tbuckley/cabot-search huggingface dataset:
Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer.
Authors: JD Lewis, AB Chagpar, EA Shaughnessy, MJ Edwards
Journal: Cancer Research (2009)

Abstract Abstract #1130 Purpose: Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators (SERMs), are therapeutically equivalent in treating metastatic breast cancer. We hypothesized that toremifene may have superior therapeutic efficacy as adjuvant therapy for early breast cancer.&amp;#x2028; Patients and Methods: The North American Fareston versus Tamoxifen Adjuvant (NAFTA) trial, a multicenter investigator-initiated randomized controlled trial, assigned 1813 female peri- or post-menopausal patients with hormone receptor positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS), defined as the time from registration to local and/or systemic recurrence, and overall survival (OS), defined as the time from registration until death from any cause. Both an intention-to-treat and a per-protocol analysis were performed.&amp;#x2028; Results: Median follow-up was 59 months. The baseline characteristics of the two treatment groups were generally well balanced, although the tamoxifen group tended to be older (median age: 68 vs. 67 years, p=0.096), with larger tumors (median tumor size: 1.3 cm vs. 1.2 cm, p=0.086), of higher grade (proportion Grade 3: 18.3% vs. 15.7%, p=0.081). Based on intention-to-treat, mean OS was not significantly different between tamoxifen and toremifene ((98.1 mo. vs. 98.6 mo., respectively, p=0.628). Similarly, mean DFS was not significantly different between tamoxifen and toremifene (96.4 mo. vs. 96.7 mo., respectively, p=0.790). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene vs. tamoxifen in terms of OS (OR = 0.951; 95% CI: 0.623-1.451, p=0.951) or DFS (OR = 1.037; 95% CI: 0.721-1.491, p=0.846). Of the 1813 patients in the study, 104 (5.7%) had a protocol violation after randomization and did not start a study drug. The proportion of such patients was evenly distributed between the tamoxifen and toremifene groups (5.2% vs. 6.3%, respectively, p=0.394). Excluding these patients, survival times were similar between the tamoxifen and toremifene groups (mean OS: 96.401 vs. 96.776, p=0.766; DFS: 98.170 vs. 98.646, p=0.607). Cox proportional hazards models for OS (p=0.951) and DFS (p=0.843) failed to demonstrate a significant difference between the two treatment arms in the per-protocol analysis.&amp;#x2028; Conclusions: Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of hormone receptor positive patients with either of these SERMs is appropriate. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1130.
Abstract 4285: C-Met signaling supports a stem-like transcriptional program and phenotype in glioblastoma
Authors: Yunqing Li, Bachchu Lal, Hugo Guerrero Cázares, Alfredo Quinones-Hinjosa, Charles Eberhart, John Laterra
Journal: Cancer Research (2010)

Abstract Neoplastic stem-like cells that efficiently propagate tumor xenograft formation exist in solid cancers including glioblastoma. These cells are considered to be responsible for therapeutic resistance and tumor recurrence. The nature of these neoplastic stem-like cells and the molecular signaling pathways that support their phenotype are incompletely defined. The receptor tyrosine kinase c-Met and its ligand HGF promote the formation and growth of multiple cancers including the gliomas. We recently found that GBM-derived neurospheres that are enriched in tumor-initiating stem-like cells widely express activated c-Met. Using flow cytometry and quantitative reverse transcription-PCR, we found that neurosphere cell subpopulations expressing c-Met at high levels also express high levels of the neuroprogenitor/stem cell markers SoX2 and Nestin in comparison to low c-Met expressing cells. Also, CD133+ cells were found to express up to 10-fold higher levels of c-Met relative to CD133- cells. We hypothesize that c-Met might function to support GBM-derived stem-like cells. To test this hypothesis, we examined the effects of c-Met activation/inhibition on the growth and gene expression patterns of established human GBM neurosphere cell lines and low passage primary neurospheres derived from GBM xenograft lines. HGF statistically significantly enhanced cell growth rates and neurosphere forming capacity, a biological marker of the stem cell phenotype. Conversely, inhibiting c-Met kinase activity with SU11274 statistically significantly diminished neurosphere formation and depleted cultures of CD133+ cells. C-Met activation by HGF activated MAPK, AKT and Stat3 and induced expression of SoX2, KLF4 and c-Myc, transcription factors that support stem cell phenotypes. Together, these findings establish a link between c-Met expression/function and the neoplastic stem-like molecular fingerprint and phenotype in GBM-derived cells. The findings suggest that c-Met inhibitors may have a role in the development of therapeutic strategies for targeting tumor-initiating stem-like cells in malignant glioma and other solid cancers. Funded by CA129192 (NIH) and the Brain Tumor Funders Collaborative. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4285.
Automatic optical diagnosis of small colorectal lesions by laser-induced autofluorescence
Authors: Teaco Kuiper, Yasser Alderlieste, Kristien Tytgat, Marije Vlug, Joyce Nabuurs, Barbara Bastiaansen, Mark Löwenberg, Paul Fockens, Evelien Dekker
Journal: Endoscopy (2014)

<b>Background and study aims:</b> Endoscopic optical diagnosis can potentially replace histopathological evaluation of small colorectal lesions. The aim of this study was to evaluate diagnostic performance of WavSTAT, a novel system for automatic optical diagnosis based on laser-induced autofluorescence spectroscopy. <b>Patients and methods:</b> Consecutive patients who were scheduled for colonoscopy were included in the study. Each detected lesion with a size of ≤ 9 mm was differentiated using high resolution endoscopy (HRE) by the endoscopist, who then reported this as a low or high confidence call. Thereafter, all lesions were analyzed using WavSTAT. Histopathology was used as the reference standard. The primary outcome measures were the accuracy of WavSTAT to differentiate between adenomatous and nonadenomatous lesions, and the accuracy of an algorithm combining HRE (lesions differentiated with high confidence) and WavSTAT (all remaining lesions). The secondary outcome measure was the accuracy of on-site recommended surveillance intervals. <b>Results:</b> At total of 87 patients with 207 small colorectal lesions were evaluated. Accuracy and negative predictive value of WavSTAT were 74.4 % and 73.5 %, respectively. The corresponding figures for the algorithm were 79.2 % and 73.9 %, respectively. Accuracy of on-site recommended surveillance interval was 73.7 % for WavSTAT alone and 77.2 % for the algorithm of HRE and WavSTAT. <b>Conclusions:</b> Both accuracy of WavSTAT alone and the algorithm combining HRE with WavSTAT proved to be insufficient for the in vivo differentiation of small colorectal lesions, and do not fulfill American Society for Gastrointestinal Endoscopy performance thresholds for assessment of diminutive lesions. Future studies should assess whether combining WavSTAT with more advanced imaging techniques could result in a higher accuracy. Netherlands Trial Registry (NTR 3235).
FRI0135 Baseline characteristics and twelve month outcomes of patients from the prague early rheumatoid arhritis clinic
Authors: H. Mann, O. Růžičková, O. Šléglová, M. Fojtíková, D. Tegzová, Š. Forejtová, L. Šenolt
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Early treatment with disease modifying anti-rheumatic drugs (DMARDs) improves outcome in patients with rheumatoid arthritis (RA). Early arthritis clinic is a useful tool which allows early treatment initiation for high risk patients. <h3>Objectives</h3> To evaluate baseline characteristics and first year treatment outcomes of patients with early RA reffered to the Prague Early Rheumatoid Arthritis Clinic (PERAC). <h3>Methods</h3> Patients with symptom duration ≤6 months were reffered by their primary care physicians in accordance with published recommendations (1). Only patients with RA fulfilling the 2010 ACR/EULAR classification criteria (2) or undifferentiated inflammatory arthritis not classifiable as another disease entity at the time of presentation, were included in the early RA (ERA) cohort. Patients were treated by rheumatologists per current guidelines. Clinical and laboratory data were collected at pre-specified time points. <h3>Results</h3> 427 patients were evaluated in the PERAC between 2008 and 2012. 131 of these were included in the ERA cohort, for baseline characteristics see Table 1. <h3>Conclusions</h3> Our data confirm that early RA patients have a very good clinical response to initial DMARD choice. Side effects of methotrexate leading to treatment discontinuation were rare. ACR/EULAR RA classification and provisional remission criteria are feasible for use in clinical practice. <h3>References</h3> Emery P, Breedveld FC, Dougados M et al. Ann Rheum Dis. 2002;61:290-7. Aletaha D, Neogi T, Silman AJ, et al. Arthritis Rheum. 2010;62:2569-81. Felson DT, Smolen JS, Wells G et al. Ann Rheum Dis. 2011;70:404-13. <h3>Acknowledgements</h3> Supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00023728 (Institute of Rheumatology) <h3>Disclosure of Interest</h3> None Declared
Abstract 4226: CD44 increases drug resistance by protecting FBXO21 mediated ubiquitination of P-glycoprotein
Authors: Abhilash K. Ravindranath, Swayamjot Kaur, Lorna Rodriguez
Journal: Cancer Research (2012)

Abstract Drug resistance and metastases are major causes of treatment failure in cancer. These two important but not clearly related aspects in the biology of cancer have been extensively studied, but not until recently has there been evidence that these phenotypes are functionally linked. Two proteins, P-glycoprotein (P-gp) and CD44 are well known determinants of multidrug resistance and metastases, respectively. P-gp, the product of the ABCBC1 gene is a transmembrane ATP-dependent transporter that confers drug resistance to cancer cells. CD44 is a membrane protein implicated in metastases and has been identified as a “stem cell” marker for various types of cancer. Previously, we reported about a physical and functional interaction between P-gp and CD44. We found that the two proteins co-immunoprecipitate and co-localize within the cell membrane. When we introduced CD44 into CD44 (-) breast cancer cell lines, we found that P-gp expression was also induced both at the mRNA and protein level and the cells became drug resistant. In the present work we created a yeast-2-hybrid system that corroborates the physical interaction between the two proteins. We generated point mutants of the CD44 intracytoplasmic domain at two different serine residues known to be phosphorylation sites and show that when Ser 291 of CD44 is mutated, P-gp function is completely inhibited and the cells revert to drug sensitive in face of P-gp expression. We therefore hypothesized that CD44 could be stabilizing P-gp. We first determined that P-gp is ubiquitinated and degraded by the proteasomal pathway. We then screened a siRNA E3 ligase library and found several candidates for P-gp E-3 ligases. We tested FBXO21, which is in the FBOX family of ligases and does not have a known function yet. We demonstrated that FBXO21 ligase binds, ubiquitinates, and degrades P-gp. Furthermore, we show that CD44 inhibits FBXO21 directed ubiquitination of P-gp. Our findings are key to the understanding of P-gp induced drug resistance and reveal a new control mechanism of P-gp expression. Our work uncovers CD44 phosphorylation at Ser 291 as an excellent and very specific new drug target that would distinctively affect drug resistant cancer cells that are CD44 positive, such as cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4226. doi:1538-7445.AM2012-4226
MTR-17MOLECULAR MACHINERY FOR AQUISITION OF TKI RESISTANCE IN GLIOBLASTOMA BY IGFBP2 THROUGH PROFILE TRANSITION FROM GMT TO STEMNESS FEATURE
Authors: Shinya Tanaka, Masumi Tsuda, Lei Wang, Mishie Tanino, Taichi Kimura
Journal: Neuro-Oncology (2015)

BACKGROUND: For GBM treatment, in addition to the advancement of surgical procedure, uncovering the therapy-resistant mechanism is a crucial issue. To date, we have revealed the significance of epiregulin-mediated stemness induction for TMZ-resistance (Kohsaka, S., et al. Neuro-Oncol, 16, 960-970, 2014), and implication of glial-mesenchymal transition (GMT) for radiation resistance (Mahabir, R., et al., 16, 671-685, 2014). Since TCGA analysis revealed the frequent mutation in receptor tyrosine kinases (TKs) in GBM, several clinical trials for TK inhibitor (TKI) have been designed but no significantly effective protocol is established mainly due to the acquisition of resistance to TKIs. PURPOSE: To investigate the molecular machinery underlying TKI resistance, therapy-resistant KMG4 GBM cells against each EGFR, MET, and PDGFR were established and long-term profiling analysis with biological features was performed until day 0 to 150. RESULTS: Against our expectation, in spite of the usage of differential chemicals against individual TK as EGFR, MET, and PDGFR, all three TKI resistant GBM cells equally exhibited GMT feature in early stage around Day 50, but in the later stage this GMT profile transited to stemness-like profile both in vitro and in vivo. By microarray analysis of expression profiling, several genes were observed to be commonly elevated in all three TKI-resistant cells, and among them, IGFBP2 (insulin-like growth factor receptor binding protein2) was confirmed to be increased in four other GBM cell lines and several patient derived culture cells. Significance of IGFBP2 was proved by knockdown analysis in which siRNA for IGFBP2 re-sensitized the treatment efficiency in all three TKI-resistant cells. CONCLUSION: In the process of TKI-resistance, GBM exhibits profile transition from GMT to stemness, and IGFBP2-mediated signal can be a universal target to prevent acquisition of TKI resistance.
False-Positive Findings in Post-Treatment Iodine-131 Whole-Body Scintigraphy in a Nasolacrimal Sac Cyst, Confirmed With SPECT/CT and MRI
Authors: Mehmet Mulazimoglu, Serhat Koca, Muge Oner Tamam, Ercan Uyanik, Tevfik Ozpacaci
Journal: Clinical Nuclear Medicine (2011)

A case of a patient with papillary thyroid carcinoma with false-positive iodine-131 accumulation in a nasolacrimal sac cyst has been reported. A 63-year-old woman underwent total thyroidectomy for multifocal papillary thyroid carcinoma. After the treatment, iodine-131 whole-body scintigraphy revealed uptake in the neck consistent with thyroid remnant tissue and focal uptake in the head. SPECT/CT revealed focal uptake in the anterior lateral wall of right nasal cavity. Magnetic resonance imaging demonstrated the area of radioiodine accumulation corresponded to cystic enlargement of the right lacrimal sac.
Autologous Bone Marrow Transplantation versus Intensive Consolidation Chemotherapy for Acute Myeloid Leukemia in Childhood
Authors: Yaddanapudi Ravindranath, Andrew M. Yeager, Myron N. Chang, C. Philip Steuber, Jeffrey Krischer, John Graham-Pole, Andrew Carroll, Susumu Inoue, Bruce Camitta, Howard J. Weinstein
Journal: New England Journal of Medicine (1996)

The value of autologous bone marrow transplantation in the treatment of children with acute myeloid leukemia (AML) is unknown. We compared autologous bone marrow transplantation with intensive consolidation chemotherapy as treatments for children with AML in first remission.
Antigen-specific recognition of autologous leukemia cells and allogeneic class-I MHC antigens by IL-2-activated cytotoxic T cells from a patient with acute T-cell leukemia
Authors: P Fisch, G Weil-Hillman, M Uppenkamp, JA Hank, BP Chen, JA Sosman, A Bridges, OR Colamonici, PM Sondel
Journal: Blood (1989)
1159 ABSENCE OF PHOTOSENSITIVITY POTENTIAL OF TMC435 IN HEALTHY VOLUNTEERS
Authors: A. Simion, L. Janssens, M. Peeters, S. Ouwerkerk-Mahadevan, K. Spittaels, G. De Smedt, S.H. Akuma, M. Beumont-Mauviel
Journal: Journal of Hepatology (2012)
OP0283 Increased Neutrophil Extracellular TRAP Formation in Rheumatoid Arthritis is Correlated with the Induction of Pathogenic Th1 And/Or TH17 Cell Responses
Authors: G. Papadaki, C. Choulaki, G. Bertsias, K. Kampas, A. Repa, D. Boumpas, P. Verginis, P. Sidiropoulos
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Neutrophils are important in rheumatoid arthritis (RA) pathogenesis, with a key role in inflammation and cartilage damage. Activated neutrophils form extracellular traps (NETs) with potent pro-inflammatory and immunostimulatory activity. <h3>Objectives</h3> Thus, we sought to assess the role of NETs in RA pathogenesis using human samples and the collagen induced arthritis (CIA) mouse model. <h3>Methods</h3> Human peripheral blood neutrophils were isolated from active RA patients (n=6) and healthy controls (HC) (n=7). NET formation, both spontaneous and following incubation with RA serum (n=7) or synovial fluid (n=7), was assessed by immunofluoresence microscopy (co-staining with myeloperoxidase (MPO) and 49,6-Diamidino-2-phenylindole dihydrochloride (DAPI)). Extracellular DNA content was quantified by fluorescence spectrometry (picogreen). Bone marrow (BM)-derived neutrophils (Ly6G<sup>+</sup>) (from CIA and control mice) were <i>in vitro</i> tested for their ability to form NETs using confocal microscopy (co-staining of extracellular DNA (DAPI) with MPO). Lymph nodes from CIA mice were isolated 9 days after the collagen immunization, cultured in the presence of bovine collagen II (CII) and the presence or absence of CIA-NETs supernatants. IFNγ/IL-17 production in culture supernatants was determined. <h3>Results</h3> Freshly isolated RA peripheral blood neutrophils underwent spontaneous NETosis at higher rates compared to healthy controls (p&lt;0.05). Incubation of healthy neutrophils with RA serum or synovial fluid induced higher NET release compared to normal serum (p&lt;0.005). Moreover, RF positive patients (n=6) exhibited significantly increased spontaneous NET formation compared to RF negative (n=8) (p=0.008, DNA quantification by picogreen). In RA mouse model, there was increased NET formation rate in CIA BM neutrophils versus naïve BM neutrophils and the presence of NETs (supernatants from CIA-NETs) significantly augmented the induction of pathogenic Th1 and/or Th17 cell responses compared to supernatants from naïve BM neutrophils (p&lt;0.05). <h3>Conclusions</h3> We found that neutrophils from RA patients have enhanced NET formation, driven by soluble factors found in RA sera and synovial fluid, and that the effect was enhanced in seropositive for RF patients. Moreover, there is an evidence for the role of CIA-NETs in the perpetuation of adaptive immune responses. Further studies will address the mechanism through which CIA-NETs enhance the priming of Th1/Th17 immune responses, and whether suppression of NETs <i>in vivo</i> may ameliorate arthritis in RA mouse models. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5315
AB0148 Leucine-Rich Alpha-2 Glycoprotein is A Potential Disease Activity Marker under IL-6 Suppression in Autoimmune Arthritis
Authors: T. Mishima, S. Serada, M. Fujimoto, K. Hattori, A. Ogata, T. Nanki, T. Takeuchi, T. Naka
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> C-reactive protein (CRP) is frequently used to evaluate inflammation in patients with rheumatoid arthritis (RA). However, CRP is normalized when IL-6 function is potently suppressed by anti-cytokine biologics such as tocilizumab. Therefore, novel biomarkers are required for accurate and sensitive assessment of the inflammation during anti-cytokine therapy. By proteomic screening of sera from patients with rheumatoid arthritis (RA), we previously identified serum leucine-rich alpha-2 glycoprotein (LRG) as a potential biomarker that reflects disease activity in RA better than CRP. <h3>Objectives</h3> This study is aimed to investigate the clinical significance of LRG as a biomarker of RA disease activity during anti-IL-6 therapy. <h3>Methods</h3> As a preclinical testing, cynomolgus monkeys with collagen induced arthritis (CIA) were treated with anti-IL-6 receptor antibody (anti-IL-6R mAb) and joint swelling and rigidity were scored for clinical assessment of arthritis throughout the experiment. At the time of sacrifice, blood samples were collected to be subjected to the measurement of LRG and CRP. RA patients treated with tocilizumab were enrolled and clinical disease activity index (CDAI) and serum levels of LRG and CRP were evaluated. <h3>Results</h3> In CIA monkeys with anti-IL-6R mAb treatment, plasma LRG levels correlated better with disease activity than plasma CRP levels, presumably due to the fact that LRG levels were elevated in some animals with negative CRP in spite of high arthritis scores. Furthermore, among tocilizumab-treated patients for 6 months with normalized CRP levels (&lt;0.2 mg/dL), serum LRG levels were significantly higher in patients with active RA (defined by CDAI&gt;10) than those with RA with low disease activity (CDAI≤10). <h3>Conclusions</h3> Our study indicates that LRG is a promising biomarker for monitoring disease activity in RA, even when CRP levels are reduced or normalized by anti-cytokine therapy. <h3>References</h3> I Navarro-Millán et al. Systematic Review of Tocilizumab for Rheumatoid Arthritis: A New Biologic Agent Targeting the Interleukin-6 Receptor Clin Ther 2012; 34: 788-802 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2180