Management of thoracic aortic graft infections with the omental flap.

BACKGROUND: Infection of thoracic aortic grafts occurs infrequently; however, once present, it is associated with high patient morbidity and mortality. We report our successful experience in the treatment of 11 patients who developed infection of their thoracic aortic graft. METHODS: This is an institutional review board-approved retrospective review of 11 patients who had documented thoracic aortic graft infections with associated mediastinitis or empyema. After diagnosis, plastic surgery consultation was obtained, and the patients underwent formal operative debridement with cardiovascular service. Intraoperative cultures were obtained, and the patients were placed on specific antibiotic regimens. After the wound bed was adequately prepared, the omentum was harvested and was based on the right gastroepiploic vessels. The flap was circumferentially wrapped around the aortic graft and simultaneously used to fill the mediastinal dead space. In a certain subset of patients, a cryopreserved homograft replaced the synthetic graft before omental flap reconstruction. RESULTS: The infections were eventually controlled in all surviving patients. Ten of 11 patients were discharged either to a rehab or to a nursing facility. There was 1 perioperative death secondary to multisystem organ failure. Mean follow-up period was 36 months and revealed a greater than 90% survival rate. Serial imaging reported no suture-line complications. CONCLUSIONS: We report our series on the treatment of patients with infection of thoracic aortic grafts. Debridement and tissue coverage with an omental flap provided these patients with successful recovery and survival.

Apurinic/apyrimidinic endonuclease is inversely associated with response to radiotherapy in pediatric ependymoma.

Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers radiation resistance in human cells. Here we examined the association between Ap endo activity and response to radiotherapy in pediatric ependymomas, tumors for which treatment options are limited and survival rates are only about 50%. We assayed Ap endo activity in 36 ependymomas and expression of Ape1/Ref-1, the predominant Ap endo activity in humans, in 44 tumors by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity or expression with progression-free survival or with overall survival. Activity varied 13-fold and was not associated with tumor or patient characteristics. In univariate models with Ap endo activity entered as a continuous variable, the hazard ratio for progression increased by a factor of 2.18 for every 0.01 unit increase in activity (p ≤ 0.003) in 24 grade II ependymomas. Risk for death increased by a factor of 1.89 (p ≤ 0.02) in the same population. The fraction of Ape1/Ref-1 immunopositive cells varied widely within individual tumors and was not associated with either progression-free or with overall survival. Suppressing Ap endo activity in pediatric ependymoma cells significantly increased radiation sensitivity, suggesting that the association of activity with radiation response reflected, at least in part, repair of radiation-induced DNA lesions. Our data indicate that Ap endo activity is predictive of outcome following radiotherapy, and suggest that Ape1/Ref-1 promotes radiation resistance in pediatric ependymomas. Our findings support the use of inhibitors of Ap endo activity to overcome resistance.

Evaluation of 5'-deoxy-5'-[F-18]fluorothymidine as a tracer of intracellular thymidine phosphorylase activity.

Two human cell lines (A549 and U937) with cytosolic thymidine phosphorylase (TP) activity were used to evaluate the potential of 5'-deoxy-5'-[F-18]fluorothymidine ([F-18]DFT) as a tracer of intracellular TP expression. Cellular metabolism of DFT led to the production of 5-[F-18]fluoro-2,5-dideoxy-D-ribose-1alpha-phosphate ([F-18]FddR-1P), in analogy to the metabolism of thymidine, which produces 2-deoxy-D-ribose-1alpha-phosphate (dR-1P). A549 cells showed the highest production rate of FddR-1P. After A549 cells were exposed to [F-18]DFT for 40 min, the relative intracellular concentration of [F-18]FddR-1P was more than sevenfold higher in cells than its precursor in the incubating medium. For the same amount of time, a twofold concentration was seen in U937 cells. However, uptake ratios did not rank with the corresponding TP activities found in cell extracts [TP activity ratio (U937:A549)=1.6] that were independently determined with a labeled thymidine/thymine cleavage assay. The discrepancy of TP activity ratios was traced to the instability of FddR-1P in cells. This was evident from the fact that cells accumulated radioactivity by producing FddR-1P, but activity also effluxed from cells over 1 h when the medium was subsequently made tracer free. The dominant labeled molecule released by cells was characterized as a neutral and lipophilic molecule, which was presumed to be a deoxynucleoside. Our results indicate that [F-18]DFT would not be effective for imaging TP expression because its initial metabolite undergoes further conversion to a diffusible secondary metabolite, allowing activity loss from cells.

Metabolism of 3'-deoxy-3'-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography.

3'-Deoxy-3'-[F-18]fluorothymidine (FLT) is under clinical evaluation as a metabolic probe for imaging cell proliferation in vivo using positron emission tomography (PET). As part of our validation effort, we followed the short-term metabolism of FLT in exponentially growing tumor cells to demonstrate the enzyme activities within the DNA salvage pathway that influence retention of radioactivity. In A549 cells, thymidine kinase-1 (TK1) activity produced FLTMP, which dominated the labeled nucleotide pool. Subsequent nucleotide phosphorylations by thymidylate kinase (TMPK) and nucleotide diphosphate kinase (NDPK) led to FLTTP. After 1h, the cellular metabolic pool contained approximately 30% FLTTP. A putative deoxynucleotidase (dNT), which degrades FLTMP to FLT, provided the primary mechanism for tracer efflux from cells. In contrast, FLTTP was resistant to degradation and highly retained. The uptake and retention characteristics of FLT were also compared to those of thymidine, FMAU (2'-arabino-fluoro-TdR) and FIAU (2'-arabino-fluoro-5-iodo-2'-dexoyuridine). Despite the fact that FLT lacks the 3'-hydroxy necessary for its incorporation into DNA it out performed both FMAU and FIAU in terms of uptake and retention.