Combined Distal Venous Arterialization and Free Flap for Patients with Extensive Tissue Loss

http://dx.doi.org/10.1016/j.avsg.2009.07.001Background : We evaluated the mid-term outcome of distal venous arterialization (DVA) and the role of a combined free flap as a bridgehead for blood supply. Methods : In the past 5 years, nine patients with extensive tissue loss and lacking graftable distal arteries underwent DVA. These consisted of four primary DVAs, three combined DVA and free flap procedures, and two adjuvant DVAs for hemodynamically failed distal bypasses. After nine primary DVAs, three redo DVAs were performed for early failure. Etiologies were four Buerger disease and five arteriosclerosis obliterans, including three dialysis patients. Results : Among the nine DVA cases, there were five primary failures: two underwent amputation, two had successful redo DVA, and the remaining one did not require redo DVA. Primary patency, secondary patency, and limb salvage rates were 44.4%, 55.6%, and 77.8%, respectively. The postoperative period was 1–36 months (median 12). Angiography demonstrated DVA was effective in the early period, and development of collaterals or a capillary network from the free flap replaced the DVA function in the intermediate period. Conclusion : DVA can be effective as a procedure for limb salvage in patients without graftable distal arteries, and a combined free flap is effective and functions as a bridgehead for blood supply to the ischemic zone

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NAD(P)H:Quinone Oxidoreductase-1 Expression Sensitizes Malignant Melanoma Cells to the HSP90 Inhibitor 17-AAG

<div><p>The KEAP1-NRF2 pathway regulates cellular redox homeostasis by transcriptional induction of genes associated with antioxidant synthesis and detoxification in response to oxidative stress. Previously, we reported that KEAP1 mutation elicits constitutive NRF2 activation and resistance to cisplatin (CDDP) and dacarbazine (DTIC) in human melanomas. The present study was conducted to clarify whether an HSP90 inhibitor, 17-AAG, efficiently eliminates melanoma with KEAP1 mutation, as the NRF2 target gene, NQO1, is a key enzyme in 17-AAG bioactivation. In melanoma and non-small cell lung carcinoma cell lines with or without KEAP1 mutations, NQO1 expression and 17-AAG sensitivity are inversely correlated. NQO1 is highly expressed in normal melanocytes and in several melanoma cell lines despite the presence of wild-type KEAP1, and the NQO1 expression is dependent on NRF2 activation. Because either CDDP or DTIC produces reactive oxygen species that activate NRF2, we determined whether these agents would sensitize NQO1-low melanoma cells to 17-AAG. Synergistic cytotoxicity of the 17-AAG and CDDP combination was detected in four out of five NQO1-low cell lines, but not in the cell line with KEAP1 mutation. These data indicate that 17-AAG could be a potential chemotherapeutic agent for melanoma with KEAP1 mutation or NQO1 expression.</p></div