Can bioprosthetic valve thrombosis be promoted by aortic root morphology? An in vitro study.

OBJECTIVES: Bioprosthetic valve thrombosis has been considered uncommon, but recent studies have shown that it is more frequent than previously thought. Insufficient washout of the aortic sinus is believed to be a risk factor for bioprosthetic valve thrombosis. The objective of this in vitro experiment was to investigate the impact of aortic root morphology on blood flow in the aortic sinus and to relate these results to in vivo data obtained in patients with a transcatheter aortic valve implant. METHODS: Two compliant aortic root phantoms with different morphologies (symmetrical and patient-specific) were fabricated with silicone. A bioprosthetic aortic valve was inserted in both phantoms. Haemodynamic measurements were performed in a pulsatile flow-loop replicating physiological flow and pressure conditions. The flow in the aortic root was visualized by injecting contrast agent (CA). The distribution of the CA was captured by a high-speed camera, and image post-processing was performed to quantify CA distribution in the aortic sinus. The results were compared with angiographic images after a transcatheter aortic valve implant. RESULTS: Blood flow in the aortic root and the washout of the sinus portion are significantly affected by aortic root morphology. CA arrives at the aortic sinus of the 2 phantoms at 0.09 s and 0.16 s after the valve opens in the symmetrical and the patient-specific phantoms, respectively. Delayed CA arrival was also observed in the patients with a transcatheter aortic valve implant. CONCLUSIONS: Aortic root morphology affects the blood flow in the aortic sinus and may be a factor in bioprosthetic valve thrombosis. Therefore, patient-specific aortic root morphology should be considered when selecting and positioning a prosthesis.

Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome.

To evaluate internal tandem duplication (ITD) insertion sites and length as well as their clinical impact in younger adult patients with FLT3-ITD-positive acute myeloid leukemia (AML), sequencing after DNA-based amplification was performed in diagnostic samples from 241 FLT3-ITD-mutated patients. All patients were treated on 3 German-Austrian AML Study Group protocols. Thirty-four of the 241 patients had more than 1 ITD, leading to a total of 282 ITDs; the median ITD length was 48 nucleotides (range, 15-180 nucleotides). ITD integration sites were categorized according to functional regions of the FLT3 receptor: juxtamembrane domain (JMD), n = 148; JMD hinge region, n = 48; beta1-sheet of the tyrosine kinase domain-1 (TKD1), n = 73; remaining TKD1 region, n = 13. ITD length was strongly correlated with functional regions (P < .001). In multivariable analyses, ITD integration site in the beta1-sheet was identified as an unfavorable prognostic factor for achievement of a complete remission (odds ratio, 0.22; P = .01), relapse-free survival (hazard ratio, 1.86; P < .001), and overall survival (hazard ratio, 1.59; P = .008). ITD insertion site in the beta1-sheet appears to be an important unfavorable prognostic factor in young adult patients with FLT3-ITD-positive AML. The clinical trials described herein have been registered as follows: AML HD93 (already published in 2003), AML HD98A (NCT00146120; http://www.ClinicalTrials.gov), and AMLSG 07-04 (NCT00151242; http://www.ClinicalTrials.gov).