Extracellular Acidosis Modulates the Expression of Epithelial-Mesenchymal Transition (EMT) Markers and Adhesion of Epithelial and Tumor Cells.

Epithelial-to-mesenchymal transition (EMT) is an important process of tumor progression associated with increased metastatic potential. EMT can be activated by external triggers such as cytokines or metabolic parameters (e.g. hypoxia). Since extracellular acidosis is a common finding in tumors, the aim of the study is to analyze its impact on the expression of EMT markers in vitro and in vivo as well as the functional impact on cell adhesion. Therefore, three tumor and two normal epithelial cell lines were incubated for 24 h at pH 6.6 and the expression of EMT markers was studied. In addition, mRNA expression of transcription and metabolic factors related to EMT was measured as well as the functional impact on cell adhesion, either during acidic incubation or after priming cells in an acidic milieu. E-cadherin and N-cadherin were down-regulated in all tumor and normal cell lines studied, whereas vimentin expression increased in only two tumor and one normal cell line. Down-regulation of the cadherins was seen in total protein and to a lesser extent in surface protein. In vivo an increase in N-cadherin and vimentin expression was found. Acidosis up-regulated Twist1 and Acsl1 but down-regulated fumarate hydratase (Fh). Cell adhesion during acidic incubation decreased in AT1 prostate carcinoma cells whereas preceding acidic priming increased their subsequent adhesion. Low tumor pH is able to modulate the expression EMT-related proteins and by this may affect the stability of the tissue structure.

Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity.

Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications. CA IX was upregulated by hypoxia as well as acidosis in prostate cancer cells. This induction did not modulate intracellular pH but led to extracellular acidification. Pharmacological inhibition of CA IX activity by U104 (SLC-0111) resulted in a reduction in tumor cell growth and an increase in apoptotic cell death. Intracellular pH was reduced under normoxic and even more so under hypoxic conditions when CA IX level was high. However, although intracellular pH regulation was disturbed, targeting CA IX in combination with daunorubicin or cisplatin did not intensify apoptotic tumor cell death. Hence, targeting CA IX in prostate cancer cells can lead to intracellular pH dysregulation and, consequently, can reduce cellular growth and elevate apoptotic cell death. Attenuation of extracellular acidification by blocking CA IX might additionally impede tumor progression and metastasis. However, no beneficial effect was seen when targeting CA IX in combination with chemotherapeutic drugs.

The effects of timing of prophylaxis, type of anesthesia, and use of mechanical methods on outcome in major orthopedic surgery - subgroup analyses from 17,701 patients in the XAMOS study.

PURPOSE: Real-world data on the use of rivaroxaban in the perioperative period in patients undergoing major orthopedic surgery are limited. Subsets of data from the Phase IV, non-interventional XAMOS study were analyzed to explore the potential influence of timing of the first thrombo prophylactic dose, type of anesthesia, and concomitant mechanical prophylaxis on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice. PATIENTS AND METHODS: In XAMOS, 8,778 patients received rivaroxaban (10 mg once daily) and 8,635 received standard-of-care (SOC) pharmacological prophylaxis (safety population). Crude incidences of symptomatic thromboembolic and treatment-emergent bleeding events were analyzed according to timing of the first postoperative thromboprophylactic dose, use of general or neuraxial anesthesia, and use of mechanical prophylaxis with pharmacological thromboprophylaxis. RESULTS: In the rivaroxaban group, the incidences of symptomatic thromboembolic events were 0.7%, 1.0%, and 0.7% in patients receiving the first thromboprophylactic dose at ≤6 hours, >6 hours to ≤10 hours, and >10 hours to ≤24 hours after surgery, respectively. In the SOC group, the incidence of symptomatic thromboembolic events was slightly higher when the postoperative dose was given at >10 hours to ≤24 hours (1.8% vs 1.1% at ≤6 hours and 1.3% at >6 hours to ≤10 hours). The antithrombotic effect of rivaroxaban was maintained in comparison to the SOC group. The incidence of major bleeding (RECORD trial definition) was low and similar between the two treatment groups and was not influenced by timing of the first thromboprophylactic dose. Neuraxial anesthesia was used more than any other form of anesthesia for both hip and knee surgery; the effectiveness of rivaroxaban was not influenced by the type of anesthesia used. No spinal hematomas were reported in patients receiving neuraxial anesthesia in either treatment group. Use of mechanical thromboprophylaxis in addition to rivaroxaban or SOC pharmacological prophylaxis did not reduce the risk of thromboembolic events further. CONCLUSION: The effectiveness and safety of rivaroxaban in patients undergoing major orthopedic surgery in routine clinical practice were maintained irrespective of timing of the first postoperative dose within 24 hours after surgery, the type of anesthesia, and the additional use of mechanical thromboprophylaxis.

XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis.

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism, poses a substantial clinical risk, and the incidence of these thrombotic-related diseases remains high. Anticoagulation aims to prevent thrombus extension and reduce the risk of recurrent events, particularly fatal pulmonary embolism. In EINSTEIN DVT, rivaroxaban was non-inferior to enoxaparin/vitamin K antagonists for the reduction of recurrent VTE, with a similar safety profile and a net clinical benefit. EINSTEIN EXT investigated patients receiving long-term treatment in whom there was no clear decision about continuing or stopping anticoagulation; rivaroxaban was superior to placebo in the reduction of recurrent VTE, showing an acceptable benefit-risk balance. Rivaroxaban has the potential to replace standard therapy, usually parenteral low molecular weight heparin overlapping with and followed by a vitamin K antagonist, for the treatment of acute symptomatic DVT and the secondary prevention of VTE. As the use of rivaroxaban for DVT treatment increases in clinical practice, a fundamental understanding of its clinical benefits in everyday patient care is essential. XALIA (XArelto for Long-term and Initial Anticoagulation in venous thromboembolism) is a multicentre, prospective, non-interventional, observational study investigating the effectiveness and safety of a single-drug approach with rivaroxaban compared with standard therapy in patients with DVT. The study cohort will include approximately 4800 patients (≥18 years old) with objectively confirmed acute DVT who will be treated for a period of ≥3 months. The primary outcomes will be the incidence of treatment-emergent adverse events (primarily major bleeding), symptomatic recurrent venous thromboembolic events and all-cause mortality. Secondary outcomes include: major cardiovascular events; patient-reported treatment satisfaction and adherence; healthcare resource utilization; reasons for drug switching or interruption of treatment; and adverse events. XALIA will follow an international cohort of patients in more than 20 European countries, and others including Israel and Canada. The first patient was enrolled in June 2012, with results expected in 2015. It is anticipated that XALIA will provide important information on the treatment of DVT in a heterogeneous, unselected patient population in a real-world setting and provide important supplementary information to that obtained from the EINSTEIN DVT phase III study.

An observational study of sucrose-formulated recombinant factor VIII for Japanese patients with haemophilia A.

The safety and efficacy of sucrose-formulated recombinant factor VIII (rFVIII-FS; Kogenate FS) under usual clinical practice were evaluated for 12 months in an observational, postmarketing surveillance study conducted at 214 treatment centres throughout Japan. The study included 631 patients with haemophilia A, 80% of whom had severe or moderately-severe disease (< or = 2% FVIII:C). Most patients (n = 477; 75.6%) had >100 prior exposure days (EDs), but the study also included 62 (9.8%) patients with <20 EDs who were at high risk for inhibitor development. A total of 71,240 infusions were administered during the observation (mean, 113 +/- 108 per patient). Physicians rated efficacy and tolerability of rFVIII-FS as "very good" or "good" in >99% of patients. FVIII inhibitors were observed in seven patients (5 de novo; 1 persistent/fluctuating; 1 recurrent). The overall de novo inhibitor incidence was 0.8% (5/631; or 5/599 among the subgroup of patients with negative baseline titre and no known inhibitor history). De novo cases represented 3.2% (2/62) of patients with <20 EDs at enrollment (2/57 in the no inhibitor subgroup) and 0.2% (1/477) of patients pretreated with >100 EDs (1/452 in the no inhibitor subgroup) at enrollment. The results of this large observational study demonstrate that rFVIII-FS is both safe and efficacious as used in the usual clinical setting for the treatment of Japanese patients with mild to severe haemophilia A. This study supports the efficacy of rFVIII-FS with an incidence of inhibitor formation no greater than in a comparable European study or previous phase III clinical studies.