Free Tissue Transfer in Sickle Cell Disease: A Case Report and Systematic Review.

Hemoglobinopathies such as sickle cell disease (SCD) are traditionally considered a relative contraindication to free tissue transfer, due to concerns that erythrocyte sickling will increase the risk of microvascular thrombosis and flap failure. This article describes a case report with the successful use of free tissue transfer in a patient with SCD and provides a systematic literature review on free tissue transfer in SCD. A retrospective chart review was performed of a patient with SCD who underwent free tissue transfer at the authors' institution. A systematic literature review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed using the keywords "free tissue transfer," "free flap," or "microsurgery" and "sickle cell" on PubMed, Ovid/Medline, and Scopus. A 29-year-old male with delayed presentation of an electrical burn to the face and scalp underwent wound closure with a free anterolateral thigh flap. Key management principles included red blood cell transfusion to keep hemoglobin S under 30% and hemoglobin greater than 10 g/dL, maintenance of hydration, normothermia, adequate analgesia, and postoperative anticoagulation. Systematic literature review identified 7 articles describing 13 cases of free tissue transfer in 10 patients with SCD, with combined complete free flap success in 10 of the 13 flaps. Free tissue transfer can be successfully performed in patients with SCD. However, evidence on the optimal management of this unique patient population in the perioperative period after free tissue transfer is limited to case reports in the literature.

Decellularized Adipose Matrices Can Alleviate Radiation-Induced Skin Fibrosis.

Objective: Radiation therapy is commonplace for cancer treatment but often results in fibrosis and atrophy of surrounding soft tissue. Decellularized adipose matrices (DAMs) have been reported to improve these soft tissue defects through the promotion of adipogenesis. These matrices are decellularized by a combination of physical, chemical, and enzymatic methods to minimize their immunologic effects while promoting their regenerative effects. In this study, we aimed at exploring the regenerative ability of a DAM (renuva®; MTF biologics, Edison, NJ) in radiation-induced soft tissue injury. Approach: Fresh human lipoaspirate or DAM was injected into the irradiated scalp of CD-1 nude mice, and volume retention was monitored radiographically over 8 weeks. Explanted grafts were histologically assessed, and overlying skin was examined histologically and biomechanically. Irradiated human skin was also evaluated from patients after fat grafting or DAM injection. However, integrating data between murine and human skin in all cohorts is limited given the genetic variability between the two species. Results: Volume retention was found to be greater with fat grafts, though DAM retention was, nonetheless, appreciated at irradiated sites. Improvement in both mouse and human irradiated skin overlying fat and DAM grafts was observed in terms of biomechanical stiffness, dermal thickness, collagen density, collagen fiber networks, and skin vascularity. Innovation: This is the first demonstration of the use of DAMs for augmenting the regenerative potential of irradiated mouse and human skin. Conclusions: These findings support the use of DAMs to address soft tissue atrophy after radiation therapy. Morphological characteristics of the irradiated skin can also be improved with DAM grafting.

JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I­expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9­mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring.

Angiogenic CD34+CD146+ adipose-derived stromal cells augment recovery of soft tissue after radiotherapy.

Radiation therapy is effective for cancer treatment but may also result in collateral soft tissue contracture, contour deformities, and non-healing wounds. Autologous fat transfer has been described to improve tissue architecture and function of radiation-induced fibrosis and these effects may be augmented by enrichment with specific adipose-derived stromal cells (ASCs) with enhanced angiogenic potential. CD34+CD146+, CD34+CD146-, or CD34+ unfractionated human ASCs were isolated by flow cytometry and used to supplement human lipoaspirate placed beneath the scalp of irradiated mice. Volume retention was followed radiographically and fat grafts as well as overlying soft tissue were harvested after eight weeks for histologic and biomechanical analyses. Radiographic evaluation revealed the highest volume retention in fat grafts supplemented with CD34+CD146+ ASCs, and these grafts were also found to have greater histologic integrity than other groups. Irradiated skin overlying CD34+CD146+ ASC-enriched grafts was significantly more vascularized than other treatment groups, had significantly less dermal thickness and collagen deposition, and the greatest improvement in fibrillin staining and return of elasticity. Radiation therapy obliterates vascularity and contributes to scarring and loss of tissue function. ASC-enrichment of fat grafts with CD34+CD146+ ASCs not only enhances fat graft vascularization and retention, but also significantly promotes improvement in overlying radiation-injured soft tissue. This regenerative effect on skin is highly promising for patients with impaired wound healing and deformities following radiotherapy.

Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis.

Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.

The antifibrotic adipose-derived stromal cell: Grafted fat enriched with CD74+ adipose-derived stromal cells reduces chronic radiation-induced skin fibrosis.

Fat grafting can reduce radiation-induced fibrosis. Improved outcomes are found when fat grafts are enriched with adipose-derived stromal cells (ASCs), implicating ASCs as key drivers of soft tissue regeneration. We have identified a subpopulation of ASCs positive for CD74 with enhanced antifibrotic effects. Compared to CD74- and unsorted (US) ASCs, CD74+ ASCs have increased expression of hepatocyte growth factor, fibroblast growth factor 2, and transforming growth factor ß3 (TGF-ß3) and decreased levels of TGF-ß1. Dermal fibroblasts incubated with conditioned media from CD74+ ASCs produced less collagen upon stimulation, compared to fibroblasts incubated with media from CD74- or US ASCs. Upon transplantation, fat grafts enriched with CD74+ ASCs reduced the stiffness, dermal thickness, and collagen content of overlying skin, and decreased the relative proportions of more fibrotic dermal fibroblasts. Improvements in several extracellular matrix components were also appreciated on immunofluorescent staining. Together these findings indicate CD74+ ASCs have antifibrotic qualities and may play an important role in future strategies to address fibrotic remodeling following radiation-induced fibrosis.

CD34+CD146+ adipose-derived stromal cells enhance engraftment of transplanted fat.

Fat grafting is a surgical technique able to reconstruct and regenerate soft tissue. The adipose-derived stromal cells (ASCs) within the stromal vascular fraction are believed to drive these beneficial effects. ASCs are increasingly recognized to be a heterogeneous group, comprised of multiple stem and progenitor subpopulations with distinct functions. We hypothesized the existence of an ASC subpopulation with enhanced angiogenic potential. Human ASCs that were CD34+CD146+, CD34+CD146-, or CD34+ unfractionated (UF) were isolated by flow cytometry for comparison of expression of proangiogenic factors and endothelial tube-forming potential. Next, lipoaspirate was enriched with either CD34+CD146+, CD34+CD146-, CD34+ UF ASCs, or was not enriched, and grafted beneath the scalp skin of immunodeficient CD-1 Nude mice (10 000 cells/200 µL/graft). Fat retention was monitored radiographically more than 8 weeks and fat grafts were harvested for histological assessment of quality and vascularization. The CD34+CD146+ subpopulation comprised ~30% of ASCs, and exhibited increased expression of vascular endothelial growth factor and angiopoietin-1 compared to CD34+CD146- and CD34+ UF ASCs, and increased expression of fibroblast growth factor-2 compared to CD34+CD146- ASCs. The CD34+CD146+ subpopulation exhibited enhanced induction of tube-formation compared to CD34+CD146- ASCs. Upon transplantation, fat enriched CD34+CD146+ ASCs underwent less resorption and had improved histologic quality and vascularization. We have identified a subpopulation of CD34+ ASCs with enhanced angiogenic effects in vitro and in vivo, likely mediated by increased expression of potent proangiogenic factors. These findings suggest that enriching lipoaspirate with CD34+CD146+ ASCs may enhance fat graft vascularization and retention in the clinical setting.

Compounding Benefits of Sentinel Lymph Node Biopsy for Perineal Melanoma: A Population-Based Retrospective Cohort Analysis.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) in the treatment of melanoma is known to provide valuable prognostic information. However, there is no literature describing an overall or disease-specific survival (DDS) benefit of SLNB. In the perineum, melanoma is often more advanced at presentation with current treatment guidelines translated from nonanatomic specific melanoma. As a result, there is little understanding surrounding the role of SLNB in melanoma of the perineum. Our objective is to better understand the therapeutic benefits of SLNB in perineal melanoma. METHODS: The Surveillance, Epidemiology, and End Results program is a large population-based cancer registry including survival data from millions of patients in the United States. The registry was used to generate patient data for analysis from 2004 to 2016. Inclusion criteria included melanoma of the perineum; Breslow depth of 0.80 mm or greater and less than 0.80 mm with ulceration; SLNB or no intervention; clinically negative nodal disease; and available overall survival data. RESULTS: For 879 patients from 2004 to 2016 with perineal melanoma, significant predictors of reduced survival include older than 75 years, Clark level IV-V, Breslow depth of greater than 4.00 mm, positive ulceration status, regional and distant nodal micrometastases, and clinically positive nodes on presentation. Aggregates for overall survival (OS) and disease-specific survival (DSS) were improved with implementation of SLNB. The 5-year survival rates with SLNB versus no SLNB were 54.0% and 43.0% for OS (P = 0.001) and 57.8% and 53.1% for DSS (P = 0.044). Stratification by Breslow depth yielded significant OS and DSS advantage for greater than 1.00 to 2.00 mm (21.3% benefit, P =0.021, and 16.8% benefit, P = 0.044) and greater than 4.00 mm (30.3% benefit, P = 0.005, and 21.0% benefit, P = 0.007) Breslow depths. CONCLUSIONS AND RELEVANCE: Sentinel lymph node biopsy may provide therapeutic benefits in addition to prognostic information for melanoma of the perineum through an increase in 5-year OS.

Pro-Fibrotic CD26-Positive Fibroblasts Are Present in Greater Abundance in Breast Capsule Tissue of Irradiated Breasts.

BACKGROUND: Breast capsular contracture is a major problem following implant-based breast reconstruction, particularly in the setting of radiation therapy. Recent work has identified a fibrogenic fibroblast subpopulation characterized by CD26 surface marker expression. OBJECTIVES: This work aimed to investigate the role of CD26-positive fibroblasts in the formation of breast implant capsules following radiation therapy. METHODS: Breast capsule specimens were obtained from irradiated and nonirradiated breasts of 10 patients following bilateral mastectomy and unilateral irradiation at the time of expander-implant exchange, under institutional review board approval. Specimens were processed for hematoxylin and eosin staining as well as for immunohistochemistry and fluorescence activated cell sorting for CD26-positive fibroblasts. Expression of fibrotic genes and production of collagen were compared between CD26-positive, CD26-negative, and unsorted fibroblasts. RESULTS: Capsule specimens from irradiated breast tissue were thicker and had greater CD26-postive cells on immunofluorescence imaging and on fluorescence activated cell sorting analysis than did capsule specimens from the nonirradiated breast. Compared with CD26-negative fibroblasts, CD26-positive fibroblasts produced more collagen and had increased expression of the profibrotic genes IL8, TGF-ß1, COL1A1, and TIMP4. CONCLUSIONS: CD26-positive fibroblasts were found in a significantly greater abundance in capsules of irradiated compared with nonirradiated breasts and demonstrated greater fibrotic potential. This fibrogenic fibroblast subpopulation may play an important role in the development of capsular contracture following irradiation, and its targeted depletion or moderation may represent a potential therapeutic option.

Fat grafting rescues radiation-induced joint contracture.

The aim of this study was to explore the therapeutic effects of fat grafting on radiation-induced hind limb contracture. Radiation therapy (RT) is used to palliate and/or cure a range of malignancies but causes inevitable and progressive fibrosis of surrounding soft tissue. Pathological fibrosis may lead to painful contractures which limit movement and negatively impact quality of life. Fat grafting is able to reduce and/or reverse radiation-induced soft tissue fibrosis. We explored whether fat grafting could improve extensibility in irradiated and contracted hind limbs of mice. Right hind limbs of female 60-day-old CD-1 nude mice were irradiated. Chronic skin fibrosis and limb contracture developed. After 4 weeks, irradiated hind limbs were then injected with (a) fat enriched with stromal vascular cells (SVCs), (b) fat only, (c) saline, or (d) nothing (n = 10/group). Limb extension was measured at baseline and every 2 weeks for 12 weeks. Hind limb skin then underwent histological analysis and biomechanical strength testing. Irradiation significantly reduced limb extension but was progressively rescued by fat grafting. Fat grafting also reduced skin stiffness and reversed the radiation-induced histological changes in the skin. The greatest benefits were found in mice injected with fat enriched with SVCs. Hind limb radiation induces contracture in our mouse model which can be improved with fat grafting. Enriching fat with SVCs enhances these beneficial effects. These results underscore an attractive approach to address challenging soft tissue fibrosis in patients following RT.

Retrospective cohort-based comparison of intraoperative liposomal bupivacaine versus bupivacaine for donor site iliac crest analgesia during alveolar bone grafting.

INTRODUCTION: Bone grafting of alveolar clefts is routinely performed with cancellous bone harvested from the iliac crest. Graft site morbidity is frequently seen, with early postoperative pain being one of the most common complaints. Liposomal bupivacaine (LB) has been demonstrated to provide improvement in postoperative pain for patients undergoing bunionectomy or hemorrhoidectomy, which may translate to patients requiring iliac crest bone graft harvest. METHODS: Thirty-eight patients undergoing iliac crest bone harvest were included in the study. Twenty-one patients underwent open iliac crest bone graft harvest with administration of 0.25% bupivacaine at the hip donor site, while 17 patients received local infiltration of 1.3% liposomal bupivacaine. Patient-reported pain scores, total narcotic use, length of stay, and postoperative steps were monitored. RESULTS: There were no significant differences in age, weight, distribution of clefts, or choice of donor hip between the two groups. There were no significant differences in length of hospitalization stay. However, differences were noted in average postoperative pain scores at five of six time points in the first 24 h, total oral morphine equivalents administered (4.7 ±â€¯5.3 vs. 14.3 ±â€¯12.0), and steps at postoperative days one to three (p < 0.001, for all three days) for patients receiving 1.3% LB versus 0.25% bupivacaine, respectively. CONCLUSION: Reduced pain scores and increased postoperative activity highlight the potential of LB to improve postoperative pain management in children undergoing iliac crest bone harvest for alveolar bone grafting.

Pediatric Laser Therapy in Pigmented Conditions.

Advances in laser therapy have led to novel therapeutic approaches to common pediatric skin conditions. As a non-invasive alternative to surgical options, laser therapy is efficacious in treating a broad range of conditions, from vascular and pigmented lesions to tattoo and hair removal. This paper reviews the basic mechanics of laser therapy, its role in common pigmented pediatric dermatoses, and special considerations for this unique age group.

Fat Chance: The Rejuvenation of Irradiated Skin.

Radiotherapy (RT) helps cure and palliate thousands of patients with a range of malignant diseases. A major drawback, however, is the collateral damage done to tissues surrounding the tumor in the radiation field. The skin and subcutaneous tissue are among the most severely affected regions. Immediately following RT, the skin may be inflamed, hyperemic, and can form ulcers. With time, the dermis becomes progressively indurated. These acute and chronic changes cause substantial patient morbidity, yet there are few effective treatment modalities able to reduce radiodermatitis. Fat grafting is increasingly recognized as a tool able to reverse the fibrotic skin changes and rejuvenate the irradiated skin. This review outlines the current progress toward describing and understanding the cellular and molecular effects of fat grafting in irradiated skin. Identification of the key factors involved in the pathophysiology of fibrosis following RT will inform therapeutic interventions to enhance its beneficial effects.

Acute Renal Failure due to a Tobramycin and Vancomycin Spacer in Revision Two-Staged Knee Arthroplasty.

Two-stage revision total knee arthroplasty (TKA) is the standard of care for prosthetic joint infections. The first stage involves removal of the infected prosthesis and placement of an antibiotic impregnated cement spacer; following a period ranging from 4 weeks to 6 months, the spacer is then removed and replaced with a permanent prosthesis. The advantage to this approach is that antibiotic impregnated spacers provide supratherapeutic levels in the joint without toxic accumulation in serum. However, it remains important for physicians and pharmacists to be aware of antibiotic associated complications in knee revisions. We present a case of a two-stage revision total knee arthroplasty in which a cement antibiotic spacer caused acute renal failure and ultimately resulted in persistent chronic kidney disease without hemodialysis at 2 months' follow-up. Our case reports the third highest serum tobramycin (13.7 mcg/ml) and second highest serum creatinine (8.62 mg/dl) for patients experiencing ARF due to an antibiotic spacer in two-stage revision TKA.