Publications by authors named "Pierre Guerreschi"

33 Publications

Crouzon syndrome: posterior fossa volume studies in vestibular orientation.

Childs Nerv Syst 2021 Apr 27. Epub 2021 Apr 27.

Department of Plastic Surgery, Lille University Hospital, Lille, France.

Introduction: With the increasing possibilities of surgical treatment addressing the complex spectrum of defects in Crouzon syndrome (CS), it is of utmost importance to obtain accurate assessment of the malformation. Evaluating the volume of the posterior fossa is of great importance since many authors, considering that its volume is always decreased, favor posterior fossa enlargement as a first step in the treatment of CS.

Material And Methods: We studied CT scans of children with CS, which were vestibular-oriented (VO) in order to conform with physiological landmarks, and we measured intracranial volume by manual segmentation; these abnormal CT scans were superposed with VO 3D-CT scanners of age-matched controls. We studied the volume index of the posterior fossa for each CS patient defined as the ratio of its volume in CS patients with the normal for age calculated from normal controls.

Results: We studied the imaging of 41 children with CS and 70 control. Among CS patients, the volume of the posterior fossa was increased in 10, compared with control. We found closure of the sphenoidal synchondrosis was correlated with age and with the width of the posterior fossa, but not with its length nor with the posterior fossa volume index.

Conclusion: Segmentation on VO-CT scanner and superposition with CT scanners of normal controls is a powerful tool for the study of the impact of CS or other synostoses on volume and shape. We found that CS is more heterogeneous than previously thought, and surgical strategies should be adapted accordingly.
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http://dx.doi.org/10.1007/s00381-021-05186-9DOI Listing
April 2021

Morphological and surgical results in sagittal synostosis: early craniectomy versus later cranioplasty.

Childs Nerv Syst 2021 Apr 22. Epub 2021 Apr 22.

Department of Plastic Surgery, Lille University Hospital, Lille, France.

Background And Purpose: Morphological correction is one of the main aims of surgery for sagittal synostosis (SSO). Different surgical techniques have been developed; however, few studies have compared the different surgical protocols. The morphological outcome is poorly documented, because a consensual evaluation tool is lacking.

Material And Methods: We performed a prospective study of children operated for SSO in our institution. Children were operated whenever possible at 4 months for craniectomy; by default, children underwent cranioplasty at or after 9 months. The morphological outcome of all children was evaluated using traditional craniometry with head circumference (HC) and the cephalic index (CI), and with the Rotterdam scaphocephaly morphology score (RSMS), a total of semi-quantitative assessments of morphological hallmarks.

Results: Craniectomy was significantly associated with a shorter operation time and hospital stay, and a better impact on HC and CI measurements, compared with cranioplasty. The RSMS was markedly improved after surgery in both groups; however, we found no significant difference in improvement between the two groups. Although the transfusion rate and the prevalence of developmental delay were lower in the craniectomy group, and reoperations for calvarial lacunae or complex craniosynostosis occurred only this group, these differences were not significant.

Conclusions: Our results support early surgery with craniectomy whenever possible; however, cranioplasty at a later age is a very acceptable by-default indication. In addition to classical craniometry, morphological evaluation using the RSMS or a similar quantitative scale appears highly desirable for future studies.
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http://dx.doi.org/10.1007/s00381-021-05178-9DOI Listing
April 2021

Linear craniectomy for early posterior decompression in craniosynostoses: technique and results.

Childs Nerv Syst 2021 Mar 13. Epub 2021 Mar 13.

Department of Plastic Surgery, Lille University Hospital, Lille, France.

Introduction: Early decompressive posterior linear craniectomy (PLC) can be indicated in very young infants with complex multisuture synostosis, which often involve the lambdoid suture (LS). The literature data on the surgical technique and its results are scarce.

Material And Methods: Based on our experience with PLC during the last 10 years, we detail our surgical technique for PLC, the possible pitfalls, and complication avoidance.

Results: We review seven observations, 5 girls and 2 boys, 6 of these with identified mutations, operated for PLC at a mean age of 3.19 months (6 days to 6.1 months). One patient died of unexplained cardiac arrest on postoperative day two, the others had a favorable outcome with good development and no visual loss. Three of these required additional cranioplasty at a later age, one of these with craniofacial distraction.

Discussion: PLC can be a salvage operation in very young patients with complex synostosis involving the LS, and with proper preparation and careful technique, allows favorable outcome. The approach must be versatile in order to anticipate further surgeries in these complex, most often syndromic cases.
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http://dx.doi.org/10.1007/s00381-021-05117-8DOI Listing
March 2021

Effects of Two Melt Extrusion Based Additive Manufacturing Technologies and Common Sterilization Methods on the Properties of a Medical Grade PLGA Copolymer.

Polymers (Basel) 2021 Feb 14;13(4). Epub 2021 Feb 14.

U1008 Controlled Drug Delivery Systems and Biomaterials, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Lille (CHU Lille), University of Lille, F-59000 Lille, France.

Although bioabsorbable polymers have garnered increasing attention because of their potential in tissue engineering applications, to our knowledge there are only a few bioabsorbable 3D printed medical devices on the market thus far. In this study, we assessed the processability of medical grade Poly(lactic--glycolic) Acid (PLGA)85:15 via two additive manufacturing technologies: Fused Filament Fabrication (FFF) and Direct Pellet Printing (DPP) to highlight the least destructive technology towards PLGA. To quantify PLGA degradation, its molecular weight (gel permeation chromatography (GPC)) as well as its thermal properties (differential scanning calorimetry (DSC)) were evaluated at each processing step, including sterilization with conventional methods (ethylene oxide, gamma, and beta irradiation). Results show that 3D printing of PLGA on a DPP printer significantly decreased the number-average molecular weight () to the greatest extent (26% loss, < 0.0001) as it applies a longer residence time and higher shear stress compared to classic FFF (19% loss, < 0.0001). Among all sterilization methods tested, ethylene oxide seems to be the most appropriate, as it leads to no significant changes in PLGA properties. After sterilization, all samples were considered to be non-toxic, as cell viability was above 70% compared to the control, indicating that this manufacturing route could be used for the development of bioabsorbable medical devices. Based on our observations, we recommend using FFF printing and ethylene oxide sterilization to produce PLGA medical devices.
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http://dx.doi.org/10.3390/polym13040572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917935PMC
February 2021

Synostosis of the lambdoid suture: a spectrum.

Childs Nerv Syst 2021 Jan 6. Epub 2021 Jan 6.

Department of Plastic Surgery, Lille University Hospital, Lille, France.

Purpose: Lambdoid synostosis (LS) is a rare condition, which is either isolated; associated with sagittal synostosis, the "Mercedes-Benz" syndrome (MBS); or with synostosis of the coronal sutures (oxycephalic form). In addition, LS is part of the phenotype of a growing number of genetic diseases. The nosology, pathophysiology, and management are controversial. We decided to review our experience with LS.

Methods: We reviewed retrospectively pediatric cases of LS proved on CT-scanner, isolated or associated with other conditions, followed in our craniofacial center during the last 15 years, regarding clinical presentation, anatomical lesions, syndromic associations, surgical management, and outcome.

Results: We reviewed 48 cases: 6 isolated LS, 22 MBS, and 20 oxycephalic. A syndromic context was present in 72% (up to 80% of oxycephalic cases), and faciostenosis was present in 23%, mostly oxycephalic cases (40%). Transverse sinus agenesis was found in 61% of documented patients. A total of 31% of children had a dystocic birth, up to 45% of MBS. Decompressive craniectomy or cranioplasty was needed in a majority of patients, often young infants, while posterior fossa decompression was mostly performed in older children.

Conclusion: LS is rarely isolated and non syndromic; most cases are found in a wide spectrum of diseases, and LS is often associated with sagittal or coronal synostosis. Genetic evaluation is mandatory for LS; conversely, geneticists may require neurosurgical advice for LS in an increasing number of very rare diseases. The surgical management of LS should be tailored according to clinical presentation, age, and syndromic context.
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http://dx.doi.org/10.1007/s00381-020-05003-9DOI Listing
January 2021

How to improve donor skin availability: Pragmatic procedures to minimize the discard rate of cryopreserved allografts in skin banking.

Burns 2021 03 15;47(2):387-396. Epub 2020 Jul 15.

CHU Lille, Lille Tissue Bank, Biology Pathology Center, F-59000 Lille, France; Univ. Lille, CNRS, Inserm, Institut de Recherche contre le Cancer de Lille, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France. Electronic address:

Background: Microbial contamination of human skin allografts is a frequent cause of allograft discard. Our purpose was to evaluate the discard rate of skin bank contaminated allografts and specific procedures used to reduce allograft contamination without affecting safety.

Methods: We conducted at the Lille Tissue Bank a retrospective study of all deceased donors (n = 104) harvested from January 2018 to December 2018. Skin procurement was split into 3 zones: the back of the body and the two legs that were processed separately. It represented 433 cryopreserved skin allograft pouches of approximatively 500 cm² each. Donors were almost equally split between brain-dead (53%, 55/104) and cadaveric (47%, 49/104) donors.

Results: Out of all donors, 42 (40.5%) had at least one sampling zone with a positive microbiological test resulting in 106 (24%) contaminated skin pouches. The contamination rate did not vary according to the harvested zone or type of donor. Traumatic deaths showed significantly less contamination rates than other death types (p < 0.05). Contamination rate decreased with time spent in the antibiotic solution. The risk of having contaminated allografts was five-fold higher when the skin spent less than 96 h in the antibiotic cocktail (p < 0.05). According to our validation protocol, most donors (32/42, 76%) had skin allografts contaminated with bacteria (mainly Staphylococcus spp) compatible with clinical use. No recipient infection was recorded as a result of skin graft contaminated with saprophytic or non-pathogenic germs. By harvesting 3 separate zones per donor, the total surface area for clinical use increased by 53% for contaminated donors. Overall, the proportion of contamination-related discarded allografts was 3.2% (14/433 of pouches).

Conclusion: Few simple pragmatic measures (including skin incubation in the antibiotic bath for at least 96 h at 4 °C, splitting the skin harvesting areas to minimize the risk of cross-infection and clinical use of allografts contaminated with saprophytic and non-pathogenic germs) can reduce the discard rate of contaminated allografts without affecting clinical safety.
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http://dx.doi.org/10.1016/j.burns.2020.07.004DOI Listing
March 2021

Rationale for the design of 3D-printable bioresorbable tissue-engineering chambers to promote the growth of adipose tissue.

Sci Rep 2020 07 16;10(1):11779. Epub 2020 Jul 16.

Centre de Biologie Pathologie - Banque de Tissus, CHU Lille, 59000, Lille Cedex, France.

Tissue engineering chambers (TECs) bring great hope in regenerative medicine as they allow the growth of adipose tissue for soft tissue reconstruction. To date, a wide range of TEC prototypes are available with different conceptions and volumes. Here, we addressed the influence of TEC design on fat flap growth in vivo as well as the possibility of using bioresorbable polymers for optimum TEC conception. In rats, adipose tissue growth is quicker under perforated TEC printed in polylactic acid than non-perforated ones (growth difference 3 to 5 times greater within 90 days). Histological analysis reveals the presence of viable adipocytes under a moderate (less than 15% of the flap volume) fibrous capsule infiltrated with CD68 inflammatory cells. CD31-positive vascular cells are more abundant at the peripheral zone than in the central part of the fat flap. Cells in the TEC exhibit a specific metabolic profile of functional adipocytes identified by H-NMR. Regardless of the percentage of TEC porosity, the presence of a flat base allowed the growth of a larger fat volume (p < 0.05) as evidenced by MRI images. In pigs, bioresorbable TEC in poly[1,4-dioxane-2,5-dione] (polyglycolic acid) PURASORB PGS allows fat flap growth up to 75 000 mm at day 90, (corresponding to more than a 140% volume increase) while at the same time the TEC is largely resorbed. No systemic inflammatory response was observed. Histologically, the expansion of adipose tissue resulted mainly from an increase in the number of adipocytes rather than cell hypertrophy. Adipose tissue is surrounded by perfused blood vessels and encased in a thin fibrous connective tissue containing patches of CD163 inflammatory cells. Our large preclinical evaluation defined the appropriate design for 3D-printable bioresorbable TECs and thus opens perspectives for further clinical applications.
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http://dx.doi.org/10.1038/s41598-020-68776-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367309PMC
July 2020

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

Plast Reconstr Surg Glob Open 2020 Mar 27;8(3):e2691. Epub 2020 Mar 27.

Department of Plastic, Cosmetic and Reconstructive Surgery, Hospital Tenon, Paris, France.

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 cm), 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.
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http://dx.doi.org/10.1097/GOX.0000000000002691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253249PMC
March 2020

Sequelae of Facial Palsy: A Comprehensive Treatment.

Plast Reconstr Surg 2019 10;144(4):682e-692e

From the Plastic Surgery Department, University Hospital of Lille; the Competence Center for Clefts and CranioFacial Malformations; and the Plastic Surgery Department, Centre Hospitalier Privé Saint Martin.

Learning Objectives: After studying this article, the participant should be able to: 1. Identify the different types of facial paralysis sequelae and define the several medical and surgical techniques commonly available today. 2. Develop a surgical plan to restore symmetry of the face at rest and in dynamic expressions and manage the patient during smile rehabilitation after dynamic smile reanimation with regional or free muscle transfer. 3. Understand the different types of facial paralysis sequelae and know the several medical and surgical techniques commonly available today. 4. Establish a comprehensive treatment plan to restore symmetry of the face at rest and in dynamic expressions and support the patient during smile rehabilitation after dynamic smile reanimation with regional or free muscle transfer.

Summary: Sequelae of facial palsy have a negative impact on the cosmetic aspect and functions of the face. They bear severe consequences for patients with regard to their body image and social relationships. There are numerous medical and surgical treatments that should be proposed to patients to achieve comprehensive facial symmetry. The key to an adapted therapeutic choice, to achieve the best outcomes for patients, is to perform a comprehensive evaluation of the paralyzed face and have broad knowledge of the several techniques described over time in the literature. The patient should be informed of the different therapeutic alternatives, their implications, and their limits. With this article, readers will be able to accurately diagnose the different types of facial paralysis sequelae to develop a surgical plan adapted to each case to restore symmetry at rest and in motion.
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http://dx.doi.org/10.1097/PRS.0000000000006079DOI Listing
October 2019

Benefits of cryopreserved human amniotic membranes in association with conventional treatments in the management of full-thickness burns.

Int Wound J 2019 Dec 19;16(6):1354-1364. Epub 2019 Aug 19.

Tissue Bank of Lille, Biology Pathology Center, CHU of Lille, Lille, France.

The use of split-thickness skin autografts (STSA) with dermal substitutes is the gold standard treatment for third-degree burn patients. In this article, we tested whether cryopreserved amniotic membranes could be beneficial to the current treatments for full-thickness burns. Swines were subjected to standardised full-thickness burn injuries, and then were randomly assigned to treatments: (a) STSA alone; (b) STSA associated with the dermal substitute, Matriderm; (c) STSA plus human amniotic membrane (HAM); and (d) STSA associated with Matriderm plus HAM. Clinical and histological assessments were performed over time. We also reported the clinical use of HAM in one patient. The addition of HAM to classic treatments reduced scar contraction. In the presence of HAM, skin wound healing displayed high elasticity and histological examination showed a dense network of long elastic fibres. The presence of HAM increased dermal neovascularization, but no effect was observed on the recruitment of inflammatory cells to the wound. Moreover, the use of HAM with classical treatments in one human patient revealed a clear benefit in terms of elasticity. These results give initial evidence to consider the clinical application of HAM to avoid post-burn contractures and therefore facilitate functional recovery after deep burn injury.
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http://dx.doi.org/10.1111/iwj.13198DOI Listing
December 2019

Three-dimensional study of 31 cases of synostotic anterior plagiocephaly before and after surgical management the Lille protocol.

J Craniomaxillofac Surg 2018 Jun 28;46(6):958-966. Epub 2018 Mar 28.

CHU Lille, Center for Clefts and Facial Malformations, Plastic Surgery Unit, F-59000, Lille, France.

Synostotic anterior plagiocephaly is a rare pathological cranial malformation. Therapeutic options are rarely studied due to the rarity of the malformation and difficulties in diagnosis and care management. The objective of this study was to analyze the results obtained with the Lille protocol based on 62 CT-scans done before and after surgery in 31 patients. A specific analysis was designed for this work. Nine cephalometric measures enabled to evidence on each CT-Scan the corrections made on the fronto-orbital bandeau and the potential impact of surgery on the craniofacial structures. Results show that surgical symmetry of the fronto-orbital bandeau in the transversal plane, according to the symmetrical axis of the semicircular canals, allows a normalization of the skull's growth and morphogenesis for the surgically affected structures but also adjacent ones.
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http://dx.doi.org/10.1016/j.jcms.2018.03.014DOI Listing
June 2018

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors.

Cell Death Dis 2018 02 27;9(3):325. Epub 2018 Feb 27.

Univ. Lille, INSERM, UMR-S1172, Jean Pierre Aubert Research Centre, 59045, Lille, France.

Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc-amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.
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http://dx.doi.org/10.1038/s41419-018-0340-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832419PMC
February 2018

Case update on cranial osteopetrosis: which is the role of the neurosurgeon?

Childs Nerv Syst 2017 Dec 31;33(12):2181-2186. Epub 2017 Jul 31.

Departement of Neuro-ophtalmology, Lille University Hospital, Lille, France.

Purpose: Osteopetrosis (OP) is a rare skeletal disease, which can affect the skull base and calvaria. A multidisciplinary approach is mandatory and patient may need neurosurgical care. Few observations have been published, and optimal management of OP is not established yet.

Method: We report a case of an infant with OP diagnosed at 5 months, who presented signs of intracranial hypertension associated with unilateral blindness. Bone marrow allograft was performed at 6 months of age. At neurosurgical first examination at 11 months, the child was hypotonic, with severe amblyopia; features of bicoronal synostosis were appreciated, with tense anterior fontanel bulging indicating synostotic oxycephaly. Head circumference had decreased from +3 SD to +1SD. Cerebral CT scan showed reduction of intracranial volume, inward thickening of the calvaria, bilateral stenosis of optic canal, ventricular dilatation, enlarged arachnoid spaces, and tonsillar herniation. We performed cranial vault expansion with frontal advancement and bi parietal decompression, thinning of the inner table, unroofing of the left orbit and optic canal in order to obtain optic nerve decompression.

Results: Postoperative course was uneventful, and the patient was discharged on day 8. Vision was unchanged but rapid improvement of axial tonus was noted. The CT scan showed satisfactory calvarial expansion with regression of tonsillar herniation.

Conclusions: Neurosurgical evaluation and care are necessary in the context of a multidisciplinary approach to the patient affected by osteopetrosis. Cranial vault remodeling and expansion should be considered in patients with sign of intracranial hypertension. Timing of optic canal decompression is to be defined.
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http://dx.doi.org/10.1007/s00381-017-3553-4DOI Listing
December 2017

Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1.

Genet Med 2017 09 16;19(9):1013-1021. Epub 2017 Mar 16.

Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.

Purpose: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown.

Methods: We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families.

Results: We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation.

Conclusion: Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.
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http://dx.doi.org/10.1038/gim.2017.11DOI Listing
September 2017

Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.

Oncotarget 2016 Jun;7(26):39473-39485

University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.7790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129946PMC
June 2016

Lengthening Temporalis Myoplasty: Virtual Animation-Assisted Technical Video.

Plast Reconstr Surg 2016 Sep;138(3):506e-509e

Lille and Caen, France; and Jeddah, Saudi Arabia.

Lengthening temporalis myoplasty is a well-established procedure for dynamic palliative reanimation of the lip in facial palsy sequelae. The particularity of this technique is that the entire temporal muscle is transferred from the coronoid process to the upper half of the lip without interposition of aponeurotic tissue. To date, no video describing the technique was available. This is the first video describing the entire procedure, from preoperative markings through postoperative rehabilitation. In the video presented herein, the authors craft virtual three-dimensional animations in addition to a live operation on a patient performed by Daniel Labbé, who first described this technique 20 years ago.
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http://dx.doi.org/10.1097/PRS.0000000000002512DOI Listing
September 2016

The Transverse Musculocutaneous Gracilis Free Flap: Virtual Animation-Assisted Dissection and Application in Breast Reconstruction.

Plast Reconstr Surg 2016 May;137(5):1384-1387

Lille and Strasbourg, France; and Jeddah, Saudi Arabia.

The transverse musculocutaneous gracilis free flap is a valuable choice for autologous tissue, unilateral or bilateral breast reconstruction. This procedure is an excellent and customized option for immediate or delayed breast reconstruction in patients with small to moderate size breasts. Few descriptions of flap dissection and breast mound shaping are available. In this first educational video, the authors report the original dissection of the transverse musculocutaneous gracilis free flap used for breast reconstruction. Virtual animations insist on surgical key points and relevant details of the harvesting of the flap.
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http://dx.doi.org/10.1097/PRS.0000000000002067DOI Listing
May 2016

Epidemiologic Overview of Synkinesis in 353 Patients with Longstanding Facial Paralysis under Treatment with Botulinum Toxin for 11 Years.

Plast Reconstr Surg 2016 08;138(2):376e-378e

Department of Plastic, Reconstructive, and Aesthetic Surgery University Hospitals of Lille Lille, France.

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http://dx.doi.org/10.1097/PRS.0000000000002348DOI Listing
August 2016

Patient-derived tumor xenograft strategies for informed management of patients with metastatic melanoma.

Melanoma Res 2016 06;26(3):245-53

aDepartment of Plastic Reconstructive Surgery, University Hospital, Hopital Roger Salengro bUnit 837 Affiliation 4 INSERM and Faculty of Medicine of Lille, II-1, Lille, France.

Metastatic melanoma has benefited from immunotherapy and targeted therapy advances. Faced with the inescapable onset of treatment resistance, the choice of a second-line treatment can be guided by a patient-derived tumor xenograft (PDTX). This new approach requires an excellent multidisciplinary collaboration where the surgeon has a key role to play. Each patient included (stage IIIC or IV) presented with subcutaneous melanoma metastasis that could be surgically resected. The surgeon performed orthotopic PDTX on CB17-SCID mice. To validate the model, tumor material was amplified over three successive generations of animals to obtain cohorts compatible with carrying out a study to compare treatment response by targeted therapy (vemurafenib versus controls). Tumors were characterized (histologically and genetically) at all stages of the generations' amplification. Functional imaging by fluorine-18 fluorodeoxyglucose PET scan was performed for the third generation PDTX. Seventeen patients with a mutated BRAF V600E subcutaneous metastasis were included, yielding 257 PDTX. Clinical, histological, and genetic characteristics of the grafted tumors were stable over the three mice generations. The treatment response to vemurafenib was observed for all PDTX. The fluorine-18 fluorodeoxyglucose PET scan evidenced a decreased in glucose uptake in the treated tumors. PDTX models are being widely used in fundamental research and are more compatible with clinical issues. If PDTX are simple and easily reproducible in metastatic melanoma, an organized multidisciplinary platform is essential to implement them. In our experience, surgeons have a key role to play in the cohesion of this new therapeutic approach.
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http://dx.doi.org/10.1097/CMR.0000000000000249DOI Listing
June 2016

Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics.

Int J Cell Biol 2015 2;2015:283145. Epub 2015 Dec 2.

Inserm UMR-S 1172, Faculté de Médecine, Université de Lille, 59045 Place Verdun Cedex, France.

Mitochondrial metabolism greatly influences cancer cell survival, invasion, metastasis, and resistance to many anticancer drugs. Furthermore, molecular-targeted therapies (e.g., oncogenic kinase inhibitors) create a dependence of surviving cells on mitochondrial metabolism. For these reasons, inhibition of mitochondrial metabolism represents promising therapeutic pathways in cancer. This review provides an overview of mitochondrial metabolism in cancer and discusses the limitations of mitochondrial inhibition for cancer treatment. Finally, we present preclinical evidence that mitochondrial inhibition could be associated with oncogenic "drivers" inhibitors, which may lead to innovative drug combinations for improving the efficacy of molecular-targeted therapy.
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http://dx.doi.org/10.1155/2015/283145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680051PMC
December 2015

Lengthening temporalis myoplasty: a surgical tool for dynamic labial commissure reanimation.

Facial Plast Surg 2015 Apr 8;31(2):123-7. Epub 2015 May 8.

Department of Plastic and Reconstructive Surgery, Clinique Saint Martin, Caen, France.

Lengthening temporalis myoplasty (LTM), first described by Labbé in 1997, ensures the transfers of the entire temporal muscle from the coronoid process to the upper half of the lip without interposition of aponeurotic tissue. The temporal muscle changes function because it is entirely mobilized toward another effector: the labial commissure. Thanks to brain plasticity, the muscle loses its chewing function, and after 6 months of speech rehabilitation it acquires its new smiling function. We describe technical points especially the coronoid process approaches both through an upper temporal fossa approach and a lower nasolabial fold approach. Rehabilitation starts 3 weeks after the surgery following a standardized protocol to move from a mandibular smile to a voluntary, then spontaneous, smile in three steps. The LTM is the main part of a one-stage global treatment of the paralyzed face. It constitutes a dynamic palliative treatment usually started at the sequelae stage, 18 month after the outcome of a peripheral facial paralysis. This one-stage procedure is a reproducible and relevant surgical technique in the difficult treatment of peripheral facial paralysis. It allows implementing an active muscle transfer to reanimate the labial commissure and re-create a mobile nasolabial fold.
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http://dx.doi.org/10.1055/s-0035-1549039DOI Listing
April 2015

Metabolic features of melanoma: a gold mine of new therapeutic targets?

Curr Cancer Drug Targets 2014 ;14(4):357-70

INSERM U 837 Faculte de Medecine, 1, place Verdun F- 59045 Lille Cedex, France.

In recent years, our knowledge regarding the metabolism of melanoma has greatly advanced and consequently new therapeutic strategies are being developed. This review is focused on metabolic pathways contributing to melanoma proliferation, the influence of BRAF inhibitors on those metabolic pathways and finally a presentation of potential therapeutic strategies aimed at blocking metabolic signaling pathways and therefore melanoma development.
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http://dx.doi.org/10.2174/1568009614666140407113124DOI Listing
January 2015

Orbital exenteration and periorbital skin cancers.

J Oral Maxillofac Surg 2014 Apr 1;72(4):811-6. Epub 2014 Jan 1.

Doctor, Department of Plastic, Reconstructive and Aesthetic Surgery, Roger Salengro Hospital, University Hospitals of Lille, Lille, France.

Purpose: Orbital exenteration is a disfiguring surgical procedure that requires thoughtful reconstruction.

Patients And Methods: We analyzed all cases of orbital exenteration done in our department since 1998.

Results: A total of 26 patients had undergone surgery during our study period, and 27 exenterations have been conducted since 1998. The reconstruction was performed in 20 patients using an ipsilateral temporal muscle flap. One patient underwent reconstruction using a temporalis fascia flap and 6 using free flaps. A total of 11 patients received postoperative radiotherapy. Data collection revealed 6 patients with an ocular prosthesis. The prosthesis had either been glued or mounted onto glasses.

Conclusions: Analyzing our results and the published data, we found that the reconstruction mode influences prosthetic rehabilitation. Thus, we have identified 2 categories. In the first category, postoperative radiotherapy will be required and coverage with a flap will be needed. In the second category, postoperative radiotherapy is not indicated and thus the healing time might be extended in favor of more space for better retention of the prosthetic rehabilitation.
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http://dx.doi.org/10.1016/j.joms.2013.09.014DOI Listing
April 2014

Mitochondrial oxidative stress is the Achille's heel of melanoma cells resistant to Braf-mutant inhibitor.

Oncotarget 2013 Nov;4(11):1986-98

Unit 837 Equipe 4 Inserm and Faculté de Médecine, Université de Lille II 1 Place Verdun 59045 Cedex, France.

Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875764PMC
http://dx.doi.org/10.18632/oncotarget.1420DOI Listing
November 2013

Trigonocephaly: Lille's surgical technique.

Childs Nerv Syst 2013 Dec 31;29(12):2183-8. Epub 2013 Jul 31.

French National Center for Rare Craniomaxillofacial Malformations, Lille University Hospital, Lille, France,

From the early beginning, in 1977, of our experience in the treatment of trigonocephaly and with the follow-up of 263 patients, we have been convinced that it was a condition related to the skull base. It is now proved thank to the comparison between patient's CT scan and normal template (normal skull of the same age) in vestibular orientation. We used to correct this condition by a frontal reshaping and a rotation of the superior and lateral orbital rim along an oblique axis. We call that movement: "valgisation."
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http://dx.doi.org/10.1007/s00381-013-2229-yDOI Listing
December 2013

Patient-derived tumor xenograft model to guide the use of BRAF inhibitors in metastatic melanoma.

Melanoma Res 2013 Oct;23(5):373-80

Inserm Unit 837 Team 4, University of Medicine, Lille, Cedex, France.

Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([(18)F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [(18)F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides 'real-time' results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this 'coclinical' trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.
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http://dx.doi.org/10.1097/CMR.0b013e328363ed92DOI Listing
October 2013

Aplasia cutis congenita: review of 29 cases and proposal of a therapeutic strategy.

Eur J Pediatr Surg 2013 Apr 17;23(2):89-93. Epub 2012 Aug 17.

Hôpital Jeanne de Flandre - Clinique de chirurgie et d'orthopédie de l'enfant, Lille, France.

Introduction: Aplasia cutis congenita (ACC) is a rare congenital disorder, which most commonly involves the scalp, and can affect the galea, the pericranium, the bone, and the dura mater. ACC thus is at risk of infection and hemorrhage. There is no consensus over the ideal management and the role for plastic surgery.

Materials And Methods: We reviewed retrospectively our experience with 29 patients treated between 1976 and 2011.

Results: The patients were 17 male and 12 female, 25 being referred immediately at birth. The size of the defect ranged from 1 to 192 cm2. Thirteen patients had bone aplasia. Initial conservative treatment was decided in five cases; 15 patients underwent excision-sutures with or without local plasty, 8 underwent pedicled scalp flap, and 1 had skin graft followed by further reconstruction by a free flap. Four patients died in neonatal period because of infection or associated ailments. All others patients achieved complete healing.

Discussion: The mortality rate of ACC remains high and increases with the size of bone defect. We propose a therapeutic strategy based on the size of the skin defect and the nature of underlying exposed structures. Cranioplasty is exceptionally necessary because of good spontaneous bone regeneration within few months or years. Cosmetic appearance can be improved later by skin expansion.

Conclusion: Aplasia cutis congenita is a rare malformation with sometimes a rapid fatal issue. A precise evaluation of surface and depth of the lesion is essential to decide if and how to operate, in order to provide rapid and efficient coverage.
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http://dx.doi.org/10.1055/s-0032-1322539DOI Listing
April 2013

Unicoronal synostotic plagiocephaly: surgical correction: Lille's technique.

Childs Nerv Syst 2012 Sep 8;28(9):1433-8. Epub 2012 Aug 8.

French National Center for Rare Craniomaxillofacial Malformations, Lille University Hospital, Lille, France.

Introduction: For 35 years, we have a tight neuro-plastic surgical cooperation for the surgical correction and long-term systematic follow-up of 125 cases of unicoronal synostotic plagiocephaly.

Methods: We have tried to understand why some patients had kept an asymmetrical facial growth pattern in spite of a good fronto orbital correction. Analysis in vestibular orientation which was available from 1993 has demonstrated a discrepancy between the ocular and the vestibular verticality referential system. So we have designed a surgical procedure to try to fix that problem.

Results And Conclusion: Preliminary results in 27 cases operated according to this procedure, for which we have pre- and post-CT scan demonstrate significative improvements of our results.
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http://dx.doi.org/10.1007/s00381-012-1793-xDOI Listing
September 2012

Atypical scaphocephaly: a review.

Childs Nerv Syst 2012 Sep 8;28(9):1319-25. Epub 2012 Aug 8.

Department of Pediatric Neurosurgery, Lille University Hospital, Lille, France.

Background And Purpose: Sagittal craniosynostosis (SCS) is common and easily recognized and corrected surgically. However, rare cases of SCS are more complex: these associate closure of the metopic or delayed closure of the coronal suture, uni- or bilaterally.

Material And Methods: We reviewed the available literature on atypical sagittal craniosynostosis (ASCS). We also reviewed retrospectively our series of SCS treated since 1980 and selected cases with simultaneous closure of the metopic (leptocephaly) or delayed closure of other sutures (plagiocephaly, oxycephaly, or Crouzon syndrome).

Results: ASCS is rare, representing <10 % of SCS. In our series, among 447 cases of SCS followed for a mean duration of 63.7 months, we identified 22 cases of ASCS: 6 with leptocephaly, 9 with non-syndromic oxycephaly, 4 with Crouzon syndrome, and 3 with plagiocephaly. Fourteen patients required a second operation, either planned initially (severe leptocephaly) or because of brain compression. The actuarial incidence of ASCS requiring reoperation was 5.3 % of SCS at 10 years. After a mean follow-up of 113 months, morphological results in ASCS were grade 1 (no defect) in 5, grade 2 (mild defect) in 2, grade 3 (minor reoperation) in 3, and grade 4 (major reoperation) in 12; one patient had visual impairment, and two had learning difficulties.

Conclusions: ACSC can be detected initially or occur with a delay in apparently standard SCS. Leptocephaly is a specific entity. Because of the implications on the management and risk for the patient, preoperative evaluation of patients with SCS with CT scanner and prolonged follow-up are necessary.
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http://dx.doi.org/10.1007/s00381-012-1807-8DOI Listing
September 2012