Gingival proteomics reveals the role of TGF beta and YAP/TAZ signaling in Raine syndrome fibrosis.

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

Extensive head and neck skin cancers: Carcinologic surgery as a cornerstone of treatment.

BACKGROUND AND OBJECTIVE: The prevalence of extensive skin cancers increases with the aging of the population. Surgical management is the gold standard of curative treatment while morbidity is not negligible. There are few data in the literature concerning extensive head and neck cutaneous cancers. The aim of this article is to report our experience of curative management of head and neck extensive skin cancers. METHOD: In this single-center retrospective observational study, we report a series of 17 patients with extensive skin facial cancers treated by surgery between 2013 and 2022 in the maxillofacial surgery department of the Pitié-Salpêtrière Hospital. We collected clinical, therapeutic, histological, and carcinologic data. RESULTS: The median age of the patients was 66 years [35-94]. There were 9 male and 8 women. Scalp (39 %) and cheek (22 %) locations were the most frequent ones. The most frequent histological types were squamous cell carcinoma (61 %) and basal cell carcinoma (17 %). Three patients received neoadjuvant treatment. The surgical treatment consisted mainly of carcinological resection followed by one-stage reconstruction by free flap for 5 (30 %) patients and without reconstruction for primary for 12 (70 %) patients, of whom 8 benefited from secondary reconstruction. Five patients received adjuvant radiotherapy or radio-chemotherapy. With a median follow-up of 40 months (2-72), the median overall survival was 40 months (12-72). CONCLUSION: We know that extensive skin cancers of the face have a good prognosis on condition that the carcinological and reconstructive requirements are respected. Surgery remains the cornerstone of treatment while the improvement of adjuvant therapies, in particular the rise of immunotherapies or other targeted therapies, may allow to limit recurrences.

Epidemiology of facial skin cancers managed in a French ambulatory surgical center.

INTRODUCTION: Approximately 80,000 cases of skin cancer are diagnosed annually in France. The management of these cancers can occur in both university hospital centers and ambulatory surgery centers. Limited data exist regarding the epidemiology of cutaneous cancers treated through ambulatory surgery centers. The objective of our study is to describe the epidemiological characteristics of cutaneous cancers managed in a tertiary ambulatory surgery center. METHODS: This is a retrospective, single-center observational study. The included patients were those who underwent surgical excision of one or more skin cancers within the maxillofacial department of a tertiary ambulatory surgery center. Clinical, therapeutic, histopathological, and follow-up data (additional surgery if margins were not clear, progression, recurrence, second cancer…) were collected. RESULTS: Among the n = 1931 patients operated for a head and neck skin tumor from September 2018 to July 2022, n = 426 (22 %) were diagnosed with cancer upon histological analysis. The median age was 76 years (31-100), with a male-to-female ratio of 1/1. The most frequent locations were the nose (23 %) and cheek (20 %). Ten percent of patients had dual-site skin cancer at initial diagnosis. The most common histological types were basal cell carcinoma (77 %) and squamous cell carcinoma (18 %). Surgical treatment primarily consisted of "excision-reconstruction with local flap" (51 %) or "excision-suture" (34 %). Resection margins were mostly clear (65 %), and only six patients (2 %) experienced local recurrence or progression during follow-up. CONCLUSIONS: Skin cancers are prevalent in ambulatory practice. Surgical treatment allows for effective control of the cancer. Photoprotection, particularly in immunocompromised patients, remains crucial for prevention.

Datasets for gene expression profiles of head and neck squamous cell carcinoma and lung cancer treated or not by PD1/PD-L1 inhibitors.

Identification of tumors harboring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. In this context, we generated targeted gene expression profiles in three and two independent cohorts of patients with HNSCC or NSCLC respectively, treated or not by PD-1/PD-L1 inhibitors. Notably, we generated two datasets including 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors. Clinical information, including detailed survival raw data, is available for each patient, allowing to test association between gene expression data and patient survival (overall and progression-free survival). Moreover, we also generated gene expression datasets of 27 paired HNSCC samples from diagnostic biopsies and versus surgically resected specimens as well as 33 paired HNSCC samples at initial diagnosis (untreated) and at recurrence. Those datasets may allow to test the stability of a given biomarker across paired samples.

Immunologically active phenotype by gene expression profiling is associated with clinical benefit from PD-1/PD-L1 inhibitors in real-world head and neck and lung cancer patients.

INTRODUCTION: Identification of tumours harbouring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. Our objective was to develop a reliable and stable scoring system to identify those immunologically active tumours. METHODS: Using gene expression profiles of 421 HNSCC, we developed a score to identify immunologically active tumours. Validation of the 'HOT' score was done in 40 HNSCC and 992 NSCLC. Stability of the 'HOT' score was tested in paired HNSCC samples from diagnostic biopsies versus surgically resected specimens, untreated versus recurrent samples, and pre-versus post-cetuximab samples in a total of 76 patients. The association between the 'HOT' score with overall survival (OS) and progression-free survival (PFS) was tested in 184 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors. RESULTS: A 27-gene expression based 'HOT' score was correlated with: (i) PD-L1 and IDO1 expression, (ii) TCD8 infiltrate and (iii) activation of the IFN-γ pathway. The HOT score concordance when comparing diagnostic biopsies and surgically resected specimens was higher than in untreated samples versus recurrent or pre-versus post-cetuximab samples. In 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors, the HOT score was associated with an improved OS and PFS in multivariate analysis. CONCLUSION: The 'HOT' score is a simple and robust approach to identify real-world patients with HNSCC and NSCLC immunologically active tumours who may benefit from PD-1/PD-L1 inhibitors.

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach.

The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis imperfecta, gingival fibromatosis and nephrocalcinosis. ERS is caused by bi-allelic mutations in the secretory pathway pseudokinase FAM20A. How mutations in FAM20A may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. We here analyzed conditioned media of gingival fibroblasts (GFs) obtained from four unrelated ERS patients carrying distinct mutations and control subjects. Secretomic analysis identified 109 dysregulated proteins whose abundance had increased (69 proteins) or decreased (40 proteins) at least 1.5-fold compared to control GFs. Proteins over-represented were mainly involved in extracellular matrix organization, collagen fibril assembly, and biomineralization whereas those under-represented were extracellular matrix-associated proteins. More specifically, transforming growth factor-beta 2, a member of the TGFß family involved in both mineralization and fibrosis was strongly increased in samples from GFs of ERS patients and so were various known targets of the TGFß signaling pathway including Collagens, Matrix metallopeptidase 2 and Fibronectin. For the over-expressed proteins quantitative RT-PCR analysis showed increased transcript levels, suggesting increased synthesis and this was further confirmed at the tissue level. Additional immunohistochemical and western blot analyses showed activation and nuclear localization of the classical TGFß effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFß targets suggesting that this pathway could be a central player in the pathogenesis of the ERS gingival fibromatosis. In conclusion our data strongly suggest that TGFß -induced modifications of the extracellular matrix contribute to the pathogenesis of ERS. To our knowledge this is the first proteomic-based analysis of FAM20A-associated modifications.

In-house 3D printing: Why, when, and how? Overview of the national French good practice guidelines for in-house 3D-printing in maxillo-facial surgery, stomatology, and oral surgery.

3D-printing is part of the daily practice of maxillo-facial surgeons, stomatologists and oral surgeons. To date, no French health center is producing in-house medical devices according to the new European standards. Based on all the evidence-based data available, a group of experts from the French Society of Stomatology, Maxillo-Facial Surgery and Oral Surgery (Société Française de Chirurgie Maxillofaciale, Stomatologie et Chirurgie Orale, SFSCMFCO), provide good practice guidelines for in-house 3D-printing in maxillo-facial surgery, stomatology, and oral surgery. Briefly, technical considerations related to printers and CAD software, which were the main challenges in the last ten years, are now nearly trivial questions. The central current issues when planning the implementation of an in-house 3D-printing platform are economic and regulatory. Successful in-house 3D platforms rely on close collaborations between health professionals and engineers, backed by regulatory and logistic specialists. Several large-scale academic projects across France will soon provide definitive answers to governance and economical questions related to the use of in-house 3D printing.

Humanitarian Maxillofacial Mission's Success Requires Experienced Surgeons, Careful Planning, and Meeting With the Local's Care Needs.

PURPOSE: Meeting with local needs of low- and middle-income countries during maxillofacial humanitarian mission is not easy. This article aimed to report on 5 years of experience in humanitarian maxillofacial surgery missions. In addition, several key points for best practices and meeting the medical needs of local populations are discussed. METHODS: In this retrospective case series, all medical charts of patients managed during humanitarian maxillofacial surgery missions organized within the department of maxillofacial surgery of Le Dantec Hospital (Senegal) were analyzed. Disease characteristics, treatments modality, and outcomes were reviewed. Moreover, missions planning and costs were studied. RESULTS: Between 2015 and 2018, 5 humanitarian missions were organized totalizing 177 patients, one-third of which were treated surgically. Tumors (35%) and sequelae from previous surgeries, cancrum oris or trauma (24%) were the most frequently treated disorders. Most patients were treated with free flap reconstructions (35%). Postoperative complications were observed for only 3 patients (5%). With a median follow-up of 13 months, no sequelae requiring specific treatment were observed. The estimated total cost for each mission was $39,000. CONCLUSION: In order to benefit both the locals and the volunteers, humanitarian maxillofacial missions should be carefully planned and volunteers appropriately prepared. Other keys to the success of such missions are setting up training and support programs, reflecting upon ethical considerations, understanding local cultural customs and ensuring mutual respect with the locals. Frequent self-evaluation and long-term mission sustainability are critical. Finally, mission costs should be evaluated.

Custom surgical management of invasive malignant tumors of the scalp.

BACKGROUND: There is no universal management protocol concerning invasive malignant tumors of the scalp with bone and dura mater invasion. The aims of this study were to report and discuss our experience in the management of these forms of tumors. METHODS: We retrospectively reviewed all consecutive patients of microsurgical scalp reconstruction performed after resection of invasive cutaneous malignancies of the scalp, calvarium, and dura mater from 2017 to 2019, at Pitié-Salpêtrière University Hospital (Paris, France). RESULTS: Five patients met inclusion criteria. There were three squamous cell carcinomas and two sarcomas. Mean age at surgery was 63.6 years. The sex ratio male/female was 4. Two received radiation prior to resection and two patients had a history of prior scalp tumor surgery. All the patients underwent craniectomy and the mean cranial defect size was 41 cm2. Cranioplasty was performed in one patient. Soft tissue coverage was provided by free tissue transfer of latissimus dorsi muscle in all patients. In four patients, split thickness skin graft was performed in a second surgical stage few weeks later. There were no intraoperative complications and no complications into the donor site for the tissue transfer or the skin graft. Two patients had flap necrosis that healed after a new free flap of latissimus dorsi. CONCLUSIONS: Wide resection with craniectomy and reconstruction with microvascular free tissue transfer provides safe and reliable treatment of recalcitrant invasive scalp skin cancers. The surgical management of these complex patients is a challenge that must be conducted by trained, experienced, and multidisciplinary teams.

Lack of efficacy of neoadjuvant chemotherapy in adult patients with maxillo-facial high-grade osteosarcomas: A French experience in two reference centers.

INTRODUCTION: Neoadjuvant chemotherapy (neo-CT) for osteosarcomas is the standard of care. Management of maxillo-facial osteosarcomas (MFOS) is challenging. In this rare disease, we collected a large cohort of patients with the aim to report the histological and radiological local response rates to neo-CT. PATIENTS AND METHODS: All consecutive adult patients treated between 2001 and 2016 in two French sarcoma referral centers (Pitié-Salpêtrière Hospital, APHP, RESAP France and Gustave Roussy Institute France), for a histologically proved MFOS were included. Clinical, histological and radiological data were independently reviewed. Tumor response to neo-CT was assessed clinically, radiologically with independent review using RECIST v1.1 criterion and pathologically (percentage of necrosis). Multivariate analysis was done for outcomes, tumor response and disease-free survival (DFS). RESULTS: A total of 35 high grade MFOS were collected. The clinical tumor response was 4% (1/24 receiving neo-CT), the radiological response was 0% (0/18 with available data) and the pathological response was 5% (1/20 with available data). Three patients (12.5%) initially resectable became unresectable due to clinical and radiological progression during neo-CT. Tumor size and R0 (clear margins) surgical resections were significantly associated with DFS. CONCLUSION: MFOS is a rare disease. This large retrospective cohort of MFOS indicates the lack of benefit and potentially deleterious effects of neo-CT. We suggest privileging primary surgery in initially localized resectable MFOS. The benefit of adjuvant chemotherapy should be prospectively studied.

In Vivo Inspection of the Olfactory Epithelium: Feasibility of Robotized Optical Biopsy.

Inspecting the olfactory cleft can be of high interest, as it is an open access to neurons, and thus an opportunity to collect in situ related data in a non-invasive way. Also, recent studies show a strong link between olfactory deficiency and neurodegenerative diseases such as Alzheimer and Parkinson diseases. However, no inspection of this area is possible today, as it is very difficult to access. Only robot-assisted interventions seem viable to provide the required dexterity. The feasibility of this approach is demonstrated in this article, which shows that the path complexity to the olfactory cleft can be managed with a concentric tube robot (CTR), a particular type of continuum robot. First, new anatomical data are elaborated, in particular for the olfactory cleft, that remains hardly characterized. 3D reconstructions are conducted on the database of 20 subjects, using CT scan images. Measurements are performed to describe the anatomy, including metrics with inter-subject variability. Then, the existence of collision-free passageways for CTR is shown using the 3D reconstructions. Among the 20 subjects, 19 can be inspected using only 3 different robot geometries. This constitutes an essential step towards a robotic device to inspect subjects for clinical purposes.

Surgical guide for the remodelling of the orbito-naso-frontal bandeau in craniosynostosis surgery.

INTRODUCTION: Craniosynostoses affecting the forehead sutures can not only cause brain damage, but can also have an esthetic impact, because of the associated orbito-naso-frontal deformations. Reshaping the orbito-naso-frontal bandeau (ONFB) is difficult to appreciate perioperatively and should ideally be customized to each child. The aim of this study was to develop a template to guide the surgeon preoperatively towards an ideal customized remodelling of the ONFB. MATERIALS AND METHODS: A previous study conducted on computed tomography scans obtained from healthy children allowed us to conclude that the whole ONFB shape could be accurately described just by the distance measured between the fronto-zygomatic sutures (FZD), independently of age and gender. Our customizable template relies on this measurement. RESULTS: A re-usable template, built around three supports adjustable to a wide range of FZD, was designed using the CAD 3D Rhinoceros® software and machined in stainless steel 316L. The prototype was used for three children with good preliminary results. DISCUSSION AND CONCLUSION: The use of a customizable surgical template allows the surgeon to perform accurate and ideal perioperative remodeling of the ONFB in children suffering from craniosynostosis affecting the forehead sutures. Our prototype is currently the only one to be adjustable according to the FZD. The utility of this device will be assessed in a future prospective clinical study.

Leap Motion Gesture Control With Carestream Software in the Operating Room to Control Imaging: Installation Guide and Discussion.

Nowadays, routine cross-sectional imaging viewing during a surgical procedure requires physical contact with an interface (mouse or touch-sensitive screen). Such contact risks exposure to aseptic conditions and causes loss of time. Devices such as the recently introduced Leap Motion (Leap Motion Society, San Francisco, CA), which enables interaction with the computer without any physical contact, are of wide interest in the field of surgery, but configuration and ergonomics are key challenges for the practitioner, imaging software, and surgical environment. This article aims to suggest an easy configuration of Leap Motion on a PC for optimized use with Carestream Vue PACS v11.3.4 (Carestream Health, Inc, Rochester, NY) using a plug-in (to download at https://drive.google.com/open?id=0B_F4eBeBQc3yNENvTXlnY09qS00&authuser=0) and a video tutorial (https://www.youtube.com/watch?v=yVPTgxg-SIk). Videos of surgical procedure and discussion about innovative gesture control technology and its various configurations are provided in this article.