Transgender Mastectomy: Incidence of High-Risk Pathologic Findings and the Need for Postoperative Cancer Surveillance.

BACKGROUND: Chest masculinization surgeries are one of the most common gender-affirming procedures performed. There is a need for better understanding of the risk of breast cancer and postsurgical screening in female to male (FtM) individuals. This study aimed to evaluate the incidence of high-risk pathologic findings in FtM transgender patients undergoing gender-affirming chest reconstructive surgery. METHODS: Medical records were reviewed from all FtM patients undergoing gender-affirming chest reconstructive surgery from January 2010 to February 2021 by 3 plastic surgeons at the University of Pittsburgh Medical Center. Relative risk of malignant progression was used to stratify pathologic data. Subsequent management of atypical, in situ, and invasive pathology were recorded. RESULTS: A total of 318 patients were included in this study; the average age at surgery was 24.6 ± 8.1 years. Eighty-six patients (27%) had a family history of breast and/or ovarian cancer. Overall, 21 patients (6.6%) had some increased risk of breast cancer: 17 (5.3%) had proliferative lesions, mean age 38.2 ± 12.4 years; 2 had atypical ductal hyperplasia, ages 33.4 and 38.3 years; and 2 had invasive ductal carcinoma, ages 35.4 and 40.6 years. CONCLUSIONS: In this study, we found that 6.6% of FtM transgender patients undergoing top surgery had an elevated risk of breast cancer, with 1.2% of patients having a greater than 2 times risk of breast cancer. These results highlight the importance of appropriate preoperative screening as well as pathological analysis of surgical specimens to help guide clinical care. The authors advocate for a thorough breast cancer risk assessment before surgery for all patients, as well as using pathologic findings to guide postoperative cancer screening and follow-up.

The Impact of the COVID-19 Pandemic on Breast Reconstruction Practices in the United States.

BACKGROUND/AIM: We employed a survey to the American Society of Plastic Surgeons (ASPS) to investigate the management of breast reconstruction across the US during the COVID-19 pandemic. PATIENTS AND METHODS: An electronic survey on breast reconstruction practice demographics, COVID-19-related restrictions on breast reconstruction, and pertinent dates of restrictions was employed. RESULTS: A total of 228 responses were obtained. Demographics were balanced for geography with most respondents located in either urban or suburban settings (91.2%). The majority proceeded with mastectomy/reconstruction as originally planned (39.0%), followed by hormonal/chemotherapy only (22.6%). The most common reconstructive option was tissue expander/implant-based reconstruction (47.7%). Most institutions implemented restrictions between March 11-20th (59%). Almost all respondents (91.8%) reported mandatory pre-operative SARS-Cov-2 testing once cases resumed. CONCLUSION: COVID-19 has forced the breast surgical team to adapt to new conditions to the detriment of women with breast cancer requiring reconstruction. Varying restrictions have limited access to breast reconstruction, carrying consequences yet to be determined.

Opioid-Prescribing Practices in Plastic Surgery: A Juxtaposition of Attendings and Trainees.

BACKGROUND: The rates of opioid abuse and overdose in America have risen in parallel with the rates of opioid prescribing by physicians. As such, we sought to examine the prescribing practices among plastic surgery attendings and trainees to determine the need for more thorough education. METHODS: A survey was distributed to all ACGME-accredited plastic surgery residency programs and included questions regarding opioid-prescribing practices and self-rated ability pertaining to opioid management. Trends in prescribing practices based on prescriber position were analyzed using cumulative odds ordinal logistic regression with proportional odds and Chi-squared tests for ordinal and nominal variables, respectively. RESULTS: We received 78 responses with a wide geographical representation from plastic surgery residency programs: 59% of respondents were male and 39.7% female, 29.5% were attendings, 26.9% senior residents, 29.5% junior residents, and 14.1% interns. Compared with attendings, interns prescribe fewer pills (p < 0.05) and were significantly more likely to prescribe oxycodone (p < 0.03). Junior residents were 4.49 times more likely (p = 0.012) and senior residents 3.65 times more likely (p = 0.029) to prescribe additional opioids to avoid phone calls and follow-up visits. Interns and senior residents were significantly less comfortable than attendings in managing patients requesting additional opioids (p < 0.02). CONCLUSIONS: The results of this survey demonstrate that knowledge deficits do exist among trainees, and that trainees are significantly less comfortable than their attending counterparts with opioid prescribing and patient management. Therefore, the implementation of a thorough postoperative pain management education in residency may be a cogent strategy in mitigating the opioid crisis. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Delayed Hypersensitivity Reaction after Nipple Tattooing: A Novel Case Report.

We present a patient who underwent bilateral 3-dimensional (3D) nipple tattooing for nipple areolar reconstruction after implant-based breast reconstruction for breast cancer. Several weeks after nipple tattooing, the patient developed a delayed hypersensitivity reaction around both of her tattooed nipple areolar complexes. This is the first case reported in the literature of a hypersensitivity reaction from 3D nipple tattooing.

Mammillary fistula revisited: Implications for immediate breast reconstruction.

We present two patients with inverted nipples who underwent bilateral nipple-sparing mastectomies (NSM) with immediate placement of tissue expanders with acellular dermal matrix (ADM). Both were complicated by postoperative infection and developed mammillary fistulae from the nipple into the breast capsule, and eroding through the ADM. For the first time, we report inverted nipples as a risk for the iatrogenic formation of mammillary fistulae and their infectious implications after NSM.

SKP2 Activation by Thyroid Hormone Receptor ß2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells.

Germline RB1 mutations strongly predispose humans to cone precursor-derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type-specific circuitry that sensitizes these different cell types to the loss of RB1 has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRß2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor-suppressive TRß1. TRß2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for RB1-mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation. In RB1 wild-type neuroblastoma cells, endogenous Rb or ectopic TRß2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRß1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRß2 counteracts TRß1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies. Cancer Res; 77(24); 6838-50. ©2017 AACR.

Creating the Perfect Umbilicus: A Systematic Review of Recent Literature.

BACKGROUND: The aim of this study was to perform an updated systematic review of the literature over the last 10 years, analyzing and comparing the many published techniques with the hope of providing plastic surgeons with a new standard in creating the perfect umbilicus in the setting of both abdominoplasty and abdominally based free-flap breast reconstruction. METHODS: An initial search using the PubMed online database with the keyword "umbilicoplasty" was performed. These results were filtered to only include articles published within the last 10 years. The remaining articles were thoroughly reviewed by the authors and only those pertaining to techniques for umbilicoplasty in the setting of abdominoplasty and abdominally based free flap were included. RESULTS: Of the 10 unique techniques yielded by our search, 9/10 (90 %) initially incised the native umbilicus with a round, oval, or vertical ellipse pattern. Of the 9 techniques that initially perform a round incision, 4 of them (44.4 %) later modify the round umbilicus with either an inferior or superior excision to create either a "U"- or "inverted U"-shaped umbilicus. In terms of the shape of the incision made in the abdominal flap for umbilical reinsertion, the most common were either a round incision or an inverted "V" or "U," both of which accounted for 4/10 (40 %) and 3/10 (30 %), respectively. Almost all of the studies (8/10; 80 %) describe "defatting" or trimming of the subcutaneous adipose tissue around the incision to create a periumbilical concavity following inset of the umbilicus. 4/10 (40 %) of the techniques describe suturing the dermis of the umbilical skin to rectus fascia. Furthermore, 3/10 (30 %) advise that stalk plication is a necessary step to their technique. 7/9 techniques (77.8 %) preferred nondissolvable sutures for skin closure, with nylon being the most common suture material used. Only 2/9 (22.2 %) used dissolvable sutures. CONCLUSION: Although future studies are necessary, it is our hope that this systematic review better elucidates the techniques and provides some guidance to both aesthetic and reconstructive plastic surgeons in the pursuit of creating the perfect umbilicus following abdominoplasty and TRAM/DIEP breast reconstruction. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Human Adipose Tissue-Derived Stromal/Stem Cells Promote Migration and Early Metastasis of Head and Neck Cancer Xenografts.

BACKGROUND: Fat grafting has become popular for repair of postsurgical/postradiation defects after head/neck cancers resection. Fat graft supplementation with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve graft viability/efficacy, although the impact of ASCs on head/neck cancer cells is unknown. OBJECTIVES: To determine whether ASCs affect growth, migration, and metastasis of human head/neck cancer. METHODS: Human Cal-27 and SCC-4 head/neck cancer cells were co-cultured human ASCs, or treated with ASC conditioned medium (CM), and cancer cell growth/migration was assessed by MTT, cell count, and scratch/wound healing assays in vitro. Co-injection of 3 × 10(6) Cal-27/green fluorescent protein (GFP) cells and ASCs into the flank of NUDE mice assessed ASC effect on tumor growth/morphology. Quantitation of human chromosome 17 DNA in mouse organs assessed ASC effects on micrometastasis. Primary tumors were evaluated for markers of epithelial-to-mesenchymal transition, matrix metalloproteinases, and angiogenesis by immunohistochemistry. RESULTS: Co-culture of Cal-27 or SCC-4 cells with ASCs from 2 different donors or ASC CM had no effect on cell growth in vitro. However, ASC CM stimulated Cal-27 and SCC-4 migration. Co-injection of ASCs from 2 different donors with Cal-27 cells did not affect tumor volume at 6 weeks, but increased Cal-27 micrometastasis to the brain. Evaluation of tumors sections from 1 ASC donor co-injection revealed that ASCs were viable and well integrated with Cal-27/GFP cells. These tumors exhibited increased MMP2, MMP9, IL-8, and microvessel density. CONCLUSIONS: Human ASCs did not alter growth of human head/neck cancer cells or tumor xenografts, but stimulated migration and early micrometastasis to mouse brain.

Regulation of inflammation and fibrosis by macrophages in lymphedema.

Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b-diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4(+) cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4(+) cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function.

Lymphaticovenous bypass decreases pathologic skin changes in upper extremity breast cancer-related lymphedema.

INTRODUCTION: Recent advances in microsurgery such as lymphaticovenous bypass (LVB) have been shown to decrease limb volumes and improve subjective symptoms in patients with lymphedema. However, to date, it remains unknown if these procedures can reverse the pathological tissue changes associated with lymphedema. Therefore, the purpose of this study was to analyze skin tissue changes in patients before and after LVB. METHODS AND RESULTS: Matched skin biopsy samples were collected from normal and lymphedematous limbs of 6 patients with unilateral breast cancer-related upper extremity lymphedema before and 6 months after LVB. Biopsy specimens were fixed and analyzed for inflammation, fibrosis, hyperkeratosis, and lymphangiogenesis. Six months following LVB, 83% of patients had symptomatic improvement in their lymphedema. Histological analysis at this time demonstrated a significant decrease in tissue CD4(+) cell inflammation in lymphedematous limb (but not normal limb) biopsies (p<0.01). These changes were associated with significantly decreased tissue fibrosis as demonstrated by decreased collagen type I deposition and TGF-ß1 expression (all p<0.01). In addition, we found a significant decrease in epidermal thickness, decreased numbers of proliferating basal keratinocytes, and decreased number of LYVE-1(+) lymphatic vessels in lymphedematous limbs after LVB. CONCLUSIONS: We have shown, for the first time, that microsurgical LVB not only improves symptomatology of lymphedema but also helps to improve pathologic changes in the skin. These findings suggest that the some of the pathologic changes of lymphedema are reversible and may be related to lymphatic fluid stasis.

Sterile inflammation after lymph node transfer improves lymphatic function and regeneration.

BACKGROUND: The aim of this study was to determine whether sterile inflammatory reactions can serve as a physiologic means of augmenting lymphangiogenesis in transplanted lymph nodes using a murine model. METHODS: The authors used their previously reported model of lymph node transfer to study the effect of sterile inflammation on lymphatic regeneration. Mice were divided into three groups: group 1 (controls) underwent lymphadenectomy followed by immediate lymph node transplantation without inflammation; group 2 (inflammation before transfer) underwent transplantation with lymph nodes harvested from donor animals in which a sterile inflammatory reaction was induced in the ipsilateral donor limb; and group 3 (inflammation after transfer) underwent transplantation with lymph nodes and then inflammation was induced in the ipsilateral limb. Lymphatic function, lymphangiogenesis, and lymph node histology were examined 28 days after transplantation and compared with those of normal lymph nodes. RESULTS: Animals that had sterile inflammation after transplantation (group 3) had significantly improved lymphatic function (>2-fold increase) on lympho scintigraphy, increased perinodal lymphangiogenesis, and functional lymphatics compared with the groups with no inflammation and inflammation before transplantation (p<0.01). Inflammation after transplantation was associated with a more normal lymph node architecture, expansion of B-cell zones, and decreased percentage of T cells compared with the other experimental groups. CONCLUSIONS: Sterile inflammation is a potent method of augmenting lymphatic function and lymphangiogenesis after lymph node transplantation and is associated with maintenance of lymph node architecture. Induction of inflammation after transplantation is the most effective method and promotes maintenance of normal lymph node B- and T-cell architecture.

Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema.

Although obesity is a major clinical risk factor for lymphedema, the mechanisms that regulate this effect remain unknown. Recent reports have demonstrated that obesity is associated with acquired lymphatic dysfunction. The purpose of this study was to determine how obesity-induced lymphatic dysfunction modulates the pathological effects of lymphatic injury in a mouse model. We used a diet-induced model of obesity in adult male C57BL/6J mice in which experimental animals were fed a high-fat diet and control animals were fed a normal chow diet for 8-10 wk. We then surgically ablated the superficial and deep lymphatics of the midportion of the tail. Six weeks postoperatively, we analyzed changes in lymphatic function, adipose deposition, inflammation, and fibrosis. We also compared responses to acute inflammatory stimuli in obese and lean mice. Compared with lean control mice, obese mice had baseline decreased lymphatic function. Lymphedema in obese mice further impaired lymphatic function and resulted in increased subcutaneous adipose deposition, increased CD45(+) and CD4(+) cell inflammation (P < 0.01), and increased fibrosis, but caused no change in the number of lymphatic vessels. Interestingly, obese mice had a significantly increased acute inflammatory reaction to croton oil application. In conclusion, obese mice have impaired lymphatic function at baseline that is amplified by lymphatic injury. This effect is associated with increased chronic inflammation, fibrosis, and adipose deposition. These findings suggest that obese patients are at higher risk for lymphedema due to impaired baseline lymphatic clearance and an increased propensity for inflammation in response to injury.

IL-6 regulates adipose deposition and homeostasis in lymphedema.

Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4(+) cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4(+) inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4(+) cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.