Oriana Cohen

Restoration of Nrf2 Signaling Normalizes the Regenerative Niche

Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)–based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia–associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.

Determining the Oncologic Safety of Autologous Fat Grafting as a Reconstructive Modality: An Institutional Review of Breast Cancer Recurrence Rates and Surgical Outcomes

Background: The increasing use of autologous fat grafting in breast cancer patients has raised concerns regarding its oncologic safety. This study evaluated patient outcomes and tumor recurrence following mastectomy reconstruction and autologous fat grafting. Methods: Retrospective chart review identified patients who underwent mastectomy followed by breast reconstruction from 2010 to 2015. Eight hundred twenty-nine breasts met inclusion criteria: 248 (30.0 percent) underwent autologous fat grafting, whereas 581 (70.0 percent) breasts did not. Patient demographics, cancer characteristics, oncologic treatment, surgical treatment, surgical complications, local recurrence, and distant metastases were analyzed. Results: Autologous fat grafting patients and control patients were of similar body mass index, smoking status, and BRCA status. Patients who underwent fat grafting were significantly younger than control patients and were less likely to have diabetes, hypertension, or hyperlipidemia. The two groups represented similar distributions of BRCA status, Oncotype scores, and hormone receptor status. Patients underwent one to four grafting procedures: one procedure in 83.1 percent, two procedures in 13.7 percent, three in 2.8 percent, and four in 0.4 percent. Mean follow-up time from initial surgery was 45.6 months in the fat grafting group and 38.8 months in controls. The overall complication rate following fat grafting was 9.4 percent. Among breasts undergoing surgery for therapeutic indications, there were similar rates of local recurrence (fat grafting group, 2.5 percent; controls, 1.9 percent; p = 0.747). Interestingly, mean time to recurrence was significantly longer in the fat grafting group (52.3 months versus 22.8 months from initial surgery; p = 0.016). Conclusions: Autologous fat grafting is a powerful tool in breast reconstruction. This large, single-institution study provides valuable evidence-based support for its oncologic safety. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Is Unilateral Implant or Autologous Breast Reconstruction Better in Obtaining Breast Symmetry

Unilateral breast reconstruction poses a special set of challenges to the reconstructive breast surgeon compared to bilateral reconstructions. No studies to date provide an objective comparison between autologous and implant based reconstructions in matching the contralateral breast. This study compares the quantitative postoperative results between unilateral implant and autologous flap reconstructions in matching the native breast in shape, size, and projection using three‐dimensional (3D) imaging. Sixty‐four patients who underwent unilateral mastectomy with tissue expander (TE)‐implant (n = 34) or autologous microvascular free transverse rectus abdominus myocutaneous (TRAM; n = 18) or deep inferior epigastric artery perforator (DIEP; n = 12) flap (n = 30) reconstruction from 2007 to 2010 were analyzed. Key patient demographics and risk factors were collected. Using 3D scans of patients obtained during pre and postoperative visits including over 1 year follow‐ups for both groups, 3D models were constructed and analyzed for total breast volume, anterior‐posterior projection from the chest wall, and 3D comparison. No significant differences in mean age, body mass index, or total number of reconstructive surgeries were observed between the two groups (TE‐implant: 52.2 ± 10, 23.9 ± 3.7, 3 ± 0.9; autologous: 50.7 ± 9.4, 25.4 ± 3.9, 2.9 ± 1.3; p > 0.05). The total volume difference between the reconstructed and contralateral breasts in the TE‐implant group was insignificant: 27.1 ± 22.2 cc, similar to the autologous group: 29.5 ± 24.7 cc, as was the variance of breast volume from the mean. In both groups, the reconstructed breast had a larger volume. A‐P projections were similar between the contralateral and the reconstructed breasts in the TE‐implant group: 72.5 ± 3.21 mm versus 71.7 ± 3.5 mm (p > 0.05). The autologous reconstructed breast had statistically insignificant but less A‐P projection compared to the contralateral breast (81.9 ± 16.1 mm versus 61.5 ± 9.5 mm; p > 0.05). Variance of A‐P projection from the mean was additionally insignificant between the contralateral and reconstructed breasts. Both groups produced similar asymmetry scores based on global 3D comparison (TE‐implant: 2.24 ± 0.3 mm; autologous: 1.96 ± 0.2 mm; p > 0.05). Lastly, when the autologous group was further subdivided into TRAM and DIEP cohorts, no significant differences in breast volume, A‐P projection or symmetry existed. Using 3D imaging, we demonstrate that both TE‐implant and autologous reconstruction can achieve symmetrical surgical results with the same number of operations. This study demonstrates that breast symmetry, while an important consideration in the breast reconstruction algorithm, should not be the sole consideration in a patient’ decision to proceed with autologous versus TE‐implant reconstruction.

A Novel Technique of Preserving Internal Mammary Artery Perforators in Nipple Sparing Breast Reconstruction

Summary: As nipple-sparing mastectomy with implant-based reconstruction has increased, attention must be paid to the viability of the nipple-areolar complex. This article describes the use of preoperative Doppler ultrasound to identify the internal mammary artery perforators. Preserving the internal mammary artery improves vascular supply to the nipple-areolar complex.

Flap coverage for the treatment of exposed left ventricular assist device (LVAD) hardware and intractable LVAD infections

Left ventricular assist devices (LVADs) have become useful adjuncts in the treatment of patients with end‐stage heart failure. LVAD implantation is associated with a unique set of problems; one such problem is device infection. We report our experience with flap salvage of infected and/or exposed LVAD hardware.

Sterile matrix grafting for onycholysis in the setting of valproic acid use

Valproic acid (VPA), a widely used antiepileptic drug and mood stabilizer, has myriad cutaneous side effects including transient alopecia, exanthems, and vasculitides.1, 2, 3 We report on a patient who, in the setting of VPA use, presented with nail nonadherence secondary to sterile matrix scarring and propose nail bed excision with sterile matrix grafting as a surgical solution.

Does the Timing of Chemotherapy Affect Post-Mastectomy Breast Reconstruction Complications?

Introduction In this study we evaluated how the timing of chemotherapy for breast cancer affects post‐reconstruction complications to determine whether there is an optimal time for breast reconstruction after chemotherapy. Patients and Methods A retrospective review identified 344 breast cancer patients who underwent chemotherapy with mastectomy and autologous/prosthetic reconstruction from 2011 to 2014. A control group of 127 breast cancer patients who underwent mastectomy and autologous/prosthetic reconstruction without chemotherapy was also identified from the same period. The 2 groups were compared and analyzed for differences in demographic characteristics, treatment, and postoperative complication rates. The chemotherapy group was subsequently stratified into 3 subgroups on the basis of the number of days between chemotherapy treatment and reconstructive surgery (≤ 30 days, 30‐60 days, > 60 days) for further analysis. Results Patients who received chemotherapy were followed for an average of 803.4 days (26.4 months) from the time of initial reconstruction (mean time to complication, 43.3 ± 82.7 days), and experienced an overall greater complication rate compared with control subjects (32.8% vs. 24.4%; P = .078). When complications were divided into minor, major, and reconstructive failure categories, analysis revealed that the chemotherapy group experienced more minor complications than the control group (18% vs. 11%; P = .067). However, there were no statistically significant differences in major complication rates (10.5% vs. 9.4%) and reconstructive failure complication rates (3.8% vs. 2.4%) between the chemotherapy group and control group. Sixty‐eight patients (19.8%) underwent surgery within 30 days of chemotherapy, 210 patients (61%) within 30 to 60 days, and 66 patients (19.2%) after 60 days. Of note, patients in the ≤ 30 days group underwent surgery at a mean time of 24.8 days with 2 patients who underwent surgery in < 15 days. The 3 groups did not differ with respect to demographic factors or breast reconstructive modality, and there were no significant differences in overall complication rates (33.8% for ≤ 30 days, 31.4% for 30‐60 days, and 36.4% for > 60 days), time to complication, complication severity, or complication type. Whereas patients who underwent surgery 30 to 60 days from the time of chemotherapy had lower rates of skin necrosis (3.8%) and infection (15.7%) compared with the ≤ 30 days and 60 to 90 days groups, this finding was not statistically significant. Conclusion Results of this study suggest that chemotherapy does increase overall breast reconstruction complications, however, a decreased time between chemotherapy and surgical reconstruction does not predispose patients to postoperative complications. Consequently, surgery might be feasible in close temporal proximity to chemotherapy administration. Micro‐Abstract This review of 344 patients who underwent chemotherapy with mastectomy and autologous/prosthetic reconstruction from 2011 to 2014 shows that chemotherapy does increase overall breast reconstruction complications, however, timing of chemotherapy with relation to surgery (≤ 30 days, 30‐60 days, > 60 days), does not affect overall complication rates, time to complication, complication severity (major vs. minor), or complication type.

Obesity Impairs Wound Healing and Neovasculogenesis

Introduction: Obesity impaired wound healing is a timely and important topic. Sixty-six percent of Americans are overweight or obese, accounting for approximately 33 million overweight and obese surgical patients annually across all surgical specialties. Surgeons anecdotally appreciate wound healing complications among obese patients, such as infection, delayed closure, dehiscence and seroma, however, little basic science research has been conducted to investigate the mechanisms behind these impairments. We hypothetized that obesity-related wound healing is impaired through a vasculogenic mecanism.