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https://www.readbyqxmd.com/read/28453615/do-patient-access-schemes-for-high-cost-cancer-drugs-deliver-value-to-society-lessons-from-the-nhs-cancer-drugs-fund
#1
A Aggarwal, T Fojo, C Chamberlain, C Davis, R Sullivan
Background: The NHS Cancer Drugs Fund (CDF) was established in 2010 to reduce delays and improve access to cancer drugs, including those that had been previously appraised but not approved by NICE (National Institute for Health and Care Excellence). After 1.3 billion GBP expenditure, a UK parliamentary review in 2016 rationalized the CDF back into NICE. Methods: This paper analyses the potential value delivered by the CDF according to six value criteria. This includes validated clinical benefits scales, cost-effectiveness criteria as defined by NICE and an assessment of real-world data...
April 27, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28449055/primary-tumor-sidedness-has-an-impact-on-prognosis-and-treatment-outcome-in-metastatic-colorectal-cancer-results-from-two-randomized-first-line-panitumumab-studies
#2
N Boeckx, R Koukakis, K Op de Beeck, C Rolfo, G Van Camp, S Siena, J Tabernero, J-Y Douillard, T André, M Peeters
Background: : Previous studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer (mCRC) and its influence on cetuximab efficacy. The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first-line mCRC patients with RAS wild-type (WT) primary tumors. Material and methods: Data from two randomized first-line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients...
April 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28447703/conserved-effects-and-altered-trafficking-of-cetuximab-antibodies-conjugated-to-gold-nanoparticles-with-precise-control-of-their-number-and-orientation
#3
Lorena García-Fernández, Javier Garcia-Pardo, Olivia Tort, Ian Prior, Mathias Brust, Eudald Casals, Julia Lorenzo, Victor F Puntes
Gold nanoparticles (17 nm) have been functionalized with the antiangiogenic monoclonal antibody drug Cetuximab at a well-defined orientation and coverage density of antibodies. Functionalization has been carried out through site-directed chemistry via the selective oxidation of the carbohydrate moiety of antibodies linked to a thiolated hydrazide. A431 tumor cells have been exposed to these conjugates for in vitro evaluation of their effects. In addition to epithelial growth factor receptor blocking, trafficking and signaling alterations were also observed...
April 27, 2017: Nanoscale
https://www.readbyqxmd.com/read/28447565/risk-factors-for-brain-metastases-in-patients-with-metastatic-colorectal-cancer
#4
Troels Dreier Christensen, Jesper Andreas Palshof, Finn Ole Larsen, Estrid Høgdall, Tim Svenstrup Poulsen, Per Pfeiffer, Benny Vittrup Jensen, Mette Karen Yilmaz, Ib Jarle Christensen, Dorte Nielsen
BACKGROUND: Brain metastases (BM) from colorectal cancer (CRC) are rare, but the incidence is suspected to rise as treatment of metastatic (m) CRC improves. The aim of this study was to identify possible biological and clinical characteristics at initial presentation of mCRC that could predict later risk of developing BM. Furthermore, we wished to estimate the incidence of BM in long-term surviving patients. MATERIAL AND METHODS: We conducted a retrospective study on a Danish multicenter cohort of patients with mCRC who received cetuximab and irinotecan (CetIri) as third-line treatment...
May 2017: Acta Oncologica
https://www.readbyqxmd.com/read/28446642/co-targeting-mtorc-and-egfr-signaling-as-a-therapeutic-strategy-in-hnscc
#5
Adam D Swick, Prashanth J Prabakaran, Margot C Miller, Amal M Javaid, Michael M Fisher, Emmanuel Sampene, Irene M Ong, Rong Hu, Mari Iida, Kwangok P Nickel, Justine Y Bruce, Deric L Wheeler, Randall J Kimple
Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. To investigate mTORC specific inhibition we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors +/- cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX)...
April 26, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28446503/sensitivity-and-specificity-of-cetuximab-irdye800cw-to-identify-regional-metastatic-disease-in-head-and-neck-cancer
#6
Eben Rosenthal, Lindsay Moore, Kiranya Tipirneni, Esther de Boer, Todd M Stevens, Yolanda E Hartman, William R Carroll, Kurt R Zinn, Jason M Warram
Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer. <p>Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n=12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3-7days following intravenous infusion of cetuximab-IRDye800CW...
April 26, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28445743/egfr-targeted-micelles-containing-near-infrared-dye-for-enhanced-photothermal-therapy-in-colorectal-cancer
#7
Ying-Hsia Shih, Tsai-Yueh Luo, Ping-Fang Chiang, Cheng-Jung Yao, Wuu-Jyh Lin, Cheng-Liang Peng, Ming-Jium Shieh
The purpose of this research was to investigate the effectiveness of epidermal growth factor receptor (EGFR) targeted micelles loaded with IR-780 (Cetuximab/IR-780/micelles) for generating tumor targeting, multimodal images, and photothermal therapy (PTT). We initially studied the cellular uptake of these micelles using the HCT-116 and SW-620 cell lines. HCT-116 (high expression of EGFR) and SW-620 (low expression of EGFR) cell lines were used to examine biodistribution and antitumor effects of Cetuximab/IR-780/micelles...
April 23, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28443380/acute-hypersensitivity-reaction-to-crotalidae-polyvalent-immune-fab-crofab-as-initial-presentation-of-galactose-%C3%AE-1-3-galactose-%C3%AE-gal-allergy
#8
Justin Rizer, Kaitlin Brill, Nathan Charlton, Joshua King
Crotalidae polyvalent immune Fab antivenom (CroFab), commonly used for the treatment of clinically significant North American crotalinae envenomation, is generally well-tolerated. A novel form of anaphylaxis due to an IgE antibody response to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) has been established following red-meat consumption as well as IV administration of cetuximab, which contain the α-gal epitope. We present a case of α-gal allergy discovered after acute hypersensitivity reaction to FabAV...
April 26, 2017: Clinical Toxicology
https://www.readbyqxmd.com/read/28440510/migration-of-oral-squamous-cell-carcinoma-cells-are-induced-by-hgf-c-met-signalling-via-lamellipodia-and-filopodia-formation
#9
Hiroki Yasui, Yuichi Ohnishi, Masahiro Nakajima, Masami Nozaki
The activation of receptor tyrosine kinases (RTKs) results in cellular effects including cell proliferation, survival, migration and invasion; RTKs also play an important role in tumourigenesis. It has been reported that EGFR signalling controls the migration of oral squamous cell carcinoma (OSCC) SAS and HSC3 cells but not of HSC4 cells, although the proliferation of HSC4 cells is regulated by EGF/EGFR. In the present study, we investigated the roles of EGFR and the c-Met signalling pathway in cell migration via filopodia and lamellipodia formation, which may be prerequisites for migration...
April 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28435452/the-yap1-six2-axis-is-required-for-ddx3-mediated-tumor-aggressiveness-and-cetuximab-resistance-in-kras-wild-type-colorectal-cancer
#10
De-Wei Wu, Po-Lin Lin, Lee Wang, Chi-Chou Huang, Huei Lee
The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in KRAS-wild-type (KRAS -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells, as already confirmed in KRAS-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models...
2017: Theranostics
https://www.readbyqxmd.com/read/28435294/patient-considerations-in-metastatic-colorectal-cancer-role-of-panitumumab
#11
REVIEW
Jane E Rogers
Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies, including colorectal cancer (CRC), making EGFR an attractive treatment option. Panitumumab and cetuximab, monoclonal antibodies (mAbs) directed at EGFR, are both currently utilized in the management of metastatic CRC (mCRC). Through the development of these agents in mCRC, key issues surrounding each mAbs use have been revealed. These key issues include negative patient outcome avoidance when determining use, the economic burden with high-cost medication, predictive biomarkers, tumor location, patient geographic location, patient quality of life, and the prevention of debilitating adverse effects...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28431161/engineering-a-high-affinity-peptide-binding-site-into-the-anti-cea-mab-m5a
#12
Cindy Zer, Kendra N Avery, Kassondra Meyer, Leah Goodstein, Krzysztof P Bzymek, Gagandeep Singh, John C Williams
We have previously identified a cyclic peptide called meditope which binds to the central cavity of the Fab portion of cetuximab and shown that this peptide binding site can be grafted, or 'meditope-enabled', onto trastuzumab. This peptide has been shown to act as a hitch for the non-covalent attachment of imaging agents to meditope-enabled antibodies. Herein, we explore the process of grafting this peptide binding site onto M5A, an anti-CEA antibody in clinical trials for cancer diagnostics. In order to explore the contributions of the amino acids, we sequentially introduced pairs of amino acid substitutions into the Fab and then we reverse-substituted key residues in the presence of the other substitutions...
April 19, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28427242/epidermal-growth-factor-receptor-variant-iii-in-head-and-neck-squamous-cell-carcinoma-is-not-relevant-for-targeted-therapy-and-irradiation
#13
Dominik Thomas Koch, Anja Pickhard, Lena Gebel, Anna Maria S Buchberger, Murat Bas, Carolin Mogler, Rudolf Reiter, Guido Piontek, Markus Wirth
BACKGROUND: The epidermal growth factor receptor (EGFR) is an important regulator of cell growth and survival, and is highly variable in tumor cells. The most prevalent variation of the EGFR extracellular domain is the EGFR variant III (EGFRvIII). Some studies imply that EGFRvIII may be responsible for the poor response to the monoclonal EGFR-antibody Cetuximab, used therapeutically in head and neck squamous cell carcinoma (HNSCC). Due to inconsistent data in the literature regarding EGFRvIII prevalence and clinical relevance in HNSCC, especially its predictive value, we examined EGFRvIII-transfected cell lines and patient tissue samples...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28425453/aptamer-mediated-impairment-of-egfr-integrin-%C3%AE-v%C3%AE-3-complex-inhibits-vasculogenic-mimicry-and-growth-of-triple-negative-breast-cancers
#14
Simona Camorani, Elvira Crescenzi, Matteo Gramanzini, Monica Fedele, Antonella Zannetti, Laura Cerchia
Current treatment options for triple-negative breast cancers (TNBCs) is limited by the absence of well-defined biomarkers, excluding a targeted therapy. Notably, epidermal growth factor receptor (EGFR) is overexpressed in a great proportion of TNBCs and is a negative prognostic factor. In clinical trials, however, existing EGFR inhibitors showed disappointing outcome. Oligonucleotide aptamers are a valid alternative to antibodies for diagnostic and therapeutic uses. Here, we prove that, when applied to aggressive TNBC cell lines with unique stem-like plasticity, the anti-EGFR CL4 aptamer, but not erlotinib or cetuximab, prevents the vasculogenic mimicry (VM) capability of the cells and destroys previously formed channels in three-dimensional culture...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424201/pik3ca-mutations-contribute-to-acquired-cetuximab-resistance-in-metastatic-colorectal-cancer-patients
#15
Jian Ming Xu, Yan Wang, You-Liang Wang, Yan Wang, Tao Liu, Ming Ni, Man-Sheng Li, Li Lin, Fei-Jiao Ge, Chun Gong, Jun-Yan Gu, Ru Jia, He-Fei Wang, Yu Ling Chen, Rong-Rui Liu, Chuan-Hua Zhao, Zhao-Li Tan, Yang Jin, Yunping Zhu, Shuji Ogino, Zhi Rong Qian
<p>Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.</p> <br /><br />Experimental Design: <p>Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28423516/the-addition-of-celecoxib-improves-the-antitumor-effect-of-cetuximab-in-colorectal-cancer-role-of-egfr-ras-foxm1-%C3%AE-catenin-signaling-axis
#16
Araceli Valverde, Jon Peñarando, Amanda Cañas, Laura M López-Sánchez, Francisco Conde, Silvia Guil-Luna, Vanessa Hernández, Carlos Villar, Cristina Morales-Estévez, Juan de la Haba-Rodríguez, Enrique Aranda, Antonio Rodríguez-Ariza
Here we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of β-catenin...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423384/cetuximab-carboplatin-5-fluorouracil-regimen-in-elderly-patients-with-recurrent-or-metastatic-head-and-neck-squamous-cell-carcinoma-a-french-retrospective-survey
#17
Mickaël Burgy, Philippe Barthélémy, François Lefevre, Agnès Dupret-Bories, Pierre Truntzer, Clement Korenbaum, Henri Flesch, Guy Bronner, Christian Borel
BACKGROUND: The cetuximab plus platinum-based chemotherapy regimen is a standard of care in the treatment of recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The feasibility in the elderly population is currently unknown. METHODS: We performed a retrospective study in order to assess the efficacy and safety of the cetuximab plus platinum-based chemotherapy regimen in patients >65 years with recurrent or metastatic HNSCC. We performed a retrospective review of all medical records from recurrent or metastatic HNSCC patients >65 years treated with the cetuximab plus platinum-based chemotherapy regimen between September 2008 and December 2013 in our institution (Centre Paul Strauss, Strasbourg, France)...
April 20, 2017: Oncology
https://www.readbyqxmd.com/read/28422758/first-in-human-trial-of-multikinase-vegf-inhibitor-regorafenib-and-anti-egfr-antibody-cetuximab-in-advanced-cancer-patients
#18
Vivek Subbiah, Muhammad Rizwan Khawaja, David S Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B Schrock, Siraj M Ali, James X Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Aung Naing, Filip Janku, Daniel D Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S Falchook
BACKGROUND: The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS: Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28416737/efficacy-of-continuous-egfr-inhibition-and-role-of-hedgehog-in-egfr-acquired-resistance-in-human-lung-cancer-cells-with-activating-mutation-of-egfr
#19
Carminia Maria Della Corte, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Vincenza Ciaramella, Teresa Troiani, Erika Martinelli, Valentina Belli, Fortunato Ciardiello, Floriana Morgillo
PURPOSE: The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors. EXPERIMENTAL DESIGN: We developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415738/tyrosine-kinase-inhibitor-induced-growth-factor-receptor-upregulation-enhances-the-efficacy-of-near-infrared-targeted-photodynamic-therapy-in-esophageal-adenocarcinoma-cell-lines
#20
Elmire Hartmans, Matthijs D Linssen, Claire Sikkens, Afra Levens, Max J H Witjes, Gooitzen M van Dam, Wouter B Nagengast
Esophageal carcinoma (EC) is a global health problem, with disappointing 5-year survival rates of only 15-25%. Near-infrared targeted photodynamic therapy (NIR-tPDT) is a novel strategy in which cancer-targeted phototoxicity is able to selectively treat malignant cells. In this in vitro report we demonstrate the applicability of antibody-based NIR-tPDT in esophageal adenocarcinoma (EAC), using the phototoxic compounds cetuximab-IRDye700DX and trastuzumab-IRDye700DX, targeting respectively epidermal growth factor receptor 1 (EGFR) and 2 (HER2)...
March 13, 2017: Oncotarget
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