Patient-Reported Outcomes After Reduction Mammoplasty Using BREAST-Q: A Systematic Review and Meta-Analysis.

BACKGROUND: The BREAST-Q questionnaire reduction module is an established tool for outcomes after reduction mammoplasty. OBJECTIVES: This systematic review and meta-analysis assess key parameters affecting pre- and postoperative scores, with specific foci on patient characteristics and tissue resection weights. METHODS: This study was conducted per PRISMA guidelines. PUBMED (National Institutes of Health; Bethesda, MD), Google Scholar (Google; Mountain View, CA), and Web of Science (Clarivate Analytics; Philadelphia, PA) were searched. All studies published before August 1, 2021, were assessed for eligibility by 2 independent reviewers. Inclusion criteria were prospective or retrospective studies in 6 languages that reported quality of life after reduction mammoplasty employing the BREAST-Q questionnaire reduction module. Quality of included studies was assessed employing the Newcastle-Ottawa-Scale. Analysis was performed per Cochrane Collaboration and the Quality of Reporting of Meta-analyses guidelines. RESULTS: A total of 28 papers were included in the systematic review, 13 for preoperative meta-analysis, and 17 for postoperative meta-analysis. Postoperative scores in all 3 quality of life domains (psychosocial, physical, and sexual well-being) and satisfaction with breasts increased significantly after reduction mammoplasty compared with preoperative scores. Satisfaction with breasts showed the greatest improvement, from 22.9 to 73.0. Preoperative scores were lower than normative data, with improvement to comparable scores as the healthy population postoperatively. Improvements in BREAST-Q scores did not correlate with patient comorbidities, complication rates, or amount of breast tissue resected. CONCLUSIONS: Reduction mammoplasty provides marked improvement in BREAST-Q patient-reported quality of life as well established in literature. However, these improvements do not correlate with tissue resection weights, warranting further inquiry of insurance-defined resection requirements.

Cutaneous leukocyte lineages in tolerant large animal and immunosuppressed clinical vascularized composite allograft recipients.

Vascularized composite allografts (VCAs) can restore fully functional anatomic units in patients with limb amputations or severe facial tissue loss. However, acute rejection of the skin is frequently observed and underscores the importance of developing tolerance induction protocols. In this study, we have characterized the skin immune system in VCAs. We demonstrate infiltration of recipient leukocytes, regardless of rejection status, and in tolerant mixed hematopoietic chimeras, the co-existence of these cells with donor leukocytes in the absence of rejection. Here we characterize the dermal T cell and epidermal Langerhans cell components of the skin immune system in our porcine model of VCA tolerance, and the kinetics of cutaneous chimerism in both of these populations in VCAs transplanted to tolerant and nontolerant recipients, as well as in host skin. Furthermore, in biopsies from the first patient to receive a hand transplant in our program, we demonstrate the presence of recipient T cells in the skin of the transplanted limb in the absence of clinical or histological evidence of rejection.

Local Immunosuppression for Vascularized Composite Allografts: Application of Topical FK506-TyroSpheres in a Nonhuman Primate Model.

Transplantation of vascularized composite allografts (VCAs) provides a means of restoring complex anatomical and functional units following burns and other disfigurement otherwise not amenable to conventional autologous reconstructive surgery. While short- to intermediate-term VCA survival is largely dependent on patient compliance with medication, the myriad of side effects resulting from lifelong systemic immunosuppression continue to pose a significant challenge. Topical immunosuppression is therefore a logical and attractive alternative for VCA. Current formulations are limited though, by poor skin penetration but this may be mitigated by conjugation of immunosuppressive drugs to TyroSpheres for enhanced delivery. Therefore, we investigated the topical application of FK506-TyroSpheres (in the form of a gel dressing) in a clinically relevant nonhuman primate VCA model to determine if allograft survival could be prolonged at reduced levels of maintenance systemic immunosuppression. Six Major Histocompatibility Complex (MHC)-mismatched cynomolgus macaques (Macaca fascicularis) served as reciprocal donors and recipients of radial forearm fasciocutaneous flaps. Standard Bacitracin ointment and FK506-TyroSpheres were applied every other day to the VCAs of animals in groups 1 (controls, n = 2) and 2 (experimental, n = 4), respectively, before gradual taper of systemic FK506. Clinical features of VCA rejection still developed when systemic FK506 fell below 10 ng/ml despite application of FK506-TyroSpheres and prolonged VCA survival was not achieved. However, unwanted systemic FK506 absorption was avoided with TyroSphere technology. Further refinement to optimize local drug delivery profiles to achieve and maintain therapeutic delivery of FK506 with TyroSpheres is underway, leveraging significant experience in controlled drug delivery to mitigate acute rejection of VCAs.

Proliferative Lesions Found at Reduction Mammaplasty: Incidence and Implications in 995 Breast Reductions.

BACKGROUND: Reduction mammaplasty relieves symptomatic macromastia. Pathologic specimens occasionally reveal unsuspected proliferative lesions or carcinoma. Few studies examine the incidence, risk factors, and outcomes in this population. METHODS: A retrospective review was performed between 2000 and 2012. The pathologic condition was categorized as benign, proliferative, or cancer. RESULTS: Five hundred seventy-two patients underwent 995 reduction mammaplasties. Cancer was detected in 23 specimens (2.3 percent) and proliferative lesions were detected in 137 (13.8 percent). Compared with patients with benign pathologic findings, patients with proliferative lesions or cancer were older (p < 0.001), had greater body mass index (p = 0.003), had increased unilateral procedures (p < 0.001), and more had history of cancer (p < 0.001). On multivariable regression analysis, age (OR, 1.058; 95 percent CI, 1.040 to 1.077; p < 0.001) and prior breast cancer (OR, 2.070; 95 percent CI, 1.328 to 3.227, p = 0.001) were independent risk factors for proliferative lesions, and age significantly predicted cancer (OR, 1.054; 95 percent CI, 1.012 to 1.097; p = 0.010). Forty-one percent of patients with proliferative lesions and no history of cancer had a change in management. If there was a history of cancer, 54 percent had a change in management. CONCLUSIONS: Proliferative lesions of the breast may be more common than previously reported. Age and a history of breast cancer increase the risk for proliferative lesions. All should be referred to oncology, as nearly half of these patients will have a change in management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Topical Delivery of Immunosuppression to Prolong Xenogeneic and Allogeneic Split-Thickness Skin Graft Survival.

Cadaveric skin allograft is the current standard of treatment for temporary coverage of large burn wounds. Porcine xenografts are viable alternatives but undergo α-1,3-galactose (Gal)-mediated hyperacute rejection and are lost by post-operative day (POD) 3 because of naturally occurring antibodies to Gal in primate recipients. Using baboons, we previously demonstrated that xenografts from GalT-KO swine (lacking Gal) provided wound coverage comparable with allografts with systemic immunosuppression. In this study, we investigate topical immunosuppression as an alternative to prolong xenograft survival. Full-thickness wounds in baboons were created and covered with xenogeneic and allogeneic split-thickness skin grafts (STSGs). Animals were treated with slow-release (TyroSphere-encapsulated) topical formulations (cyclosporine-A [CSA] or Tacrolimus) applied 1) directly to the STSGs only, or 2) additionally to the wound bed before STSG and 1). Topical CSA did not improve either xenograft or allograft survival (median: treated grafts = 12.5 days, control = 14 days; P = 0.27) with similar results when topical Tacrolimus was used. Pretreatment of wound beds resulted in a significant reduction of xenograft survival compared with controls (10 vs 14 days; P = 0.0002), with comparable results observed in allografts. This observation was associated with marked reduction of inflammation on histology with Tacrolimus and not CSA. Prolongation of allograft and xenograft survival after application to full-thickness wound beds was not achieved with the current formulation of topical immunosuppressants. Modulation of inflammation within the wound bed was effective with Tacrolimus pretreatment before STSG application and may serve as a treatment strategy in related fields.

Nipple Loss following Nipple-Sparing Mastectomy.

BACKGROUND: Nipple preservation at the time of mastectomy is increasingly performed to enhance the overall result from the reconstruction. Unfortunately, some of these patients may lose their nipples for oncologic reasons or because of necrosis. Several studies have investigated risk factors associated with nipple loss, but few data exist on the incidence of cancer in the nipple specimen, nipple removal for cosmesis or symmetry, and whether these patients subsequently pursue nipple reconstruction. METHODS: A retrospective review was performed on nipple-sparing mastectomies and immediate reconstruction from 2007 to 2013. RESULTS: Of 443 patients (775 breasts), 51 nipples (6.6 percent) were removed. Of the 51 nipple losses, 76 percent had total nipple or nipple-areola complex loss and 24 percent had partial loss. Twenty-five of the nipples (49 percent) required excision for oncologic reasons, 18 nipples (35 percent) were either partially or totally lost because of necrosis, and one nipple (2 percent) was excised for cosmetic reasons. In cases of bilateral reconstruction and unilateral nipple loss, 65 percent of contralateral normal nipples were retained and 35 percent (n = 7) were removed for symmetry. Fourteen nipples had residual cancer or atypia, whereas 37 had normal pathologic findings. Twenty-one nipples (40 percent) were reconstructed and 30 were not. CONCLUSIONS: In this series, the incidence of nipple loss following nipple-sparing mastectomy was 6.6 percent and related primarily to positive oncologic margins. The rate of removal for cosmesis was low, suggesting that for most patients the nipple lies in an acceptable position. After removal, 40 percent of patients had nipple reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Assessment of patient factors, surgeons, and surgeon teams in immediate implant-based breast reconstruction outcomes.

BACKGROUND: Outcome studies of immediate implant-based breast reconstruction have focused largely on patient factors, whereas the relative impact of the surgeon as a contributing variable is not known. As the procedure requires collaboration of both a surgical oncologist and a plastic surgeon, the effect of the surgeon team interaction can have a significant impact on outcome. This study examines outcomes in implant-based breast reconstruction and the association with patient characteristics, surgeon, and surgeon team familiarity. METHODS: A retrospective review of 3142 consecutive implant-based breast reconstruction mastectomy procedures at one institution was performed. Infection and skin necrosis rates were measured. Predictors of outcomes were identified by unadjusted logistic regression followed by multivariate logistic regression. Surgeon teams were grouped according to number of cases performed together. RESULTS: Patient characteristics remain the most important predictors for outcomes in implant-based breast reconstruction, with odds ratios above those of surgeon variables. The authors observed significant differences in the rate of skin necrosis between surgical oncologists with an approximately two-fold difference between surgeons with the highest and lowest rates. Surgeon teams that worked together on fewer than 150 procedures had higher rates of infection. CONCLUSIONS: Patient characteristics are the most important predictors for surgical outcomes in implant-based breast reconstruction, but surgeons and surgeon teams are also important variables. High-volume surgeon teams achieve lower rates of infection. This study highlights the need to examine modifiable risk factors associated with optimum implant-based breast reconstruction outcomes, which include patient and provider characteristics and the surgical team treating the patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Genetically modified porcine split-thickness skin grafts as an alternative to allograft for provision of temporary wound coverage: preliminary characterization.

Temporary coverage of severely burned patients with cadaver allograft skin represents an important component of burn care, but is limited by availability and cost. Porcine skin shares many physical properties with human skin, but is susceptible to hyperacute rejection due to preformed antibodies to α-1,3-galactose (Gal), a carbohydrate on all porcine cells. Our preliminary studies have suggested that skin grafts from α-1,3-galactosyltransferase knock out (GalT-KO) miniature swine might provide temporary wound coverage comparable to allografts, since GalT-KO swine lack this carbohydrate. To further evaluate this possibility, eight non-human primates received primary autologous, allogeneic, GalT-KO, and GalT+xenogeneic skin grafts. Additionally, secondary grafts were placed to assess whether sensitization would affect the rejection time course of identical-type grafts. We demonstrate that both GalT-KO xenografts and allografts provide temporary coverage of partial- and full-thickness wounds for up to 11 days. In contrast, GalT+xenografts displayed hyperacute rejection, with no signs of vascularization and rapid avulsion from wounds. Furthermore, secondary GalT-KO transplants failed to vascularize, demonstrating that primary graft rejection sensitizes the recipient. We conclude that GalT-KO xenografts may provide temporary coverage of wounds for a duration equivalent to allografts, and thus, could serve as a readily available alternative treatment of severe burns.

Lower extremity soft tissue defect reconstruction with the serratus anterior flap.

Reconstruction of limb-threatening lower extremity defects presents unique challenges. The selected method must provide adequate coverage of exposed bone, joints, and tendons while maximizing function of the limb. The traditional workhorse flaps, the free latissimus dorsi and rectus abdominis flaps, have been associated with donor site morbidity and bulkiness that can impair rehabilitation. We report a case series (n = 18) in which the free serratus anterior muscle flap and split thickness skin graft (STSG) was used for lower limb soft tissue coverage. Injuries were due to diabetes (9/18), trauma (7/18), and chronic venous stasis (2/18). A 94% flap survival rate was observed and all but one patient was ambulatory. No donor site morbidity was reported. Our series demonstrates that serratus anterior is an advantageous, reliable free flap with minimal donor site morbidity.

Wnt signaling can substitute for estrogen to induce division of ERalpha-positive cells in a mouse mammary tumor model.

The interaction of estrogen with the estrogen receptor (ER, principally ERalpha) induces growth of human breast tumor cells. In contrast, ERalpha-positive cells have been described as non-dividing cells in normal breast (though estrogen stimulation of ERalpha cells directs the division of neighboring cells). However, there is a small sub-population of cells in normal mammary tissue that are ERalpha-positive, that can divide, and therefore share this property with human breast tumor cells. In order to investigate their pattern of growth regulation, we measured the fraction of dividing ERalpha(+) cells during normal growth and compared that to glands stimulated by oncogenic Wnt effectors. First, we found there was no difference between the rate of division of ERalpha(+) cells and ERalpha(-) cells, whether the population was responding to estrogen or Wnt mitogens. The proportion of dividing ERalpha(+) mammary epithelial cells was increased (10x) in response to pregnancy, and similar increases were observed in response to ectopic Wnt signaling. We propose that Wnt signaling can substitute for estrogen to drive total population growth (that includes ERalpha(+) cells). Although the E-ERalpha-derived mitogenic response is situated in a minority of the luminal cells, and the Wnt-LRP5/6-derived mitogenic response is situated in a minority of basal cells, overall, the growth response of the mammary epithelial population is remarkably similar.