International consensus recommendations on face transplantation: A 2-step Delphi study.

Face transplantation is a viable reconstructive approach for severe craniofacial defects. Despite the evolution witnessed in the field, ethical aspects, clinical and psychosocial implications, public perception, and economic sustainability remain the subject of debate and unanswered questions. Furthermore, poor data reporting and sharing, the absence of standardized metrics for outcome evaluation, and the lack of consensus definitions of success and failure have hampered the development of a "transplantation culture" on a global scale. We completed a 2-round online modified Delphi process with 35 international face transplant stakeholders, including surgeons, clinicians, psychologists, psychiatrists, ethicists, policymakers, and researchers, with a representation of 10 of the 19 face transplant teams that had already performed the procedure and 73% of face transplants. Themes addressed included patient assessment and selection, indications, social support networks, clinical framework, surgical considerations, data on patient progress and outcomes, definitions of success and failure, public image and perception, and financial sustainability. The presented recommendations are the product of a shared commitment of face transplant teams to foster the development of face transplantation and are aimed at providing a gold standard of practice and policy.

BIA-ALCL and BIA-SCC: Updates on Clinical Features and Genetic Mutations for Latest Recommendations.

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) and Breast Implant-Associated Squamous Cell Carcinoma (BIA-SCC) are emerging neoplastic complications related to breast implants. While BIA-ALCL is often linked to macrotextured implants, current evidence does not suggest an implant-type association for BIA-SCC. Chronic inflammation and genetics have been hypothesized as key pathogenetic players, although for both conditions, the exact mechanisms and specific risks related to breast implants are yet to be established. While the genetic alterations in BIA-SCC are still unknown, JAK-STAT pathway activation has been outlined as a dominant signature of BIA-ALCL. Recent genetic investigation has uncovered various molecular players, including MEK-ERK, PI3K/AKT, CDK4-6, and PDL1. The clinical presentation of BIA-ALCL and BIA-SCC overlaps, including most commonly late seroma and breast swelling, warranting ultrasound and cytological examinations, which are the first recommended steps as part of the diagnostic work-up. While the role of mammography is still limited, MRI and CT-PET are recommended according to the clinical presentation and for disease staging. To date, the mainstay of treatment for BIA-ALCL and BIA-SCC is implant removal with en-bloc capsulectomy. Chemotherapy and radiation therapy have also been used for advanced-stage BIA-ALCL and BIA-SCC. In-depth characterization of the tumor genetics is key for the development of novel therapeutic strategies, especially for advanced stage BIA-ALCL and BIA-SCC, which show a more aggressive course and poor prognosis.

The Medical Historical Cultural Foundations of Western Nasal Surgery from Ancient Greece to the Middle Ages.

The manuscript aims to clarify the origins of Western rhinosurgery through the ancient texts of the greatest physicians of the past, up to the Byzantine Era, focusing on the "exchange of knowledge" between peoples. This excursus is carried out by quoting the texts of the greatest doctors of the past, such as Hippocrates, Galen and Celsus and by analysing the works of Byzantine authors such as Oribasius, Aetius, Antillus, which, more than others, represent the moment of fusion and interpenetration of Ancient Medical knowledge, paving the way for the Medieval Scholae Medicae in the West. The aim, therefore, is to fill that sort of "great gap" (from the foundation of Constantinople in the 4th century AD to the early Arab culture in the 11th century AD) due to the fact that figures such as Branca, Vianeo and, finally, Tagliacozzi, are considered direct actors of a recovery of the "ancient knowledge" of classic authors. This literature tends to less evaluate, instead, that important and huge cultural exchange -literally osmotic- in medical and surgical knowledge between peoples and civilizations, that find a trait d'union in the application of medical knowledge and surgical practical techniques matured in the Byzantine, Arab and Early Medieval period. In final analysis, through the History of Rhinosurgery, this paper aims to highlight how Western medical knowledge is made up of the ensemble of cultures which are apparently distant and different from each other, which merge themselves in a truly universal and transcultural knowledge: the Medical knowledge. 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 .

Mechanical and Enzymatic Digestion of Autologous Fat Grafting (A-FG): Fat Volume Maintenance and AD-SVFs Amount in Comparison.

BACKGROUND: Currently, several techniques for autologous fat graft (A-FG) preparation aimed at obtaining purified tissue exist. Both mechanical digestions via centrifugation, filtration, and enzymatic digestion were considered the most effective with different impacts in terms of adult adipose-derived stromal vascular fraction cells (AD-SVFs) amount that volume maintenance. OBJECTIVES: This article aimed to report the in vivo and in vitro results, represented by fat volume maintenance and AD-SVFs amount, obtained by four different procedures of AD-SVFs isolation and A-FG purification based on centrifugation, filtration, centrifugation with filtration, and enzymatic digestion. METHODS: A prospective, case-control study was conducted. In total, 80 patients affected by face and breast soft tissue defects were treated with A-FG and divided into four groups: n=20 were treated with A-FG enhanced with AD-SVFs obtained by enzymatic digestion (study group 1 [SG-1]); n=20 were treated with A-FG enhanced with AD-SVFs obtained by centrifugation with filtration (SG-2); n=20 were treated with A-FG enhanced with AD-SVFs obtained by only filtration (SG-3); n=20 were treated with A-FG obtained by only centrifugation according to the Coleman technique (control group [CG]). Twelve months after the last A-FG session, the volume maintenance percentage was analyzed by magnetic resonance imaging (MRI). Isolated AD-SVF populations were counted using a hemocytometer, and cell yield was reported as cell number/mL of fat. RESULTS: Starting with the same amount of fat analyzed (20 mL), 50,000 ± 6956 AD-SVFs/mL were obtained in SG-1; 30,250 ± 5100 AD-SVFs/mL in SG-2; 33.333 ± 5650 AD-SVFs/mL in SG-3, while 500 AD-SVFs/mL were obtained in CG. In patients treated with A-FG enhanced with AD-SVFs obtained by automatic enzymatic digestion, a 63% ± 6.2% maintenance of fat volume restoring after 1 year was observed compared with 52% ± 4.6% using centrifugation with filtration, 39% ± 4.4% using only centrifugation (Coleman), and 60% ± 5.0% using only filtration. CONCLUSIONS: In vitro AD-SVFs cell analysis indicated that filtration was the most efficient system-between mechanical digestion procedures-thanks to the highest amount of cells obtained with fewer cell structure damage, producing in vivo, the most volume maintenance after 1 year. Enzymatic digestion produced the best number of AD-SVFs and the best fat volume maintenance. 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 http://www.springer.com/00266 .

CD146 expression regulates osteochondrogenic differentiation of human adipose-derived stem cells.

Tissue engineering aims to develop innovative approaches to repair tissue defects. The use of adipose-derived stem cells (ASCs) in tissue regeneration was extensively investigated for osteochondrogenesis. Among the ASC population, ASCs expressing the CD146 were demonstrated to be multipotent and considered as perivascular stem cells, although the functional role of CD146 expression in these cells remains unclear. Herein, we investigated the influence of CD146 expression on osteochondrogenic differentiation of ASCs. Our results showed that, in two-dimensional culture systems, sorted CD146+ ASCs proliferated less and displayed higher adipogenic and chondrogenic potential than CD146- ASCs. The latter demonstrated a higher osteogenic capacity. Besides this, CD146+ ASCs in three-dimensional Matrigel/endothelial growth medium (EGM) cultures showed the highest angiogenic capability. When cultured in three-dimensional collagen scaffolds, CD146+ ASCs showed a spontaneous chondrogenic differentiation, further enhanced by the EGM medium's addition. Finally, CD146- ASCs seeded on hexafluoroisopropanol silk scaffolds displayed a greater spontaneous osteogenetic capacity. Altogether, these findings demonstrated a functional and relevant influence of CD146 expression in ASC properties and osteochondrogenic commitment. Exploiting the combination of specific differentiation properties of ASC subpopulations and appropriate culture systems could represent a promising strategy to improve the efficacy of new regenerative therapies.

Cartilage Remodeling in Nasal Tip Rhinoplasty Using "Lateral Crural Steal" and "Tongue in Groove" Strategies: A Randomized Controlled Trial.

BACKGROUND: The authors present their experience using "Lateral Crural Steal" (LCS) and "Tongue in Groove" (TING) techniques in nasal tip remodeling. OBJECTIVES: The paper aimed to evaluate the efficacy and safety of the use of LCS and TING in nasal tip remodeling for aesthetic improvement. METHODS: A randomized controlled trial was conducted. Thirty-five patients affected by low and boxy nasal tips were treated with LCS and TINGs (study group [SG]), comparing results with the control group (CG) (n = 30) treated with cartilage grafts. The preoperative analysis has been performed with an accurate clinical evaluation, a photographic assessment, and a computed tomography scan. Postoperative follow-up took place at 1, 2, and 4 weeks, 3, 6, and 12 months, and then annually. RESULTS: A total of 82.9% (n = 29) of SG patients showed excellent cosmetic and functional results after 1 year compared with the CG patients, who showed the same results in only 40% (n = 12) of cases. The tip projection maintenance and contour restoring in the SG were higher than that in the CG ( P  < 0.0001 versus CG). CONCLUSIONS: The use of LCS and TING was safe and effective in this series of cases performed.

Nasal Tip Remodeling Using Autologous Cartilage Grafts: Systematic Review.

OBJECTIVE: The objective of this study was to perform a systematic review of the literature to assess the clinical outcomes and safety profile of autologous cartilage grafts (A-CGs) in nasal tip remodeling (NTR). METHODS: The protocol was developed following the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses-Protocols guidelines. A multistep search of the PubMed, MEDLINE, Embase, Scopus database, and Cochrane databases has been performed to identify papers on A-CGs use in NTR. Of the 253 articles initially identified, only 39 articles providing either retrospective (n = 35) or prospective (n = 4) data about outcomes, descriptions, and complications of the A-CGs use in NTR were selected. Of these, 3 articles focused on alloplastic grafts were excluded. RESULTS: The nasal septum, concha, and ribs have been the main donor sites to build A-CGs to be used in NTR. Septal cartilage turned out to a specific and versatile, useful for many types of grafts tools, presenting a low rate of resorption, extrusion, and warping. Auricular concha cartilage has been used to correct both the internal and external nasal valve collapse, whereas rib chondral grafts have been used to improve the structural support when septal cartilage was not available. Crushed cartilage, minced cartilage, and diced cartilage have been used in noses with thinner soft tissues. CONCLUSIONS: Eighty percent of the analyzed studies focused on the description of the adopted surgical technique and A-CGs procedures of preparation, displaying encouraging aesthetic and functional outcomes with generally low levels of complications. Collected data confirmed the safety and efficacy of A-CGs-related interventions in NTR without major side effects.

Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives.

Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia-reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.

Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives.

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.

Endothelial Progenitor Cell-Derived Extracellular Vesicles: Potential Therapeutic Application in Tissue Repair and Regeneration.

Recently, many studies investigated the role of a specific type of stem cell named the endothelial progenitor cell (EPC) in tissue regeneration and repair. EPCs represent a heterogeneous population of mononuclear cells resident in the adult bone marrow. EPCs can migrate and differentiate in injured sites or act in a paracrine way. Among the EPCs' secretome, extracellular vesicles (EVs) gained relevance due to their possible use for cell-free biological therapy. They are more biocompatible, less immunogenic, and present a lower oncological risk compared to cell-based options. EVs can efficiently pass the pulmonary filter and deliver to target tissues different molecules, such as micro-RNA, growth factors, cytokines, chemokines, and non-coding RNAs. Their effects are often analogous to their cellular counterparts, and EPC-derived EVs have been tested in vitro and on animal models to treat several medical conditions, including ischemic stroke, myocardial infarction, diabetes, and acute kidney injury. EPC-derived EVs have also been studied for bone, brain, and lung regeneration and as carriers for drug delivery. This review will discuss the pre-clinical evidence regarding EPC-derived EVs in the different disease models and regenerative settings. Moreover, we will discuss the translation of their use into clinical practice and the possible limitations of this process.

Correction of cicatricial ectropion using non-ablative fractional laser resurfacing.

Lower eyelid malposition is the most frequent and severe complication after blepharoplasty and ectropion is observed in 1% of patients after surgery. This article describes a non-surgical method to treat lower eyelid cicatricial ectropion using a non-ablative laser as an alternative to surgery. Twelve patients with unilateral or bilateral lower lid cicatricial ectropion, following surgery or trauma, underwent laser therapy from 2012 to 2016. Laser therapy was performed with a fractional non-ablative laser emitting at a wavelength of 1540 nm. Ten patients had a full correction of their ectropion and two patients had a partial recovery after laser therapy at 6-month follow-up visit. No serious adverse events were reported. Non-ablative fractional laser resurfacing can successfully treat cicatricial ectropion by remodeling the periocular scar tissue and improving the scar texture, and as such may be considered as a valuable alternative to surgery in selected patients.

Incidence and Prevention of Cicatricial Scleral Show in the Subciliary Access in Patients With Orbital Fractures.

: Orbital fractures can involve floor, lateral and medial wall. Surgical access depends on fracture's severity, ocular trauma and patient's age. Subciliary, subtarsal, infraorbital or transconjunctival approaches are the main access to the orbit. Surgical interventions in the eyelid may induce scar tissue formation and, consequently, the cicatricial scleral show. The authors present a study with the aim to evaluate the incidence of cicatricial scleral show in patients treated for orbital fractures with or without simultaneous Tarsal Sling Canthopexy in our Plastic Surgery Department. METHODS: The authors evaluated 50 patients divided in 2 groups: Group 1, subciliary approach and reconstruction of orbital floor without simultaneous Canthopexy Tarsal Sling; Group 2: reconstruction of orbital floor through subciliary approach with simultaneous Canthopexy Tarsal Sling. RESULTS: Patients, who underwent Canthopexy Tarsal Sling, did not have any scleral show. Instead patients, who did not undergo this prevention technique, had scleral show even if a minor entity. DISCUSSION: Although there was no muscle or skin removed, in our procedure, but only cutaneous incision, scleral show can appear as a complication. Canthal ligament and tarsus' elasticity influence the incidence of post-surgical scleral show, which is more frequent in elderly patients. Therefore, the authors suggest to prevent it routinely with Tarsal Sling Canthopexy. CONCLUSION: Canthopexy Tarsal Sling is procedure that stretch tarsal structure and it may help to prevent scleral show.

Adipose-Derived Stem Cells in Cancer Progression: New Perspectives and Opportunities.

Growing importance has been attributed to interactions between tumors, the stromal microenvironment and adult mesenchymal stem cells. Adipose-derived stem cells (ASCs) are routinely employed in regenerative medicine and in autologous fat transfer procedures. To date, clinical trials have failed to demonstrate the potential pro-oncogenic role of ASC enrichment. Nevertheless, some pre-clinical studies from in vitro and in vivo models have suggested that ASCs act as a potential tumor promoter for different cancer cell types, and support tumor progression and invasiveness through the activation of several intracellular signals. Interaction with the tumor microenvironment and extracellular matrix remodeling, the exosomal release of pro-oncogenic factors as well as the induction of epithelial-mesenchymal transitions are the most investigated mechanisms. Moreover, ASCs have also demonstrated an elective tumor homing capacity and this tumor-targeting capacity makes them a suitable carrier for anti-cancer drug delivery. New genetic and applied nanotechnologies may help to design promising anti-cancer cell-based approaches through the release of loaded intracellular nanoparticles. These new anti-cancer therapies can more effectively target tumor cells, reaching higher local concentrations even in pharmacological sanctuaries, and thus minimizing systemic adverse drug effects. The potential interplay between ASCs and tumors and potential ASCs-based therapeutic approaches are discussed.

Concise Review: The Use of Adipose-Derived Stromal Vascular Fraction Cells and Platelet Rich Plasma in Regenerative Plastic Surgery.

Tissue engineering has emerged at the intersection of numerous disciplines to meet a global clinical need for technologies to promote the regeneration of tissues. Recently, many authors have focused their attention on mesenchymal stem/stromal cells (MSCs) for their capacity to differentiate into many cell lineages. The most widely studied cell types are bone marrow mesenchymal stem cells and adipose-derived stem cells (ASCs), which display similar results. Biomaterials, cells, and growth factors are needed to design a regenerative plastic surgery approach in the treatment of organ and tissue defects, but not all tissues are created equal. The aim of this article is to describe the advances in tissue engineering through the use of ASCs, platelet rich plasma, and biomaterials to enable regeneration of damaged complex tissue. Stem Cells 2017;35:117-134.

Long-term follow-up comparison of two different bi-layer dermal substitutes in tissue regeneration: Clinical outcomes and histological findings.

Double layer dermal substitute (DS) consist of a 3-dimensional collagen structures and a superficial silicon layer that are positioned within the defect provide to promote tissue regeneration in skin wounds. DS often have unique physical characteristics due to differences in manufacturing techniques. The aim of this study is the clinical and histological comparison of Nevelia and Integra double layer DSs in patients with post-traumatic injury wounds. Thirty patients with post-traumatic wounds localised on the inferior limbs were randomised in 2 groups Nevelia or Integra, followed by autologous dermal epidermal graft (DEG). Clinical results were evaluated through the healing time; Manchester Scar Scale (MSS) and Visual Analog Scale (VAS) at 1, 2, and 3 weeks and after 1 and 3 years. Histological and immunohistochemical evaluation were performed at 0, 2, and 3 weeks. The difference in healing time between groups (P = .467, log-rank test), pain and self-estimation was not statistically significant after 35, 42, and 49 days and at 1-year follow up. Histological data showed evident healing of wound after 2 weeks compared with preoperative with both DSs. At 3 weeks reepithelialisation and dermal regeneration were evident with both substitutes; however Nevelia showed early regenerative properties in terms of epidermal proliferation and dermal renewal compared with Integra. Nevelia showed also a more evident angiogenesis vs Integra evaluated as α-SMA immunohistochemistry. Differences in the MSS score were statistically significant at 3 years follow up in favour of Nevelia group (P = .001). At long-term follow up, Nevelia showed a better clinical outcome measured as MSS score vs Integra measured as MSS. Histological and immunohistochemistry data showed that Nevelia allows faster neoangiogenesis and tissue regeneration with neoformed tissue architecture closer to the physiology of the skin.

Treatment of the Crooked Nose: The Final Steps to Perfection.

Perfection is sometimes approached in treatment of the crooked nose today but not fully achieved due to the continued existence of flaws. While the traditional surgical algorithm envisages the use of 2 series of procedures to straighten the nasal bones and cartilaginous septum, the addition of a third appears very useful with a view to obtaining truly excellent results, above all in the case of marked deviation. The authors present their experience in the use of certain procedures designed to correct asymmetry of the upper lateral and lower lateral cartilages, as well as the soft covering tissues where necessary.A retrospective study was carried out on 105 patients treated for crooked nose over a 3-year period, 90% of the patients being due to trauma and the remaining 10% to congenital malformation. All the patients involved severe deviation of the nasal pyramid.The mean follow-up period was 18 months (range: 8-36 months). The use of these additional surgical procedures made it possible to obtain excellent final results in 83 (97.6%) patients with crooked nose of traumatic origin and in 17 (85%) patients with crooked nose due to congenital malformation. No major complication was registered, although 3 patients did present minor complications not connected with the nasal deviation.In conclusion, more modern approach to correction of the crooked nose should involve not only realignment of the osteocartilaginous axis but also treatment of the neighboring structures.

Evaluation of Not-Activated and Activated PRP in Hair Loss Treatment: Role of Growth Factor and Cytokine Concentrations Obtained by Different Collection Systems.

Platelet rich plasma (PRP) was tested as a potential therapy for androgenetic alopecia (AGA) through two different clinical protocols in which one population (18 participants) received half-head treatment with autologous non-activated PRP (A-PRP) produced by CPunT Preparation System (Biomed Device, Modena, Italy) and the other half-head with placebo, and a second separated population in which all participants (n = 6, 3 participants per group) received treatment with calcium-activated PRP (AA-PRP) produced from one of two different PRP collection devices (Regen Blood Cell Therapy or Arthrex Angel System). For the A-PRP study, three treatments were administered over 30-day intervals. Trichoscan analysis of patients, three months post-treatment, showed a clinical improvement in the number of hairs in the target area (36 ± 3 hairs) and in total hair density (65±  5 hair cm2), whereas negligible improvements in hair count (1.1±  1.4 hairs) and density (1.9 ± 10.2 hair cm2) were seen in the region of the scalp that received placebo. Microscopic evaluation conducted two weeks after treatment showed also an increase in epidermal thickness, Ki67+ keratinocytes, and in the number of follicles. The AA-PRP treatment groups received a singular set of injections, and six months after the treatments were administered, notable differences in clinical outcomes were obtained from the two PRP collection devices (+90 ± 6 hair cm2 versus -73 ± 30 hair cm2 hair densities, Regen versus Arthrex). Growth factor concentrations in AA-PRP prepared from the two collection devices did not differ significantly upon calcium activation.