Total pulmonary vein occlusion as a consequence of catheter ablation for atrial fibrillation mimicking primary lung disease

INTRODUCTION: Catheter ablation has recently been used for curative treatment of atrial fibrillation. METHODS AND RESULTS: Three of 239 patients who underwent ablation close to the pulmonary vein (PV) ostia at our institute developed severe hemoptysis, dyspnea, and pneumonia as early as 1 week and as late as 6 months after the ablation. Because the patients were arrhythmia-free, the treating physician initially attributed the symptoms to new-onset pulmonary disease (e.g., bronchopulmonary neoplasm). After absent PV flow was confirmed by transesophageal echocardiography, transseptal contrast injection depicted a totally occluded PV in all three patients. Successful recanalization, even in chronically occluded Pvs, was performed in all patients. During follow-up, Doppler flow measurements by transesophageal echocardiography demonstrated restenosis in all primarily dilated PV, which led to stent implantation. CONCLUSION: PV stenosis/occlusion after catheter ablation of atrial fibrillation occurs in a subset of patients. However, because in-stent restenosis occurred in two patients after 6 to 10 weeks, final interventional strategy for PV stenosis or occlusion remains unclear. To prevent future PV stenosis or occlusion, a decrease in target temperature and energy of radiofrequency current or the use of new energy sources (ultrasound, cryothermia, microwave) seems necessary.     

Targeting of hyperactivated mTOR signaling in high-risk acute lymphoblastic leukemia in a pre-clinical model

Despite increasingly successful treatment of pediatric ALL, up to 20% of patients encounter relapse. By current biomarkers, the majority of relapse patients is initially not identified indicating the need for prognostic and therapeutic targets reflecting leukemia biology. We previously described that rapid engraftment of patient ALL cells transplanted onto NOD/SCID mice (short time to leukemia, TTL^short) is indicative of early patient relapse. Gene expression profiling identified genes coding for molecules involved in mTOR signaling to be associated with TTL^short/early relapse leukemia.Here, we now functionally address mTOR signaling activity in primograft ALL samples and evaluate mTOR pathway inhibition as novel treatment strategy for high-risk ALL ex vivo and in vivo. By analysis of S6-phosphorylation downstream of mTOR, increased mTOR activation was found in TTL^short/high-risk ALL, which was effectively abrogated by mTOR inhibitors resulting in decreased leukemia proliferation and growth. In a preclinical setting treating individual patient-derived ALL in vivo, mTOR inhibition alone, and even more pronounced together with conventional remission induction therapy, significantly delayed post-treatment leukemia reoccurrence in TTL^short/high-risk ALL.Thus, the TTL^short phenotype is functionally characterized by hyperactivated mTOR signaling and can effectively be targeted ex vivo and in vivo providing a novel therapeutic strategy for high-risk ALL.     

Mutation analysis of CD95 (APO-1/Fas) in childhood B-lineage acute lymphoblastic leukaemia

The CD95 system plays an important role in lymphocyte homeostasis, has been implicated in the development of lymphoid malignancies, exerts a tumour suppressor function, and contributes to drug-induced cytotoxicity. We hypothesized that mutations of CD95 may occur in childhood B-lineage acute lymphoblastic leukaemia (ALL), a disease known for its constitutive resistance towards CD95-mediated apoptosis. We investigated 32 primary B-lineage ALL of childhood and five B-lineage ALL cell lines. All primary leukaemias expressed CD95 and bcl-2 to a variable degree. Most of the leukaemias were resistant towards CD95-mediated apoptosis. However, using SSCP analysis, no mutations in the coding and proximal promoter region could be detected. We conclude that the resistance towards CD95-mediated apoptosis observed in most de novo B-lineage ALL is not caused by mutations of the CD95 death receptor.