tbuckley/cabot-search huggingface dataset:
Clinical and pathologic correlation of the activated form of the estrogen receptor (ER) in breast cancer (BC).
Authors: Jacques Bonneterre, Erard M. Gilles, Alexander A. Zukiwski, Jacques Bosq, Alexander Valent, Emilie Hutt, Suzanne A.W. Fuqua
Journal: Journal of Clinical Oncology (2013)

592 Background: About 50% of ER positive (ER pos ) BC are resistant to hormone treatment. In absence of ligand, ERs are evenly distributed in nuclei in normal tissue. Upon ligand binding, ERs dimerizes and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of ER. This ER FDP is observed in BC. We hypothesized that in BC that the presence/absence of ER in the FDP could predict antiestrogen activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 archived BC biopsies were obtained along with clinical and pathology data. Biopsies were analyzed for standard HES, ER, progesterone receptor (PR) and Ki67. PR positivity was determined with distinct antibodies to the A and B isoforms. The A-ER and D-ER nuclear patterns were analyzed at x1000 magnification. Results: Mean age; 58 (17 -89). Histology: ductal 85% lobular 13%, other 2%; 84% ER pos and 84% either PRA pos or PRB pos , 7% ER pos and 7% PRA pos or PRB pos only. All but 3 ER pos cases had received AntiEs; Adj. chemotherapy 51%, Stage: I 51%, II 43%, III 6 %. Grade: I 24%, II 51%, III 25%. Median follow up 31 months (mo). Local or distant progression (PD) was 19%. ER status was D-ER in 78% and A-ER in 22% of the biopsies and PD was associated with the D-ER pattern (p = 0.06), e.g. the hypothetically non-functional pattern D-ER was associated with a higher rate of PD (4 vs 35). With DFS defined as time to PD or death (5 year cut off), ER pos was better that ER neg (HR= 0.38, p = 0.016). For ER pos BC, A-ER was numerically better than D-ER (HR =0.3, p=0.24 two-sided). In univariate analyses, A-ER pattern was associated with higher grade (p=0.035), anisonucleosis (p=0.06), mitotic index (p=0.02), and Ki67 (=0.08). No association was found between ER pattern and age, stage or HER2 status. Conclusions: This study supports the hypothesis that AntiEs are mainly active in BC with A-ER pattern, which is targetable by AntiEs. A larger number of events are needed to reach significance in time-dependent analyses and confirmatory studies are warranted.
Development of non-pyrogenic magnetosome minerals coated with poly-l-lysine leading to full disappearance of intracranial U87-Luc glioblastoma in 100% of treated mice using magnetic hyperthermia
Authors: Edouard Alphandéry, Ahmed Idbaih, Clovis Adam, Jean-Yves Delattre, Charlotte Schmitt, François Guyot, Imène Chebbi
Journal: Biomaterials (2017)
A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel / carboplatin followed by epirubicin / cyclophosphamide as neoadjuvant chemotherapy in patients with HER2-negative early breast cancer and homologous recombination deficiency (HRD): GeparOLA.
Authors: Peter A. Fasching, Jens Uwe Blohmer, Nicole Burchardi, Serban Dan Costa, Carsten Denkert, Claus Hanusch, Jens Bodo Huober, Gunter Von Minckwitz, Stefan Paepke, Andreas Schneeweiss, Sherko Kümmel, Michael Untch, Sibylle Loibl, Christian Jackisch
Journal: Journal of Clinical Oncology (2016)

TPS1096 Background: The efficacy of olaparib in breast cancer (BC) patients with HRD score high tumors +/- a germline or tumor BRCA 1/2 mutation is not well described. Toxicity data for the combination with chemotherapy is also scarce. Carboplatin (Cb) increased the pathological complete response (pCR) rate in triple-negative BC patients (GeparSixto, CALBG 40603). pCR (ypT0/is ypN0) rates were even higher in patients with gBRCA 1/2 mutations (65%) and HRD score high (63%). GeparOLA will assess the efficacy of olaparib in HER2-negative early BC and HRD [BRCA 1/2 mutations and/or HRD score high]. Methods: GeparOLA will randomize 102 patients to paclitaxel 80 mg/m² weekly (Pw) plus olaparib 100 mg twice daily for 12 weeks (PwO) or Pw plus Cb AUC 2 weekly for 12 weeks (PwCb), each followed by epirubicin/cyclophosphamide (EC). Randomization will be stratified by hormone-receptor status (HR+ vs HR-) and age ( < 40 vs ≥ 40 years). Patients with untreated primary cT2 - cT4a-d or cT1c with either cN+ or pNSLN+ or ER- and PR-neg or Ki67 > 20% can be enrolled, with either g/tBRCA mutation or high HRD score. Primary objective will be pCR (ypT0/is ypN0). Secondary objectives will be other pCR definitions (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0), breast conservation rate, tolerability and safety. Exploratory analyses will relate germline and tumor mutations (by next generation sequencing) and pCR. A pCR rate of ≤ 55% should be excluded (α = 0.1; 80% power) to support a subsequent phase III study. Assuming a pCR rate of 70%, 65 patients are needed for PwO, the study being positive, if pCR is ≥ 65% (90% confidence interval (CI) not including 55%). Based on previous results, pCR rate for PwCb will be 50-60% and 37 patients will provide a point estimate (90% CI of 27% width). Results: Recruitment will start in QI/2016 within approximately 40-50 sites in Germany. Conclusions: GeparOLA will assess whether a platinum agent in addition to paclitaxel or olaparib with paclitaxel will result in a higher pCR rate in patients with HER2-negative early BC with HRD. Clinical trial information: EudraCT No.: 2015-003509-41.
Current Clinical Challenges in Childhood Ependymoma: A Focused Review
Authors: Thomas E. Merchant
Journal: Journal of Clinical Oncology (2017)

Ependymoma is a locally aggressive tumor with metastatic potential that arises in diverse locations throughout the brain and spine in children. Tumor and treatment may result in significant morbidity. Cure remains elusive for many patients owing to diverse biology and resistance to conventional therapy. The implementation of systematic postoperative irradiation in clinical trials during the past 20 years has increased the proportion of patients achieving durable disease control with excellent results, as measured by objective functional outcome measures. Clinical, pathologic, and molecular risk stratification should be used to refine treatment regimens for children with ependymoma to reduce the risk of complications associated with therapy and increase the rate of disease control in the setting of combined modality or more intensive therapy. This review covers standards of care and current clinical trials for children with ependymoma, emphasizing the history and evolution of treatment regimens during the past 20 years and the clinical questions they hoped to address.
Improving prodrug cancer chemotherapy through enzyme evolution and molecular imaging
Authors: Yoram Barak, Stephen Thorne, Jianghong Rao, Christopher Contag, A Matin
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5654 

Reductive prodrugs, such as mitomycin C (MMC) and 5-aziridinyl-2,4-dinitrobenzamide (CB 1954), are nontoxic in their native form, but generate a highly toxic species when reduced. Given that only a small fraction of cells actively replicate in human tumor at a given time, these drugs are particularly advantageous because they can target both growing and non-growing cells. Reductive chemotherapy is presently based on the fact that the concentration of certain prodrug-reducing enzymes, such as the mammalian DT-diaphorase (NQO1), increases in tumor cells, making them more susceptible to their killing action. However, reduction of prodrugs also occurs in normal cells because reducing enzymes are present also in such cells, producing severe side effects. We constructed a mutant (ChrR6) of the newly discovered E. coli nitroreductase ChrR (formerly called YieF) using directed evolution. ChrR6 kills HeLa spinners, JC and 4T1 tumor cells with >6 fold greater efficiency than the wild type enzyme. The screening procedure employed to find ChrR6 was indirect. We recently developed a direct screening method for large mutants libraries of nitroreductases employing 6-chloro-9-nitro-5-oxo-5H-benzo[a]phenoxazine (CNOB), which is an analogue of CB 1954. Reduction of CNOB generates a highly fluorescent compound (aminophenoxazine) and thus permits rapid and direct screening for prodrug-reducing activity. To monitor reduction of CNOB in vivo we used the attenuated Salmonella typhimurium SL 7838 strain as a delivery vehicle for our enzymes. Using confocal microscopy we located SL 7838, expressing GFP and the tested enzyme, in the cytosol of HeLa cells. Furthermore, CNOB reduction was visualized in the same location. The reduction of CNOB by HeLa cells alone was undetectable. We also report, for the first time, that CNOB can act as prodrug with the same efficiency as CB1954 in in vitro as well as in vivo. As its cytotoxic product is fluorescent, it can be monitored in vivo . The novel ability to track both the delivery vehicle and prodrug reduction is unique and opens exciting possibilities for improving prodrug cancer gene therapy.
The Unique Ontogeny Of Natural Killer Cells As Revealed By Genetic Barcoding In The Nonhuman Primate Model
Authors: Chuanfeng Wu, Jan K. Davidson-Moncada, Rong Lu, Brian Li, Allen E. Krouse, Mark E. Metzger, Robert E. Donahue, Irving L. Weissman, Richard Childs, Cynthia E. Dunbar
Journal: Blood (2013)
Quels sont les résultats du traitement des hémorragies ulcéreuses par sérum adrénaline et thermocoagulation dans la vraie vie?
Authors: N Festou, F Fein, A Weber, S Koch, AC Dupont-Gossart, J Crouzet, P Mathieu, B Heyd, GA Mantion, F Carbonnel
Journal: Endoscopy (2006)

L'association d'un traitement thermique à une sclérothérapie endoscopique par serum adrénaliné est plus efficace que la sclérothérapie seule (Gastroenterology 2004; 126: 441). Ce résultat est le fruit d'études contrôlées conduites dans des centres de référence asiatiques (BMJ 1997; 314: 1407 et Gut 1999; 44: 715). On ignore s'il est valable en France où ce traitement est peu employé (Gastroentérol Clin 2005; 29: 140).
Temperature Sensors: Review of Flexible Temperature Sensing Networks for Wearable Physiological Monitoring (Adv. Healthcare Mater. 12/2017)
Authors: Qiao Li, Li‐Na Zhang, Xiao‐Ming Tao, Xin Ding
Journal: Advanced Healthcare Materials (2017)

Wearable temperature detection demands sensors with sufficient sensitivity and accuracy that could directly attach to non-planar skin surface with different gesture and motion for continuous measurement. Xiao-Ming Tao, Xin Ding, and co-workers exploit a comprehensive investigation onto recent advances in flexible and stretchable temperature sensor networks for wearable physiological monitoring with emphasis on critical issues and new trends in article number 1601371.
Circulating microrna as novel early biomarker of concussion in elite athletes
Authors: Zhangjie SU, Valentina Di pietro, David Davies, Michael Wang, Shaun Evans, Lisa Hill, Michael Grey, Antonio Belli
Journal: British Journal of Sports Medicine (2017)

Objective This study aims to investigate the role of microRNAs in early and late assessments of concussed athletes. Our hypothesis is that expression of certain microRNAs is altered following concussion, and these microRNAs have the potential to become novel biomarkers for early detection and monitoring of concussion. Design Prospective observational case control study. Setting University research centre, single centre. Participants 15 concussed athletes divided into 2 groups: Group A (n=9, assessed within a week post-concussion, median 4 days) and B (n=6, assessed over 2 weeks, median 31 days); and 8 age-matched healthy volunteers. Inclusion criteria: male/female elite athletes in contact sports (aged 18-40) who suffered concussion(s) in the games, and being symptomatic with normal neuro-radiological findings at enrolment. Outcome measures Levels of microRNAs (miR-21, miR-335, miR-425-5p, and miR-502) were measured in blood samples obtained from all participants. Main results miR425-5p was significantly down-regulated in Group A compared with Group B and healthy volunteers (grouping effect p=0.014; post hoc tests p=0.009 and 0.028, respectively). The level of miR425-5p correlated with the interval between assessment and concussion (r2=0.88, p&lt;0.001). No differences were found in other microRNA assessed between the groups. Conclusions miR-425-5p is down-regulated in the early phase following sport concussion, and reaches normal levels in the late period, suggesting that it may be a unique microRNA signature for concussion. This makes miR-435-5p a promising candidate biomarker for early evaluation of concussion and monitoring of its recovery. Further longitudinal studies are on-going to establish the time course of miR-425-5p normalisation after concussion. Competing interests None. Abstract 5 Figure 1
Colorectal cancer and vascular invasion: what is the prognostic implication?
Authors: RK Choudhary, D Debnath, KA Gunning
Journal: Endoscopy (2006)

Aims: Vascular invasion influences staging of certain cancers. However, such impact of vascular invasion in staging of colorectal cancer is not well known. We aimed to assess the association between vascular invasion and Dukes' stage of colorectal cancer.
Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis
Authors: Wanderson Kleber de Oliveira, Giovanny Vinícius Araújo de França, Eduardo Hage Carmo, Bruce Bartholow Duncan, Ricardo de Souza Kuchenbecker, Maria Inês Schmidt
Journal: The Lancet (2017)
Response to: ’Artery tertiary lymphoid organs in giant cell arteritis are not exclusively located in the media of temporal arteries' by Graver <i>et al</i>
Authors: Francesco Ciccia, Aroldo Rizzo, Carlo Salvarani, Giovanni Triolo
Journal: Annals of the Rheumatic Diseases (2017)

We thank Graver  et al 1 for their interest in our recently published article on artery tertiary lymphoid organs (ATLOs) in giant cell arteritis (GCA).2

The authors stained temporal artery biopsies of 21 biopsy-proven GCA patients (71% female, mean duration of disease of 2.3±0.9 months) that fulfilled the 1990 American College of Rheumatology classification criteria with anti-CD20 and anti-CD3 antibodies. On the basis of this experimental approach, they confirmed the presence of ATLOs only in the adventitia of inflamed arteries of GCA patients and not in the media as demonstrated in our study. This statement, however, is not supported in our opinion by the experimental approach chosen …
FUS–DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma
Authors: Marcel Trautmann, Jasmin Menzel, Christian Bertling, Magdalene Cyra, Ilka Isfort, Konrad Steinestel, Sandra Elges, Inga Grünewald, Bianca Altvater, Claudia Rossig, Stefan Fröhling, Susanne Hafner, Thomas Simmet, Pierre Åman, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann
Journal: Clinical Cancer Research (2017)

Purpose: Myxoid liposarcoma is an aggressive disease with particular propensity to develop hematogenic metastases. Over 90% of myxoid liposarcoma are characterized by a reciprocal t(12;16)(q13;p11) translocation. The resulting chimeric FUS-DDIT3 fusion protein plays a crucial role in myxoid liposarcoma pathogenesis; however, its specific impact on oncogenic signaling pathways remains to be substantiated. We here investigate the functional role of FUS-DDIT3 in IGF-IR/PI3K/Akt signaling driving myxoid liposarcoma pathogenesis.Experimental Design: Immunohistochemical evaluation of key effectors of the IGF-IR/PI3K/Akt signaling axis was performed in a comprehensive cohort of myxoid liposarcoma specimens. FUS-DDIT3 dependency and biological function of the IGF-IR/PI3K/Akt signaling cascade were analyzed using a HT1080 fibrosarcoma-based myxoid liposarcoma tumor model and multiple tumor-derived myxoid liposarcoma cell lines. An established myxoid liposarcoma avian chorioallantoic membrane model was used for in vivo confirmation of the preclinical in vitro results.Results: A comprehensive subset of myxoid liposarcoma specimens showed elevated expression and phosphorylation levels of various IGF-IR/PI3K/Akt signaling effectors. In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant IGF-IR/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the IGF2 gene. Conversely, RNAi-mediated FUS-DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished IGF2 mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition in vitro and in vivoConclusions: Our preclinical study substantiates the fundamental role of the IGF-IR/PI3K/Akt signaling pathway in myxoid liposarcoma pathogenesis and provides a mechanism-based rationale for molecular- targeted approaches in myxoid liposarcoma cancer therapy. Clin Cancer Res; 23(20); 6227-38. ©2017 AACR.
Predictive value of ultra-high ESR1 mRNA expression in early breast cancer.
Authors: Ralph M. Wirtz, Iris Scheffen, Frederik Marme, Mark Laible, Kornelia Schlombs, Roland Hake, Claudia Schumacher, Andreas Schneeweiss, Sebastian Eidt, Hans-Peter Sinn
Journal: Journal of Clinical Oncology (2016)

e12045 Background: Ultrahigh ESR1 mRNA expression in luminal breast tumors is predictive for benefit from adjuvant tamoxifen compared to placebo treatment in NSABP B14, while protein determination by IHC or LBA is not (Kim et al JCO 2011).The predictive cut-off value at ER score 10 by Oncotype is significantly higher than the diagnostic cut-off at 6.5. Here we tested wether the ultrahigh expression of ESR1 mRNA determined by MammaTyper is predictive for survival after NAC treatment of advanced PBC. Methods: Pretreatment biopsies from n = 54 patients with PBC treated within a randomized NAC phase II trial were examined (2). RNA was extracted from FFPE sections using the RNXtract kit and ESR1 mRNA from each section was measured with the MammaTyper kit (BioNTech Diagnostics GmbH). ESR1 mRNA values by Oncotype DX and MammaTyper from n = 113 surgical samples were compared. Statistical analysis were performed using the SAS JMP 9.0.0 software. Results: Quantification of ESR1 mRNA expression in luminal tumors (n = 113) by different commercial RT-qPCR assays resulted in high correlation of continuous expression results (Spearman r = 0,85; p < 0,0001) and high concordance with ER status by IHC ( > 95%). The median expression of ER score and ESR1 40-DDCq was high (10,2 and 39,8, respectively). Hence, the Tamoxifen benefit cut-off of ER score 10 by Oncotype is comparable with a 40-DDCqvalue of 39,6 for ESR1 mRNA determination by MammaTyper. Partition test in the independent NAC cohort revealed, that optimal discrimination for overall survival (OS) could be achieved by an elevated ESR1 mRNA expression exactly at 39,6 resulting in 100% OS for ultra-high expressors and 75 % OS for lower ESR1mRNA expression after 5 years (p = 0,006). Conclusions: Previous data suggest that ultrahigh expression of ESR1 mRNA is predictive for improved overall survival and tamoxifen benefit (1). Here we show that ultrahigh expression of ESR1mRNA is also prognostic in more advanced breast tumors after NAC. These findings validate the importance of quantitative determination of estrogen receptor expression and substantiate the understanding of receptor expression being a continuous determinant with indication specific cut-off values. 1) Kim et al, JCO 2011 2) Schneeweiss et al, Ann Oncol 2011
Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM).
Authors: Martin J. Van Den Bent, Hui Kong Gan, Andrew B. Lassman, Priya Kumthekar, Ryan Merrell, Nicholas A. Butowski, Zarnie Lwin, Tom Mikkelsen, Louis B. Nabors, Kyriakos P. Papadopoulos, Marta Penas-Prado, John Simes, Helen Wheeler, Erica J. Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Earle E. Bain, Kyle D. Holen, David A. Reardon
Journal: Journal of Clinical Oncology (2016)

2542 Background: Recurrent GBM (rGBM) has dismal prognosis. Almost 50% GBM tumors harbor amplified (amp) EGFR. ABT-414 is a tumor specific ADC combining an antibody targeting a unique conformation of EGFR (ABT-806) to a microtubule cytotoxin, monomethyl auristatin F (MMAF). Here we report the safety and efficacy of ABT-414 monotherapy at recommended phase 2 dose (RPTD) in EGFR amp, rGBM. Methods: M12-356 (NCT01800695) is an open-label, phase 1, 3-arm study: Arm A (ABT-414+radiation/temozolomide (TMZ) in newly diagnosed GBM (nGBM)), Arm B (ABT-414+TMZ in nGBM as adjuvant therapy, or in rGBM) and Arm C (ABT-414 monotherapy in rGBM). Each arm had an escalation cohort to determine the RPTD and an expansion cohort to establish the safety and preliminary efficacy at RPTD. Results of Arm C expansion cohort at 1.25 mg/kg RPTD (IV infusion) are shown here. Eligible patients (pts) were adults with KPS score ≥ 70, EGFR amp (confirmed centrally), rGBM, normal end-organ function and no prior bevacizumab. Results: As of January 7, 2016, 48 EGFR amp, rGBM pts were treated in this cohort. The median age was 59 years (range, 35-80). Most pts had prior therapies: 40% had 1, 48% had 2, 10% had ≥ 3 prior therapies. Most common treatment emergent adverse events (TEAEs) ( ≥ 25% pts) were blurred vision (60%), headache, photophobia (29% each), dry eye, eye pain, fatigue (27% each). The most common serious AE ( > 1 pt) was seizure (8%). Grade 3/4 TEAEs ( > 1 pt) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis, hyperglycemia, muscular weakness, seizure (6% each), blurred vision, ulcerative keratitis (4% each). No dose-limiting toxicities were reported. Best RANO responses of 44 pts with complete data were: 2 partial responses, 18 stable disease, 24 progressive disease. The 6-month progression-free survival (PFS6) estimate was 30% [95% CI = 17, 44]. Conclusions: ABT-414 monotherapy, at 1.25 mg/kg RPTD, displayed frequent yet reversible ocular toxicities. An encouraging tumor stability/response and PFS6 were observed in this highly refractory EGFR amp, rGBM. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFR amp, rGBM (NCT02343406). Clinical trial information: NCT01800695.
Inadvertent Arterial Injection of 123I-MIBG Does Not Necessarily Cause Any Symptoms
Authors: Wei Zhang, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2017)

An 123I-MIBG scan was obtained to evaluate a right adrenal mass in a 10-year-old boy, which showed no elevated activity in the lesion. However, diffuse increased activity was noted in the right forearm with typical manifestation of an "arterial injection." Different from a prior case report, no symptoms or signs related to arterial injection were observed in our patient.