Plastic and Reconstructive Surgery, Global Open
PURPOSE: Scarce cost analysis exists comparing oncoplastic breast surgery (OBS) with standard lumpectomy (SL). Our goal was to perform a cost-utility analysis comparing OBS with SL for breast cancer in the large breasted patient. METHODS: Cost-utility methodology involved a systematic literature review compiling outcomes and their probabilities for the treatment of unilateral breast cancer using either oncoplastic resection/reconstruction with contralateral symmetry operations or unilateral
... ectomy operations. Utility score surveys were used for each outcome to estimate qualityadjusted life years. Medicare payment data represented costs. A decision analysis tree and incremental cost-utility ratio analysis portrayed the more cost-effective strategy. Sensitivity analyses were performed. RESULTS: The literature review noted that OBS led to fewer positive margins compared with the SL (10% vs 18%). Utility scores for a successful operation favored the OBS patients (92.6 vs 86.55) but for positive margins favored SL patients (74.2 vs 70.2). OBS costs more than SL ($6782.36 vs $2399.99). Decision tree analysis revealed that OBS was more cost-effective with an incremental cost-utility ratio of $2473.54/quality-adjusted life years. Sensitivity analysis noted that SL became cost-effective when obtaining a utility score for successful surgery of greater than 92.33 (vs its surveyed value of 86.55). CONCLUSIONS: OBS in the large breasted patient provides a cost-effective treatment option when compared with SL and should be considered as a primary treatment option. PURPOSE: We have shown previously that transforming growth factor (TGF)-β1 plays a critical fibrogenic role in lymphedema. The purpose of this study was to determine the cellular source(s) of TGF-β1, understand the effects of TGF-β1 on lymphatic endothelial cells (LECs), and investigate the efficacy of a novel anti-TGF-β1 compound in preclinical mouse models of lymphedema. METHODS: We developed 3 distinct transgenic mice with selective knockout of TGF-β1 from T or myeloid cells and a non-functional TGF-β receptor on LECs. These mice underwent microsurgical lymphatic ligation in the tail or popliteal lymphadenectomy. To study the efficacy of our novel anti-TGF-β1 compound, we compared this treatment with control mice after lymphatic injury. RESULTS : TGF-β1 production was significantly decreased in T cell but not myeloid TGF-β1 knockout transgenic mice (50% reduction; P < 0.01). Furthermore, TGF-β1 knockout T-cell transgenic mice displayed decreased fibrosis, inflammation, and adipose deposition compared with controls or TGF-β1 knockout myeloid mice. Blockade of TGF-β1 activity in LECs had no effect on the pathological changes of lymphedema but did increase lymphangiogenesis. Systemic or topical application of a novel anti-TGF-β1 compound decreased fibrosis, improved lymphatic function, and reversed the established swelling in the tail model. CONCLUSIONS: We have shown for the first time that T cells are the primary source of TGF-β1 in lymphedema and that inhibition with a novel anti-TGF-β1 compound potently decreases tissue fibrosis after lymphatic injury. Furthermore, we have shown that the primary mechanism in which TGF-β1 causes lymphatic dysfunction is because of tissue fibrosis rather than the direct effects on LECs. PURPOSE: Lymphatic endothelial cell (LEC) function is regulated by the activation of VEGFR-3 by VEGF-C, and recent studies suggest that this signaling pathway is disturbed in obesity. Therefore, the purpose of this study was to develop a transgenic mouse model to selectively examine the effects of VEGFR-3 signaling in the lymphatic system and to use this model to understand how lymphatic defects modulate metabolic syndrome in obesity. METHODS: To activate VEGFR-3 signaling in LECs independent of VEGF-C, we mated FLT4-Cre mice with PTEN-LoxP mice. Because FLT4 is an LEC-specific promoter, activation of Cre with tamoxifen results in knockout of PTEN, an intracellular inhibitor of VEGFR3, only in LECs thereby increasing the activation of VEGFR-3 downstream pathways. We used this model to analyze lymphatic function and metabolic parameters in a high-fat diet model of obesity. RESULTS : PTEN knockout in LECs markedly increased lymphatic function in response to inflammation. More importantly, the loss of PTEN in obese mice significantly decreased the deleterious effects of obesity on the lymphatic system compared with controls. Moreover, even though PTEN knockout mice became obese when fed a high-fat diet, these mice were protected from metabolic syndrome and hepatic steatosis suggesting that lymphatic function is a significant regulator of these outcomes after weight gain. CONCLUSIONS: We have shown that impaired VEGF-C/ VEGFR-3 signaling in LECs is a major regulator of obesityinduced lymphatic dysfunction. More importantly, we have shown that increasing downstream signaling pathways of VEGFR-3 only in LECs significantly decreases metabolic syndrome and hepatic steatosis. PURPOSE: Lymphedema is a morbid disease, and lymph node transfer (LNT) is considered the most promising treatment. The mechanism of LNT remains unclear, and its effectiveness in restoring immune function is not well explored. Therefore, the purpose of this study was to analyze lymphatic and immune function after LNT. METHODS: Hindlimb lymphedema was induced in a transgenic mouse model by ablating the lymphatic system using diphtheria toxin. Two weeks later, experimental animals underwent popliteal LNT, whereas controls were treated with popliteal incision alone. Limb swelling, immune cell trafficking, and immune responses were then analyzed 8 weeks later. RESULTS: LNT animals had a marked (85%) reduction in foot swelling from baseline (ie, 2 weeks after lymphatic ablation); in contrast, control animals had no improvement in swelling during this period of time. These measurements were confirmed with histological studies demonstrating a more than 90% increase in adipose deposition in the control animals compared with LNT. In addition, animals treated with LNT had decreased infiltration of T cells and marked increase in lymphangiogenesis and lymphatic regeneration. Moreover, animals treated with LNT were able to traffic dendritic cells to their lymph nodes (426% increase) and had significant increases in antibody responses compared with controls. In response to DNFB, systemic immune responses were restored in LNT group. CONCLUSIONS: LNT markedly induces lymphangiogenesis and improves lymphatic function in a mouse model of lymphedema. Transplanted lymph nodes maintain immunologic function and can support migration of antigen-presenting cells. AAPS and PSRC Abstract Supplement PURPOSE: Pathologic fractures and associated nonunions arising in irradiated bone are complex management dilemmas for reconstructive surgeons. We developed an implantable, sustained-release nanoparticle formulation of a known angiogenic small molecule, deferoxamine (DFO) that obviates the need for serial injections of standard DFO. Here, we investigate the efficacy of nano-DFO compared with standard DFO in its ability to improve metrics of mineralization, mechanical strength, and bony union. METHODS: Rats (n = 44) were divided into 4 groups: fracture, radiated fracture, radiated fracture with standard DFO, and radiated fracture with nano-DFO. Radiated groups received radiotherapy 2 weeks before mandibular osteotomy. The nano-DFO group received implantation of the drug at the time of surgery. After a 40-day healing period, mandibles were assessed for bony union, imaged with micro-computed tomography, and mechanically tested to failure. Analysis of variance was used for comparison (P < 0.05). RESULTS: We observed decreases in all metrics for the radiation group that were remediated with the addition of both DFO and nano-DFO therapies. For metrics of bone mineral density, total mineral density, bone volume fraction, stiffness, and failure load, there was no difference between the 2 treatments. However, there was a clinically relevant increase in bony unions with nano-DFO therapy that was 24% higher than standard DFO (67% vs 91%). CONCLUSIONS: Our data demonstrate in vivo efficacy for the mineralization and biomechanical properties of implanted nano-DFO when compared with normal DFO. We support the continued investigation of this promising treatment in its translation for the management of pathologic fractures and associated nonunions after radiotherapy. PURPOSE: Heterotopic ossification (HO) occurs with severe trauma causing significant functional limitations. Identification of progenitor cells and signaling mechanisms that cause these processes is critical for identifying therapeutic options. METHODS: C57Bl/6 mice underwent Achilles' tenotomy and 30% TBSA burn to induce HO. Immunostaining and mRNA quantification were performed for the tendon lineage marker, Scleraxis. Separately, mice expressing hyperactive bone morphogenetic protein receptor (Scx-creERT/caACVR1 fl/fl ) were generated and they received cardiotoxin to induce intramuscular HO followed by histologic analysis after 3 weeks. Given its known effects on tendon, ciprofloxacin was used to treat mesenchymal cells in vitro followed by mRNA quantification of Scx and osteogenic differentiation assays. Finally, mice treated with control or ciprofloxacin (10 mg/kg) received burn/tenotomy followed by micro-computed tomography after 9 weeks (n = 4/group). RESULTS: Burn/tenotomy increased Scleraxis expression at the tenotomy site (A). Scleraxis lineage cells with hyperactive bone morphogenetic protein receptor activity were sufficient to form intramuscular HO after trauma (B). Ciprofloxacin significantly reduced Scleraxis gene expression in vitro, with a corresponding decrease in osteogenic differentiation (C). Treatment of burn/tenotomy mice with ciprofloxacin significantly reduced HO after 9 weeks (8.50 v 3.67 mm 3 , P < 0.05; D). CONCLUSIONS: Muscle-and tendon-resident progenitor cells marked by expression of Scleraxis, a tendon lineage marker, are capable of forming cartilage and osseous lesions. Targeted inhibition of Scleraxis gene expression using ciprofloxacin, a readily available therapeutic is a powerful treatment for patients at risk for muscle fibrosis and HO. PURPOSE: The purpose of this study was to conduct a metaanalysis to determine whether irrigation of breast implant pockets with antimicrobial agents reduces the rate of capsular contracture. Capsular contracture is the most common complication after primary augmentation mammoplasty, yet its etiology remains cryptogenic. METHODS: PubMed was searched for publications from January 1, 2000, through October 2015. Studies with the following criteria were included: primary breast augmentation with implants, use of antimicrobial irrigation, and documentation of capsular contracture. Our primary outcome was incidence of capsular contracture. The quality of included studies was assessed independently. Studies were meta-analyzed to obtain a pooled odds ratio (OR) describing the effect of antimicrobial irrigation on capsular contracture. RESULTS: The meta-analysis included 8 studies and totaled 8538 patients. Five thousand two hundred fifty-five patients received antimicrobial irrigation, and 3544 patients did not. Analysis revealed that combined antimicrobial irrigation, the antibiotic irrigation subgroup, and iodine subgroup were associated with an increased incidence of capsular contracture [OR, 2.60; 95% (confidence interval) CI, 2.3-2.94; OR, 1.41; 95% CI, 1.17-1.70; OR, 3.19; 95% CI, 2.23-4.56; P < 0.00001; I 2 = 99.9], respectively. CONCLUSIONS: Antimicrobial irrigation of implant pockets does not reduce the incidence of capsular contracture. The authors recommend that further prospective multicenter trials be conducted to further elucidate the role of antibiotic irrigation in capsular contracture.