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Bil J.,Medical University of Warsaw | Winiarska M.,Medical University of Warsaw | Nowis D.,Medical University of Warsaw | Bojarczuk K.,Medical University of Warsaw | And 6 more authors.
Blood | Year: 2010

Unresponsiveness to rituximab treatment develops in many patients prompting elucidation of underlying molecular pathways. It was recently observed that rituximab-resistant lymphoma cells exhibit up-regulation of components of the ubiquitin-proteasome system (UPS). Therefore, we investigated in more detail the role of this system in the regulation of CD20 levels and the influence of proteasome inhibitors on rituximab-mediated complement-dependent cytotoxicity (R-CDC). We observed that incubation of Raji cells with rituximab leads to increased levels of ubiquitinated CD20. However, inhibition of the UPS was not associated with up-regulation of surface CD20 levels, although it significantly increased its ubiquitination. Short-term (24 hours) incubation of Raji cells with 10 or 20nM bortezomib did not change surface CD20 levels, but sensitized CD20+ lymphoma cells to R-CDC. Prolonged (48 hours) incubation with 20nM bortezomib, or incubation with 50nM bortezomib for 24 hours led to a significant decrease in surface CD20 levels as well as R-CDC. These effects were partly reversed by bafilomycin A1, an inhibitor of lysosomal/autophagosomal pathway of protein degradation. These studies indicate that CD20 levels are regulated by 2 proteolytic systems and that the use of proteasome inhibitors may be associated with unexpected negative influence on R-CDC. © 2010 by The American Society of Hematology. Source


Vrdoljak E.,University of Split | Rini B.,Cleveland Clinic | Schmidinger M.,Medical University of Vienna | Omrcen T.,University of Split | And 3 more authors.
Anti-Cancer Drugs | Year: 2013

Skeletal involvement is common in patients with renal cell carcinoma (RCC): ∼30% of patients with metastatic RCC (mRCC) will develop bone metastases. Inhibition of vascular endothelial growth factor (VEGF) has been pursued as a therapeutic target in the treatment of metastatic clear-cell RCC (m-ccRCC). Tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, sorafenib, and the monoclonal antibody bevacizumab, became the therapy of choice for patients with m-ccRCC. Besides the undisputed efficacy of TKI in the treatment of m-ccRCC, the problem of metastatic bone disease still remains. There is evidence that the presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on survival and potentially on the outcome of VEGF-targeted therapy. Also, a relatively common practice in the treatment of such patients is bone-directed therapy with bisphosphonates (BPs). Recent evidence shows a potentially synergistic effect on efficacy but also the potential for increased toxicity of combining TKIs and BPs. This review article highlights the importance of this subject and aims to facilitate further research and optimize the treatment of this important and common group of RCC patients. © 2013 Wolters Kluwer Health/ Lippincott Williams & Wilkins. Source


Sokol-Kobielska E.,Military Medical Institute
Anaesthesiology Intensive Therapy | Year: 2013

Neuromuscular blocking agents are a substantial element of anaesthesia in almost every surgical field. Nevertheless, their use has been associated with rise in mortality and morbidity. Of importance are: the general health state of the patient, liver and renal function, metabolism and excretion, active metabolites, side effects of muscle relaxants and, above all, residual paralysis. Prophylaxis of insufficient block reversal consists of blockade monitoring using acceleromyography and pharmacologic reversal of blockade. An ideal antagonistic agent should be characterised by rapid and complete reversal of blockade, disregarding its depth and total dose of muscle relaxant, lack of side effects and 100% excretion. These criteria are met by cyclodextrine gamma - sugammadex. In kontrast to anticholinergic agents, which enhance the acetylcholine amount in the postsynaptic part of the neuromuscular junction, sugammadex encapsulates myorelaxing agent removing it from the junction. Sugammadex binds specifically only muscle relaxants of aminosteroid structure. In this paper, we present the current understanding of the characteristics, dosing, indications and side effects of sugammadex. Source


Terslev L.,Copenhagen University | Naredo E.,Hospital General Universitario Gregorio Maranon | Iagnocco A.,University of Rome La Sapienza | Balint P.V.,National Institute of Rheumatology and Physiotherapy | And 12 more authors.
Arthritis Care and Research | Year: 2014

Objective To standardize ultrasound (US) in enthesitis. Methods An initial Delphi exercise was undertaken to define US-detected enthesitis and its core components. These definitions were subsequently tested on static images taken from spondyloarthritis patients in order to evaluate their reliability. Results Excellent agreement (>80%) was obtained for including hypoechogenicity, increased thickness of the tendon insertion, calcifications, enthesophytes, erosions, and Doppler activity as core elementary lesions of US-detected enthesitis. US definitions were subsequently obtained for each elementary component. On static images, the intraobserver reliability showed a high degree of variability for the detection of elementary lesions, with kappa coefficients ranging from 0.13-1. The interobserver kappa values were variable, with the lowest kappa coefficient for enthesophytes (0.24) and the highest coefficient for Doppler activity at the enthesis (0.63). Conclusion This is the first consensus-based US definition of enthesitis and its elementary components and the first step performed to ensure a higher degree of homogeneity and comparability of results between studies and in daily clinical work. © 2014, American College of Rheumatology. Source


Gore M.E.,Royal Marsden Hospital | Hariharan S.,Pfizer | Porta C.,University of Pavia | Bracarda S.,Ospedale San Donato | And 8 more authors.
Cancer | Year: 2011

Background: In a broad patient population with metastatic renal cell carcinoma (RCC), enrolled in an open-label, expanded access program (EAP), the safety profile of sunitinib was manageable, and efficacy results were encouraging. Here, the authors report results for patients with baseline brain metastases participating in this global EAP. Methods: Previously treated and treatment-naive metastatic RCC patients ≤ yen;18 years received sunitinib 50 mg orally, once daily, on Schedule 4/2. Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, consisting of all patients who received ≤ yen;1 dose of sunitinib. Results: As of December 2007, 4564 patients had enrolled in 52 countries. Of these enrollees, 4371 were included in the modified ITT population, of whom 321 (7%) had baseline brain metastases and had received a median of 3 treatment cycles (range 1-25). Reasons for their discontinuation included lack of efficacy (32%) and adverse events (8%). The most common grade 3-4 treatment-related adverse events were fatigue and asthenia (both 7%), thrombocytopenia (6%), and neutropenia (5%), the incidence of which were comparable to that for the overall EAP population. Of 213 evaluable patients, 26 (12%) had an objective response. Median progression-free survival and overall survival were 5.6 months (95% CI, 5.2-6.1) and 9.2 months (95% CI, 7.8-10.9), respectively. Conclusions: In patients with brain metastases from RCC, the safety profile of sunitinib was comparable to that in the general metastatic RCC population, and sunitinib showed evidence of antitumor activity. © 2010 American Cancer Society. Source

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