Avant-propos.

Hard-to-heal wounds are a problem for both patients and caregivers. The biofi lm is one of the local factors of delayed healing. Wound hygiene carried out in 4 steps (cleansing, debridement, refashion - care of the edges, and dressing) constitutes the basis of proactive and curative anti-biofi lm strategies.

IL-34 deficiency impairs FOXP3+ Treg function in a model of autoimmune colitis and decreases immune tolerance homeostasis.

BACKGROUND: Immune homeostasis requires fully functional Tregs with a stable phenotype to control autoimmunity. Although IL-34 is a cytokine first described as mainly involved in monocyte cell survival and differentiation, we recently described its expression by CD8+ Tregs in a rat model of transplantation tolerance and by activated FOXP3+ CD4+ and CD8+ Tregs in human healthy individuals. However, its role in autoimmunity and potential in human diseases remains to be determined. METHODS: We generated Il34-/- rats and using both Il34-/- rats and mice, we investigated their phenotype under inflammatory conditions. Using Il34-/- rats, we further analyzed the impact of the absence of expression of IL-34 for CD4+ Tregs suppressive function. We investigated the potential of IL-34 in human disease to prevent xenogeneic GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, taking advantage of a biocollection, we investigated the correlation between presence of IL-34 in the serum and kidney transplant rejection. RESULTS: Here we report that the absence of expression of IL-34 in Il34-/- rats and mice leads to an unstable immune phenotype, with production of multiple auto-antibodies, exacerbated under inflammatory conditions with increased susceptibility to DSS- and TNBS-colitis in Il34-/- animals. Moreover, we revealed the striking inability of Il34-/- CD4+ Tregs to protect Il2rg-/- rats from a wasting disease induced by transfer of pathogenic cells, in contrast to Il34+/+ CD4+ Tregs. We also showed that IL-34 treatment delayed EAE in mice as well as GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, we show that presence of IL-34 in the serum is associated with a longer rejection-free period in kidney transplanted patients. CONCLUSION: Altogether, our data emphasize on the crucial necessity of IL-34 for immune homeostasis and for CD4+ Tregs suppressive function. Our data also shows the therapeutic potential of IL-34 in human transplantation and auto-immunity. HIGHLIGHTS: -Absence of expression of IL-34 in Il34-/- rats and mice leads to an unstable immune phenotype, with a production of multiple auto-antibodies and exacerbated immune pathology under inflammatory conditions. -Il34-/- CD4+ Tregs are unable to protect Il2rg-/- rats from colitis induced by transfer of pathogenic cells. -IL-34 treatment delayed EAE in mice, as well as acute GVHD and human skin allograft rejection in immune-humanized immunodeficient NSG mice.

Preliminary Results of the "Capasquelet" Technique for Managing Femoral Bone Defects-Combining a Masquelet Induced Membrane and Capanna Vascularized Fibula with an Allograft.

We describe the preliminary results of a novel two-stage reconstruction technique for extended femoral bone defects using an allograft in accordance with the Capanna technique with an embedded vascularized fibula graft in an induced membrane according to the Masquelet technique. We performed what we refer to as "Capasquelet" surgery in femoral diaphyseal bone loss of at least 10 cm. Four patients were operated on using this technique: two tumors and two traumatic bone defects in a septic context with a minimum follow up of one year. Consolidation on both sides, when achieved, occurred at 5.5 months (4-7), with full weight-bearing at 11 weeks (8-12). The functional scores were satisfactory with an EQ5D of 63.3 (45-75). The time to bone union and early weight-bearing with this combined technique are promising compared to the literature. The osteoinductive role of the induced membrane could play a positive role in the evolution of the graft. Longer follow up and a larger cohort are needed to better assess the implications. Nonetheless, this two-stage technique appears to have ample promise, especially in a septic context or in adjuvant radiotherapy in an oncological context.

Lessons Learned From Twenty-Eight Cases of Burns Following Breast Reconstruction: An Underestimated Complication Requiring Inclusion in Consent Information.

BACKGROUND: There has over recent years been a constant increase in annual breast reconstruction figures. Although reports indicate that burns following breast reconstruction are a rare occurrence, there has nevertheless been a relative increase in cases. The key underlying causes of this type of condition remain unknown. OBJECTIVES: The authors launched a new study on the demographic characteristics of burns in the breast reconstruction population with the inclusion of up-to-date data to assess cases and contributing factors. METHODS: The study was a multicenter retrospective review of patients who underwent any type of breast reconstruction and subsequently sustained burn injuries. RESULTS: Twenty-eight cases of burn injury following breast reconstruction were documented; 6 involved autologous flaps and 22 involved implants. Nine of the 10 implant exposure cases had previous history of radiotherapy, but there was no statistically significant difference between previous radiotherapy history and implant exposure (P = 0.32). Of the 13 cases sustaining full-thickness burns, a large number included implant-based reconstruction (n = 12, 92%), although no statistically significant difference was observed between type of reconstruction and incidence of full-thickness burns (P = 0.17). CONCLUSIONS: Each patient undergoing breast reconstruction should be advised of the potential risks and instructed to avoid significant heat exposure and steer clear of dark-colored bathing suits. At the time of writing, this information has yet to be included in the vast majority of surgery-related informed consent documents.

A Novel Absorbable Stapler Provides Patient-Reported Outcomes and Cost-Effectiveness Noninferior to Subcuticular Skin Closure: A Prospective, Single-Blind, Randomized Clinical Trial.

BACKGROUND: Deep dermal suturing is critical for scar quality outcomes. The authors evaluated a new, fast medical device for dermal suturing, with the hypothesis of noninferiority with regard to clinical scar and cost-effectiveness. METHODS: A prospective, patient-blind, randomized, multicenter noninferiority study in 26 French hospitals was conducted. Patients were randomized 1:1 to suturing with conventional thread or a semiautomatic stapler. The Patient Scar Assessment Scale was rated at 3 months for primary endpoint effectiveness. Secondary endpoints were cost-effectiveness of the two suturing methods, prevalence of complications, suturing/operating time, Observer Scar Assessment Scale and Patient Scar Assessment Scale score, scar aesthetic quality 18 months after surgery, and occupational exposure to blood during surgery. RESULTS: Six hundred sixty-four patients were enrolled, 660 were randomized, and 649 constituted the full analysis (stapler arm, n = 324; needle arm, n = 325). Primary endpoint Patient Scar Assessment Scale score in the stapler arm was not inferior to that in the needle arm at 3 months or after 18 months. The mean operating time was 180 minutes in the stapler arm and 179 minutes in the needle arm (p = not significant). The mean suturing time was significantly lower in the stapler arm (p < 0.001). There were seven occupational exposures to blood in the needle arm and one in the stapler arm. The two arms did not differ significantly in terms of complications (p = 0.41). The additional cost of using the device was &OV0556;51.57 for the complete-case population. CONCLUSION: Wound healing outcome was no worse than with conventional suturing using a semiautomatic stapler and associated with less occupational exposure to blood. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

ALGINATE versus NPWT in the Preparation of Surgical Excisions for an STSG: ATEC Trial.

A calcium alginate dressing (ALGINATE) and negative pressure wound therapy (NPWT) are frequently used to treat wounds which heal by secondary intention. This trial compared the healing efficacy and safety of these 2 treatments. METHODS: This randomized, non-inferiority trial enrolled patients who underwent skin excision (>30 cm2), which was left open to heal by secondary intention. They received ALGINATE or NPWT by a centralized randomization. Follow-up was performed weekly until optimal granulation tissue was obtained. The primary outcome was time to obtain optimal granulation tissue for a split thickness skin graft take (non-inferiority margin: 4 days). Secondary outcomes were occurrence of adverse events (AEs) and impact of the treatments on the patient's daily life. RESULTS: ALGINATE and NPWT were applied to 47 and 48 patients, respectively. The mean time to optimal granulation was 19.98 days (95% CI, 17.7-22.3) with ALGINATE and 20.54 (95% CI, 17.6-23.5) with NPWT. Between group difference was -0.56 days (95% CI -4.22 to 3.10). The non-inferiority of ALGINATE versus NPWT was demonstrated. No AE related to the treatment occurred with ALGINATE versus 14 AEs with NPWT. There was no difference in the impact of the treatments on the patient's daily life. CONCLUSION: This trial demonstrates that ALGINATE has a similar healing efficacy to that of NPWT and that is markedly better with regard to patient safety.

Human CD8+ Tregs expressing a MHC-specific CAR display enhanced suppression of human skin rejection and GVHD in NSG mice.

Polyclonal CD8+CD45RClow/- Tregs are potent regulatory cells able to control solid organ transplantation rejection and even induce tolerance. However, donor major histocompatibility complex (MHC)-specific Tregs are more potent than polyclonal Tregs in suppressing T-cell responses and preventing acute as well as chronic rejection in rodent models. The difficulty of identifying disease-relevant antigens able to stimulate Tregs has reduced the possibility of obtaining antigen-specific Tregs. To bypass this requirement and gain the advantage of antigen specificity, and thus improve the therapeutic potential of CD8+ Tregs, we stably introduced a chimeric antigen receptor (CAR) derived from a HLA-A*02 antigen-specific antibody (A2-CAR) in human CD8+ Tregs and developed a clinically compatible protocol of transduction and expansion. We demonstrated that A2-CAR CD8+ Tregs were not phenotypically altered by the process, were specifically activated, and did not exhibit cytotoxic activity toward HLA-A*02+ kidney endothelial cells (ECs). We showed that A2-CAR CD8+ Tregs were more potent suppressors of immune responses induced by HLA-A*02 mismatch than control-CAR CD8+ Tregs, both in vitro and in vivo, in models of human skin graft rejection and graft-versus-host disease (GVHD) in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. We showed that integrity of human skin graft was preserved with A2-CAR CD8+ Tregs at least 100 days in vivo after administration, and that interaction between the A2-CAR CD8+ Tregs and HLA-A*02+ kidney ECs resulted in a fine-tuned and protolerogenic activation of the ECs without cytotoxicity. Together, our results demonstrated the relevance of the CAR engineering approach to develop antigen-specific CAR-CD8+ Tregs for clinical trials in transplantation, and potentially in other diseases.

CICAFAST: comparison of a biological dressing composed of fetal fibroblasts and keratinocytes on a split-thickness skin graft donor site versus a traditional dressing: a randomized controlled trial.

BACKGROUND: Wound repair is one of the most complex biological processes of human life. Allogeneic cell-based engineered skin substitutes provide off-the-shelf temporary wound coverage and act as biologically active dressings, releasing growth factors, cytokines and extracellular matrix components essential for proper wound healing. However, they are susceptible to immune rejection and this is their major weakness. Thanks to their low immunogenicity and high effectiveness in regeneration, fetal skin cells represent an attractive alternative to the commonly used autologous and allogeneic skin grafts. METHODS/DESIGN: We developed a new dressing comprising a collagen matrix seeded with a specific ratio of active fetal fibroblasts and keratinocytes. These produce a variety of healing growth factors and cytokines which will increase the speed of wound healing and induce an immunotolerant state, with a slight inflammatory reaction and a reduction in pain. The objective of this study is to demonstrate that the use of this biological dressing for wound healing at the split-thickness skin graft (STSG) donor site, reduces the time to healing, decreases other co-morbidities, such as pain, and improves the appearance of the scar. This investigation will be conducted as part of a randomized study comparing our new biological dressing with a conventional treatment in a single patient, thus avoiding the factors that may influence the healing of a graft donor site. DISCUSSION: This clinical trial should enable the development of a new strategy for STSG donor-wound healing based on a regenerative dressing. The pain experienced in the first few days of STSG healing is well known due to the exposure of sensory nerve endings. Reducing this pain will also reduce analgesic drug intake and the duration of sick leave. Our biological dressing will meet the essential need of surgeons to "re-crop" from existing donor sites, e.g., for thermal-burn patients. By accelerating healing, improving the appearance of the scar and reducing pain, we hope to improve the conditions of treatment for skin grafts. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03334656 . Registered on 7 November 2017.

Ten-Year Safety Data for Eurosilicone's Round and Anatomical Silicone Gel Breast Implants.

BACKGROUND: Although silicone breast implants have been available for over 60 years, their safety and efficacy continue to be assessed via long-term clinical and vigilance studies. Complications often associated with breast implant surgery include but are not limited to capsular contracture and rupture. OBJECTIVE: The authors investigate and evaluate the safety and performance of Eurosilicone's (Eurosilicone S.A.S, Apt Cedex, France) Cristalline Paragel breast implants at least 10 years postimplantation. METHODS: Nine hundred and ninety-five of Eurosilicone's textured mammary implants were implanted in 526 women undergoing primary (423 patients) and revision surgery (103 patients) at 17 centers throughout France. Complications were recorded at 3 months and annually thereafter for 10 years. Descriptive statistics were used and the Kaplan-Meier method was utilized to analyze key complications. RESULTS: Seventy-four women (98 implants) experienced capsular contracture across all cohorts. The Kaplan-Meier 10-year cumulative risk of capsular contracture (Baker Grade III/IV) per implant was 11.5% in the primary augmentation cohort and 25.2% in the primary reconstruction cohort. Sixteen implant ruptures were observed by surgeon examination giving a Kaplan-Meier risk of 3.8% per patient and 3.5% per implant. Surgical re-intervention (explantation/exchange) was reported 80 times resulting in a Kaplan-Meier cumulative risk of 13.3% and 31.6% for primary augmentation and primary reconstruction, respectively, per patient. Local complication rates including infection and seroma were low with risk rates of 0.6% and 0.2% by subject. CONCLUSIONS: This multicenter clinical study demonstrates the long-term safety and efficacy profile through 10 years for Eurosilicone round and anatomical silicone gel breast implants.

Ten years of myocutaneous flaps for pressure ulcers in patients with spinal lesions: Analysis of complications in the framework of a specialised medical-surgical pathway.

INTRODUCTION: The objective of the study is to analyse complications associated with surgery for pelvic pressure ulcers in terms of their frequency, nature and rate of surgical revisions. The secondary aims are to analyse the rate of recurrence, length of stay and time to healing, and to determine factors associated with complications and recurrence. METHODS: It is a single-centre, retrospective cohort study with a 10-year follow-up setting in Nantes University Hospital, France, a specialist centre for spinal cord injury (SCI). All patients who were admitted to the Neurological Physical Medicine and Rehabilitation (PMR) department for surgery (flap coverage) for pelvic pressure ulcers between 1st of January 2004 and 30th September 2014 were included. The main outcome measures were the rate of complications, rate of recurrence, length of stay and time to healing, as well as factors associated with complications and recurrence. RESULTS: One hundred and sixty-six patients underwent 252 flap procedures in 239 operations. The majority of patients had SCI (78.3%). The ulcer sites were mainly ischial (67%), sacral (20%) and trochanteric (12%). Gluteus maximus was used most often (75.3% of flaps) (ischial and sacral ulcers), followed by tensor fascia lata (16.2%) (trochanteric ulcers). The rate of complications that delayed return to wheelchair at 6 weeks was 34.5%. The factors associated with complications were more than one surgical ulcer and drainage time greater than 10 days. The rate of recurrence was 20.04%. The factors related to recurrence were young age, scoliosis and an oblique pelvis. CONCLUSIONS: Management within a specialised medical-surgical pathway limited post-operative complications and recurrences in this sample of subjects who mostly had SCI.

Generation of Immunodeficient Rats With Rag1 and Il2rg Gene Deletions and Human Tissue Grafting Models.

BACKGROUND: Immunodeficient mice are invaluable tools to analyze the long-term effects of potentially immunogenic molecules in the absence of adaptive immune responses. Nevertheless, there are models and experimental situations that would beneficiate of larger immunodeficient recipients. Rats are ideally suited to perform experiments in which larger size is needed and are still a small animal model suitable for rodent facilities. Additionally, rats reproduce certain human diseases better than mice, such as ankylosing spondylitis and Duchenne disease, and these disease models would greatly benefit from immunodeficient rats to test different immunogenic treatments. METHODS: We describe the generation of Il2rg-deficient rats and their crossing with previously described Rag1-deficient rats to generate double-mutant RRG animals. RESULTS: As compared with Rag1-deficient rats, Il2rg-deficient rats were more immunodeficient because they partially lacked not only T and B cells but also NK cells. RRG animals showed a more profound immunossuppressed phenotype because they displayed undetectable levels of T, B, and NK cells. Similarly, all immunoglobulin isotypes in sera were decreased in Rag1- or Il2rg-deficient rats and undetectable in Rats Rag1 and Il2rg (RRG) animals. Rag1- or Il2rg-deficient rats rejected allogeneic skin transplants and human tumors, whereas animals not only accepted allogeneic rat skin but also xenogeneic human tumors, skin, and hepatocytes. Immune humanization of RRG animals was unsuccessful. CONCLUSIONS: Thus, immunodeficient RRG animals are useful recipients for long-term studies in which immune responses could be an obstacle, including tissue humanization of different tissues.