ERG regulates lymphatic vessel specification genes and its deficiency impairs wound healing-associated lymphangiogenesis.

OBJECTIVE: Rarefaction of blood and lymphatic vessels in the skin has been reported in SSc (systemic sclerosis, scleroderma). ERG and FLI1 are important regulators of angiogenesis, but their role in lymphatic vasculature is less known. The goal of this study was to determine the role of ERG and FLI1 in postnatal lymphangiogenesis and SSc lymphatic system defects. METHODS: Immunofluorescence was used to detect ERG and FLI1 in SSc and healthy control (HC) skin biopsies. Transcriptional analysis of ERG or FLI1 silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG/FLI1 deficiency on in vitro tubulogenesis in human dermal LECs was examined using a Matrigel assay. Erg and Fli1 endothelial specific knockouts and Erg lymphatic specific knockouts were generated to examine vessel regeneration in mice. RESULTS: ERG and FLI1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsies. ERG was shown to regulate genes involved in lymphatic vessel specification, including VEGFR3/FLT4, LYVE-1, SOX18, and PROX1, while FLI1 enhanced the function of ERG. ERG/FLT4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of Erg or Fli1 similarly impaired the function of blood vessels in mice. However, only Erg deficiency affected the regeneration of lymphatic vessels during wound healing. CONCLUSION: ERG and FLI1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI1 in SSc endothelial cells, may contribute to impairment of blood and lymphatic vasculature in SSc patients.

Targeting the Epigenome Reduces Keloid Fibroblast Cell Proliferation, Migration and Invasion.

Keloids are pathological fibroproliferative scars resulting from abnormal collagen deposition within and beyond the margins of the initial cutaneous insult. Keloids negatively impact quality of life functionally and cosmetically, with current treatment modalities unsatisfactory. Recent studies indicate that epigenetic dysregulation is central to the development and progression of keloids. Here we evaluate the functional significance of epigenetic targeting strategies in vitro using patient-derived keloid fibroblasts treated with small molecule inhibitors of HDACs, LSD1, CoREST and p300, as potential therapies for keloids. We find that both the dual-acting CoREST inhibitor, corin, and the HDAC inhibitor, entinostat, reduce fibroblast proliferation more than the LSD1 inhibitor, GSK-LSD1; additionally, corin was the most effective inhibitor of migration and invasion across keloid fibroblasts. RNA-seq analysis of keloid fibroblasts treated with corin demonstrates coordinate upregulation of many genes including key mediators of cell adhesion such as claudins. Corin also downregulates gene sets involved in cell cycle progression, including reduced expression of cyclins A1 and B2 compared to DMSO. These results highlight a significant role for epigenetic regulation of pathologic mediators of keloidal scarring and suggest that inhibitors of the epigenetic CoREST repressor complex may prove beneficial in the prevention and/or treatment of keloidal scarring in patients.

Leveraging Artificial Intelligence to Optimize the Care of Peripheral Artery Disease Patients.

Peripheral artery disease is a major atherosclerotic disease that is associated with poor outcomes such as limb loss, cardiovascular morbidity, and death. Artificial intelligence (AI) has seen increasing integration in medicine, and its various applications can optimize the care of peripheral artery disease (PAD) patients in diagnosis, predicting patient outcomes, and imaging interpretation. In this review, we introduce various AI applications such as natural language processing, supervised machine learning, and deep learning, and we analyze the current literature in which these algorithms have been applied to PAD.

Technical and Clinical Differences Between Transgender and Cisgender Females Undergoing Breast Augmentation.

BACKGROUND: Gender-affirming surgery is a quickly expanding field. However, it is facing a shortage of specialized surgeons for a population exceeding 1.4 million individuals. Many studies comparing outcomes between cisgender and transgender patients fail to describe the technical differences of the operation. Breast augmentation in the transgender female patient involves important anatomical, technical, and clinical features that differ from the cisgender female. In this study, we aimed to describe and compare these characteristics between these 2 groups to better inform the new generation of gender-affirming surgeons. METHODS: A retrospective cohort study of patients who underwent primary breast augmentation between 2009 and 2019 at a specialized tertiary center for transgender care was performed. Mastopexy, secondary augmentation, and reconstructive procedures were excluded. Demographic, operative, and clinical data were collected from medical records. All patients had a minimum of 1 year of follow-up after the initial surgery. Bivariate analysis was performed. RESULTS: A total of 250 cisgender females and 153 transgender females were included. The transgender group showed higher rates of smoking ( P < 0.0001), immunosuppression ( P < 0.0001), obesity ( P < 0.0001), mental health disorders ( P < 0.0001), and hypertension ( P = 0.002). Median base width ( P < 0.0001), sternal notch to nipple distance ( P < 0.0001), and implant size (500 mL [interquartile range, 425-600 mL] vs 350 mL [interquartile range, 325-385 mL]; P < 0.0001) were larger in transgender patients. Transgender patients also demonstrated a stronger correlation between implant size and body surface area ( r = 0.71, P < 0.0001). Readmission, reoperation, and complication rates were similar between the groups; however, transgender females had a higher incidence of surgical site infections (3.9% vs 0.4%, P < 0.013). Capsular contracture was the most common complication and indication for reoperation in both groups. CONCLUSIONS: There are important anatomical, clinical, and technical differences between reconstructive gender-affirming breast augmentation in transgender female patients and cosmetic breast augmentation in the cisgender female. The gender-affirming surgeon must know these differences to provide the best quality of care and help patients achieve better congruence between their gender identity and body image.

Assessment of Risk Factors Correlated with Outcomes of Traumatic Lower Extremity Soft Tissue Reconstruction.

Identifying risk factors for traumatic lower extremity reconstruction outcomes has been limited by sample size. We evaluated patient and procedural characteristics associated with reconstruction outcomes using data from almost four million patients. Methods: The National Trauma Data Bank (2015-2018) was queried for lower extremity reconstructions. Univariable and multivariable analyses determined associations with inpatient outcomes. Results: There were 4675 patients with lower extremity reconstructions: local flaps (77%), free flaps (19.2%), or both (3.8%). Flaps were most commonly local fasciocutaneous (55.1%). Major injuries in reconstructed extremities were fractures (56.2%), vascular injuries (11.8%), and mangled limbs (2.9%). Ipsilateral procedures prereconstruction included vascular interventions (6%), amputations (5.6%), and fasciotomies (4.3%). Postoperative surgical site infection and amputation occurred in 2% and 2.6%, respectively. Among survivors (99%), mean total length of stay (LOS) was 23.2 ± 21.1 days and 46.8% were discharged to rehab. On multivariable analysis, vascular interventions prereconstruction were associated with increased infection [odds ratio (OR) 1.99, 95% confidence interval (CI) 1.05-3.79, P = 0.04], amputation (OR 4.38, 95% CI 2.56-7.47, P < 0.001), prolonged LOS (OR 1.59, 95% CI 1.14-2.22, P = 0.01), and discharge to rehab (OR 1.49, 95% CI 1.07-2.07, P = 0.02). Free flaps were associated with prolonged LOS (OR 2.08, 95% CI 1.74-2.49, P < 0.001). Conclusions: Prereconstruction vascular interventions were associated with higher incidences of adverse outcomes. Free flaps correlated with longer LOS, but otherwise similar outcomes. Investigating reasons for increased complication and healthcare utilization likelihood among these subgroups is warranted.

Impact of Race, Ethnicity, Primary Language, and Insurance on Reconstruction after Mastectomy for Patients with Breast Cancer at an Urban, Academic Safety-Net Hospital.

BACKGROUND: Disparities in breast reconstruction have been observed in national cohorts and single-institution studies based on race, ethnicity, insurance, and language. However, little is known regarding whether safety-net hospitals deliver more or less equitable breast reconstruction care in comparison with national cohorts. STUDY DESIGN: We performed a retrospective study of patients with either invasive breast cancer or ductal carcinoma in situ diagnosed and treated at our institution (January 1, 2009, to December 31, 2014). The rate of, timing of, and approach to breast reconstruction were assessed by race, ethnicity, insurance status, and primary language among women who underwent mastectomy. Reasons for not performing reconstruction were also analyzed. RESULTS: A total of 756 women with ductal carcinoma in situ or nonmetastatic invasive cancer were identified. The median age was 58.5 years, 56.2% were non-White, 33.1% were non-English-speaking, and 48.9% were Medicaid/uninsured patients. A total of 142 (18.8%) underwent mastectomy during their index operation. A total of 47.9% (n = 68) did not complete reconstruction. Reasons for not performing reconstruction included patient preference (n = 22), contraindication to immediate reconstruction (ie, locoregionally advanced disease prohibiting immediate reconstruction) without follow-up for consideration of delayed reconstruction (n = 12), prohibitive medical risk or contraindication (ie, morbid obesity; n = 8), and progression of disease, prohibiting reconstruction (n = 7). Immediate and delayed reconstruction were completed in 43.7% and 8.5% of patients. The rate of reconstruction was inversely associated with tumor stage (odds ratio 0.52, 95% CI 0.31 to 0.88), but not race, ethnicity, insurance, or language, on multivariate regression. CONCLUSIONS: At a safety-net hospital, we observed rates of reconstruction at or greater than national estimates. After adjustment for clinical attributes, rates did not vary by race, ethnicity, insurance or language. Future research is needed to understand the role of reconstruction in breast cancer care and how to advance shared decision-making among diverse patients.

Cellular Senescence in Aging, Tissue Repair, and Regeneration.

SUMMARY: Society and our healthcare system are facing unprecedented challenges due to the expansion of the older population. As plastic surgeons, we can improve care of our older patients through understanding the mechanisms of aging that inevitably impact their outcomes and well-being. One of the major hallmarks of aging, cellular senescence, has recently become the focus of vigorous research in academia and industry. Senescent cells, which are metabolically active but in a state of stable cell cycle arrest, are implicated in causing aging and numerous age-related diseases. Further characterization of the biology of senescence revealed that it can be both detrimental and beneficial to organisms depending on tissue context and senescence chronicity. Here, we review the role of cellular senescence in aging, wound healing, tissue regeneration, and other domains relevant to plastic surgery. We also review the current state of research on therapeutics that modulate senescence to improve conditions of aging.

Impact of Patient Primary Language upon Immediate Breast Reconstruction After Mastectomy.

BACKGROUND: Preoperative decision-making in patients who speak a primary language other than English is understudied. We investigated whether patient primary language is associated with differences in immediate breast reconstruction (IBR) after mastectomy. PATIENTS AND METHODS: This retrospective observational study analyzed female patients undergoing mastectomy in the New Jersey State Inpatient Database (2009-2014). The primary outcome was the odds of IBR with a prespecified subanalysis of autologous tissue-based IBR. We used multivariable logistic regression and hierarchical generalized linear mixed models to control for patient characteristics and nesting within hospitals. RESULTS: Of 13,846 discharges, 12,924 (93.3%) specified English as the patient's primary language, while 922 (6.7%) specified a language other than English. Among English-speaking patients, 6178 (47.8%) underwent IBR, including 2310 (17.9%) autologous reconstructions. Among patients with a primary language other than English, 339 (36.8%) underwent IBR, including 93 (10.1%) autologous reconstructions. Unadjusted results showed reduced odds of IBR overall [odds ratio (OR) 0.64, 95% CI 0.55-0.73], and autologous reconstruction specifically (OR 0.52, 95% CI 0.41-0.64) among patients with a primary language other than English. After adjustment for patient factors, this difference persisted among the autologous subgroup (OR 0.64, 95% CI 0.51-0.80) but not for IBR overall. A hierarchical model incorporating both patient characteristics and hospital-level effects continued to show a difference among the autologous subgroup (OR 0.75, 95% CI 0.58-0.97). CONCLUSIONS: Primary language other than English was an independent risk factor for lower odds of autologous IBR after adjustments for patient and hospital effects. Focused efforts should be made to ensure that patients who speak a primary language other than English have access to high-quality shared decision-making for postmastectomy IBR.

Elevated skin senescence in young mice causes delayed wound healing.

Although there is growing evidence that cellular senescence influences wound healing, a clear understanding of how senescence can be beneficial and/or detrimental to wound healing is unknown. Wound healing may also be influenced by the baseline tissue senescence, which is elevated in aging and chronic wounds, both of which have significant healing delays. To study the effects of skin senescence on wound healing, we developed an elevated skin senescence model based on the subcutaneous transfer of irradiated fibroblasts into young 8-week-old wild-type C57BL/6 male mice. This senescent cell transfer significantly increased skin senescence levels compared to control transfers of non-irradiated fibroblasts. There was an increased presence of SA-ß-Gal- and p21-positive senescent cells throughout the skin. Furthermore, the entire skin showed significantly elevated gene expression of senescence (p16, p21) and SASP markers (IL-6, MCP-1, MMP-3, MMP-9, and TGF-ß). Subsequent wound healing in the skin with elevated senescence was markedly delayed and had similar kinetics to naturally aged 2-year-old mice. After the wounds had healed, the skin developed persistently elevated senescence. Our results demonstrate that states of elevated skin senescence can delay wound healing and result in sustained senescence after healing. Therefore, the accumulation of senescent cells in aged skin or chronic wounds may be a driver of delayed healing and can be considered a potential target to improve healing.

Epigenetic Regulation of Cellular Senescence.

Senescence is a complex cellular stress response that abolishes proliferative capacity and generates a unique secretory pattern that is implicated in organismal aging and age-related disease. How a cell transitions to a senescent state is multifactorial and often requires transcriptional regulation of multiple genes. Epigenetic alterations to DNA and chromatin are powerful regulators of genome architecture and gene expression, and they play a crucial role in mediating the induction and maintenance of senescence. This review will highlight the changes in chromatin, DNA methylation, and histone alterations that establish and maintain cellular senescence, alongside the specific epigenetic regulation of the senescence-associated secretory phenotype (SASP).

An Insight into Aging, Senescence, and Their Impacts on Wound Healing.

Cellular senescence has been found to have beneficial roles in development, tissue regeneration, and wound healing. However, in aging senescence increases, and the ability to properly repair and heal wounds significantly declines across multiple tissues. This age-related accumulation of senescent cells may cause loss of tissue homeostasis leading to dysregulation of normal and timely wound healing processes. The delays in wound healing of aging have widespread clinical and economic impacts, thus novel strategies to improve wound healing in aging are needed and targeting senescence may be a promising area.

Daily Ultrasound Imaging for Patients Undergoing Postprostatectomy Radiation Therapy Predicts and Ensures Dosimetric Endpoints.

PURPOSE: Patients who receive radiation therapy (RT) for prostate cancer are routinely positioned through radiographic means. We set out to establish a data-driven process that defines bladder volume required to meet V40/65 constraints using daily bladder ultrasound (US) and comparative cone beam CT (CBCT) before placing a patient on the treatment table. METHODS AND MATERIALS: This was a single institution retrospective study of 20 patients (390 CBCT scans) who received postprostatectomy RT. Each patient received a daily US before treatment. CBCT alignment was performed 3 times a week. The bladder and rectum were contoured on each CBCT and a session dose was recorded. A mixed-effect model was used to estimate trajectory slopes of radiation exposure with organs-at-risk volume increase. Slope differences by V40/65 for prostate fossa (PF) and pelvic lymph nodes (PF/pLN) were tested using a 3-way-interaction term with Bonferroni correction. RESULTS: For the 20 patients, 10 received treatment to PF and 10 received RT to the PF/pLN. Predefined bladder constraints were V65 < 50%, V40 < 70%, and rectal constraints were V65 < 35%, V40 < 55%. The CBCT bladder volume (76-578 cm3) was greater than the pretreatment bladder US (87-466 cm3) due to volume filling between measurements (r = 0.8 ± 0.05). Mixed model detected a statistically significant 3-way interaction (P < .01) for bladder volume and V40/65. Both PF and PF/pLN patients showed improvement in V40/65 with an increase in bladder volume. For PF patients, bladder constraints were met when the US volume was >108 cm3 and for PF/pLN patients when the US bladder volume was >200 cm3. Rectal filling showed no association with CBCT volume. CONCLUSIONS: Daily US of the bladder before postprostatectomy RT allows for dosimetric predictions before daily treatment. This should translate into fewer CBCT for the patient and improved machine throughput. This technique is easy to institute and ensures organs-at-risk volumetric constraints are met based on daily US measurements.

Dissecting Cellulitis of the Scalp: A Review and Case Studies of Surgical Reconstruction.

Dissecting cellulitis of the scalp (DCS) is a part of the follicular occlusion tetrad (hidradenitis, acne conglobata, and pilonidal disease). It is a spectrum disorder that can be severe and refractory to medical management. The authors describe 3 such cases successfully treated with surgical resection and reconstruction and present a scoring system for timely referral of such patients to a reconstructive surgical team. METHODS: A literature review of all available cases of DCS was undertaken, and the treatments and outcomes were reviewed. Our institution has had 3 recent cases that demonstrated delayed presentation common in the severe spectrum of this condition. All underwent radical surgical resection and reconstruction with skin grafting that was very positively received by all the patients. RESULTS: Three cases of DCS were treated with radical scalpectomy, and split-thickness skin grafting was done with a good cosmetic outcome and a high degree of subjective patient satisfaction. All would have received timely referral if the presented scoring system had been applied earlier. CONCLUSIONS: DCS is a rare but debilitating condition that may progress to a medically refractory condition requiring surgical intervention. Surgical resection and skin grafting offer a durable cure, but delayed presentations are common. Use of a scoring system may reduce the time to surgical referral for refractory cases.

Fractional Laser-assisted Hair Regrowth and Microneedling for the Treatment of Alopecia Areata: A Review.

Alopecia areata (AA) affects approximately 2.1% of the population, with women being affected more often than men. Current therapies consisting of topical corticosteroids or intralesional injections are often the first choices for treatment, but are limited by unsatisfactory outcomes or risks to patients. Recently, fractional lasers and microneedling, with or without the addition of topical agents, have been examined as treatment options. A literature review was performed to evaluate the efficacy of fractional lasers in the treatment of AA. A total of six fractional lasers and two microneedling studies consisting of small prospective and retrospective studies, and case reports were reviewed. The number of trials and participants are limited, but evidence suggests that fractional lasers and microneedling may be effective therapeutic approaches when coupled with topical agents. Larger studies are required to better understand the effects of these treatment modalities for AA.

Technique to Promote Symmetry in 2-Staged Bilateral Breast Reconstruction in the Setting of Unilateral Postmastectomy Radiation.

BACKGROUND: Bilateral breast reconstruction in the setting of unilateral postmastectomy radiation therapy (PMRT) remains one of the most difficult reconstructive challenges due to significant radiation-induced asymmetry from capsular contracture and superior migration of the irradiated reconstructed breast. We describe a novel and straightforward intraoperative technique for creating compensatory asymmetry to maximize postradiation symmetry in immediate bilateral tissue expander (TE) and acellular dermal matrix (ADM) reconstruction requiring unilateral PMRT. METHODS: A cohort of 25 bilateral TE/ADM breast reconstructions with planned unilateral PMRT was performed using this approach, and outcomes were reviewed. On the PMRT side, the ADM edge was inset to a lower inframammary fold (IMF) position resulting in a near "bottoming-out" effect. On the non-PMRT side, the ADM was inset using a triple point stitch onto the IMF in a higher chest wall location. The planned PMRT side TE was overexpanded and second-stage exchanges were performed 6+ months post-PMRT. RESULTS: Post-PMRT results showed improved symmetry as the PMRT side migrated superiorly to match the contralateral non-irradiated side. Minimal pocket or IMF adjustments were required during second-stage procedures, with just 6 patients (24%) requiring minor lowering and 1 patient (4%) requiring elevation of the PMRT side IMF. Thus, most (72%) patients undergoing bilateral mastectomy and unilateral PMRT did not require any IMF modifications during the second-stage procedure. CONCLUSIONS: A differential ADM inset and TE pocket creation for bilateral TE/ADM breast reconstructions with planned unilateral PMRT can minimize the typical adverse aesthetic effects of PMRT on reconstruction results and maximize symmetry.