Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Background

Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.

Methods

EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.

Conclusions

EINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.

Trial registration

Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

     

Second malignancies after treatment of childhood non-Hodgkin lymphoma – a report of the Berlin-Frankfurt-Muenster study group

Second malignant neoplasms (SMN) pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for SMN in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma.3,590 patients <15 years of age at diagnosis, registered between 01/1981 and 06/2010, were analyzed. SMN were reported by the treating institutions and the German Childhood Cancer Registry. After a median follow-up of 9.4 years (quartile [Q] range, Q1 6.7 and Q3 12.1) 95 SMN were registered (26 carcinomas including nine basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 central nervous system [CNS]-tumors, and 16 others). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio, excluding basal cell carcinomas, was 19.8 (95% Confidence Interval [CI]: 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range, 0.2-30.3 years). Acute-lymphoblasticleukemia- type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (hazard ratio [HR] 1.87, 95% CI: 1.23-2.86, P=0.004), CNS-involvement (HR 2.24, 95% CI: 1.03-4.88, P=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI: 1.69-3.97, P<0.001), and cancer-predisposing condition (HR 11.2, 95% CI: 5.52-22.75, P<0.001) retained an independent risk. Carcinomas were the most frequent SMN after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for SMN-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies.     

Right Ventricular Longitudinal Strain Predicts Survival in Patients With Functional Tricuspid Regurgitation

BackgroundFunctional tricuspid regurgitation (TR) is a frequent finding in echocardiography. Despite general consent that right ventricular (RV) dysfunction impacts outcome of patients with TR, it is still unknown which echocardiographic parameters most accurately reflect prognosis. In this study we aimed to evaluate the prevalence of RV dysfunction and its prognostic value in patients with TR.MethodsData from 1089 consecutive patients were analysed. Tricuspid annular plane systolic excursion (TAPSE), fractional area change, and right ventricular free wall longitudinal strain (RV strain) were used to define RV dysfunction. Patients were followed for 2-year all-cause mortality. For prediction of survival, reclassification and C statistics of RV functional parameters using TR grade as reference model were performed.ResultsAmong the patients studied, 13.9% showed no TR, 61.2% had mild TR, 19.6% had moderate TR, and 5.3% had severe TR. The TR grade was associated with increased mortality (log rank, P < 0.001). Impaired RV strain and TAPSE were independent predictors for mortality (RV: hazard ratio [HR], 1.130; 95% confidence interval [CI], 1.099-1.160; P < 0.001; TAPSE: HR, 1.131; 95% CI, 1.085-1.175; P < 0.001). Both RV strain and TAPSE improved the reference model for survival prediction (RV: integrated discrimination improvement [IDI], 0.184; 95% CI, 0.146-0.221; P < 0.001; TAPSE: IDI, 0.057; 95% CI, 0.037-0.077; P < 0.001).ConclusionsEchocardiographic evaluation of RV function appears to useful for patients with TR. Assessment of RV strain provides additional value for prediction of 2-year mortality.     

Role of prothrombin 19911 A>G polymorphism,blood group and male gender in patients with venous thromboembolism: Results of a German cohort study

Journal of Thrombosis and Thrombolysis - The role of the A&gt;G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism...     

Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma

Objectives:  Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and – among other mechanisms – results in a reduced nuclear factor-kappa B (NF-κB) activity. HDACi promote histone acetylation, and also interfere with NF-κB signaling.
Methods:  Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H₂DCFDA. In addition, activated caspases, proteasome- and NF-κB activity were quantified.
Results:  Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N -acetyl- l -cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-κB activity.
Conclusions:  This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.     

Adverse effects of nitroglycerin treatment on endothelial function,vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits

OBJECTIVE: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL). BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO(-)). METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 microM) and CLA-enhanced chemiluminescence. Vascular ONOO(-) formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP). RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO(-) production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants (alpha- and beta-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity. CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of alpha- and beta-carotene may be at least in part due to a decrease in EC-SOD activity.