Severe adverse events during sirolimus "off-label" therapy for vascular anomalies.

OBJECTIVES: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. METHODS: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. RESULTS: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis. CONCLUSIONS: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Ulceroglandular tularemia in a toddler in Germany after a mosquito bite.

INTRODUCTION: Although tularemia is a long-known disease, its significance had diminished over the last decades in Middle Europe. However, over the past years, there is new evidence suggesting that tularemia has re-emerged in Germany. In 2007, the highest number of human cases for almost 50 years has been notified. Beside typical vectors, new ways of transmission seem to gain significance. So far, mosquito bite-transmitted tularemia has only been known from Scandinavia but not from Middle Europe. CASE REPORT: We report the first case of a 1-year-old toddler from Southwestern Germany with mosquito bite-associated ulceroglandular tularaemia. The new and interesting features of this case are the young age of the patient and the unusual transmission route. The available data suggesting changes in the epidemiology for tularemia in Germany are reviewed. This is an interesting case of infantile tularemia with a very unusual transmission route, highlighting ongoing changes in the epidemiology of tularemia in Germany.

Lepirudin treatment in a boy with suspected HIT II after surgery because of tetralogy of Fallot.

UNLABELLED: Heparin-induced thrombocytopenia (HIT II) in childhood is rare. Suspected HIT II requires immediate diagnostic and therapeutic measures in order to avoid potentially life threatening complications. Heparin must be stopped immediately. We report on a 6-year old boy who required cardiac surgery due to tetralogy of Fallot. To our knowledge he had been exposed to heparin for the first time during cardiac catheterization on the day before surgery. Preoperatively, platelet count was normal. Postoperatively (3 days after heparin exposure), he developed pulmonary and renal failure and required inotropic cardiac support and dialysis. He also developed progressive (severe) thrombocytopenia under heparin therapy on day 2-3 postoperatively. The dialysis filter required daily exchanges due to clotting despite increasing heparin doses. The first ELISA for HIT on postop day 4 was negative. 3 days later a repeated test was positive. Von Willebrand factor antigen and D-dimers were markedly increased. The patient was immediately switched to lepirudin and subsequently stabilized slowly. No major systemic thrombosis occurred. After lepirudin treatment for 6 weeks the patient was fully recovered and HIT II-testing was negative again. CONCLUSION: In children with progressive thrombocytopenia in the setting of heparin exposure and signs of major or micro thrombosis HIT II must be ruled out. Even if a first early test turns out negative repeated testing should be performed. Lepirudin anticoagulation is effective and should be monitored correctly. Platelet transfusion should be avoided in HITII.

Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodgkin-like post-transplant lymphoproliferative disease.

The development of lymphomas after SOT is a well-known complication of the immunosuppressive therapy necessary to prevent graft rejection. Epstein-Barr virus plays a central role in the pathogenesis of lymphomas because of its ability to transform infected cells. Differentiating PTLD from malignant lymphomas, especially HL can be challenging. We report on two patients, who developed EBV-associated lymphomas several years after SOT. A histological examination of lymph nodes led to a diagnosis of HL in both patients, who were started on chemotherapy according to current treatment protocols. A rapid and complete remission in one patient prompted us to analyze the expression pattern of EBV-latency genes. In this patient, the EBV expression profile revealed a latency type III suggesting the diagnosis of Hodgkin-like PTLD. The other patient required six courses of chemotherapy plus radiotherapy to reach a complete remission. In his tumor cells, a restricted EBV-latency type II pattern was found, suggesting a diagnosis of classical HL. These two cases demonstrate that in post-transplant lymphomas with histological features of HL, an analysis of the expression pattern of EBV proteins might aid in the differentiation between PTLD and HL.

Simulations of ionic liquids, solutions, and surfaces.

We have been using atomistic simulation for the last 10 years to study properties of imidazolium-based ionic liquids. Studies of dissolved molecules show the importance of electrostatic interactions in both aromatic and hydrogen-bonding solutes. However, the local structure strongly depends upon ion-ion and solute-solvent interactions. We find interesting local alignments of cations at the gas-liquid and solid-liquid interfaces, which give a potential drop through the surface. If the solid interface is charged, this charge is strongly screened over distances of a few nanometres and this screening decays on a fast time scale. We have studied the sensitivity of the liquid structure to force-field parameters and show that results from ab initio simulations can be used in the development of force fields.