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James J Hsieh, David Chen, Patricia I Wang, Mahtab Marker, Almedina Redzematovic, Ying-Bei Chen, S Duygu Selcuklu, Nils Weinhold, Nancy Bouvier, Kety H Huberman, Umesh Bhanot, Michael S Chevinsky, Parul Patel, Patrizia Pinciroli, Helen H Won, Daoqi You, Agnes Viale, William Lee, A Ari Hakimi, Michael F Berger, Nicholas D Socci, Emily H Cheng, Jennifer Knox, Martin H Voss, Maurizio Voi, Robert J Motzer
BACKGROUND: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. OBJECTIVE: To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients...
October 14, 2016: European Urology
Jinhyun Cho, Jeeyun Lee, Jusun Kim, Seung Tae Kim, Sujin Lee, Sun Young Kim, Sang Yun Ha, Cheol-Keun Park, Ho Yeong Lim
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus...
October 2016: Translational Oncology
Rei Mimoto, Naoe T Nihira, Shinichi Hirooka, Hiroshi Takeyama, Kiyotsugu Yoshida
Mammalian target of rapamycin (mTOR) inhibitor, everolimus, provides benefit for metastatic hormone receptor positive breast cancer after failure of the endocrine therapy. The present report highlights Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 (DYRK2) as a predictive marker for everolimus sensitivity. The key node and KEGG pathway analyses revealed that mTORC1 pathway is activated in DYRK2-depleted cells. Everolimus was more effective in DYRK2-depleted cells compared with control cells. In xenograft model, everolimus treatment significantly inhibited tumor growth compared with vehicle or eribulin treatment...
October 13, 2016: Cancer Letters
Jessica E Maxwell, Scott K Sherman, James R Howe
Pancreatic neuroendocrine tumors (PNET) are rare tumors, but have been increasing in incidence. Although typically thought of as indolent, more than half of patients present with metastatic disease. For many years, the only mutations commonly known in these tumors were those in the MEN1 gene. Recently, the genetics underlying PNETs have been further defined through exome sequencing. The most frequent alterations found in sporadic PNETs are in MEN1, DAXX/ATRX, and a variety of genes in the mTOR pathway. Confirmation of these mutations has prompted trials with a number of drugs active in these pathways, and two drugs were eventually approved in 2011-sunitinib and everolimus...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Umberto Maggiore, Julio Pascual
Cancer immunotherapy, especially the use of checkpoint inhibitors, is expanding and can be efficacious in organ transplant recipients with malignant neoplasia. In this review, we summarize clinical findings and evolution of several patients treated with CTL4-4 or PD-1 inhibitors reported in the literature. The CTL-4 inhibitor ipilimumab has been safely used in several liver and kidney allograft recipients. PD1-inhibitors look promising for tumor shrinking, but acute rejection is the rule, so they should be avoided in recipients of life-saving organs...
September 2016: Advances in Chronic Kidney Disease
Joshua Augustine, Donald E Hricik
Although calcineurin inhibitor drugs have been the mostly used therapy in modern immunosuppression in kidney transplantation, their effect on kidney allograft dysfunction has been suboptimal as far as preservation of kidney function is concerned. Additionally, there are metabolic and other nonmetabolic effects including increased risk of malignancy that has necessitated the use of mammalian target of rapamycin inhibitors to reduce exposure to calcineurin inhibitors. Mammalian target of rapamycin inhibitors, both sirolimus and everolimus, have been studied in several trials to facilitate preservation of kidney function with variable effects on kidney allograft function and immunogenicity...
September 2016: Advances in Chronic Kidney Disease
M Gastaca, I Bilbao, M Jimenez, J Bustamante, C Dopazo, R Gonzalez, R Charco, J Santoyo, J Ortiz de Urbina
Our aim was to study the safety and efficacy of immunosuppression with everolimus (EVL) within the 1st month after orthotopic liver transplantation (LT) when calcineurin inhibitors are not recommended. For this purpose, 28 recipients who had been treated with EVL within the 1st month after adult LT were eligible to enter in a retrospective multicenter study. Patients were followed up for 12 months after LT. EVL therapy was initiated at a median of 14 days (range, 4-24) after LT. The reason for early EVL was neurotoxicity in 14 cases, renal dysfunction in 12, and acute cellular rejection combined with renal impairment in 2...
September 2016: Transplantation Proceedings
Armando Orlandi, Carmela Di Dio, Maria Alessandra Calegari, Carlo Barone
Everolimus and exemestane represent a standard treatment for metastatic hormone receptor-positive/HER2-negative advanced breast cancer resistant to aromatase inhibitors. CA 15-3 serum levels detect soluble forms of MUC-1, a transmembrane oncoprotein aberrantly overexpressed in breast cancers. In clinical practice, CA 15-3 may be used to indicate treatment failure in the absence of readily measurable disease during cytotoxic therapy. In the targeted therapy era, it is important to note that the C-terminal subunit of MUC-1 interacts with PI3K/AKT pathway, inducting cell growth...
October 13, 2016: Biomarkers in Medicine
Xi Zhang, Yuge Ran, Kunjie Wang, Yuanxue Zhu, Jinghua Li
PURPOSE: Anti-programmed cell death receptor-1 (PD-1) antibodies have demonstrated antitumor activity in many cancer entities. Hepatic adverse events (AEs) are one of its major side effects, but the overall risks have not been systematically evaluated. Thus, we conducted this meta-analysis to investigate the overall incidence and risk of developing hepatic AEs in cancer patients treated with PD-1 inhibitors. METHODS: PubMed, Embase, and oncology conference proceedings were searched for relevant studies...
2016: Drug Design, Development and Therapy
Su Hyun Seok, Seung-Yeob Kang, Jeong-Woong Seo, Su-Hyeon Kim, Kyu-Mok Hwang, Eun-Seok Park
The aims of this study were to improve in vitro dissolution property of poorly water-soluble everolimus (EVR) for enhanced bioavailability without using organic solvents and characterize the effects of microfluidization and freeze-drying on physicochemical properties of EVR nanosuspension and nanoparticle, respectively. EVR nanosuspension was prepared using microfluidization with various types and concentrations of stabilizers. After that, it was solidified into nanoparticle using freeze-drying with various concentrations of xylitol, a cryoprotectant...
2016: Chemical & Pharmaceutical Bulletin
Li Chen, Yanjun Zhang, Daojing Li, Nong Zhang, Ruiqiong Liu, Bin Han, Changjuan Wei, Haijie Liu, Xiaolin Xu, Junwei Hao
Vascular dementia (VaD) is a widely prevalent and devastating disease. Despite the tremendous complexity that limits understanding of the pathophysiology of VaD, microglial dysfunction has been attributed, in part, to immune microenviroment disorder and finally leads to cognitive deficits. Considered the mammalian target of rapamycin complex 1 (mTORC1) is a key player in regulation of glial function, our work focused on whether the mTOR inhibitor everolimus (RAD001) could overcome the destructive microglial function, change the phenotype and ameliorate cognitive decline induced by chronic cerebral hypoperfusion...
October 15, 2016: Journal of Neuroimmunology
Ming Guo, Yunsong Cao, Jingzhe Yang, Jingfeng Zhang
PURPOSE: The purpose of this study was to conduct network meta-analysis to assess drug resistances of the Food and Drug Administration-approved drugs for advanced renal cell carcinoma. MATERIALS AND METHODS: Database searches were conducted to identify randomized controlled trials reporting results for eligible treatments. After searching for PubMed, MEDLINE, EMBASE, and ISI Web of Science, 22 studies (n = 7854 patients) were included for the comparison of drug resistance in the present meta-analysis...
October 2016: Journal of Cancer Research and Therapeutics
Lingling Chang, Ying An, Shuling Yang, Xiaosu Zhang
PURPOSE: A meta-analysis of published data was conducted to investigate the therapeutic effects in patients with renal cell carcinoma (RCC) who were receiving antiangiogenic drugs. METHODS: A computerized search through electronic databases, including PubMed (until February 2016), was performed to obtain eligible randomized controlled trials that compared the effectiveness of antiangiogenic with control groups (everolimus, placebo, and interferon [IFN] alfa) in patients with RCC...
October 2016: Journal of Cancer Research and Therapeutics
Yohei Sotomi, Yoshinobu Onuma, Pannipa Suwannasom, Hiroki Tateishi, Erhan Tenekecioglu, Yaping Zeng, Rafael Cavalcante, Hans Jonker, Jouke Dijkstra, Nicolas Foin, Jaryl Ng Chen Koon, Carlos Collet, Robbert J de Winter, Joanna J Wykrzykowska, Gregg W Stone, Jeffrey J Popma, Ken Kozuma, Kengo Tanabe, Patrick W Serruys, Takeshi Kimura
AIMS: The current study aimed to assess the difference in lumen dimension measurements between optical coherence tomography (OCT) and quantitative coronary angiography (QCA) in the polymeric bioresorbable scaffold and metallic stent. METHODS AND RESULTS: In the randomised ABSORB Japan trial, 87 lesions in the Absorb arm and 44 lesions in the XIENCE arm were analysed. Post-procedural OCT-QCA lumen dimensions were assessed in matched proximal/distal non-stented/non-scaffolded reference (n=199), scaffolded (n=145) and stented (n=75) cross-sections at the two device edges using the Bland-Altman method...
October 10, 2016: EuroIntervention
Hongqing Zhuang, Jing Bai, Joe Y Chang, Zhiyong Yuan, Ping Wang
OBJECTIVE: To investigate the effects of mTOR inhibition on drug resistance in lung adenocarcinoma after combined radiation and erlotinib therapy. RESULTS: Combined radiation and erlotinib therapy produced clear radiosensitization effects both in vitro and in vivo; however, tumor cells remained drug resistant. Additionally, combined radiation and erlotinib therapy significantly increased p-AKT and p-P70 levels. After mTOR inhibition, the number of surviving cells significantly decreased compared with that before inhibition, and the in vivo growth curve was significantly reduced...
October 4, 2016: Oncotarget
Yukiyoshi Hirayama, Min Gi, Shotaro Yamano, Hirokazu Tachibana, Takahiro Okuno, Satoshi Tamada, Tatsuya Nakatani, Hideki Wanibuchi
Immunotherapy based on blockade of the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) axis has shown promising clinical activity for renal cell carcinoma (RCC) patients; however, the most effective use of these agents in combination with conventional targeted therapy remains to be resolved. Here we evaluated the therapeutic efficacy of the combination of the mTOR inhibitor everolimus (EVE) and anti-PD-L1 using an immunocompetent mouse model of RCC. We first assessed the in vitro effect of EVE on PD-L1 expression in the human 786-O and mouse RENCA RCC cell lines and found that EVE up-regulated PD-L1 expression in these RCC cell lines...
October 6, 2016: Cancer Science
Manuel C D F Maia, Delmar Muniz Lourenço, Rachel Riechelmann
BACKGROUND: Approximately 10% of pancreatic neuroendocrine tumors (NET) are associated with familial syndromes, with the most common type being multiple endocrine neoplasia type 1 (MEN-1). However, the available evidence on how to treat NET comes from studies in sporadic NET. CASE REPORT: Here we report the case of a 51-year-old male patient with a metastatic MEN-1-associated pancreatic NET and hypercalcemia related to primary hyperparathyroidism and tumor-secreted parathyroid-related protein...
2016: Oncology Research and Treatment
Josep Gomez-Lara, Salvatore Brugaletta, Francisco Jacobi, Luis Ortega-Paz, Marcos Ñato, Gerard Roura, Rafael Romaguera, Jose-Luis Ferreiro, Luis Teruel, Montserrat Gracida, Victoria Martin-Yuste, Xavier Freixa, Monica Masotti, Joan-Antoni Gomez-Hospital, Manel Sabate, Angel Cequier
BACKGROUND: The main causes of late (>1 month) stent thrombosis (ST) are stent uncoverage, malapposition, and neoatherosclerosis. First-generation drug-eluting stents were associated with higher rate of late ST compared with bare-metal stents (BMS), especially in patients with ST-segment-elevation myocardial infarction. Second-generation everolimus-eluting stents (EES) have shown similar rate of late ST than BMS. The aims of the study are to compare the ratio of uncovered to total struts per cross-section ≥30% and other optical coherence tomographic findings associated with ST between EES and BMS in patients with ST-segment-elevation myocardial infarction at 5 years...
October 2016: Circulation. Cardiovascular Interventions
Qianqian Zhao, Zhaopeng Wang, Zhaoxia Wang, Licun Wu, Weidong Zhang
Aspirin is known to have inhibitory effects on growth development in various types of tumor. In previous studies, it was observed to inhibit angiogenesis by downregulating the expression of vascular endothelial growth factor-A (VEGF-A). In the present study, murine H22 hepatocarcinoma and S180 sarcoma models were used to ascertain whether aspirin could inhibit angiogenesis and promote autophagy in tumors. Tumor-bearing mice were randomly divided into four groups with 10 mice per group: i) no treatment; ii) low-dose aspirin (100 mg/kg); iii) high-dose aspirin (400 mg/kg); iv) everolimus group (4 mg/kg)...
October 2016: Oncology Letters
Simona Falletta, Stefano Partelli, Corrado Rubini, Dominik Nann, Andrea Doria, Ilaria Marinoni, Vanessa Polenta, Carmelina Di Pasquale, Ettore C Degli Uberti, Aurel Perren, Massimo Falconi, Maria Chiara Zatelli
Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However the extent of therapeutic response cannot be predicted. The present study was aimed to identify possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance...
October 3, 2016: Endocrine-related Cancer
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