Mikael Hivelin

The world's experience with facial transplantation: What have we learned thus far?

The objective of this review article is to summarize the published details and media citations for all seven face transplants performed to date to point out deficiencies in those reports so as to provide the basis for examining where the field of face transplantation stands, and to act as a stimulus to enhance the quality of future reports and functional outcomes. Overall long-term function of facial alloflaps has been reported satisfactorily in all seven cases. Sensory recovery ranges between 3 and 6 months, and acceptable motor recovery ranges between 9 and 12 months. The risks and benefits of facial composite tissue allotransplantation, which involves mandatory lifelong immunosuppression analogous to kidney transplants, should be deliberated by each institution’s multidisciplinary face transplant team. Face transplantation has been shown thus far to be a viable option in some patients suffering severe facial deficits which are not amenable to modern-day reconstructive technique.

Extracorporeal photopheresis: from solid organs to face transplantation.

Composite tissue allotransplantations (CTA), were introduced with the first successful hand transplantation and are now a part of reconstructive surgery armamentarium. These reconstructive procedures for non life-threatening indications remain rare due to adverse effects of the associated lifelong immunosuppressive therapy. Indeed, despite recent progress, immunosuppressive therapies remain non-specific to the type of donor and still bear significant risks of serious side effects. Extracorporeal photopheresis (ECP), also called photochemotherapy, has been introduced in the composite tissue allotransplantation field as a part of acute rejection treatment in face transplantations. ECP has been performed after solid organ transplantations as a supportive therapy for acute rejection episodes. It has also been used to treat graft versus host diseases, which can occur after bone marrow or stem cell transplantations. ECP is also used to treat dermatologic diseases, such as cutaneous T-cell lymphoma, or autoimmune diseases, such as scleroderma or pemphigus vulgaris. The principle of ECP is to induce leucocyte apoptosis with UVA radiation after their presentation by psoralens. These leucocytes are immediately re-infused into the patient, where they undergo early apoptosis. Following apoptosis, the leucocytes are engulfed by macrophage or other antigen-presenting cells, such as immature dendritic cells, in an anti-inflammatory cytokine environment. The anti-inflammatory cytokine secretion pattern, with a switch from TH1 to TH2 for CD4+ lymphocytes, and the engulfment by immature cells without co-stimulatory molecules induces anergy, by deleting effector T-cells that responded to the presented antigens. An increase in regulatory T-cells (T-regs) is also induced after ECP and may contribute to allograft acceptance by the recipient. ECP has already been used for the great majority of solid organ transplantations to cure acute rejection episodes or in an attempt to prevent or cure chronic rejections, such as bronchitis obliterans, which occurs after lung transplantation. Considering composite tissue allotransplantations, ECP was used in two face transplantations after the occurrence of second rejection episodes triggered by viral infections. ECP therapy, associated with maintenance immunosuppressive therapy and doses of methylprednisolone, and the control of viral infection, succeeded to reverse the rejection process without the development of other side effects. Despite the fact that the mechanism of action of ECP has not been fully elucidated, this therapy could be a useful supportive therapy during the treatment of acute rejection episodes in composite tissue allotransplantations. In this review, we introduce the interest of ECP implementation in CTA in face allotransplantations.

Ultrasound-guided bilateral transversus abdominis plane block for postoperative analgesia after breast reconstruction by DIEP flap.

Background: Autologous breast reconstruction by deep inferior epigastric perforator (DIEP) flap provides higher postoperative pain at the abdominal donor site than at the thoracic one. The authors evaluated the analgesic efficacy of ultrasound-guided transverse abdominis plane block for postoperative analgesia after immediate breast reconstruction by DIEP flap. Methods: The authors conducted an open prospective study of 30 consecutive women undergoing immediate DIEP flap breast reconstruction after modified radical mastectomy for cancer. The last 15 patients received a bilateral ultrasound-guided block with 1.5 mg/kg ropivacaine on each side after DIEP flap harvesting, under general anesthesia. All patients received postoperative acetaminophen and patient-controlled intravenous morphine and were assessed for morphine use, satisfaction with pain relief, and adverse effects. Results: Morphine requirements were significantly lower in the block group than in the control group for the 0- to 12-hour (17.7 mg versus 22.7 mg, p = 0.0047) and 12- to 24-hour (14.2 mg versus 17.4 mg, p = 0.01) intervals but not for the 24- to 36-hour (11.3 mg versus 12.2 mg, p = 0.30) and 36- to 48-hour (8.6 mg versus 8.4 mg, p = 0.65) intervals. Cumulative morphine use was lower in the block group than in the control group for the first 24 hours (32.0 mg versus 40.2 mg, p = 0.0057) and the first 48 hours (51.7 mg versus 60.5 mg, p = 0.03). There was no complication attributable to the block, with an average follow-up of 9 months. Conclusions: Bilateral ultrasound-guided transversus abdominis plane block after breast reconstruction by DIEP flap reduces the interval and cumulative morphine requirements for the first 24 and 48 hours, respectively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. Figure. No caption available.

The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis

Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies. Experimental Design: The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial–mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines. Results: The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active β-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann–mesenchymal transition. Conclusion: We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis. Clin Cancer Res; 20(2); 358–71. ©2013 AACR.

Face transplantation program in France: a cost analysis of five patients.

Background Among 18 face transplantations (FTs) performed worldwide, seven were performed at the Henri Mondor Hospital, Paris, France. Their feasibility and risk-benefit ratios have been reported, whereas this study analyzed the costs of FT for our first five patients. Materials and Methods The first five FT patients transplanted at the Henri Mondor Hospital presented disfigurements due to neurofibromatosis, severe burns, or ballistic trauma and had no relevant comorbidity. All were socially isolated and unemployed. We analyzed the costs of preoperative investigations, operative procedures, and hospitalization for each patient. A public research program (PHRC) financed the procedures, and the clinical research department refunded each FT’s cost. To allow comparisons between health care systems, the cost of FT was compared with the mean costs of heart, liver, and kidney transplantations performed at the same institution. Results If all the five patients survived the FT procedure, one patient died during subsequent revisions procedures for sepsis. The overall costs for the operation and its subsequent hospitalization for each patient ranged from (20AC)103,108 to (20AC)170,071, depending on the transplant required, the technical pitfalls, the outcomes, and mainly postoperative intensive cares. Conclusions In our institution, the transplantation of a face led to higher costs than heart or any other solid organ and represented twice the costs faced for a liver transplantation. FT is currently performed in a research setting, and cost might decrease with teams’ experiences, which may shorten postoperative intensive care and overall hospital stays.

Restoration of the donor after face graft procurement for allotransplantation: report on the technique and outcomes of seven cases.

Background: After organ retrieval, restoration of the donor is a legal and ethical necessity; this is particularly true in facial transplantation. However, very few data are available regarding this procedure. Methods: This article reviews the seven facial masks produced during seven consecutive face transplants carried out at Henri Mondor Hospital in Paris, France. The time of production, morphologic outcome, and donor family feedback were recorded. Technical tips and pitfalls are also discussed. Results: Recording an impression of the donors face with alginate required less than 25 minutes and, in all cases, the production of a resin mask was completed before the surgical harvesting was finished. Although all morphologic results were satisfactory or very satisfactory, the best outcomes were achieved using a total face mask, avoiding color discrepancies. Family feedback was positive, and none of the funeral ceremonies was disturbed by the procedure. Conclusions: The production of a full-face resin mask is a reliable and reproducible technique. This procedure restores donor integrity and gives a very satisfactory morphologic and aesthetic outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The use of lipofilling to treat congenital hypoplastic breast anomalies: preliminary experiences.

BackgroundTreatment options for congenital hypoplastic breast anomalies are often open, including radial scoring, parenchymal flaps, and insertion of expanders and implants. Drawbacks of open techniques involve scarring, the use of drains, and inpatient stays. The use of lipofilling to treat breast deformities is increasing, as more research is completed in this area. Patients and MethodsWe report a retrospective study of 10 patients below the age of 20 following autologous fat transfer between January 1, 2003 and January 1, 2004. (2 Poland syndrome, 3 bilateral tuberous breast, and 5 unilateral micromastia). Age, cup size, the number of sessions, time interval between each session, volumes injected, and complications were recorded. Postoperative mammography, ultrasonography, and MRI were assessed by a specialized radiologist. Patients answered a questionnaire 1 year after the procedure. ResultsMean follow-up was 68 months (60–77 months) and mean age was 17.5 years (15–20 years). Mean number of fat injection sessions was 2 (1–4) and mean volume injected 285 mL per breast (200–500 mL). The time interval between each session was 5 months (3–6 months). Cup size remained unchanged after at least 5 years of follow-up. One case underwent a contralateral breast reduction. The cosmetic results considered satisfactory in almost all the patients after 1 year of follow-up. None of our patients complained of scars or defects at the donor site. All breasts imaging were normal except 1 patient with oil cysts. ConclusionOur preliminary results using lipofilling to treat young patients with breast hypoplasia with lipofilling are very encouraging. The authors believe it is an alternative of choice for the correction of the young woman’s breast deformities if the avoidance of scarring is preferred.

Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive “active-site” mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.

Split-Thickness Skin Graft Harvested From the Scalp for the Coverage of Extensive Temple or Forehead Defects in Elderly Patients

OBJECTIVE To review our experience of facial reconstruction with split-thickness skin grafts (STSGs) harvested from the scalp. METHODS We included all patients undergoing STSG harvested from the scalp for the reconstruction of extensive forehead or temple defects after cancer resection. We recorded the size of resection before surgery and after healing, and we calculated the resulting contraction rate. Time of healing and occurrence of complication were also recorded. RESULTS Forty patients were included. Their mean age was 87 years, and the mean size of resection was 26 cm(2). The duration of healing at the donor site was shorter than 12 days, and pain levels were low. The rate of contraction at the recipient site was 11% after healing. Good morphologic outcomes were reported by both patients and surgeon. CONCLUSION Extensive forehead and temple defects can be covered in this way with a low morbidity; rapid, painless healing; and a high success rate, making this procedure particularly suitable for elderly patients.

Low Rates of Blood Transfusion in Elective Resections of Neurofibromas in a Cohort Study: Neurofibroma Length as a Predictor of Transfusion Requirement.

Background: Neurofibromas in neurofibromatosis type 1 induce aesthetic and functional morbidity. Perioperative bleeding has been reported as an obstacle to neurofibroma resections. The authors studied the requirement for blood transfusion during surgical treatment of neurofibromatosis type 1. Methods: Six hundred twenty-two procedures performed on 390 neurofibromatosis type 1 patients at the national referral center from 1995 to 2011 were analyzed in two chronologic sets of patients: set 1 (February of 1995 to September of 2007), in which only one surgeon operated; and set 2 (October of 2007 to January of 2011), in which two additional surgeons were involved. Malignant peripheral nerve sheath tumors, reconstructive procedures, and spontaneous hemorrhages were excluded from the analysis. Age, sex, preoperative hemoglobin concentration, location, length, estimated volume and histologic features of the largest neurofibroma (cumulative values for multiple neurofibromas), and procedure duration were studied as potential predictors of blood transfusion that were measured in terms of units of packed red blood cells. Results: Seventy reconstructive procedures, two cases of spontaneous hemorrhage, and 32 malignant peripheral nerve sheath tumor resections were excluded. Among 516 procedures (318 and 198 in sets 1 and 2, respectively), 17 (2.7 percent) required blood transfusions. The requirement for transfusion was associated with neurofibroma length in both sets, with an optimal cutoff value of 13 cm in both sets. Conclusions: Contrary to the literature, the requirement for blood transfusion was found to be low (2.7 percent of the cases) during elective resection of neurofibromas in neurofibromatosis type 1. Elective resections of benign neurofibromas less than 13 cm in length were not associated with a requirement for blood transfusion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.