The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Gyorgy Losonczy - One of the best experts on this subject based on the ideXlab platform.
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necitumumab plus gemcitabine and Cisplatin versus gemcitabine and Cisplatin alone as first line therapy in patients with stage iv squamous non small cell lung cancer squire an open label randomised controlled phase 3 trial
Lancet Oncology, 2015Co-Authors: Nick Thatcher, Fred R Hirsch, Alexander V Luft, Aleksandra Szczesna, Tudor Ciuleanu, Mircea Dediu, R Ramlau, Rinat Galiulin, Beatrix Balint, Gyorgy LosonczyAbstract:Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and Cisplatin versus gemcitabine and Cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m 2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and Cisplatin 75 mg/m 2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and Cisplatin (n=545) or gemcitabine and Cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and Cisplatin group than in the gemcitabine and Cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the necitumumab plus gemcitabine and Cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and Cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and Cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and Cisplatin group vs six [1%] of 541 in the gemcitabine and Cisplatin group) and grade 3 rash (20 [4%] vs one [ Interpretation Our findings show that the addition of necitumumab to gemcitabine and Cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
Nick Thatcher - One of the best experts on this subject based on the ideXlab platform.
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necitumumab plus gemcitabine and Cisplatin versus gemcitabine and Cisplatin alone as first line therapy in patients with stage iv squamous non small cell lung cancer squire an open label randomised controlled phase 3 trial
Lancet Oncology, 2015Co-Authors: Nick Thatcher, Fred R Hirsch, Alexander V Luft, Aleksandra Szczesna, Tudor Ciuleanu, Mircea Dediu, R Ramlau, Rinat Galiulin, Beatrix Balint, Gyorgy LosonczyAbstract:Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and Cisplatin versus gemcitabine and Cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m 2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and Cisplatin 75 mg/m 2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and Cisplatin (n=545) or gemcitabine and Cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and Cisplatin group than in the gemcitabine and Cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the necitumumab plus gemcitabine and Cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and Cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and Cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and Cisplatin group vs six [1%] of 541 in the gemcitabine and Cisplatin group) and grade 3 rash (20 [4%] vs one [ Interpretation Our findings show that the addition of necitumumab to gemcitabine and Cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
Brian W Reeves - One of the best experts on this subject based on the ideXlab platform.
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tnf α mediates chemokine and cytokine expression and renal injury in Cisplatin nephrotoxicity
Journal of Clinical Investigation, 2002Co-Authors: Ganesan Ramesh, Brian W ReevesAbstract:The purpose of these studies was to examine the role of cytokines in the pathogenesis of Cisplatin nephrotoxicity. Injection of mice with Cisplatin (20 mg/kg) led to severe renal failure. The expression of cytokines, chemokines, and ICAM-1 in kidney was measured by ribonuclease protection assays and RT-PCR. We found significant upregulation of TNF-α, TGF-β, RANTES, MIP-2, MCP-1, TCA3, IL-1β, and ICAM-1 in kidneys from Cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-α measured by ELISA were increased by Cisplatin. Inhibitors of TNF-α production (GM6001, pentoxifylline) and TNF-α Ab’s reduced serum and kidney TNF-α protein levels and also blunted the Cisplatin-induced increases in TNF-α, TGF-β, RANTES, MIP-2, MCP-1, and IL-1β, but not ICAM-1, mRNA. In addition, the TNF-α inhibitors also ameliorated Cisplatin-induced renal dysfunction and reduced Cisplatin-induced structural damage. Likewise, TNF-α–deficient mice were resistant to Cisplatin nephrotoxicity. These results indicate Cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-α appears to play a central role in the activation of this cytokine response and also in the pathogenesis of Cisplatin renal injury.
Zheng Dong - One of the best experts on this subject based on the ideXlab platform.
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microrna 375 is induced in Cisplatin nephrotoxicity to repress hepatocyte nuclear factor 1 β
Journal of Biological Chemistry, 2017Co-Authors: Lin Li, Qing Sheng Mi, Guangyu Wu, Zheng DongAbstract:Abstract Nephrotoxicity is a major adverse effect of Cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of Cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in Cisplatin-induced nephrotoxicity. We show that Cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in Cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up- regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in Cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased Cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of p53 or NF-κB attenuated Cisplatin-induced miR-375 expression, supporting a role of p53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (Hnf-1β) as a key downstream target of miR-375. Of note, we further demonstrated that Hnf-1β protected renal cells against Cisplatin-induced apoptosis. Together, these results suggest that upon Cisplatin exposure, p53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses Hnf-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity.
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The copper transporter Ctr1 contributes to Cisplatin uptake by renal tubular cells during Cisplatin nephrotoxicity.
American Journal of Physiology-renal Physiology, 2009Co-Authors: Navjotsingh Pabla, Robert F. Murphy, Zheng DongAbstract:The usefulness and efficacy of Cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of Cisplatin in renal tubular cells is high, leading to Cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of Cisplatin nephrotoxicity, much less is known about the mechanism of Cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in Cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for Cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased Cisplatin uptake. Consistently, downregulation of Ctr1 suppresses Cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate Cisplatin uptake. Notably, cimetidine can further reduce Cisplatin uptake and Cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in Cisplatin uptake and nephrotoxicity.
Suehong Wang - One of the best experts on this subject based on the ideXlab platform.
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galangin ameliorates Cisplatin induced nephrotoxicity by attenuating oxidative stress inflammation and cell death in mice through inhibition of erk and nf kappab signaling
Toxicology and Applied Pharmacology, 2017Co-Authors: Yuching Huang, Mingshiun Tsai, Peichi Hsieh, Jhenghong Shih, Tsushing Wang, Yichun Wang, Suehong WangAbstract:Abstract Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, Cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on Cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the Cisplatin-induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by Cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced IκBα phosphorylation, NF-κB phosphorylation and nuclear translocation, and then inhibited Cisplatin-induced secretions of pro-inflammatory TNF-α, IL-1β and IL-6. In addition, Cisplatin-induced ERK and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the Cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit Cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates Cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERK and NF-κB signaling pathways. Galangin might be a potential adjuvant for clinical Cisplatin therapy.