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.     

Spatial distribution of mosquito larvae and the potential for targeted larval control in The Gambia

We examined the distribution of aquatic stages of malaria vectors in a 400-km(2) area in rural Gambia to assess the practicality of targeting larval control. During the rainy season, the peak period of malaria transmission, breeding sites were 70% more likely to have anopheline larvae in the floodplain of the Gambia River than upland sites (P < 0.001). However, mosquitoes were found in some examples of all habitats, apart from moving water. Habitats most often colonized by anopheline larvae were the largest water bodies, situated near the landward edge of the flood-plain, where culicine larvae were present. In the wet season, 49% of sites had anophelines versus 19% in the dry season (P < 0.001). Larval control targeted at specific habitats is unlikely to be successful in this setting. Nonetheless, larval control initiated at the end of the dry season and run throughout the rainy season could help reduce transmission.     

Murine model of implantable glucose sensors: a novel model for glucose sensor development

Although implantable glucose sensors have existed for over 30 years, their function deteriorates in hours to days, in large part as a result of tissue responses to the implanted sensor (i.e., acute and chronic inflammation, fibrosis, and vessel regression). Little is known about the mediators and mechanisms that control these tissue responses to implantable glucose sensors. In the present study, we developed and validated a murine model for implantable glucose sensors, which suitably parallel sensor function in humans. Using special care in implantation and implant retaining techniques, we demonstrated that (1) sensor function deteriorates rapidly within days post-implantation and (2) loss of glucose sensor function correlated with tissue reactions at the sites of sensor implantation, especially in the vicinity of the glucose oxidase-based working electrode. These studies establish a murine model that can be used to evaluate implantable glucose sensors in vivo. This model should provide the foundation for future studies to understand the factors and mechanisms that control sensor function in vivo.     

Activation of Epac stimulates integrin-dependent homing of progenitor cells

Cell therapy is a novel promising option for treatment of ischemic diseases. Administered endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. However, the number of cells that home to ischemic tissues is restricted. The GTPase Rap1 plays an important role in the regulation of adhesion and chemotaxis. We investigated whether pharmacologic activation of Epac1, a nucleotide exchange protein for Rap1, which is directly activated by cAMP, can improve the adhesive and migratory capacity of distinct progenitor cell populations. Stimulation of Epac by a cAMP-analog increased Rap1 activity and stimulated the adhesion of human EPCs, CD34(+) hematopoietic progenitor cells, and mesenchymal stem cells (MSCs). Specifically, short-term stimulation with a specific Epac activator increased the beta2-integrin-dependent adhesion of EPCs to endothelial cell monolayers, and of EPC and CD34(+) cells to ICAM-1. Furthermore, the Epac activator enhanced the beta1-integrin-dependent adhesion of EPCs and MSCs to the matrix protein fibronectin. In addition, Epac1 activation induced the beta1- and beta2-integrin-dependent migration of EPCs on fibronectin and fibrinogen. Interestingly, activation of Epac rapidly increased lateral mobility of beta1- and beta2-integrins, thereby inducing integrin polarization, and stimulated beta1-integrin affinity, whereas the beta2-integrin affinity was not increased. Furthermore, prestimulation of EPCs with the Epac activator increased homing to ischemic muscles and neovascularization-promoting capacity of intravenously injected EPCs in the model of hind limb ischemia. These data demonstrate that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells and enhances their in vivo therapeutic potential. These results may provide a platform for the development of novel therapeutic approaches to improve progenitor cell homing.