Faculty Bibliography

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 siRNA-based therapy to restore redox homeostasis within diabetic wounds. Western blot 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.

Background Surgical management of head and neck cancer is resource intensive and physiologically demanding. In patients with incurable disease, although the indications for surgery are not well defined, palliative benefit can be significant. The goal of this investigation was to compare outcomes of patients who underwent resection and reconstruction of head and neck cancer with curative intent with those who underwent similar procedures with palliative intent. Methods A retrospective review of patients who underwent reconstruction for head and neck cancer between 2008 and 2014 was conducted. Patients were divided into curative and palliative groups. Outcomes assessed included postoperative complications and survival. Results A total of 147 patients who underwent 156 operations met inclusion criteria (27 palliative and 129 curative). In both cohorts, the most common histology was squamous cell carcinoma (SCC) and the most common primary tumor site was the oral cavity. There was no significant difference between the cohorts in the rates of systemic and reconstructive complications, postoperative hospital length of stay, 30-day mortality, and flap survival. Overall survival in palliative patients was significantly shorter compared with curative patients (median OS, 6.2 months vs. 56.1 months, respectively; p < 0.0001). Among patients undergoing palliative surgery, patients without carotid involvement and those with non-SCC were significantly more likely to have longer survival. Conclusion Surgical resection with reconstruction is possible in head and neck oncologic patients undergoing palliative treatment. Palliative patients have similar short-term outcomes when compared with patients undergoing resection for curative intent. Quality-of-life and economic implications of these approaches deserve closer scrutiny.

BACKGROUND: Approximately 20 percent of women select autologous tissue for postmastectomy breast reconstruction, and most commonly choose the abdomen as the donor site. An increasing proportion of women are seeking muscle-sparing procedures, but the benefit remains controversial. It is therefore important to determine whether better outcomes are associated with these techniques, thereby justifying longer operative times and increased costs. METHODS: Patients from five North American centers were eligible if they underwent reconstruction by means of the deep inferior epigastric artery perforator (DIEP) flap, muscle-sparing free transverse abdominis myocutaneous (TRAM) flap, free TRAM flap, or the pedicled TRAM flap. Patients were sent the BREAST-Q. Demographics and complications were collected. RESULTS: The authors analyzed 1790 charts representing 670 DIEP, 293 muscle-sparing free TRAM, 683 pedicled TRAM, and 144 free TRAM patients with an average follow-up of 5.5 years. Flap loss did not differ by flap type. Partial flap loss was higher in pedicled TRAM compared with DIEP (p = 0.002). Fat necrosis was higher in pedicled TRAM compared with DIEP and muscle-sparing free TRAM (p < 0.001). Hernia/bulge was highest in pedicled TRAM (p < 0.001). Physical well-being (abdomen) scores were higher in DIEP compared with pedicled TRAM controlling for confounders. CONCLUSIONS: Complications and patient-reported outcomes differ when comparing abdominally based breast reconstruction techniques. The results of this study show that the DIEP flap was associated with the highest abdominal well-being and the lowest abdominal morbidity compared with the pedicled TRAM flap, but did not differ from muscle-sparing free TRAM and free TRAM flaps. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

BACKGROUND: Despite the increasing use of nasoalveolar molding in early cleft treatment, questions remain about its effectiveness. This study examines clinician and caregiver appraisals of primary cleft lip and nasal reconstruction with and without nasoalveolar molding in a nonrandomized, prospective, multicenter study. METHODS: Participants were 110 infants with cleft lip/palate (62 treated with and 48 treated without nasoalveolar molding) and their caregivers seeking treatment at one of six high-volume cleft centers. Using the Extent of Difference Scale, standard photographs for a randomized subset of 54 infants were rated before treatment and after surgery by an expert clinician blinded to treatment group. Standard blocked and cropped photographs included frontal, basal, left, and right views of the infants. Using the same scale, caregivers rated their infants' lip, nose, and facial appearance compared with the general population of infants without clefts before treatment and after surgery. Multilevel modeling was used to model change in ratings of infants' appearance before treatment and after surgery. RESULTS: The expert clinician ratings indicated that nasoalveolar molding-treated infants had more severe clefts before treatment, yet both groups were rated equally after surgery. Nasoalveolar molding caregivers reported better postsurgery outcomes compared with no-nasoalveolar molding caregivers (p < 0.05), particularly in relation to the appearance of the nose. CONCLUSIONS: Despite having a more severe cleft before treatment, infants who underwent nasoalveolar molding were found by clinician ratings to have results comparable to those who underwent lip repair alone. Infants who underwent nasoalveolar molding were perceived by caregivers to have better treatment outcomes than those who underwent lip repair without nasoalveolar molding. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

This study evaluated the effect of microrobotized blasting of titanium endosteal implants relative to their manually blasted counterparts. Two different implant systems were utilized presenting two different implant surfaces. Control surfaces (Manual) were fabricated by manually grit blasting the implant surfaces while experimental surfaces (Microblasted) were fabricated through a microrobotized system that provided a one pass grit blasting routine. Both surfaces were created with the same ~50microm average particle size alumina powder at ~310KPa. Surfaces were then etched with 37% HCl for 20min, washed, and packaged through standard industry procedures. The surfaces were characterized through scanning electron microscopy (SEM) and optical interferometry, and were then placed in a beagle dog radius model remaining in vivo for 3 and 6 weeks. The implant removal torque was recorded and statistical analysis evaluated implant system and surface type torque levels as a function of time in vivo. Histologic sections were qualitatively evaluated for tissue response. Electron microscopy depicted textured surfaces for both manual and microblasted surfaces. Optical interferometry showed significantly higher Sa, Sq, values for the microblasted surface and no significant difference for Sds and Sdr values between surfaces. In vivo results depicted that statistically significant gains in biomechanical fixation were obtained for both implant systems tested at 6 weeks in vivo, while only one system presented significant biomechanical gain at 3 weeks. Histologic sections showed qualitative higher amounts of new bone forming around microblasted implants relative to the manually blasted group. Microrobotized blasting resulted in higher biomechanical fixation of endosteal dental implants and should be considered as an alternative for impant surface manufacturing.

Complex periorbital subunit reconstruction is challenging because the goals of effective reconstruction vary from one individual to another. The purpose of this article is to explore the indications and anatomic feasibility of periorbital transplantation by reviewing our institutional repository of facial injury. METHODS: Institutional review board approval was obtained at the R Adams Cowley Shock Trauma Center for a retrospective chart review conducted on patients with periorbital defects. Patient history, facial defects, visual acuity, and periorbital function were critically reviewed to identify indications for periorbital or total face (incorporating the periorbital subunit) vascularized composite allotransplantation. Cadaveric allograft harvest was then designed and performed for specific patient defects to determine anatomic feasibility. Disease conditions not captured by our patient population warranting consideration were reviewed. RESULTS: A total of 7 facial or periorbital transplant candidates representing 6 different etiologies were selected as suitable indications for periorbital transplantation. Etiologies included trauma, burn, animal attack, and tumor, whereas proposed transplants included isolated periorbital and total face transplants. Allograft recovery was successfully completed in 4 periorbital subunits and 1 full face. Dual vascular supply was achieved in 5 of 6 periorbital subunits (superficial temporal and facial vessels). CONCLUSIONS: Transplantation of isolated periorbital structures or full face transplantation including periorbital structures is technically feasible. The goal of periorbital transplantation is to re-establish protective mechanisms of the eye, to prevent deterioration of visual acuity, and to optimize aesthetic outcomes. Criteria necessary for candidate selection and allograft design are identified by periorbital defect, periorbital function, ophthalmologic evaluation, and defect etiology.

Background The internal mammary vessels are the most commonly used recipients for microsurgical breast reconstructions. Often, the costal cartilage is sacrificed to obtain improved vessel exposure. In an effort to reduce adverse effects associated with traditional rib sacrifice, recent studies have described less-invasive, rib-sparing strategies. Methods After obtaining institutional review board's approval, a retrospective review of all patients undergoing microsurgical breast reconstruction at a single institution between November 2007 and December 2013 was conducted. Patients were divided into two cohorts for comparison: rib-sacrificing and rib-sparing internal mammary vessel harvests. Results A total of 547 reconstructions (344 patients) met inclusion criteria for this study. A total of 64.9% (n = 355) underwent rib-sacrificing internal mammary vessel harvest. Cohorts were similar in baseline patient characteristics, indications for surgery, and cancer therapies. However, patients undergoing rib-sparing reconstructions had significantly shorter operative times (440 vs. 476 minutes; p < 0.01), and significantly less postoperative pain on postoperative day (POD) 1 (2.8/10 vs. 3.4/10; p = 0.033) and POD2 (2.4/10 vs. 3.0/10; p = 0.037). Furthermore, patients undergoing rib-sparing techniques had greater incidence of fat necrosis requiring excision (12.5 vs. 2.8%; p < 0.01) and a trend toward higher incidence of hematoma, venous thrombosis, and arterial thrombosis when compared with rib-sacrificing patients. Conclusions Rib-sparing harvest of internal mammary vessels is a feasible technique in microsurgical breast reconstruction. However, given the significant increase in fat necrosis requiring surgical excision, the trend toward increased postoperative complications, and no significant difference in postoperative revision rates, the purported benefits of this technique may fail to outweigh the possible risks.

BACKGROUND: Abdominal tissue is the preferred donor source for autologous breast reconstruction, but in select patients with inadequate tissue, additional volume must be recruited to achieve optimal outcomes. Stacked flaps are an effective approach in these cases, but can be limited by the need for adequate recipient vessels. This article reports outcomes for the use of the retrograde internal mammary system for stacked flap breast reconstruction in a large number of consecutive patients. METHODS: Fifty-three patients underwent stacked autologous tissue breast reconstruction with a total of 142 free flaps. Thirty patients underwent unilateral stacked deep inferior epigastric perforator (DIEP) flap reconstruction, five had unilateral stacked profunda artery perforator flap reconstruction, one had bilateral stacked DIEP/superior gluteal artery perforator flap reconstruction, and 17 underwent bilateral stacked DIEP/profunda artery perforator flap reconstruction. In all cases, the antegrade and retrograde internal mammary vessels were used for anastomoses. In situ manometry studies were also conducted comparing the retrograde internal mammary arteries in 10 patients to the corresponding systemic pressures. RESULTS: There were three total flap losses (97.9 percent flap survival rate), two partial flap losses, four reexplorations for venous congestion, and three patients with operable fat necrosis. The mean weight of the stacked flaps for each reconstructed breast was 622.8 g. The retrograde internal mammary mean arterial pressures were on average 76.6 percent of the systemic mean arterial pressures. CONCLUSIONS: The results demonstrate that the retrograde internal mammary system is capable of independently supporting free tissue transfer. These vessels provide for convenient dissection and improved efficiency of these cases, with successful postsurgical outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

BACKGROUND: The profunda artery perforator free flap has not gained traction for nonbreast reconstruction, likely because of the presence of a proven workhorse in the anterolateral thigh flap. The authors believe that the profunda artery perforator flap offers similar coverage characteristics with the benefits of a medial donor site, a more consistent anatomy, and relatively easy dissection. The authors review their indications, technique, and outcomes in seven patients requiring eight free flap reconstructions. METHODS: The authors applied the use of the vertically oriented profunda artery perforator flap to both lower extremity and head and neck reconstructions in which an anterolateral thigh flap would normally have been used. Details reviewed include soft-tissue defect, perforator location, flap size, recipient vessel, and complications. RESULTS: Eight soft-tissue defects were covered with a vertically oriented profunda artery perforator flap in seven patients. Six reconstructions were for distal lower extremity and two were for head and neck reconstruction, both trauma and oncologic reconstructions. Flap sizes ranged from 40 to 92 cm. The pedicle length ranged from 7 to 10 cm. There were no partial or complete flap losses. One complication of seroma at the donor site requiring washout and closure was encountered. CONCLUSIONS: The profunda artery perforator flap is a safe and effective option for perforator-based free flap reconstruction with relative ease of harvest and an inconspicuous donor site. This flap offers an excellent alternative to the anterolateral thigh flap. In certain patient demographics, the profunda artery perforator flap should be considered as a primary option. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

BACKGROUND:Current data addressing the role of robotic surgery for the management of colorectal disease are primarily from single-institution and case-matched comparative studies as well as administrative database analyses. The purpose of this study was to compare minimally invasive surgery outcomes using a large regional protocol-driven database devoted to surgical quality, improvement in patient outcomes, and cost-effectiveness. METHODS:This is a retrospective cohort study from the prospectively collected Michigan Surgical Quality Collaborative registry designed to compare outcomes of patients who underwent elective laparoscopic, hand-assisted laparoscopic, and robotic colon and rectal operations between July 1, 2012 and October 7, 2014. We adjusted for differences in baseline covariates between cases with different surgical approaches using propensity score quintiles modeled on patient demographics, general health factors, diagnosis, and preoperative co-morbidities. The primary outcomes were conversion rates and hospital length of stay. Secondary outcomes included operative time, and postoperative morbidity and mortality. RESULTS:A total of 2735 minimally invasive colorectal operations met inclusion criteria. Conversion rates were lower with robotic as compared to laparoscopic operations, and this was statistically significant for rectal resections (colon 9.0 vs. 16.9%, p < 0.06; rectum 7.8 vs. 21.2%, p < 0.001). The adjusted length of stay for robotic colon operations (4.00 days, 95% CI 3.63-4.40) was significantly shorter compared to laparoscopic (4.41 days, 95% CI 4.17-4.66; p = 0.04) and hand-assisted laparoscopic cases (4.44 days, 95% CI 4.13-4.78; p = 0.008). There were no significant differences in overall postoperative complications among groups. CONCLUSIONS:When compared to conventional laparoscopy, the robotic platform is associated with significantly fewer conversions to open for rectal operations, and significantly shorter length of hospital stay for colon operations, without increasing overall postoperative morbidity. These findings and the recent upgrades in minimally invasive technology warrant continued evaluation of the role of the robotic platform in colorectal surgery.