A Cost-Utility Analysis Comparing the Sartorius versus the Rectus Femoris Flap in the Treatment of the Infected Vascular Groin Graft Wound.

BACKGROUND: The purpose of this study was to examine the sartorius and rectus femoris flaps as reasonable coverage options for the infected vascular groin graft wound. The authors' goal was to perform a cost-utility analysis of the sartorius flap versus the rectus femoris flap in the treatment of an infected vascular groin graft. METHODS: Cost-utility methodology involved a literature review compiling outcomes for specific flap interventions, obtaining utility scores for complications to estimate quality-adjusted life-years, accruing costs using Diagnosis-Related Group and Current Procedural Terminology codes for each intervention, and developing a decision tree that could portray the more cost-effective strategy. The authors also performed sensitivity analysis to check the robustness of their data. Szilyagi III and Samson III and IV grades of infected groin grafts were included in the study. RESULTS: Twenty-six studies were used pooling 296 patients (234 sartorius flaps and 62 rectus flaps). Decision tree analysis noted that the rectus femoris flap was the more cost-effective option. It was the dominant treatment option given that it was more clinically effective by an additional 0.30 quality- adjusted life-years, with the sartorius flap option costing an additional $2241.88. The sartorius flap had a 13.68 percent major complication rate versus an 8.6 percent major complication rate for the rectus femoris flap. One-way sensitivity analysis showed that the sartorius flap became a cost-effective option if its major complication rate was less than or equal to 8.89 percent. CONCLUSION: The rectus femoris flap in the treatment of the infected vascular groin graft is a cost-effective option compared with the sartorius flap.

Cost-Utility Analysis: Sartorius Flap versus Negative Pressure Therapy for Infected Vascular Groin Graft Managment.

BACKGROUND: Sartorius flap coverage and adjunctive negative pressure wound therapy (NPWT) have been described in managing infected vascular groin grafts with varying cost and clinical success. We performed a cost-utility analysis comparing sartorius flap with NPWT in managing an infected vascular groin graft. METHODS: A literature review compiling outcomes for sartorius flap and NPWT interventions was conducted from peer-reviewed journals in MEDLINE (PubMed) and EMBASE. Utility scores were derived from expert opinion and used to estimate quality-adjusted life years (QALYs). Medicare current procedure terminology and diagnosis-related groups codes were used to assess the costs for successful graft salvage with the associated complications. Incremental cost-effectiveness was assessed at $50,000/QALY, and both univariate and probabilistic sensitivity analyses were conducted to assess robustness of the conclusions. RESULTS: Thirty-two studies were used pooling 384 patients (234 sartorius flaps and 150 NPWT). NPWT had better clinical outcomes (86.7% success rate, 0.9% minor complication rate, and 13.3% major complication rate) than sartorius flap (81.6% success rate, 8.0% minor complication rate, and 18.4% major complication rate). NPWT was less costly ($12,366 versus $23,516) and slightly more effective (12.06 QALY versus 12.05 QALY) compared with sartorius flap. Sensitivity analyses confirmed the robustness of the base case findings; NPWT was either cost-effective at $50,000/QALY or dominated sartorius flap in 81.6% of all probabilistic sensitivity analyses. CONCLUSION: In our cost-utility analysis, use of adjunctive NPWT, along with debridement and antibiotic treatment, for managing infected vascular groin graft wounds was found to be a more cost-effective option when compared with sartorius flaps.

Neuroendocrine responses mediate macrophage function after trauma.

BACKGROUND: Clearly understanding the interactions between macrophage (M phi)-generated inflammatory mediators and the neuroendocrine system in regulating immune function after traumatic injury may aid in reversing trauma-mediated immune dysfunction and diminish the incidence and severity of infection in the traumatized patient. METHODS: Trauma consisted of an open femur fracture and 40% retro-orbital hemorrhage (Trauma) or anesthesia alone (Control). Female Balb/C mice (6-8 weeks) with intact adrenal glands (Intact) or a bilateral adrenalectomy (ADX) were used. For glucocorticoid studies, corticosterone or a vehicle was administered via intraperitoneal (ip) injection 2 hours before the trauma. Splenic M phis were harvested and prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) production, and mRNA, cyclooxygenase-2 (COX-2) protein, and nuclear factor kappa B (NF-kappa B) activity were measured. RESULTS: M phi, PGE(2) and IL-6 production in Trauma+Intact mice was significantly increased compared with Control+Intact mice. Adrenalectomy decreased these levels to Control levels. Similar changes were observed for COX-2 and IL-6 expression. M phi nuclear NF-kappa B levels were increased in Trauma+Intact mice compared with controls. Adrenalectomy abrogated this increase. Treating Trauma+Intact mice with RU-486 did not restore PGE(2) and IL-6 production or COX-2 and IL-6 messenger RNA to control levels. Administering exogenous glucocorticoid to Intact mice did not increase PGE(2) and IL-6 production or COX-2 and IL-6 mRNA to Trauma levels. CONCLUSIONS: The neuroendocrine system upregulates certain M phi inflammatory mediators, including PGE(2), IL-6, and NF-kappa B, after trauma. This upregulation does not seem to be mediated via glucocorticoids and possibly may be mediated via catecholamines. Elucidation of the interactions between the neuroendocrine system, the immune system, and inflammatory mediator secretion might provide novel therapeutic strategies for the injured patient.

Analysis of gene expression in the tumor-associated macrophage.

INTRODUCTION: The tumor-associated macrophage (TAM) is at the front line of the host's defense against malignancy and provides an attractive target for immune-modulatory therapy. However, factors present within the tumor microenvironment can alter macrophage phenotype, preventing its cytotoxic activity and reducing its susceptibility to interferon-gamma and lipopolysaccharide-mediated stimulation. METHODS: Macrophages were isolated from subcutaneous B16 melanoma tumors implanted in C57 BL/6 mice. Wound macrophages were harvested from subcutaneously-implanted PVA sponges, and resting peritoneal macrophages were harvested by peritoneal lavage. Gene expression was analyzed using an Atlas cDNA array (Clontech, Mountain View, CA). RESULTS: TAM demonstrated a pattern of gene expression distinct from both wound and peritoneal macrophage. There is an increase in proliferation-associated genes and in genes encoding the ultrastructural proteins cofillin, zyxin, and vimentin more commonly associated with fibroblast-like cells. In addition, an observed decrease in expression of the CD14 gene, and increase in inhibitory pathways including osteopontin and its receptor CD44, the inositol 1,4,5-triphosphate receptor, and the receptors for interleukin-4 and granulocyte monocyte-colony stimulating factor could explain the resistance of TAM to lipopolysaccharide-mediated stimulation. There was also a significant decrease in the expression of the interferon-gamma second messenger, IRF-1. CONCLUSIONS: This study has identified a number of pathways involved in the suppression of TAM function. Targeting of these pathways may allow for the generation of more effective immune-modulatory anti-neoplastic therapy.

Altered cyclooxygenase-2 expression and nitric oxide metabolism following major elective surgery.

BACKGROUND AND AIMS: Postoperative variation in immune function leads to increased susceptibility to infections. Cyclooxygenase-2 (COX-2)-generated Prostaglandin-E(2) (PGE(2)), which signals through the PGE(2) receptor (EP receptor), as well as nitric oxide metabolites (NOx), appear to be important in postoperative immune dysfunction. It is unclear, however, how these substrates and receptors change over time. This study was conducted to evaluate postoperative changes in inflammatory mediator production and monocyte COX-2 and EP receptor expression. MATERIALS AND METHODS: Nineteen patients had blood drawn preoperatively and up to 1 week postoperatively. Plasma NOx levels were measured. Peripheral blood mononuclear cell (PBMC) COX-2 and EP receptor mRNA expression were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). PBMC PGE(2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-10 productions were evaluated by enzyme-linked immunosorbent assay (ELISA) kits. Statistical analyses were by ANOVA and Student's t tests. RESULTS: Postoperatively, PBMC mean PGE(2) and IL-6 productions were significantly increased at all time points. Mean TNF-alpha production was maximal on postoperative day 2, while mean IL-10 production was unchanged. Mean circulating NOx levels demonstrated a biphasic response decreasing early postoperatively and normalizing at postoperative day (POD) 7. PBMC COX-2 enzyme and EP receptor mRNA expression were unchanged. CONCLUSIONS: Altered PBMC PGE(2) production and plasma NOx levels support a role for altered macrophage activity, which may contribute to immune dysfunction in the postoperative period.

Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages.

BACKGROUND: Glucocorticoids are widely used in treating inflammatory diseases. The contribution of adrenal glucocorticoids to inflammatory regulation is unknown. Endogenous glucocorticoids, as distinct from synthetic analogues, not only suppress but also enhance immune functions. Elevated circulating cortisol levels are characteristic of injured patients. In a model of trauma, an early glucocorticoid surge occurs concomitantly with decreased cellular cytokine responses. Cytokine production elevated late after injury is associated with increased mortality. We hypothesized that this glucocorticoid surge mediates the later heightened macrophage responses. MATERIALS AND METHODS: The murine macrophage like cells RAW 264.7 were incubated with corticosterone (35 ng/mL), or vehicle control, for 1 h, after which the cells were washed and corticosterone-free medium added. At 0, 3, 6, 12, and 24 h after removal of the corticosterone, the cells were stimulated with lipopolysaccharide (LPS) and interferon-gamma. Supernatant tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and nitrite levels were measured. In separate experiments the effect of pretreatment with corticosterone on TNF-alpha, IL-6, and nitrite mRNA expression as well as nuclear factor-kappaB and glucocorticoid receptor activity was determined. CD14 receptor expression was determined by flow cytometry. RESULTS: Glucocorticoid pretreatment caused significantly increased RAW 264.7 cell production of nitrite, IL-6 and TNF-alpha. mRNA for these inflammatory mediators was induced 6 h after the corticosterone pretreatment, and was associated with activation of nuclear factor-kappaB in the presence of activated glucocorticoid receptor. Cell surface-expression of CD14 was likewise increased. CONCLUSIONS: The results of this study demonstrate a novel role for glucocorticoids and provide a mechanism for the late upregulation in macrophage function after injury.

Renal cell carcinoma induces prostaglandin E2 and T-helper type 2 cytokine production in peripheral blood mononuclear cells.

BACKGROUND: Patients with renal cell carcinoma (RCC) do not develop an effective antitumor immune response, despite significant infiltration by lymphocytes. Tumor production of immunosuppressive factors may account for this failure. The object of this study was to investigate the production of immunosuppressive mediators, especially prostaglandin E(2) (PGE(2)), by RCC. METHODS: Peripheral blood mononuclear cells (PBMC) were cocultured with conditioned medium (CM) from human RCC cell lines in the presence or absence of NS-398, a selective cyclooxygenase 2 (COX-2) inhibitor. Supernatants were analyzed for levels of PGE(2), interleukin (IL)-10, IL-6, IL-2, interferon-gamma, and IL-12. The effects of RCC CM on PBMC proliferation were also examined. The expression of basal and stimulated COX-2 messenger RNA in the cell lines was assessed by reverse transcriptase-polymerase chain reaction. RESULTS: RCC CM significantly increased PGE(2) production by PBMC. T-helper type 2 (Th2) cytokine production was also significantly increased. Th1 cytokines were unchanged or decreased. RCC CM increased proliferation of PBMC. Coculture with NS-398 reduced PBMC PGE(2) production to below control levels and significantly decreased IL-6 production and PBMC proliferation. NS-398 had no effect on cellular production of IL-10 or Th1 cytokines. CONCLUSIONS: Human RCC inhibits the host antitumor immune response by promoting PGE(2) production and Th2 cytokines in PBMC. Selective inhibition of COX-2 may have a role in abrogating this effect.

Cyclooxygenase-2 inhibition improves macrophage function in melanoma and increases the antineoplastic activity of interferon gamma.

BACKGROUND: Melanoma inhibits macrophage tumoricidal activity and increases the expression of cyclooxygenase-2 (COX-2). In this study, we sought to determine whether inhibition of COX-2 could restore macrophage function and hence maximize the antitumor activity of the immune stimulant interferon gamma (IFN gamma). METHODS: Peritoneal macrophages were exposed to B16 melanoma-conditioned medium for 24 hours with or without the COX-2 inhibitor NS-398 and then were stimulated with lipopolysaccharide and IFN gamma. Cytotoxic activity, nitrite production, and cytokine production by the stimulated macrophages were measured. In addition, B16 melanoma cells were implanted intradermally into mice treated with IFN gamma (14,000 U on alternate days) alone or with a combination of IFN gamma and a COX-2 inhibitor (NS-398 or nimesulide). Mice were assessed for tumor growth and survival. RESULTS: Macrophage cytotoxicity and nitrite production were significantly suppressed by melanoma-conditioned medium (P <.01). This was prevented by 200 micro M of NS-398 (P <.05). In vivo, combined treatment with IFN gamma and a COX-2 inhibitor caused a significant inhibition of tumor growth (P <.01) and improved survival (P =.02) compared with controls. CONCLUSIONS: COX-2 inhibition reversed melanoma-induced suppression of macrophage function, and combined treatment of IFN gamma plus a COX-2 inhibitor was maximally effective in reducing tumor growth and improving survival.