA from PBS (69% recovery of the 10-ng sample). Phenol:chloroform extraction gave the highest yield with pooled plasma samples. Conclusions: The combination of an optimized DNA extraction method, clearing the plasma DNA sample of amplifiable WT DNA by restriction digestion, and mutation-specific fluorescent PCR provides a highly sensitive assay for detection of somatic mutations in plasma. No significant financial relationships to disclose.
P05.07 * A LOWER-DOSE CISPLATIN-ETOPOSIDE REGIMEN FOR CHILDREN WITH HYPOTHALAMIC/CHIASMATIC TUMOR AND DIENCEPHALIC CACHEXIA
Authors: S. Cardellicchio, S. Farina, C. Bresci, V. Settimelli, S. Chiaro, M. Massimino, L. Genitori, I. Sardi
Journal: Neuro-Oncology (2014)

Diencephalic Syndrome (DS) is a rare but potentially lethal condition, which may complicate the clinical course of infants with hypothalamic/chiasmatic tumors, usually low-grade gliomas, either pilocytic (WHO-grade I) or pilomyxoid (WHO-grade II) astrocytomas. The mean survival of DS patients who do not receive any treatment after diagnosis, is usually less than 12 months. Yet, effective therapy is hampered by the tumor location preventing its complete resection, and by significant neurocognitive and endocrinological sequelae associated with potentially curative radiotherapy. The aim of our study was to induce an objective tumor response and to obtain a rapid weight recovery, using ten three-day courses of reduced dose cisplatin-etoposide. Between 2004 and 2009, 8 pediatric patients with DS due to a hypothalamic tumor and a median age at diagnosis of 6.5 months (range: 4-60 months) received 10 monthly courses of cisplatin (25 mg/m2/d on days 1 to 3) and etoposide (100 mg/m2/d on days 1 to 3). All patients had a rapid weight recovery and a tumor response in 6 (75%;partial response in four and minimal response in two), while the remaining two had a stable disease at completion of treatment. Mean time to weight recovery was 6 months (range, 5 - 7 months) for pilomyxoid astrocytoma patients, and 3.3 months (range, 3 - 4 months) for those with pilocytic astrocytoma. DS patients who received nutritional support (enteral or parenteral nutrition) had a mean time of weight recovery of 5 months (range: 3 - 7 months), while children who were able to assume high energy diet by oral route had a mean time of weight recovery of 8.66 months (range 3 - 19 months). After a follow-up time ranging from 22 to 89 months (median, 38 months), all patients are alive. In conclusion, a chemotherapy program with ten three-day courses of reduced dose cisplatin-etoposide, according to a LGG type schedule, seems appropriate and effective in far most cases of DS, with lower ototoxicity and myelosuppression compared with other LGG regimens.
A1.10 The GM-CSF/CCL17 axis in the rheumatoid synovial environment
Authors: SV Kidger, CD Ellson, IB McInnes, MA Sleeman, MJ Robinson, CS Goodyear
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> GM-CSF is a pivotal growth factor/cytokine that can drive aspects of RAimmunopathogenesis. In particular, GM-CSF can activate monocytes and induce their differentiation towards alternative phenotypes. The synovial environment also contains additional factors that can influence monocyte activation such as damage associated molecular patterns (DAMPs); many of which signal via TLR4. However, the impact of GM-CSF on monocytes in a synovial setting is not well understood and therefore we aimed to investigate the response of monocytes to GM-CSF in the context of synovial fluid (SF) co-stimulation. <h3>Materials and methods</h3> Monocytes isolated from human blood or murine bone marrow were cultured in the presence or absence of GM-CSF (1ng/ml) and co-stimulated with SF (2.5%/5%) from RA or OA patients. Supernatants were harvested after 24 h and chemokine and cytokine secretion was analysed by ELISA and/or MSD. Immune complexes were made by incubating human IgG and Staphylococcal Protein A at a ratio of 4:2 respectively. <h3>Results</h3> Monocytes from healthy individuals and RA patients, secreted substantial amounts of CCL17 upon stimulation with GM-CSF. In healthy monocytes, GM-CSF driven induction of CCL17 was significantly inhibited (P &lt; 0.01) upon co-stimulation with RA-SF but not OA-SF, whilstthe expression of other chemokines and cytokines was un-affected. GM-CSF induced phosphorylation of STAT5 was not affected by RA-SF exposure, suggesting the inhibition was downstream of receptor and proximal signalling. Furthermore, inhibition of CCL17-induction via RA-SF was TLR-independent, as RA-SF could inhibit CCL17 induction in MyD88/TRIF double knockout murine monocytes. In addition to DAMPs, SF also contains immune complexesand cytokines. We tested if TNF, IL1a or IL-6 could reproduce the effect of SF, but none of these cytokines impacted GM-CSF induction of CCL17. To investigate if the inhibitory capacity of SF may be due to immune complexes, small immune complexes were made, and these did inhibit GM-CSF-mediated production of CCL17 in monocytes. <h3>Conclusions</h3> GM-CSF&nbsp;induced production of CCL17 in monocytes is inhibited by RA-SF. The underlying mechanism is not known, however, our work shows that it is TLR-independent and downstream of STAT5 phosphorylation. Immune complexes also inhibit GM-CSF induction of CCL17 suggesting these may contribute to the phenomenon.
Menthol and Nonmenthol Cigarette Smoking
Authors: Heather M. Munro, Robert E. Tarone, Thomas J. Wang, William J. Blot
Journal: Circulation (2016)

In contrast to whites, black smokers prefer menthol cigarettes over nonmenthol cigarettes by a large margin and tend to have higher mortality from several smoking-related diseases than whites, raising the possibility that menthol cigarettes contribute to racial disparities in risk. Evidence for differential associations between menthol and nonmenthol cigarettes indicates lower cancer risk for menthol smokers, but for cardiovascular disease (CVD) mortality, evidence has been inconsistent.
Bi-weekly dosing preserves the efficacy of rituximab in elderly patients with poor-prognosis DLBCL: Results from the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study group (DSHNHL)
Authors: J. Schubert, M. Reiser, M. Wenger, M. Kloess, E. Lengfelder, A. Franke, H. B. Steinhauer, M. Clemens, N. Schmitz, M. Loeffler, M. Pfreundschuh
Journal: Journal of Clinical Oncology (2006)

7536 Background: The addition of rituximab (R) to 3-weekly CHOP-21 improved overall results in elderly patients with DLBCL, but was more effective in good-prognosis (g-p: IPI = 1,2) than poor-prognosis (p-p: IPI = 3,4,5) patients (JCO 23:4117, 2005). Similarly, addition of R to bi-weekly CHOP-14 in the RICOVER-60 trial resulted in improved time to treatment failure (TTF) in 828 elderly (61–80 years) DLBCL patients (Blood 106:9a, 2005). To study the effects of R when combined with CHOP-14 in different subgroups of elderly DLBCL patients. Methods: Intention-to-treat-analysis of the primary endpoint time-to-treatment-failure (TTF) and the secondary endpoint overall survival (OS) in the subgroup of g-p and p-p patients treated within the RICOVER trial which compared 6 and 8 cycles of CHOP-14, both with and without R. Results: Of 828 evaluable patients (61–80 years, stage I-IV), 503 had g-p (CHOP-14 = 252; R-CHOP-14 = 251) and 325 p-p (CHOP-14 = 161; R-CHOP-14 = 163). After a median observation of 26 months, there was no difference between 6 and 8 cycles in either subgroup. In contrast, addition of R resulted in a similar improvement of TTF in both g-p (67% vs. 81%, p = 0.001) and p-p (36% vs. 52%, p = 0.004) patients. The improvement of survival is not yet different in either group: g-p: 82% (CHOP-14) vs. 88% (R-CHOP-14), p = 0.458; p-p: 58% (CHOP-14) vs. 64% (R-CHOP-14), p = 0.146. Pharmacokinetic studies show a pronounced nadir of R levels after the first R-CHOP-14, with R levels increasing after each subsequent cycle. The R nadir after the first R-CHOP is expected to be even more pronounced in a 3-weekly schedule and might explain the small improvement reproted for 3-weekly R in elderly patients with p-p DLBCL. Conclusions: Our subgroup and pharmacokinetic analysis indicate that not only dose-dense chemotherapy, but also dose-dense rituximab contribute to the excellent results of the RICOVER-60 trial. Supported by Deutsche Krebshilfe. [Table: see text]
AB0476 Superoxide dismutase is associated to large vessels involvement in behcet syndrome
Authors: O. Harzallah, R. Klii, D. Brahem, M. Kechida, S. Mahjoub
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In Behçet’s Syndrome (BS), all polymorphonuclear cells (PMN) capacities are enhanced: chemoattraction, phagocytosis and free radicals (FR) production (1, 2). The excess of FR, responsible for an oxidative stress (OS) state, could present an endothelial toxicity (3) and could be implicated in tissue lesions genesis in BS. <h3>Objectives</h3> The aim of our work was to analyze the correlation between oxidative stress biological markers and main vessels involvement in BS. <h3>Methods</h3> 40 BD patients (27 males, 13 females; mean age: 38.8 years) were prospectively enrolled in the study. Plasma malondialdehyde (MDA), erythrocyte superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-PX) were analyzed. Levels of these parameters were compared between patients having or not neurological (NI), ocular (OI) and large vascular involvement (LVI). <h3>Results</h3> There were 16 patients with large vessels involvement (LVI), 10 with neurological involvement and 13 having Behçet’s eye disease. Patients with LVI were: 14 with deep venous thromboses and 2 with arterial aneurysms. Only SOD was significantly decreased (p = 0.01) in patients having LVI when compared to patients without LVI (table 1). There were any differences in MDA, SOD, catalase and GSH-PX levels when comparing patients with and without ocular; with and without neurological involvement. <h3>Conclusions</h3> SOD is decreased in patients with LVI in BS. This preliminary result deserves further investigation by other studies with larger samples. However, it probably indicates that SOD, the first line anti-oxidant enzymatic defense, has a probable role in the endothelial membrane protection against free radicals aggression in BS. <h3>References</h3> Takeno M, Kariyone AI, Yamashita N et al. Excessive functions of peripheral blood neutrophils frompatients with Behçet’s disease and from HLA B51 transgenic mice. Arthritis Rheum 1995; 3:426 –33 Harzallah O, Kerkeni A, Baati T. Oxidative stress: Correlation with Behçet’s activity and severity European Journal of Internal Medicine 2008; 19: 541– 7 Niwa Y, Miyake S, Sakane T. Autooxidative damage in Behçet’s disease-endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 1982; 49: 247–55 <h3>Disclosure of Interest</h3> None Declared
CORONARY PLAQUE CHARACTERISTICS IN PATIENTS WITH HYPERTENSION: A 3-VESSEL OPTICAL COHERENCE TOMOGRAPHY STUDY
Authors: Rocco Vergallo, Shoichi Kuramitsu, So-Yeon Choi, Shiro Uemura, Bo Yu, Yoshiyasu Minami, Tsunenari Soeda, Haibo Jia, Ik-Kyung Jang
Journal: Journal of the American College of Cardiology (2015)
FRI0552 Systematic review of patient reported outcome measures used to measure stiffness in patients with rheumatoid arthritis
Authors: L. H. van Tuyl, W. F. Lems, M. Boers
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) often experience stiffness of joints, with considerable impact on functional capacity. While morning stiffness (MS) has been excluded from the core set due to poor measurement properties, recent qualitative research from our group suggests stiffness is an important symptom to patients when striving for remission (in preparation). <h3>Objectives</h3> This systematic review aims to identify available patient-oriented measurement instruments that have been developed to assess stiffness in patients with rheumatoid arthritis. <h3>Methods</h3> To identify measurement instruments for patient reported stiffness, an extensive Pubmed search was undertaken to identify existing, feasible measurement instruments or subscales of existing instruments for patient perceived stiffness, that have been developed or used within RA research. Eligible studies included reports of patient reported stiffness in RA patients 1) comparing stiffness as an outcome in relation to other core set disease activity measures, 2) aiming to develop a patient reported tool to measure stiffness, or 3) comparing two different tools to measure aspects of stiffness. <h3>Results</h3> Of 788 titles, 13 relevant studies were included in this review. Six questionnaires with stiffness as a subdomain were identified; 6 studies compared two or more stiffness scales with each other and 8 studies correlated stiffness to a core set measure. No specific stiffness questionnaires were identified. Measures of stiffness generally showed good correlation with core set measures (especially pain and function), and moderate correlation with each other, but did not adequately discriminate RA from non-inflammatory conditions or osteoarthritis. Compared to duration, severity of stiffness was superior in terms of sensitivity to change over time, responsiveness to therapy, differentiation between active and inactive disease and inter-patient variation. Two studies investigated whether MS levels differed between patients with active and inactive disease. One showed a significant relation between MS duration and disease activity levels (1); in the other the number of patients with current MS did not differ between active and inactive RA, but patients with active disease experienced significantly higher severity scores (2). <h3>Conclusions</h3> Measurement of stiffness in RA has been limited to the assessment of either morning stiffness duration or severity of (morning) stiffness. These two measures correlate moderately well with each other and other core set measures. Severity outperforms duration of MS, but data on measurement properties of MS in the spectrum of low disease activity or remission is scare. <h3>References</h3> Khan et al, 2009 Hazes et al, 1993 <h3>Disclosure of Interest</h3> L. van Tuyl Grant/research support from: Pfizer (unconditional grant), W. Lems: None Declared, M. Boers: None Declared
Abstract B53: Evaluation of HIF-1α mRNA inhibitor as antimultiple myeloma agent
Authors: Enrica Borsi, Giulia Perrone, Carolina Terragna, Sandra Durante, Marina Martello, Michele Baccarani, Michele Cavo
Journal: Cancer Research (2011)

Abstract Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that plays a critical role in survival and angiogenesis. In solid tumors, elevated expression of HIF-1α, in response to hypoxia or activation of growth factor pathways, is associated with tumor proliferation, metastasis, and drug resistance and correlated with poor prognosis. In contrast to solid tumours, the role of HIF-1α in hematological malignancies is not completely known. In particular in multiple myeloma (MM) HIF-1α has been suggested to be constitutively expressed and HIF-1α knockdown cell lines have shown higher sensitivity to standard chemotherapy, suggesting a role in the pathophysiology of MM. In the present study, we explored the effect of EZN2968, an antisense oligonucleotide against HIF-1α, as a molecular target in MM. We showed that the expression of HIF-1α in several MM cell lines is detectable in either normoxia or hypoxia conditions and is increased in the presence of growth stimuli (IL-6 and stroma cells). In vitro, EZN2968 induced selective and stable down-modulation of HIF-1α mRNA and protein expression, either in normoxia or hypoxia conditions. Immunofluorescence analysis confirmed the reduction of the protein after 24 hours of treatment, as well as a lower expression of VEGF. Clinically achievable doses of EZN2968 induced cell cycle arrest and cell death (10% to 60% of apoptotic cells compared to the controls after 24 to 96 hours, respectively) in MM cell lines. The activation of the apoptotic pathway was confirmed by western blot analysis at different time points. Moreover we observed an irreversible commitment to cell death after 48 hours of exposure. To evaluate the effect of microenvironment, MM cells treated with EZN2968 were exposed to IL-6 and stroma cells for additional 24 hours. EZN2968 overcame the proliferative effect induced by cytokines. EZN2968 showed moderate increase in efficacy in combination with conventional agents such as Melphalan, and immunomodulatory agents (Thalidomide and Lenalidomide). No significant effect on cell viability was observed on peripheral blood mononuclear cells and CD34+ cells from healthy donors treated with increasing doses of EZN2968. Evaluation of gene expression profiling modulation induced by EZN 2968 is ongoing. Our data suggest that HIF-1α inhibitor is an attractive therapeutic target for MM patients and provide the rationale for clinical evaluation of HIF inhibitor in combination with currently used MM agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B53.
P353Effects of mobilized stem cells on left ventricular function and remodeling in patients with heart failure
Authors: H Lim, D Lindarto, U Zein
Journal: Cardiovascular Research (2014)

Purpose: The ability of granulocyte colony-stimulating factor (GCSF) to mobilize endothelial progenitor cells (EPCs), as well as to protect cardiomyocytes at risk and to regenerate cardiomyocyte has attracted considerable attention. We hypothesized that G-CSF could improve left ventricular function and remodeling in patients with post-myocardial infarction heart failure. Methods: G-CSF (5.0 mg/kg/day) for 5 days, was administered subcutaneously to 24 patients with post-myocardial infarction heart failure (NYHA functional class II-III). Global left ventricular ejection fraction and left ventricular end-systolic and end-diastolic volumes were assessed by echocardiography. The effects of G-CSF on blood were measured by auto hematology analyzer and semi-auto chemistry analyzer. Flow cytometric analysis of circulating CD34+ hematopoietic progenitor cells was performed. Results: G-CSF increased the white blood cells significantly in the circulation (from 7.7 ±0.3 to 25.2±0.9 x103/ml, p<0.001) and CD34+ cells (from 1.37±0.12 to 23.51±5.37 cells/mL, p<0.001). Indices of platelets, hemoglobin, alanine aminotransferase, lactic dehydrogenase, and uric acid were not changed by treatment. At 1 month post-treatment, there was significant improvement of global left ventricular ejection fraction (43.05 ± 2.94 versus 53.91 ± 2.60 %, p<0.01); and improved left ventricular end-systolic (178.0 ± 8.3 versus 117.3 ± 5.3 ml, p<0.01) and end-diastolic volume (247.0 ± 11.0 versus 180.0± 7.5 ml, p<0,01). All patients reported mild myalgia which were easily managed with acetaminophen. Conclusions: The results show that G-CSF mobilizes stem cells from bone marrow and improve left ventricular function and remodeling in patients with heart failure. The treatment strategy was safe and tolerable in patients with post-myocardial infarction heart failure.
SAT0472 Accuracy of Systemic Lupus International Collaborating Clinics Classiffication Criteria Applied to Juvenile Systemic Lupus Erythematosus Patients
Authors: M. M. Katsicas, E. R. Borgia, R. A. Russo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background: Background/Purpose</h3> Systemic lupus erythematosus (SLE) is a prototype autoimmune disease. The most widely used classification criteria for SLE were those developed by the American College of Rheumatology (ACR) in 1982. The Systemic Lupus Collaborating Clinics (SLICC) revised the ACR SLE classification criteria and validated new criteria in adults. <h3>Objectives</h3> To assess sensitivity and specificity of revised and validated new SLICC SLE classification criteria in a cohort of Juvenile SLE (JSLE). <h3>Methods</h3> The SLICC criteria rule for SLE classification requires: 1) four criteria, with at least one clinical criterion and one immunological criterion or 2) lupus nephritis alone in the presence of ANA or anti-DNA antibodies. Cases were JSLE patients who have attended a single tertiary center in the past 10 years. JSLE had been diagnosed on clinical and immunological grounds by experienced pediatric rheumatologist. Controls were patients with rheumatic diseases other than SLE: Juvenile Idiopathic Arthritis (JIA); Juvenile Dermatomyositis (JDM), Autoimmune Hepatitis (AH), Juvenile Systemic Sclerosis (JSS), ANCA-associated vasculitis (AAV) and Henoch Schönlein Purpura (HSP). Clinical, immunological and pathological were reviewed from prospectively developed databases and medical records in order to establish the number and frequency of new criteria. Statistics included overall sensitivity and specificity. McNemar`s test was used to assess differences between ACR criteria and new current criteria. <h3>Results</h3> Cases: 107 patients with JSLE were included (F: 89 M: 18), age at onset: 12 (3-16) yo. Controls: 124 patients with JIA (36 patients); JDM (28), AH (28), JSS (10), AAV(12), HSP (10) F:95 M: 29, age at onset: 11 (2-16)yo. SLICC SLE criteria sensitivity was 100 % vs 86% ACR criteria, while specificity was 98% vs 96% (p=0.009). Six patients with a clinical diagnosis of JSLE were correctly classified by SLICC but not by ACR criteria. <h3>Conclusions</h3> The SLICC new criteria performed better than the ACR 1997 criteria in a cohort of patients with JSLE. Validation of these criteria in a wider, multiethnic cohort of patients with JSLE is necessary. <h3>References</h3> <h3>Disclosure of Interest</h3> None Declared