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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.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.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.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.

Tregs fail to migrate to the tumor in Ccr2-/- mice but accumulate in the dLN

The CCL2 chemokine receptor CCR2 drives cancer by mediating the recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. In this study, we extend the significance of CCR2 in this setting by identifying a new role for it in mediating recruitment of CD4+ T regulatory cells (Treg). Following tumor initiation, an expanded population of CCR2+ Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. This Treg subset was enriched in the fraction of tumor antigen–specific cells in the dLN, where they displayed an activated immunosuppressive phenotype. Notably, in mouse models, low-dose cyclophosphamide treatment preferentially depleted CCR2+ Treg, enhancing priming of tumor-specific CD8+ T cells. In the MMTV-PyMT transgenic mouse model of breast cancer and in oral squamous cell carcinoma patients, tumor development was associated with decreased blood frequency and inversely increased tumor frequency of CCR2+ Tregs. Our results define a novel subset of CCR2+ Treg involved in tumoral immune escape, and they offer evidence that this Treg subset may be preferentially eradicated by low-dose cyclophosphamide treatment. Cancer Res; 76(22); 6483–94. ©2016 AACR.

CCL2-AF647 staning allows specific characterization of CCR2 receptor expression on Tregs

The dynamic of Tregs is reduced in the dLN of Ccr2-/- mice compared to WT mice

Non-cycling Treg accumulate in the dLN of Ccr2-/- mice compare to WT mice

Includes mat and methods and legends relative to supplementary figures

BACKGROUND Head and neck spindle cell carcinoma (HNSpCC) is a rare histological variant associated with worse outcomes. Our objective was to identify clinicopathological factors associated with survival in patients with HNSpCC compared to patients with conventional head and neck squamous cell carcinoma (HNSCC). METHODS Using clinical data from the Surveillance, Epidemiology, and End Results database, we performed a survival analysis in patients with HNSpCC or HNSCC between 2004 and 2016. RESULTS A total of 458 HNSpCC and 77 104 HNSCC were identified, including 17% and 16% female, respectively. Five-year disease-specific survival (DSS) was 63.90% and 73.90% in patients with HNSpCC and HNSCC, respectively. Sex (hazard ratio [HR] for females = 2.816; CI: 1.139-6.965; p = 0.025) was significantly associated with DSS in HNSpCC while no association was observed between sex and DSS in HNSCC. CONCLUSION HNSpCC in women is a specific subgroup of HNSCC, which is associated with a poor prognosis.

Resumen Las cirugias oncologicas otorrinolaringologicas (ORL) y maxilofaciales implican sobre todo a los tumores de las vias aerodigestivas superiores. Suelen ser procedimientos mayores, debido a su caracter prolongado y al traumatismo tisular que provocan. Dado que los principales factores de riesgo de estos tumores son el consumo de alcohol y de tabaco, los pacientes candidatos a este tipo de cirugia suelen presentar patologias cardiovasculares y respiratorias, asi como desnutricion secundaria al proceso tumoral. Por tanto, la evaluacion preoperatoria de estos pacientes es una etapa esencial del tratamiento y debe ser multidisciplinaria. Se dirige a la instauracion de medidas de prehabilitacion para mejorar el pronostico de los pacientes, en particular mediante la correccion de una posible desnutricion o anemia. El manejo de las vias aereas es la principal dificultad a la que puede enfrentarse la anestesia en el quirofano para este tipo de pacientes. La videolaringoscopia resulta util en las situaciones de dificultades de acceso de las vias aereas. La intubacion vigil con fibroendoscopia es una tecnica alternativa que deben dominar todos los anestesistas en ORL y cirugia maxilofacial. Los elementos esenciales del manejo peroperatorio son la profilaxis antibiotica, la optimizacion hemodinamica, el manejo de la hemorragia quirurgica y la prevencion de la hipotermia. El tratamiento postoperatorio debe realizarse por lo general en una unidad de cuidados continuos, para vigilar, por una parte, las complicaciones medicas (infeccion respiratoria, descompensacion de patologias subyacentes, sindrome de abstinencia, enfermedad tromboembolica) y, por otra, las complicaciones quirurgicas (infeccion y hemorragia del sitio quirurgico, obstruccion de las vias aereas, disfuncion vascular de los colgajos). Por tanto, las enfermedades concurrentes frecuentes, las dificultades de acceso de las vias aereas, la multiplicidad de procedimientos y la importancia de las tasas de complicaciones postoperatorias requieren en esta especialidad una colaboracion estrecha entre los equipos de anestesia y de cirugia.

Riassunto La chirurgia oncologica oto-rino-laringoiatrica (ORL) e maxillofacciale riguarda principalmente i tumori delle vie aerodigestive superiori. Si tratta, generalmente, di procedure importanti, per via del loro carattere lungo e demolitivo. Dal momento che i fattori di rischio di questi tumori sono, in primo luogo, le intossicazioni etilica e da tabacco, i pazienti candidati a questo tipo di intervento chirurgico sono spesso portatori di patologie cardiovascolari e respiratorie, nonche di denutrizione derivante dal processo tumorale. La valutazione preoperatoria di questi pazienti e, dunque, una fase essenziale della gestione e deve essere multidisciplinare. Si concentra sull’attuazione di misure di preabilitazione per migliorare la prognosi dei pazienti, in particolare attraverso la correzione di eventuali denutrizione o anemia. La gestione delle vie aeree e la principale difficolta che l’anestesista puo incontrare in sala operatoria per questa tipologia di pazienti. La videolaringoscopia si rivela utile nelle situazioni in cui le vie aeree siano di accesso difficile. L’intubazione vigile sotto fibroscopia e una tecnica alternativa, che deve essere ben padroneggiata da qualsiasi anestesista in ORL e chirurgia maxillofacciale. Gli elementi essenziali della gestione intraoperatoria sono la profilassi antibiotica, l’ottimizzazione emodinamica, la gestione del sanguinamento chirurgico e la prevenzione dell’ipotermia. La gestione postoperatoria deve, generalmente, essere effettuata in un reparto di cure continue, al fine di monitorare, da un lato, le complicanze mediche (infezione respiratoria, scompenso delle patologie sottostanti, sindrome da astinenza, malattia tromboembolica) e, dall’altro, le complicanze chirurgiche (infezione e sanguinamento del sito chirurgico, ostruzione delle vie aeree, disfunzione vascolare dei lembi). Pertanto, le frequenti comorbilita, le difficolta di accesso alle vie aeree, la molteplicita delle procedure e l’alto tasso di complicanze postoperatorie richiedono, in questo ambito, una stretta collaborazione tra le equipe di anestesia e di chirurgia.

Background Lichen planus (LP) is a pathology that affects the skin and the mucosa. The lips are rarely involved but represent a diagnostic challenge in those cases. Oral lichenoid lesions (OLL) are defined as lesions that resemble oral lichen planus (OLP) but do not fully meet the clinical and/or histologic criteria for OLP. This study aimed to present our case series and to study the correlation between the location of the lesion and the dental factor (resin composite, amalgams, crowns, abrasive teeth, and mandibular crossbite) that could cause the lesion. Methods We conducted a retrospective observational study of 23 patients with LP/OLL of the lips treated in the Department of Oral Mucosal Pathology of the Department of Stomatology and Maxillofacial Surgery of the Pitié-Salpêtrière Hospital in Paris between January 2017 and February 2021. We noted the location of the lesion (upper, lower, or both lips), medical history, treatments, smoking habits, and the aspect of the teeth facing the lesion. Patients received a local corticoid treatment and were monitored via follow-up. Results Sixteen patients had lesions on the upper lip, two on the lower lip, and five on both lips, and most patients (n = 14, 60.1%) had a dental factor facing the lesion (e.g., abrasive teeth, resin composites, dental crowns, and mandibular crossbite). Six patients received clobetasol propionate, and 15 patients received a preparation combining betamethasone and benzocaine (Orabase, ConvaTec, Deeside, UK). Fourteen patients returned for post-treatment follow-up consultations approximately two months after treatment. Seven patients saw clinical improvement, five had partial improvement, and two had no improvement. Conclusions Lesions of the labial mucosa appear to be a rare condition in LP/OLL. The difference between LP and OLL can be difficult, even with histological analysis. Its pathogenesis remains unknown, although some studies found evidence of lichenoid reactions of the lips in contact with dental composite restorations. In our study, 14 of our patients had a dental factor facing the lesions. However, our study failed to show a correlation between the presence of an inducing factor and the lesion. In a future study, the potential effect of dental inducing factor removal could be studied. This topic requires further investigations, particularly regarding the inducing factor and the optimal therapeutic approach.

Background: Our goal was to identify a gene-expression-based surrogate of genomic instability (GI) associated with the transformation of oral potentially malignant disorder (OPMD) into oral squamous cell carcinoma (OSCC). Methods: GI was defined as the fraction of genome altered (FGA). Training sets included the CCLE and TCGA databases. The relevance of the enrichment score of the top correlated genes, referred to as the GIN score, was evaluated in eight independent public datasets from the GEO repository, including a cohort of patients with OPMD with available outcome. Results: A set of 20 genes correlated with FGA in head and neck SCC were identified. A significant correlation was found between the 20-gene based GIN score and FGA in 95 esophagus SCC (r = 0.59) and 501 lung SCC (r = 0.63), and in 33 OPMD/OSCC (r = 0.38). A significantly increased GIN score was observed at different stages of oral carcinogenesis (normal–dysplasia –OSCC) in five independent datasets. The GIN score was higher in 10 OPMD that transformed into oral cancer compared to 10 nontransforming OPMD (p = 0.0288), and was associated with oral-cancer-free survival in 86 patients with OPMD (p = 0.0081). Conclusions: The GIN score is a gene-expression surrogate of GI, and is associated with oral carcinogenesis and OPMD malignant transformation.

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.

BackgroundHead and Neck Squamous Cell Carcinoma is the 8th leading cancer worldwide and it is associated with significant morbidity and mortality.1 2 Tumor microenvironment (TME) is dynamic and it plays an important role in head and neck carcinogenesis.3 4 Cytotoxic T-cells, immune checkpoint molecules such as programmed cell death 1 (PD-1), its ligand (PD-L1), and other checkpoints molecules have been described in these tumors.1 3 This study aimed to characterize the TME of oral squamous cell carcinoma (OSCC) and compare with their pathology features.MethodsFour microns thickness consecutives slides from representative OSCC (N=46) cases were stained and analyzed using 11 biomarkers (CK, CD3, CD8, CD68, PD1, PDL1, LAG3, TIM3, ICOS, VISTA, OX40) placed in two multiplex immunofluorescence panels to characterize the TME. For image analysis, the samples were divided in tumor, stroma and peritumoral compartment. Co-expression of markers (cell phenotypes) where analyzed as densities by mm2 in each compartment. For PD-L1 expression by malignant cells (CK+PD-L1+) we set up a cutoff of positive case as ≥ than 1%. Cell phenotypes were correlated with anatomopathological information retrieved from records such as tumor size, margin status, stage and perineural, lymphovascular, and bone invasion among others. Statistical analyses and plots were performed using SPSS and Graphpad prism8 software packages.ResultsWe found significant higher cell density for CK+PDL1+ (P= 0.038), CD3+PDL1+ (P= 0.027), CD3+CD8+PDL1+ (P=0.040) in female patients compared with the male population. Interestingly, smaller tumor size (≤ median, 25mm) showed higher densities of CD3+ (P= 0.006), CD3+CD8+ (P= 0.007), CD3+PDL1+ (P= 0.037), CD3+CD8+PDL1+ (P= 0.016), CD3+ICOS+ (P= 0.036), CD3+VISTA+ (P= 0.001), CD68+ (P= 0.001) and CD68+PD-L1+ (P= 0.008) than large tumors. Additionally, high cell density CD3+OX40+ (P= 0.011) was observed in tumors without margin invasion and high cell density for macrophages CD68+ (p= 0.005) in tumors without bone invasion. In ulcerative and infiltrative tumor pattern we observed higher cell density of CD3+PDL1+ (P= 0.020), CD3+CD8+PDL1+ (P=0.006) and CD3+OX40+ (P= 0.022) than non-ulcerate and no infiltrative pattern. Lastly, 58.7% of cases were PDL1+.ConclusionsOur findings of a diminished immune response in larger tumors might be correlated to their potential role in tumor aggressiveness and progression. Furthermore, high cell density of macrophages on tumor bone invasion may suggest an immune suppressive M2 response supported by the presence of PDL1+ expression. All these results can be the first approach for the development of a treatment based of immune interception.AcknowledgementsThis study was supported by a strategic alliance between the Translational Molecular Pathology-Immunoprofiling las (TMP-IL) at the Department Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center and the Université Claude Bernard Lyon, Centre de Recherche en Cancérologie de Lyon and the Department of Translational Medicine, Centre Léon Bérard, Lyon, France. The authors would acknowledge ITMO Cancer 2020, ”Formation à la Recherche Fondamentale et Translationnelle en Cancérologie” (JB); CLARA 2020 ”Soutien à la mobilité des jeunes chercheurs en oncologie, N° CVPPRCAN000198” (JB); Fondation de France 2020 ”Aide à la mobilité international de médecins et pharmaciens, N° 00112162” (JB); Ligue contre le cancer 2021, comité de Saône-et-Loire (PS); 2017-INCa-DGOS-Inserm_12563: INCa SIRIC-LYriCAN INCa-DGOS-Inserm_12563 (PS)ReferencesCohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer 2019;7(1):184. Bouaoud J, Foy JP, Tortereau A, Michon L, Lavergne V, Gadot N, et al. Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival. Oncoimmunology 2021;10(1):1944554.Mei Z, Huang J, Qiao B, Lam AK. Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma. Int J Oral Sci 2020;12(1):16.Yokota T, Homma A, Kiyota N, Tahara M, Hanai N, Asakage T, et al. Immunotherapy for squamous cell carcinoma of the head and neck. Jpn J Clin Oncol 2020;50(10):1089–96.Ethics ApprovalThe study was conducted in accordance with all applicable laws, rules, and requests of French and European government authorities. Written informed consent was obtained from all patients and the study was approved by the Centre Leon Bérard institutional review board (Lyon, France). Samples were obtained from the CRB Centre Léon Bérard (n°BB-0033-00050) which is quality certified according NFS96-900 French standard and ISO 9001 for clinical trials.

Introduction In surgical approaches to condylar fractures, there is a risk of damage to the transverse facial artery (TFA) which may in turn account for impaired blood supply to the temporomandibular joint (TMJ). In order to investigate the risk of damage to the TFA, and prevent lesions to this artery resulting from TMJ surgical procedures, we studied the distance between the TFA and the head of the condylar process. Methodology A dissection study was conducted on 10 fresh cadavers (20 condylar specimens dissected), involving fifty CT scans of the face with intravenous contrast. Vertical distance from the TFA to the top of the mandibular condyle head and distance from the TFA to the lateral aspect of the mandibular condyle were measured. Results The lateral aspect of the mandibular condyle is vascularized by branches emanating from the superficial temporal artery (STA) and the TFA. The TFA was located 1.84 ± 0.6 cm below the condylar process of the mandible and ran 1.09 ± 0.54 mm lateral to the head of the mandibular condyle. Discussion In order to spare the TFA in fractures involving the condylar neck, surgical approaches to the condyle should preserve the uppermost 2 cm of the lateral surface of the condyle during dissection. Due to the necessity for periosteal elevation of the lateral surface of the condyle in condylar head fractures, it is possible to spare the TFA, running lateral to the condylar neck, and the medial condylar surface in order to leave the branches that derive from the maxillary artery (MA) intact.

Background Maxillofacial surgery for free flap reconstructions is associated with many complications due to technical complexity and comorbidity of patients. With a focus on critical care, the authors studied the impact of complications to highlight predictors of poor postoperative outcomes in order to implement optimization protocols. Methods This case-control study analyzed the relationship between perioperative variables and postoperative medical and surgical complications of patients who underwent head and neck surgery using fibular and forearm free flaps. The primary objective was the incidence of prolonged intensive care unit (ICU) length of stay (LOS). Secondary objectives were the incidence of ICU readmissions, postoperative infections, and 1-year mortality. A univariable logistic regression model was used. A study of mortality was performed with survival analysis. Regarding our primary objective, we performed a Benjamini-Hochberg procedure and a multivariable Poisson regression with defined variables of interest. Results The data of 118 hospital stays were included. Prolonged ICU LOS was observed in 47% of cases and was associated with chronic obstructive pulmonary disease, pneumopathies, intraoperative blood transfusion, and surgical duration. Medical and surgical complications were associated with prolonged ICU LOS. After the Benjamini-Hochberg procedure, infectious complications, complications, major complications, total number of pneumopathies, and operative time remained significant. At least one complication was experienced by 71% of patients during the hospitalization, and 33% of patients suffered from major complications. Infectious complications were the most common (40% of patients) and were mainly caused by pneumonia (25% of patients); these complications were associated with low preoperative hemoglobin level, intraoperative blood transfusion, accumulation of reversible cardiovascular risk factors, chronic alcohol consumption, and duration of surgery. Pneumonia was specifically associated with chronic obstructive pulmonary disease. The ICU readmission rate was 10% and was associated with lower preoperative hemoglobin level, pneumopathies, surgical duration, and use of a fibular flap. The 1-year mortality was 12%, and the survival analysis showed no association with prolonged ICU LOS. Poisson regression showed that ICU LOS was prolonged by smoking history, lower preoperative hemoglobin level, intraoperative blood transfusion, major complication, and pneumopathies. Conclusions Practices such as blood management and respiratory prehabilitation could be beneficial and should be evaluated as a part of global improvement strategies.

The early detection and management of oral premalignant lesions (OPMDs) improve their outcomes. Animal models that mimic histological and biological processes of human oral carcinogenesis may help to improve the identification of OPMD at-risk of progression into oral squamous cell carcinoma and to develop preventive strategies for the entire field of cancerization. No animal model is perfectly applicable for investigating human oral carcinogenesis. However, the 4-nitroquinoline 1-oxide (4-NQO) mouse model is well established and mimics several morphological, histological, genomic and molecular features of human oral carcinogenesis. Some of the reasons for the success of this model include its reproducible experimental conditions with limited variation, the possibility of realizing longitudinal studies with invasive intervention or gene manipulation, and sample availability for all stages of oral carcinogenesis, especially premalignant lesions. Moreover, the role of histological and molecular alterations in the field of cancerization (i.e., macroscopically healthy mucosa exposed to a carcinogen) during oral carcinogenesis can be easily explored using this model. In this review, we discuss the advantages and drawbacks of this model for studying human oral carcinogenesis. In summary, the 4-NQO-induced murine oral cancer model is relevant for investigating human oral carcinogenesis, including the immune microenvironment, and for evaluating therapeutic and chemoprevention agents.

International audience; Understanding the dynamics of the immune microenvironment is critical to the development of immunobased strategies for the prevention of oral potentially malignant disorders transformation to oral squamous cell carcinoma (OSCC). We used laser capture microdissection and RNA-sequencing to profile the expression of 13 matched pairs of epithelial versus stromal compartments from normal mucosa, hyperplasia, dysplasia, and invasive tumors in the 4-nitroquinolein (4-NQO) murine model of oral carcinogenesis. Genes differentially expressed at each step of transformation were defined. Immune cell deconvolution and enrichment scores of various biological processes including immune-related ones were computed. Immunohistochemistry was also performed to characterize the immune infiltrates by T-cells (T-cells CD3+, helper CD4+, cytotoxic CD8+, regulatory FoxP3+), B-cells (B220+), and macrophages (M1 iNOS+, M2 CD163+) at each histological step. Enrichment of three independent M2 macrophages signatures were computed in 86 oral leukoplakia with available clinical outcome. Most gene expression changes were observed in the stromal compartment and related to immune biological processes. Immune cell deconvolution identified infiltration by the macrophage population as the most important quantitatively especially at the stage of dysplasia. In 86 patients with oral leukoplakia, three M2 macrophages signatures were independently associated with improved oral cancer-free survival. This study provides a better understanding of the dynamics of the immune microenvironment during oral carcinogenesis and highlights an unexpected association of M2 macrophages gene expression signatures with oral cancer free survival in patients with oral leukoplakia.

International audience; The ongoing shortage in healthcare services and the increasing cancer incidence, highlight the need for new strategies to ensure optimal treatments, cares and follow-up for all patients. Digitalized healthcare, which includes various concepts (digital health, telemedicine, telemonitoring and digital therapeutics), are a promising option to meet these needs. In this scoping review, we provide an overview of the recent available research evidence on digitalized healthcare for HNC patients and caregivers. Through the interrogation of PubMed and Cochrane Library databases, a total of 32 relevant articles reporting the use of digitalized healthcare in different settings of HNC patients' care management, were analyzed. Overall, HNC patients as well as caregivers were highly satisfied, especially because digitalized healthcare allows the early detection of health disorders, improve patient's management, quality of life, self-confidence and communication. Furthermore, digitalized healthcare were significantly time- and cost-effective. While the benefits digitalized healthcare has been reported to be feasible and clinically relevant, our future efforts should focus on the demonstration of their clinical utility in well-designed clinical trials. It is tempting to anticipate that this approach will improve patients' management and quality of life and change the way patients interact with family and professional health care givers.

International audience; Craniofacial fractures management is challenging to teach due to the complex anatomy of the head, even when using three-dimensional CT-scan images. DIVA is a software allowing the straightforward visualization of CT-scans in a user-friendly three-dimensional virtual reality environment. Here, we assess DIVA as an educational tool for craniofacial trauma for undergraduate medical students. Three craniofacial trauma cases (jaw fracture, naso-orbital-ethmoid complex fracture and Le Fort 3 fracture) were submitted to 50 undergraduate medical students, who had to provide diagnoses and treatment plans. Each student then filled an 8-item questionnaire assessing satisfaction, potential benefit, ease of use and tolerance. Additionally, 4 postgraduate students were requested to explore these cases and to place 6 anatomical landmarks on both virtual reality renderings and usual slice-based three-dimensional CT-scan visualizations. High degrees of satisfaction (98%) without specific tolerance issues (86%) were reported. The potential benefit in a better understanding of craniofacial trauma using virtual reality was reported by almost all students (98%). Virtual reality allowed a reliable localization of key anatomical landmarks when compared with standard three-dimensional CT-scan visualization. Virtual reality interfaces such DIVA are beneficial to medical students for a better understanding of craniofacial trauma and allow a reliable rendering of craniofacial anatomy.

International audience; Background: Adenoid cystic carcinoma (ACC) accounts for 1% of malignant head and neck tumours [1] and 10% of salivary glands malignant tumours. The main objective of our study is to investigate the prognostic factors influencing the event-free survival (EFS) of patients with ACC. Patients and methods: A multicentre prospective study was conducted from 2009 to 2018. All 470 patients with ACC whose survival data appear in the REFCOR database were included in the study. The main judgement criterion was EFS. Both a bivariate survival analysis using log-rank test and a multivariate using Cox model were performed using the R software. Results: Average age was 55 years. Females accounted for 59.4% of the cohort. The body mass index (BMI) was normal in 86% of cases. Tumours were located in minor salivary glands in 60% of cases. T3/T4 stages represented 58%; 89% of patients were cN0. histological grade III was observed on 21% of patients. The EFS and overall 5-year survival rates were 50% and 85%, respectively. After adjustment, the most significant pejorative prognostic factors were age >= 65 years (hazard ratio [HR] = 1.67), BMI

International audience; Head and neck squamous cell carcinomas (HNSCC) are the seventh most frequent cancers. Among HNSCCs, oral squamous cell carcinomas (OSCCs) include several anatomical locations of the oral cavity, but exclude the oropharynx. The known risk factors for OSCCs are mainly alcohol consumption and tobacco use for at least 75-80% of cases. In addition to these risk factors, Human papillomavirus (HPV) types 16 and 18, classified as high-risk (HR) HPV genotypes, are considered as risk factors for oropharyngeal cancers, but their role in the development of OSCC remains unclear. We tested the hypothesis of viral etiology in a series of 68 well-characterized OSCCs and 14 potentially malignant disorders (PMD) in non-smoking, non-drinking (NSND) patients using broad-range, sensitive molecular methodologies. Deep-sequencing of the transcriptome did not reveal any vertebrate virus sequences other than HPV transcripts, detected in only one case. In contrast, HPV DNA was detected in 41.2% (28/68) and 35.7% (5/14) of OSCC and PMD cases, respectively. Importantly, 90.9% (30/33) of these belonged to the Betapapillomavirus genus, but no viral transcripts were detected. Finally, high-throughput sequencing revealed reads corresponding to transcripts of the Trichomonas vaginalis virus (TVV), which were confirmed by RT-PCR in two OSCCs. Our results strongly suggest that Alphapapillomavirus genotypes classified as HR are not involved in the development of OSCCs in NSND patients and that known oncogenic infectious agents are absent in these specific OSCCs. Any possible direct or indirect role of Betapapillomavirus genus members and TVV in OSCCs remains speculative and requires further investigation.

Background and aim Hypoglossal nerve stimulation (HNS) decreases obstructive sleep apnoea (OSA) severity via genioglossus muscle activation and decreased upper airway collapsibility. This study assessed the safety and effectiveness at 6 months post-implantation of a novel device delivering bilateral HNS via a small implanted electrode activated by a unit worn externally, to treat OSA: the Genio™ system. Methods This prospective, open-label, non-randomised, single-arm treatment study was conducted at eight centres in three countries (Australia, France and the UK). Primary outcomes were incidence of device-related serious adverse events and change in the apnoea–hypopnoea index (AHI). The secondary outcome was the change in the 4% oxygen desaturation index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring and device use. This trial was registered with ClinicalTrials.gov, number NCT03048604. Results 22 out of 27 implanted participants (63% male, aged 55.9±12.0 years, body mass index (BMI) 27.4±3.0 kg·m−2) completed the protocol. At 6 months BMI was unchanged (p=0.85); AHI decreased from 23.7±12.2 to 12.9±10.1 events·h−1, a mean change of 10.8 events·h−1 (p5 days per week, and 77% reported use for >5 h per night. No device-related serious adverse events occurred during the 6-month post-implantation period. Conclusions Bilateral HNS using the Genio™ system reduces OSA severity and improves quality of life without device-related complications. The results are comparable with previously published HNS systems despite minimal implanted components and a simple stimulation algorithm., A new method of hypoglossal nerve stimulation to treat sleep apnoea does so bilaterally via an implanted neurostimulator activated externally. Its simplicity and relative non-invasiveness have not compromised its effectiveness relative to older methods. http://bit.ly/2lDCeif

Background Patterns of nodal involvement in adenoid cystic carcinoma (ACC) of the head and neck have not been sufficiently assessed to guide a decision of prophylactic neck dissection (ND). The objective of this study is to analyse the influence of ND on event-free survival (EFS) for patients with cN0 ACC. Patients and methods A multicentre prospective study was conducted between 2009 and 2018. Patients presenting cN0 non-metastatic ACC on any site, and who received surgery on the tumour, were included. EFS was the main judgement criterion. A comparative survival analysis between the groups that received a ND versus those that did not was performed, using a propensity score. Analyses were carried out using the R software. Results Between 2009 and 2018, 322 patients with cN0 ACC were included, out of which 58% were female. The average age was 53 years. Tumours were in minor salivary glands in 58% of cases, and 52% had T3/T4 stages. ND was performed on 46% of patients. Out of them, seven had histological lymph node invasion, out of which six had tumour infiltration in the mucosa of oral cavity. After propensity score, the median EFS for N0 patients with ND was 72 months (95% Confidence Interval (CI) [48–81]), compared to 73 months (95% CI [52–85]) for patients without ND (HR = 1.33; 95% CI [0.82–2.16]; p = 0.2). Conclusion ND of cN0 patients does not provide any benefit on EFS, which suggests that its application on such patients is not necessary.

Objectives There is no consensus for the specific management of elderly patients presenting with oral cavity squamous cell carcinomas (OC SCC). We report our findings in the treatment of primary OC SCC, for patients of 70 years of age or more, in a French university hospital center. Patients and methods One hundred and twenty five patients diagnosed between 2000 and 2010, were included retrospectively. Independent risk factors of post-operative complications were identified using a logistic regression. The overall survival (OS) was estimated using the Kaplan Meier method. Independent factors of survival were calculated using a Cox model. Results The patient's median age was 78. Women presented significantly more premalignant lesions, less alcohol intoxication, and less tobacco consumption. Half of the population sample was staged T4 in the TNM classification. Eighty eight percent of the patients received a curative treatment. The independent risk factors for post-operative complications were T3/T4 stages (OR 4.3 [1.3–14.4]), lymph node metastasis (OR 6.9 [2.1–22.7]), and alcohol abuse (OR 3.5 [1.1–11.0]). The median OS was 14.0 months. The independent negative prognostic factors for OS for patients treated curatively were: age >79 years (HR 1.9 [1.2–3.2]), stage T2/T3/T4 tumor vs. T1 (HR = 3.0 [1.5–6.0], P = 0.001) and substandard surgery (HR = 1.8 [1.1–2.9], P = 0.03). Conclusions The management of OC SCC in elderly patients is complex and requires collaboration among gerontologists, surgeons and oncologists. The treatment choice is related to the disease extent and preoperative morbid conditions.

Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and somatostatin (SRIF), and a gastrointestinal hormone, ghrelin. The neurotransmitter acetylcholine (ACh) is involved in tuning GH secretion, and its GH-stimulatory action has mainly been shown in adults but is not clearly documented during development. ACh, together with these hormones and their receptors, is expressed before birth, and somatotroph cells are already responsive to GHRH, SRIF, and ghrelin. We thus hypothesized that ACh could contribute to the modulation of the main components of the somatotropic axis during development. In this study, we generated a choline acetyltransferase knockout mouse line and showed that heterozygous mice display a transient deficit in ACh from embryonic day 18.5 to postnatal day 10, and they recover normal ACh levels from the second postnatal week. This developmental ACh deficiency had no major impact on weight gain and cardiorespiratory status of newborn mice. Using this mouse model, we found that endogenous ACh levels determined the concentrations of circulating GH and IGF-1 at embryonic and postnatal stages. In particular, serum GH level was correlated with brain ACh content. ACh also modulated the levels of GHRH and SRIF in the hypothalamus and ghrelin in the stomach, and it affected the levels of these hormones in the circulation. This study identifies ACh as a potential regulator of the somatotropic axis during the developmental period.

Background Oral squamous cell carcinoma is a major cause of cancer-associated morbidity and mortality and may develop from oral erythroplakia and leukoplakia (OEL), the most common oral potentially malignant lesions. Our objective was to provide a descriptive overview of the global research activity on OEL over the past decades. Methods We performed a systematic bibliometric analysis of articles and reviews on OEL up to December 31st 2016 using the SCOPUS database. Contribution of each country was analyzed by density-equalizing mapping (DEMP). The overall scientific productivity was analyzed for each journal and country. Results A total of 5098 published items (articles or reviews) were identified. They are expected to double by 2040, with an expected number of 400 items per year. Only 4% of all research on oral oncology is focused on OEL. Together with the increasing number of publications since 1980s, an increasing number of international collaborative studies were observed. Journal of Oral Pathology and Medicine and Oral Oncology are the leading journals in terms of number of published items. The US, India, and the UK were the most prolific countries in terms of publications overtime. Conclusions We identified the leading journals as well as the leading authors and countries contributing to the research on OEL. International collaborative studies in the field are to be encouraged to refine strategies of oral cancer prevention.

BackgroundOral squamous cell carcinomas (OSCC) prognosis remains poor. While AJCC TNM 8th edition has slightly improved patients‘ stratification with regard to prognostic, innovative approaches to are still needed. As in other tumor types, tumor immune microenvironment (TiME) might represent an opportunity to improve prognostic assessment.MethodsTiME landscape of 47 HPV-negative OSCC was analyzed using multiplex immunofluorescence (mIF). Markers for tumor cells (PanCK), tumor infiltrating lymphocytes (CD3, CD8), macrophages (CD68), inhibitory (PD-1, PD-L1, TIM3, LAG3, VISTA) or stimulatory (OX40, ICOS) immune checkpoints (ICP) were studied. Regions of interest (ROI), 5 in the tumor core and 5 at the invasion front, were subjected to cell markers identification and quantification (scoring) as well as tissue compartmentalization to divide them in tumor-epithelial and tumor-stroma compartments, respectively. A total of 20 cell phenotypes were defined based on previous work (CK+, CK+PD-L1+, CD3+, CD3+CD8+, CD3+PD-1+, CD3+CD8+PD-1+, CD3+PD-L1+, CD3+CD8+PD-L1+, CD3+PD-L1+PD-1+, CD3+CD8+PD-L1+PD-1+, CD68+, CD68+PD-L1+, CK+OX40+, CD3+VISTA+, CD3+ICOS+, CD3+LAG3+, CD3+OX-40+, CD3+TIM3+). Results were correlated with clinical features including disease-specific survival (DSS) using the Kaplan-Meier method and a multivariate Cox model. A multivariate general linear model (GLM) was built to test the specific association of each variable with a given cell density by correcting the possible confusion due to other variables.ResultsImmune cells densities were significantly higher overall in the stroma. The intra-tumor stroma showed a significant enrichment of in CD3+PD-1+ T cells compared to peri-tumor stroma. None of the clinical or pathological (resection margin, tumor stage, lymph node invasion, perineural invasion) was significantly associated with DSS. In contrast, the following cell phenotypes in the tumor invasion front were strongly associated with a poor DSS, including CD3+PD-L1+ (P-value= 0.004), CD3+PD1+PD-L1+ (P-value= 0.02) and CD3+OX40+ (P-value= 0.02) T cells as well as CD3+CD8+PD-1+ (P-value= 0.048), CD3+CD8+PD-L1+ (P-value= 0.008) and CD3+CD8+PD1+PD-L1+ (P-value= 0.01) cytotoxic T cells. In the tumor core, CD68+PD-L1- macrophages (P-value= 0.06) were marginally associated with better DSS. Using a GLM, we found that tumor from smoker-drinker patients and/or with pN+, were significantly more infiltrated by PD-1- and/or PD-L1-positive immune cells. On the other hand, floor of mouth and gingiva-mandibular OSCC were significantly less infiltrated than others.ConclusionsThe prognostic value of PD-1+ and/or PD-L1+ cells in the invasion front of resected OSCC was remarkable, underlying the importance of this area when studying the TiME. Incorporating TiME analysis in the invasion front may improve prognostic evaluation of patients treated for OSCC, especially in the context of immunotherapy.AcknowledgementsThis study was supported by a strategic alliance between the Translational Molecular Pathology-Immunoprofiling las (TMP-IL) at the Department Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center and the Université Claude Bernard Lyon, Centre de Recherche en Cancérologie de Lyon and the Department of Translational Medicine, Centre Léon Bérard, Lyon, France. The authors would acknowledge ITMO Cancer 2020, ”Formation à la Recherche Fondamentale et Translationnelle en Cancérologie” (JB); CLARA 2020 ”Soutien à la mobilité des jeunes chercheurs en oncologie, N° CVPPRCAN000198” (JB); Fondation de France 2020 ”Aide à la mobilité international de médecins et pharmaciens, N° 00112162” (JB); Ligue contre le cancer 2021, comité de Saône-et-Loire (PS); 2017-INCa-DGOS-Inserm_12563: INCa SIRIC-LYriCAN INCa-DGOS-Inserm_12563 (PS)Ethics ApprovalThe study was conducted in accordance with all applicable laws, rules, and requests of French and European government authorities. Written informed consent was obtained from all patients and the study was approved by the Centre Leon Bérard institutional review board (Lyon, France). Samples were obtained from the CRB Centre Léon Bérard (n°BB-0033-00050) which is quality certified according NFS96-900 French standard and ISO 9001 for clinical trials.ConsentWritten informed consent was obtained from all patients and the study was approved by the Centre Leon Bérard institutional review board (Lyon, France)

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.

Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality. Although OSCC may develop from easily accessible oral preneoplastic lesions (OPLs), no intervention has been reported so far that reduces the rate of malignant transformation. A comprehensive molecular characterization of oral carcinogenesis may help refining treatment strategies both in patients with OPLs and OSCC. Herein, we review main molecular alterations occurring at different steps during oral carcinogenesis and show how molecularly-based medicine and surgery may impact the outcome of OSCC in the future.

Introduction Hypoglossal Nerve Stimulation (HGNS) decreases obstructive sleep apnea (OSA) severity by contracting the tongue and decreasing upper airway collapsibility. This study assessed the safety and effectiveness of a new implantable device that delivers bilateral HGNS: the Genio™ system. Methods The BLAST OSA study (BiLAteral Hypoglossal Nerve Stimulation for Treatment of Obstructive Sleep Apnea), was a prospective, open-label, non-randomized, single arm treatment study conducted at eight centres in three countries (Australia, France, UK). Primary outcomes were the incidence of device-related Serious Adverse Events (SAEs) and change in the Apnea-Hypopnea Index (AHI). The secondary outcome was change in the 4% Oxygen Desaturation Index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring, and device use. Participants were eligible if: 21-75 years old; BMI ≤ 32 kg/m2; obstructive AHI 20-60 events/hr and combined central and mixed AHI < 10 events/hr; no positional OSA; no Complete Concentric Collapse of the soft palate during Drug Induced Sleep Endoscopy; and failed to tolerate or accept Positive Airway Pressure treatments. Results 27 participants were implanted (63% male, aged 55.9±12.0 years, BMI 27.4±3.0 kg/m2). 22 completed the protocol. At 6 months, AHI decreased from 23.7±12.2 to 12.9±10.1 events/hr [p5 days per week, and 77% used it >5 hours per night. The number of bed partners reporting disruptive snoring decreased from 96% to 35%. No device-related SAE occurred. Conclusion In a targeted population of individuals with moderate-to-severe OSA, the Genio system reduced OSA severity and sleepiness, improved quality of life, and was associated with high adherence and an acceptable safety profile. Support This study trial was funded by Nyxoah S.A. This trial was registered with ClinicalTrials.gov, number NCT03048604.

Objectif Evaluer l’innocuite et l’efficacite, a 6 mois post implantation, d’un nouveau dispositif implantable (Genio®, NYXOAH S.A.) delivrant une stimulation bilaterale du XII pour le traitement du SAHOS modere a severe. Methodes Etude prospective, ouverte, multicentrique (8 centres, Australie, France et Royaume-Uni) chez des patients avec un IAH entre 20 et 60/h, en echec de traitement par PPC et orthese, avec, comme objectifs principaux, la survenue d’evenements indesirables graves (EIG) lies au dispositif et la variation de l’IAH et comme objectifs secondaires, la variation de l’index de desaturations en O2 (IDO), du score d’Epworth, de la qualite de vie et du ronflement et l’observance. Resultats Sur 27 sujets implantes (63 % d’hommes, âge 55,9 ± 12,0 ans, IMC 27,4 ± 3,0 kg/m2), 22 ont termine le protocole. Aucun EIG lie au dispositif n’est survenu au cours des 6 mois suivant l’implantation. A 6 mois, l’IAH a diminue de 23,7 ± 12,2 a 12,9 ± 10,1/h (p Conclusion La stimulation cyclique et bilaterale du XII par le systeme Genio® ameliore de maniere significative plusieurs parametres du SAHOS modere a severe avec un profil de securite et d’adhesion au traitement satisfaisant.

Hypoglossal Nerve Stimulation (HGNS) can decrease Obstructive Sleep Apnea (OSA) severity via tongue contraction and decreased upper airway collapsibility and thus be an alternative for patients who do not tolerate Positive Airway Pressure. To assess the safety and effectiveness at 6 months post-implantation of a novel device delivering bilateral HGNS to treat OSA: the Genio™ system, a prospective, open-label, non-randomized, single arm treatment study was conducted at eight centers in three countries (Australia, France, UK). Primary outcomes were the incidence of device-related Serious Adverse Events (SAEs) and change in the Apnea-Hypopnea Index (AHI). The secondary outcome was the change in the 4% Oxygen Desaturation Index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring, and device use. From 27 implanted participants (63% male, aged 55.9±12.0 years, BMI 27.4±3.0 kg/m²), 22 completed the protocol. At 6 months, AHI decreased from 23.7±12.2 to 12.9±10.1, a mean change of 10.8 events/hr [p 5 days per week, and 77% reported use for >5 hours per night. No device-related SAE occurred during the 6-months post-implantation period. In conclusion, bilateral HGNS using the Genio™ system can reduce OSA severity and improve quality of life with an acceptable safety profile.

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 (Pitie-Salpetriere 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.