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Onoufrios Tsavaris, Panagiota Economopoulou, Ioannis Kotsantis, Lazaros Reppas, Chrysanthi Avgerinou, Nikolaos Spathas, Maria Prevezanou, Amanda Psyrri
Chondrosarcoma is a rare malignancy characterized by the production of cartilage matrix, displaying heterogeneous histopathology and clinical behavior. Due to lack of effective treatment for advanced disease, the clinical management of metastatic chondrosarcoma is exceptionally challenging. Chondrosarcomas harbor molecular abnormalities, such as overexpression of platelet-derived growth factor receptor (PDGFR)-alpha and PDGFR-beta, which are required for cancer development, progression, and metastasis. Pazopanib is a potent and selective multitargeted tyrosine kinase inhibitor, which co-inhibits stem cell growth factor receptor (c-KIT), fibroblast growth factor receptor (FGFR), PDGFR, and vascular endothelial growth factor receptor (VEGFR) and has demonstrated clinical activity in patients with advanced previously treated soft tissue sarcoma...
2018: Frontiers in Oncology
Evelina Cardoso, Thomas Mercier, Anna Dorothea Wagner, Krisztian Homicsko, Olivier Michielin, Kim Ellefsen-Lavoie, Laurène Cagnon, Manuel Diezi, Thierry Buclin, Nicolas Widmer, Chantal Csajka, Laurent Decosterd
A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards...
February 8, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
G Lendínez-Cano, I Osman García, C B Congregado Ruiz, J M Conde Sánchez, R A Medina López
OBJECTIVES: To analyse the learning curve for the management of tyrosine kinase inhibitors as the first line of treatment for patients with metastatic renal cancer. MATERIAL AND METHODS: We evaluated 32 consecutive patients treated in our department for metastatic renal cancer with tyrosine kinase inhibitors (pazopanib or sunitinib) as first-line treatment between September 2012 and November 2015. We retrospectively analysed this sample. We measured the time to the withdrawal of the first-line treatment, the time to progression and overall survival using Kaplan-Meier curves...
March 7, 2018: Actas Urologicas Españolas
Brian I Rini
Higher concentrations of TKIs such as pazopanib are associated with improved outcomes in advanced RCC. A phase 3 trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome.
March 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ingrid M E Desar, Emmy D G Fleuren, Winette T A van der Graaf
Synovial sarcoma (SS) is a rare, yet highly malignant, type of soft tissue sarcoma (STS), for which survival has not improved significantly during the past years. In this review, we focus on systemic treatment in adults. Compared to other STS, SS are relatively chemosensitive. Ifosfamide and ifosfamide combinations are active in different lines of treatment. In high-risk extremity and chest wall STS, neoadjuvant doxorubicin and ifosfamide has shown as much activity as high-dose ifosfamide. There are indications that combination chemotherapy with doxorubicin and ifosfamide in this setting improves outcome...
March 7, 2018: Current Treatment Options in Oncology
Marie Cantaloube, Laurence Moureau-Zabotto, Lena Mescam, Audrey Monneur, Valeria Deluca, Jerome Guiramand, Delphine Perrot, François Bertucci
Pulmonary artery intimal sarcoma (PAIS) is a very rare tumour with a very poor prognosis. In advanced stages, chemotherapy and radiotherapy are poorly efficient, and no standard chemotherapy guideline is currently available. Here, we report on a 37-year-old woman with PAIS initially treated with surgical resection who developed metastatic relapse refractory to anthracycline-based chemotherapy, then trabectedin, then pazopanib. The patient was then given carboplatin-vinorelbine chemotherapy. The treatment was well tolerated, and, rapidly, a CT scan showed an objective response that lasted 8 months despite the 4th therapeutic line...
January 2018: Case Reports in Oncology
Kenji Nakano, Shunji Takahashi
Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib's approval as a treatment for gastrointestinal stromal tumors (GISTs) has been a great achievement...
March 5, 2018: International Journal of Molecular Sciences
Feng Wang, Hongyan Li, Ela Markovsky, Ryan Glass, Elisa de Stanchina, Simon N Powell, Gary K Schwartz, Adriana Haimovitz-Friedman
Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation...
February 6, 2018: Oncotarget
Hikaru Sugihara, Lynne S Taylor
Salts of weakly basic active pharmaceutical ingredients are widely used to improve aqueous solubility and/or dissolution rate. However, these compounds are prone to precipitation due to the lower solubility of the unionized species at the higher pH in the intestinal region, and this can result in poor and/or variable absorption. The goal of this study was to investigate the degree of supersaturation achieved following dissolution of different amounts of pazopanib hydrochloride at low pH, followed by rapid pH increase...
March 5, 2018: Molecular Pharmaceutics
Renee K McAlister, Jonathan Aston, Megan Pollack, Liping Du, Tatsuki Koyama, David D Chism
BACKGROUND: Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown...
February 27, 2018: Oncologist
Claire Pressiat, Huu-Hien Huynh, Alain Plé, Hélène Sauvageon, Isabelle Madelaine, Cécile Chougnet, Christine Le Maignan, Samia Mourah, Lauriane Goldwirt
BACKGROUND: A simple, rapid, and sensitive LC-MS/MS method has been developed and validated for the quantification of ruxolitinib, olaparib, vismodegib, and pazopanib in human plasma. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an UPLC system coupled with MS/MS in a positive ionization mode. The mobile phase consisted of a gradient elution of 10 mmol/L formate ammonium buffer containing 0.1% (v/v) formic acid (phase A) and acetonitrile with 0...
February 22, 2018: Therapeutic Drug Monitoring
Yu Qiao, Jihong Yang, Lili Liu, Yixin Zeng, Jie Ma, Jing Jia, Li Zhang, Xiaoguang Li, Peihong Wu, Wenchao Wang, Dongge Liu, Huan Chen, Yunbo Zhao, Huan Xi, Yao Wang
BACKGROUND: Primary hepatic angiosarcoma (PHA) is a rare and aggressive solid tumor, with high rates of local recurrence and distant metastasis, and poor prognosis. There are no established treatment guidelines for PHA. CASE PRESENTATION: A 78-year-old asymptomatic man with PHA that was successfully treated with pazopanib plus PD-1 inhibitor and RetroNectin-activated killer cells (RAK cells). After one month of treatment, there was a clear reduction in the size and number of the liver metastases; and after nearly 15 months, most of the lesions were stable, no new lesions had developed, and the side effect of treatment was minor...
February 21, 2018: BMC Cancer
Simone Fulda
Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases...
February 21, 2018: Cell Cycle
Michael W van Kalleveen, Maudy Walraven, Mathijs P Hendriks
Introduction Tumor lysis syndrome (TLS) is a life-threatening emergency caused by rapid cell death as a result of anti-tumor therapy. In the era of targeted therapy it has increasingly been observed in solid malignancies such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Case We describe the case of a 58-year old man with the medical history of a memorial sloan kettering cancer centre (MSKCC) poor prognosis metastasized clear cell renal cell carcinoma (mRCC) who developed TLS within six days after initiating therapy with the tyrosine kinase inhibitor (TKI) pazopanib...
February 20, 2018: Investigational New Drugs
Annelies Verbiest, Gabrielle Couchy, Sylvie Job, Laure Caruana, Evelyne Lerut, Raymond Oyen, Aurélien de Reyniès, Lorenzo Tosco, Steven Joniau, Hendrik Van Poppel, Dirk Van Raemdonck, Kathleen Van Den Eynde, Agnieszka Wozniak, Jessica Zucman-Rossi, Benoit Beuselinck
BACKGROUND: Metastasectomy is routinely performed in selected patients with metastatic clear-cell renal cell carcinoma (ccRCC) as an alternative to systemic therapy. In the absence of randomized trials, the benefit and best way of patient selection remain unclear. Earlier, we described four molecular ccRCC-subtypes (ccrcc1-4) that have a prognostic and predictive value upon first-line sunitinib or pazopanib. OBJECTIVE: Assess the prognostic value of ccrcc1-4 subtypes after complete metastasectomy...
February 17, 2018: European Urology
Lin Yang, Anna Alyasova, Dingwei Ye, Antonia Ridolfi, Luca Dezzani, Robert J Motzer
BACKGROUND: RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients...
February 17, 2018: BMC Cancer
Joseph G Parambil, Troy D Woodard, Omer N Koc
Hereditary hemorrhagic telangiectasia (HHT) most commonly manifests with nasal mucosal telangiectasias, and vascular endothelial growth factor (VEGF) plays a significant role in this angiodysplasia. We describe a patient with HHT with epistaxis recalcitrant to several endonasal procedures and six cycles of intravenous bevacizumab, for which he was dependent on iron infusions and packed red blood cells transfusions. He then started pazopanib at 100 mg with dramatic improvements in epistaxis and normalization of hemoglobin and iron levels, without replenishment needs for 12 months...
February 16, 2018: Laryngoscope
Marco Bandini, Ariane Smith, Michele Marchioni, Raisa S Pompe, Tristan F Martel, Luca Cindolo, Francesco Montorsi, Shahrokh F Shariat, Alberto Briganti, Anil Kapoor, Umberto Capitanio, Pierre I Karakiewicz
To conduct a review of literature on adjuvant therapy in nonmetastatic renal-cell carcinoma (nmRCC) treated with nephrectomy and to describe the efficacy of adjuvant agents on cancer control outcomes. A review of the literature was performed in January 2018 to identify all studies evaluating adjuvant therapy in patients with nmRCC treated with nephrectomy using PubMed, Embase, Medline, and Cochrane Library databases. The following keywords were used: adjuvant therapy, renal-cell carcinoma, nonmetastatic, targeted molecular therapy, kidney cancer...
February 2, 2018: Clinical Genitourinary Cancer
Jamie E Moscovitz, Amit S Kalgutkar, Kelly Nulick, Nathaniel Johnson, Zhiwu Lin, Theunis C Goosen, Yan Weng
The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug disposition genes via activation of nuclear receptors (NRs) such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and/or aryl hydrocarbon receptor (AhR) remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR/CAR/AhR-specific drug metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO) and AhR (omeprazole)...
February 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Maxim Sorokin, Roman Kholodenko, Anna Grekhova, Maria Suntsova, Margarita Pustovalova, Natalia Vorobyeva, Irina Kholodenko, Galina Malakhova, Andrew Garazha, Artem Nedoluzhko, Raif Vasilov, Elena Poddubskaya, Olga Kovalchuk, Leila Adamyan, Vladimir Prassolov, Daria Allina, Denis Kuzmin, Kirill Ignatev, Andreyan Osipov, Anton Buzdin
Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks...
January 12, 2018: Oncotarget
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