Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema.

Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

BACKGROUND: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. METHODS: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. RESULTS: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. CONCLUSIONS: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

Use of a bovine pericardial patch angioplasty for completion of a complicated end to side anastomosis of a recipient vessel in the free flap reconstruction of a radiated wound: A case report.

Soft tissue sarcomas treated by extensive surgical resection and adjuvant radiation can lead to large tissue deficits that require free flap repair. Significant radiation can further compromise vessels necessitating novel therapeutic approaches. We describe an 82-year-old man who presented with a posterior thigh sarcoma and underwent wide local tumor resection and immediate reconstruction with a microvascular free flap. Due to radiated recipient vessels, this case required bovine patch angioplasty as a conduit for end to side anastomosis. Initial resection and pathology revealed a large myxofibrosarcoma. Wide local resection and radiotherapy resulted in a large irradiated soft tissue defect of 26 x 15 x 4 cm with exposed, radiation damaged neurovascular structures, and a lack of available regional flap options. The planned free flap, a 30 x 8 cm skin island from the left latissimus dorsi muscle with end-to-side anastomosis to the popliteal artery was complicated by friability of the vessel wall and insufficient perfusion. Given the extent of resection and radiation, there were no alternative recipient vessels present within the field. A bovine pericardial patch angioplasty of 2.5 cm in length was performed to the diseased popliteal vessel and an end to side anastomosis was successfully performed between the thoracodorsal artery and the patch. Improved reperfusion of the free flap was noted immediately following anastomosis indicating completion of the anastomosis of our complicated recipient vessel. During the uncomplicated postoperative course, the flap had good perfusion with Doppler signals present, and incision sites intact at discharge from acute hospitalization. Recurrent sarcomas that have undergone extensive resection and radiotherapy pose significant reconstructive challenges. For defects that require free tissue reconstruction when there are limited options for healthy, recipient vessels, bovine pericardial patch angioplasty may act as a robust conduit for diseased vessels.

Urinary Bladder Matrix Improves Irradiated Wound Healing in a Murine Model.

ABSTRACT: Radiation skin damage is associated with chronic wounds and poor healing. Existing localized treatment modalities have limited benefit. Therefore, there has been increased interest in biologically based solutions. In this study, we aimed to determine the effect of topical urinary bladder matrix (UBM) on chronic irradiated skin wounds using an established murine model. Our findings demonstrated that topical urinary bladder matrix significantly accelerated the healing of irradiated wounds on day 7 (P = 0.0216), day 14 (P = 0.0140), and day 21 (P = 0.0393). Histologically, urinary bladder matrix treatment was associated with higher-quality reorganization and reepithelialization of wounds, an increased density of myofibroblasts (P = 0.0004), and increased collagen deposition (P < 0.0001). In addition, quantitative real-time polymerase chain reaction data demonstrated decreased expression of profibrotic mediators (P = 0.0049). We conclude that urinary bladder matrix may be a useful, noninvasive, adjunctive therapy for the treatment of chronic irradiated skin wounds.

Risk Factors for Wound Complications After Soft Tissue Sarcoma Resection.

ABSTRACT: Soft tissue sarcomas are a heterogenous group of malignant tumors that represent approximately 1% of adult malignancies. Although these tumors occur throughout the body, the majority involved the lower extremity. Management may involve amputation but more commonly often includes wide local resection by an oncologic surgeon and involvement of a plastic surgeon for reconstruction of larger and more complex defects. Postoperative wound complications are challenging for the surgeon and patient but also impact management of adjuvant chemotherapy and radiation therapy. To explore risk factors for wound complications, we reviewed our single-institution experience of lower-extremity soft tissue sarcomas from April 2009 to September 2016. We identified 127 patients for retrospective review and analysis. The proportion of patients with wound complications in the cohort was 43.3%. Most notably, compared with patients without wound complications, patients with wound complications had a higher proportion of immediate reconstruction (34.5% vs 15.3%; P = 0.05) and a marginally higher proportion who received neoadjuvant radiation (30.9% vs 16.7%; P = 0.06).

A Survey of Current Preferences of Plastic Surgeons Regarding the Assessment and Reduction of Preoperative Patient Anxiety.

BACKGROUND: Preoperative anxiety is a common phenomenon in plastic surgery that has been associated with numerous negative patient outcomes. Little is known about the preferences of plastic surgeons regarding management of patient preoperative anxiety OBJECTIVE: To determine the preferences of plastic surgeons regarding the assessment and reduction of adult preoperative patient anxiety in their primary practice setting. METHODS: The membership of the American Council of Academic Plastic Surgeons (ACAPS) was surveyed using an anonymous, online questionnaire from April to June of 2020. RESULTS: A total of 100 participants from a membership of 532 responded (19%). The majority of respondents (63%) did not formally assess patient anxiety but supported the use of standardized scales to measure anxiety (57%). Most plastic surgeons preferred patient education (81%), family member presence (69%), and visit from the anesthesiologist (54%) to reduce patient anxiety. Plastic surgeons also allocated the most responsibility to anesthesiologists (63%) and plastic surgeons (62%) to reduce preoperative anxiety. DISCUSSION: Most plastic surgeon members of ACAPS did not assess their patients' anxieties preoperatively but appeared willing to use anxiety scales. Plastic surgeons also supported several measures to reduce anxiety, especially patient education, family member preferences, and anesthesiologist visits. Although plastic surgeons appeared to hold multiple parties responsible to manage preoperative anxiety, they held themselves and anesthesiologists most responsible. Future studies are needed to determine whether these views cohere with those of other healthcare providers and whether these preferences change for pediatric patients. LEVEL OF EVIDENCE V: 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 .

Prevention of postsurgical lymphedema via immediate delivery of sustained-release 9-cis retinoic acid to the lymphedenectomy site.

BACKGROUND AND OBJECTIVES: Previously, we have shown that 9-cis retinoic acid (9-cis RA) stimulates lymphangiogenesis and limits postsurgical lymphedema in animal models when administered via daily intraperitoneal injections. In this study, we investigate whether a single-use depot 9-cis RA drug delivery system (DDS) implanted at the site of lymphatic injury can mitigate the development of lymphedema in a clinically relevant mouse limb model. METHODS: Hind limb lymphedema was induced via surgical lymphadenectomy and irradiation. Animals were divided into two treatment groups: (1) 9-cis RA DDS, (2) placebo DDS. Outcomes measured included paw thickness, lymphatic clearance and density, epidermal thickness, and collagen deposition. RESULTS: Compared with control animals, 9-cis RA-treated animals had significantly less paw swelling from postoperative week 3 (P = .04) until the final timepoint at week 6 (P = .0007). Moreover, 9-cis RA-treated animals had significantly faster lymphatic clearance (P < .05), increased lymphatic density (P = .04), reduced lymphatic vessel size (P = .02), reduced epidermal hyperplasia (P = .04), and reduced collagen staining (P = .10). CONCLUSIONS: Animals receiving 9-cis RA sustained-release implants at the time of surgery had improved lymphatic function and structure, indicating reduced lymphedema progression. Thus, we demonstrate that 9-cis RA contained within a single-use depot DDS has favorable properties in limiting pathologic responses to lymphatic injury and may be an effective strategy against secondary lymphedema.

ORAI1 Activates Proliferation of Lymphatic Endothelial Cells in Response to Laminar Flow Through Krüppel-Like Factors 2 and 4.

RATIONALE: Lymphatic vessels function to drain interstitial fluid from a variety of tissues. Although shear stress generated by fluid flow is known to trigger lymphatic expansion and remodeling, the molecular basis underlying flow-induced lymphatic growth is unknown. OBJECTIVE: We aimed to gain a better understanding of the mechanism by which laminar shear stress activates lymphatic proliferation. METHODS AND RESULTS: Primary endothelial cells from dermal blood and lymphatic vessels (blood vascular endothelial cells and lymphatic endothelial cells [LECs]) were exposed to low-rate steady laminar flow. Shear stress-induced molecular and cellular responses were defined and verified using various mutant mouse models. Steady laminar flow induced the classic shear stress responses commonly in blood vascular endothelial cells and LECs. Surprisingly, however, only LECs showed enhanced cell proliferation by regulating the vascular endothelial growth factor (VEGF)-A, VEGF-C, FGFR3, and p57/CDKN1C genes. As an early signal mediator, ORAI1, a pore subunit of the calcium release-activated calcium channel, was identified to induce the shear stress phenotypes and cell proliferation in LECs responding to the fluid flow. Mechanistically, ORAI1 induced upregulation of Krüppel-like factor (KLF)-2 and KLF4 in the flow-activated LECs, and the 2 KLF proteins cooperate to regulate VEGF-A, VEGF-C, FGFR3, and p57 by binding to the regulatory regions of the genes. Consistently, freshly isolated LECs from Orai1 knockout embryos displayed reduced expression of KLF2, KLF4, VEGF-A, VEGF-C, and FGFR3 and elevated expression of p57. Accordingly, mouse embryos deficient in Orai1, Klf2, or Klf4 showed a significantly reduced lymphatic density and impaired lymphatic development. CONCLUSIONS: Our study identified a molecular mechanism for laminar flow-activated LEC proliferation.

Analysis of the Microsurgery Match from 2014 to 2018 Reveals Increased Competition for Microsurgery Fellowship Positions.

BACKGROUND: There has been no peer-reviewed published data analyzing the microsurgery match since it was established. The aim of this study is to present and analyze match data to inform residents and programs regarding outcomes. METHODS: Anonymized data were requested from the San Francisco Match, which was plotted and analyzed utilizing Pearson's Chi-square, unpaired t-test, and one-way analysis of variance (ANOVA). RESULTS: Match data was obtained from the years 2014 to 2018. The match rate decreased from 84.6% in 2015 to 67.3% in 2018, mean = 73.7 (8.29%), and (p = 0.01735). The position fill rate fluctuated from 82.9% in 2014 to 90.0% in 2016, mean = 86.5 (3.0%). In 2014 and 2015, 66.7% of applicants matched their first or second choice compared to 48.0% in 2018, mean = 58.7 (8.3%), (p =.04785). Matched applicants ranked mean = 6.6 (1.4%) programs versus 3.4 (1.3) for unmatched, (p < 0.0001). Filled programs ranked a greater number of applicants per position, mean = 8.5 (1.8%), compared to partially filled, mean = 4.6 (2.6%), and unfilled mean = 3.6 (3.4%), programs (p = 0.0014). In 2015, 55.0% of programs matched their first or second choice compared to 30.4% of programs in 2018, mean = 43.0 (10.1%). CONCLUSION: The application process for microsurgery has become more competitive. Matched applicants rank more programs than do unmatched. Fully filled programs rank more applicants per position than do unfilled or partially filled. Applicants and programs are increasingly less likely to match their top choices.

Local Administration of Interleukin-1 Receptor Antagonist Improves Diabetic Wound Healing.

Impaired healing of the skin is a notable cause of patient morbidity and mortality. In diabetic individuals, dysregulated inflammation contributes to delayed wound healing. Specific immunomodulatory agents may have a role in the treatment of diabetic wounds. One of these molecules is interleukin-1 receptor antagonist (Anakinra; Amgen Corp.). Although interleukin-1 receptor antagonist (Anakinra; Amgen Corp.) is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, little is known about the local use this drug in cutaneous wound healing. Therefore, the aim of this study is to determine the effect of locally administered interleukin-1 receptor antagonist on delayed wound healing, specifically, in a diabetic mouse model. Two 6-mm full-thickness wounds were created on the dorsa of diabetic (db/db) mice and stented. One-hour postwounding, wound margins were subcutaneously injected with either (1) low-dose interleukin-1 receptor antagonist in a gelatin-transglutaminase gel vehicle or (2) the gel vehicle only. Wounds were imaged on days 0, 7, 14, and 21 postwounding, and wound area was determined. Wound biopsies were collected on day 21 and immunohistochemically stained for neutrophil and macrophage infiltration. Wounds treated with interleukin-1 receptor antagonist had significantly smaller wound area than nontreated wounds on day 7 and day 14 postwounding. Treated wounds also showed significantly less neutrophil and macrophage infiltration. These findings support the hypothesis that interleukin-1 receptor antagonist may have an important role in cutaneous wound healing, possibly by promoting successful resolution of acute inflammation and hence accelerating wound closure. Thereby, administration of IL-1Ra may be useful in the treatment of nonhealing wounds.

Prevention of Postsurgical Lymphedema by 9-cis Retinoic Acid.

OBJECTIVE: To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema. BACKGROUND: 9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema. METHODS: Lymphedema was induced in the right hind limb after a single fraction of 20 Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08 mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis. RESULTS: Using our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle-treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05). CONCLUSIONS: We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.

Analysis of risk factors associated with microvascular free flap failure using a multi-institutional database.

BACKGROUND: There are numerous factors that may contribute to microvascular free flap failure. Although technical issues are dominant factors, patient and clinical characteristics are also contributory. The aim of this study was to investigate non-technical variables associated with microsurgical free flap failure using a multi-institutional dataset. METHODS: Utilizing the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP) database, we identified all patients who underwent microvascular free tissue transfer from 2005 through 2009. Univariate analysis was performed to determine the association of flap failure with the following factors: age, gender, ethnicity, body mass index, intraoperative transfusion, diabetes, smoking, alcohol, American Society of Anesthesiologists classification, year of operation, operative time, number of flaps, and type of reconstruction. Factors with a significance of P < 0.2 in the univariate analysis were included in the multivariate logistic regression model to identify independent risk factors. RESULTS: A total of 639 patients underwent microsurgical free flap reconstruction with 778 flaps over the 4-year study period; 139 patients had two free flaps during the same operation. The overall incidence of flap failure was 4.4% (34/778) (95% confidence interval [CI]: 3.0%, 6.2%). Operative time was identified as an independent risk factor for free flap failure. After adjusting for other factors, those whose operative time was equal to or greater than the 75th percentile (625.5 min) were twice as likely to experience flap failure (AOR 2.09; 95% CI: 1.01-4.31; P = 0.045). None of the other risk factors studied were significant contributors. CONCLUSIONS: In this series, the overall flap loss rate of was 4.4%. Operative time was a significant independent risk factor for flap failure.

Determination of a perfusion threshold in experimental perforator flap surgery using indocyanine green angiography.

Indocyanine green (ICG) angiography has been used in the evaluation of flap perfusion but the viability threshold has not been elucidated. In this study, we determined the threshold by comparing perfusion, using ICG imaging (SPY imaging system, LifeCell Corporation), to clinical evidence of nonviability in rat abdominal perforator flaps. Abdominal flaps, based on a single perforator, were elevated and re-inset in Sprague-Dawley rats. ICG imaging and clinical assessments were conducted preoperatively, as well as 0, 24, and 48 hours postoperatively. SPY-Q software allowed standardization of the perforator's perfusion for comparison purposes. A total of 278 random percentage measurements were made from postoperative day 0 giving a mean (SE) percentage perfusion of 26.8% (1.6%) and 59.1% (1.3%), respectively, for necrosis and survival (P<0.05). We demonstrate that ICG angiography can be readily analyzed in a perforator flap environment allowing a determination of the perfusion threshold.

Review of treatment strategies after lymphadenectomy: from molecular therapeutics to immediate microsurgical lymphatic reconstruction.

OBJECTIVE: Lymphedema is a common complication of cancer treatment, such as lymphadenectomy and radiation therapy. It is a debilitating condition with pathologic tissue changes that hinder effective curative treatment and jeopardize patients' quality of life. Various attempts to prevent the development of lymphedema have been made, with improvements in the incidence of the pathology. However, it is still prevalent among survivors of cancer. In this paper, we review both molecular therapeutics and immediate surgical lymphatic reconstruction as treatment strategies after lymphadenectomy. Specifically, we discuss pro-lymphangiogenic molecules that have proved efficient in animal models of lymphedema and clinical trials, and review currently available microsurgical techniques of immediate lymphatic reconstruction. METHODS: A literature search was conducted in PubMed, Embase, Cochrane Library, and Google Scholar through May 2022. Searches were done separately for molecular therapeutics and microsurgical techniques for immediate lymphatic reconstruction. Search terms used for (1) non-surgical methods include 'lymphangiogenesis,' 'lymphedema,' 'growth factor,' and 'gene therapy.' Search terms used for (2) surgical methods include 'lymphedema,' 'lymph node excision,' 'lymphatic vessels,' 'primary prevention,' and 'microsurgery.' RESULTS: Various pro-lymphangiogenic factors with therapeutic potential include VEGF-C, VEGF-D, HGF, bFGF, PDGF, IGF, Retinoic acid, Ang-1, S1P, TLR4, and IL-8. Microsurgical lymphatic reconstruction for prevention of secondary lymphedema includes lymphovenous anastomosis, vascularized lymph node flap transfer, and lymph-interpositional flap transfer, with promising clinical outcomes. CONCLUSIONS: With growing knowledge of the lymphangiogenic pathway and lymphedema pathology and advances in microsurgical techniques to restore lymphatic channels, molecular and surgical approaches may represent a promising method for primary prevention of lymphedema.

Determining Accurate Dye Combinations for Sentinel Lymph Node Detection: A Systematic Review.

Background: Lymphatic dyes are commonly used to map the drainage path from tumor to lymphatics, which are biopsied to determine if spread has occurred. A blue dye in combination with technetium-99 is considered the gold standard for mapping, although many other dyes and dye combinations are used. Not all of these substances have the same detection efficacy. Methods: A systematic review of PubMed, SCOPUS, Web of Science, and Medline was performed. The predefined search terms were (indocyanine green OR isosulfan blue OR lymphazurin OR patent blue OR methylene blue OR fluorescein OR technetium-99) AND combination AND dye AND (sentinel lymph node biopsy OR lymphedema OR lymphatics OR lymph OR microsurgery OR cancer OR tumor OR melanoma OR carcinoma OR sarcoma). Results: The initial search returned 4267 articles. From these studies, 37 were selected as candidates that met inclusion criteria. After a full-text review, 34 studies were selected for inclusion. Eighty-nine methods of sentinel lymph node (SLN) detection were trialed using 22 unique dyes, dye combinations, or other tracers. In total, 12,157 SLNs of 12,801 SLNs were identified. Dye accuracy ranged from 100% to 69.8% detection. Five dye combinations had 100% accuracy. Dye combinations were more accurate than single dyes. Conclusions: Combining lymphatic dyes improves SLN detection results. Replacing technetium-99 with ICG may allow for increased access to SLN procedures with comparable results. The ideal SLN tracer is a low-cost molecule with a high affinity for lymphatic vessels due to size and chemical composition, visualization without specialized equipment, and no adverse effects.

9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema.

BACKGROUND: The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction caused by genetic defects, or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swelling often associated with fibrosis and recurrent infections with no available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema. METHODS AND RESULTS: We report that RAs promote proliferation, migration, and tube formation of cultured lymphatic endothelial cells by activating fibroblast growth factor receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27(Kip1), p57(Kip2), and the aurora kinases through both an Akt-mediated nongenomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals in mouse trachea, Matrigel plug, and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration. CONCLUSION: These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients.

Silicone Breast Implant Surface Texture Impacts Gene Expression in Periprosthetic Fibrous Capsules.

BACKGROUND: Silicone breast implants with smooth outer shells are associated with higher rates of capsular contracture, whereas textured implants have been linked to the development of breast implant-associated anaplastic large cell lymphoma. By assessing the gene expression profile of fibrous capsules formed in response to smooth and textured implants, insight into the development of breast implant-associated abnormalities can be gained. METHODS: Miniature smooth or textured silicone implants were surgically inserted into female rats ( n = 10) and harvested for the surrounding capsules at postoperative week 6. RNA sequencing and quantitative polymerase chain reaction were performed to identify genes differentially expressed between smooth and textured capsules. For clinical correlation, the expression of candidate genes was assayed in implant capsules harvested from human patients with and without capsular contracture. RESULTS: Of 18,555 differentially expressed transcripts identified, three candidate genes were selected: matrix metalloproteinase-3 ( MMP3 ), troponin-T3 ( TNNT3 ), and neuregulin-1 ( NRG1 ). In textured capsules, relative gene expression and immunostaining of MMP3 and TNNT3 was up-regulated, whereas NRG1 was down-regulated compared to smooth capsules [mean relative fold change, 8.79 ( P = 0.0059), 4.81 ( P = 0.0056), and 0.40 ( P < 0.0001), respectively]. Immunostaining of human specimens with capsular contracture revealed similar gene expression patterns to those of animal-derived smooth capsules. CONCLUSIONS: An expression pattern of low MMP3 /low TNNT3 /high NRG1 is specifically associated with smooth implant capsules and human implant capsules with capsular contracture. The authors' clinically relevant breast implant rat model provides a strong foundation to further explore the molecular genetics of implant texture and its effect on breast implant-associated abnormalities. CLINICAL RELEVANCE STATEMENT: The authors have demonstrated that there are distinct gene expression profiles in response to smooth versus textured breast implants. Since surface texture may be linked to implant-related pathology, further molecular analysis of periprosthetic capsules may yield strategies to mitigate implant-related complications.

Prospective, multicenter study of antimicrobial-coated, noncrosslinked, acellular porcine dermal matrix (XenMatrix™ AB Surgical Graft) for hernia repair in all centers for disease control and prevention wound classes: 24-month follow-up cohort.

Prospective, multicenter, single-arm study of antimicrobial-coated, noncrosslinked, acellular porcine dermal matrix (AC-PDM) in a cohort involving all centers for disease control and prevention wound classes in ventral/incisional midline hernia repair (VIHR). Materials and methods: Seventy-five patients (mean age 58.6±12.7 years; BMI 31.3±4.9 kg/m2) underwent ventral/incisional midline hernia repair with AC-PDM. Surgical site occurrence (SSO) was assessed in the first 45 days post-implantation. Length of stay, return to work, hernia recurrence, reoperation, quality of life, and SSO were assessed at 1, 3, 6, 12, 18, and 24 months. Results: 14.7% of patients experienced SSO requiring intervention within 45 days post-implantation, and 20.0% thereafter (>45 d post-implantation). Recurrence (5.8%), definitely device-related adverse events (4.0%), and reoperation (10.7%) were low at 24 months; all quality-of-life indicators were significantly improved compared to baseline. Conclusion: AC-PDM exhibited favourable results, including infrequent hernia recurrence and definitely device-related adverse events, with reoperation and SSO comparable to other studies, and significantly improved quality of life.

Effect of immediate reconstruction on postmastectomy surgical site infection.

INTRODUCTION: Surgical site infections (SSI) are a source of significant postoperative morbidity and cost. Although immediate breast reconstruction after mastectomy has become routine, the data regarding the incidence of SSI in immediate breast reconstruction is highly variable and series dependent. METHODS: Using the National Surgical Quality Improvement Program database, all female patients undergoing mastectomy, with or without immediate reconstruction, from 2005 to 2009 were identified. Only "clean" procedures were included. The primary outcome was incidence of SSI within 30 days of operation. Stepwise logistic regression analysis was used to identify risk factors associated with SSI. RESULTS: A total of 48,393 mastectomies were performed during the study period, of which 9315 (19.2%) had immediate breast reconstruction. The incidence of SSI was 3.5% (330/9315) (95% CI [confidence interval]: 3.2%-4%) in patients undergoing mastectomy with reconstruction and 2.5% (966/39,078) (95% CI: 2.3%-2.6%) in patients undergoing mastectomy without reconstruction (P < 0.001). Independent risk factors for SSI include increased preoperative body mass index (BMI), heavy alcohol use, ASA (American Society of Anesthesiologists) score greater than 2, flap failure, and operative time of 6 hours or longer. CONCLUSIONS: Immediate breast reconstruction is associated with a statistically significant increase in risk of SSI in patients undergoing mastectomy (3.5% vs 2.5%). However, this difference was not considered to be clinically significant. In this large series, increased BMI, alcohol use, ASA class greater than 2, flap failure, and prolonged operative time were associated with increased risk of SSI.

A systematic review and meta-analysis of complications associated with acellular dermal matrix-assisted breast reconstruction.

BACKGROUND: Multiple outcome studies have been published on the use of acellular dermal matrix (ADM) in breast reconstruction with disparate results. The purpose of this study was to conduct a systematic review and meta-analysis to determine an aggregate estimate of risks associated with ADM-assisted breast reconstruction. METHODS: The MEDLINE, Web of Science, and Cochrane Library databases were queried, and relevant articles published up to September 2010 were analyzed based on specific inclusion criteria. Seven complications were studied including seroma, cellulitis, infection, hematoma, skin flap necrosis, capsular contracture, and reconstructive failure. A pooled random effects estimate for each complication and 95% confidence intervals (CI) were derived. For comparisons of ADM and non-ADM, the pooled random effects odds ratio (OR) and 95% CI were derived. Heterogeneity was measured using the I2 statistic. RESULTS: Sixteen studies met the inclusion criteria. The pooled complication rates were seroma (6.9%; 95% CI, 5.3%-8.8%), cellulitis (2.0%; 95% CI, 1.2%-3.1%), infection (5.7%; 95% CI, 4.3%-7.3%), skin flap necrosis (10.9%; 95% CI, 8.7%-13.5%), hematoma (1.3%; 95% CI, 0.6%-2.4%), capsular contracture (0.6%; 95% CI, 0.1%-1.7%), and reconstructive failure (5.1%; 95% CI, 3.8%-6.7%). Five studies reported findings for both the ADM and non-ADM patients and were used in the meta-analysis to calculate pooled OR. ADM-assisted breast reconstructions had a higher likelihood of seroma (pooled OR, 3.9; 95% CI, 2.4-6.2), infection (pooled OR, 2.7; 95% CI, 1.1-6.4), and reconstructive failure (pooled OR, 3.0; 95% CI, 1.3-6.8) than breast reconstructions without the use of ADM. The relation of ADM use to hematoma (pooled OR, 2.0; 95% CI, 0.8-5.2), cellulitis (pooled OR, 2.0; 95% CI, 0.9-4.3), and skin flap necrosis (pooled OR, 1.9; 95% CI, 0.6-5.4) was inconclusive. CONCLUSIONS: In the studies evaluated, ADM-assisted breast reconstructions exhibited a higher likelihood of seroma, infection, and reconstructive failure than prosthetic-based breast reconstructions using traditional musculofascial flaps. ADM is associated with a lower rate of capsular contracture. A careful risk/benefit analysis should be performed when choosing to use ADM in implant-based breast reconstruction.