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BACKGROUND: France has the sixth highest incidence of oropharyngeal cancer (OPC) in Europe, but the epidemiological impact of high-risk HPV (HR-HPV) remains poorly documented. The objective of our study was to assess the proportion of OPCs caused by HR-HPV in Paris, and its suburbs, over the four past decades. This area accounts for almost one-fifth of the total population of France. METHODS: OPCs diagnosed in 1981, 1986, 1991, 1996, 2001, 2006, 2011, 2016 and 2020/2021 in two of the main referral cancer centers for HNCs in Paris and its suburbs were retrieved from the tumor biobanks. HPV status was determined by p16-staining and HPV-DNA detection. Samples were considered HPV-driven if both assays were positive. Results were compared to the French cancer registry data. RESULTS: Samples from 697 OPC patients were assessed (including 82â¯% of all samples diagnosed in 2001, 2006, 2011, 2016, 2021). The proportion of HPV-driven cases rose from 2.7â¯% to 53â¯% between 1981 and 2021. HPV16 was the dominant genotype during the study period. Of patients with HPV-driven OPC, 81â¯% were male and 42â¯% were smokers versus 80â¯% and 92â¯% in their HPV-negative counterparts. The age of OPC patients increased significantly, during the study period, independent of their HPV status CONCLUSION: The proportion of HPV-driven OPCs has significantly increased in Paris and its suburbs, during the last four decades. OPCs has become the 2nd predominant type of head and neck cancer, in France. This may be linked to the rise in HPV-driven cases and the decrease of tobacco and alcohol consumption in men.
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Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Neoplasias Orofaríngeas/virología , Neoplasias Orofaríngeas/epidemiología , Masculino , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Femenino , Persona de Mediana Edad , Paris/epidemiología , Anciano , Incidencia , AdultoRESUMEN
INTRODUCTION: Primary laryngeal mucosal melanoma is a rare tumour with a poor prognosis. Its often difficult diagnosis should rule out laryngeal metastatic localization of cutaneous melanoma. CASE PRESENTATION: We report a case of primary laryngeal mucosal melanoma diagnosed in a 65-year-old man, treated 6 years previously with radio-chemotherapy and surgery for squamous cell carcinoma of the right lateral oropharyngeal region. The definitive diagnosis of primary laryngeal mucosal melanoma was made on the resection specimen, whereas the initial biopsy of the epilaryngeal mass discovered during the patient's surveillance had concluded that it was a laryngeal recurrence of the known squamous cell carcinoma. DISCUSSION: Through this case, we propose to remind the main characteristics and the diagnostic pitfalls of these tumours.
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Juvenile onset recurrent respiratory papillomatosis is a lifelong benign squamous lesion associated with HPV infection, particularly HPV6 and HPV11 genotypes. These lesions are rare, but can lead to laryngeal obturations, which can cause disabling dyspnea, or transform into squamous cell carcinoma. The aim here is to provide an epidemiological, biological and clinical overview of this pathology, particularly in children, in order to understand the issues at stake in terms of research and the development of medical and therapeutic management tools.
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Infecciones por Papillomavirus , Infecciones del Sistema Respiratorio , Humanos , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/patología , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/epidemiología , Niño , Papillomavirus Humano 6/genética , Papillomavirus Humano 11/genética , Neoplasias Laríngeas/epidemiología , Neoplasias Laríngeas/virología , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/terapia , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/terapiaRESUMEN
Chronic Human Papilloma Virus (HPV) infection is supplanting alcohol and tobacco intoxications as the leading cause of oropharyngeal cancer in developed countries. HPV-related squamous cell carcinomas of the oropharynx (HPV + OSC) present better survival and respond better to radiotherapy and chemotherapy. Regulatory T cells (TREG) are mainly described as immunosuppressive and protumoral in most solid cancers. However, TREG are paradoxically associated with a better prognosis in HPV + OSCs. The transcription factor FoxP3 is the basis for the identification of TREG. Among CD4 + FoxP3 + T cells, some have effector functions. A medical hypothesis is formulated here: the existence of a CD137 (4.1BB)-Eomesodermin (Eomes) activated pathway downstream of TCR-specific activation in a subpopulation of CD4 + FoxP3 + T cells may explain this effector function. Evidence suggest that this axis may exist either in CD4 + FoxP3 + T cells or CD8 + T cells. This pathway could lead T cells to strong antitumor cytotoxic activity in a tumor-specific manner. Furthermore, CD137 is one of the most expected targets for the development of agonist immunotherapies. The identification of CD137 + Eomes + FoxP3+/- T cells could be a key element in the selective activation of the most anti-tumor cells in the HPV + OSC microenvironment.
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Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Infecciones por Papillomavirus/complicaciones , Linfocitos T CD4-Positivos , Linfocitos T Reguladores , Neoplasias Orofaríngeas/etiología , Neoplasias Orofaríngeas/patología , Factores de Transcripción Forkhead , Microambiente TumoralRESUMEN
PURPOSE: Laryngeal chondrosarcoma is a rare tumor that mostly affects the cricoid cartilage. The aim of this study was to compare outcomes between the various treatments of this pathology as there are no official guidelines for this pathology. METHODS: A retrospective analysis of the pathology database of nine French tertiary care centers was conducted. Outcomes of patients treated by total laryngectomy were compared with those treated by more conservative approaches (endoscopic debulking, median thyrotomy, partial laryngectomy). Two Kaplan-Meier survival analyses were performed: one to assess the overall survival rate and the other to assess laryngeal preservation over time. RESULTS: A total of 43 patients were enrolled: 12 with total laryngectomy as the initial treatment, and 31 who initially underwent laryngeal-preserving treatment. With conservative treatment, laryngeal function was preserved in 96% and 75% of patients at 1 and 5 years, respectively. Conservative treatment did not reduce the overall survival rate. CONCLUSION: These results suggest that laryngeal preservation should be considered as the initial treatment in cases of laryngeal chondrosarcoma.
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Neoplasias Óseas , Condrosarcoma , Neoplasias Laríngeas , Laringe , Humanos , Estudios Retrospectivos , Condrosarcoma/cirugía , Laringe/patología , Neoplasias Laríngeas/cirugía , Laringectomía/métodos , Neoplasias Óseas/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Diagnosis of head and neck (HN) squamous dysplasias and carcinomas is critical for patient care, cure, and follow-up. It can be challenging, especially for grading intraepithelial lesions. Despite recent simplification in the last WHO grading system, the inter- and intraobserver variability remains substantial, particularly for nonspecialized pathologists, exhibiting the need for new tools to support pathologists. METHODS: In this study we investigated the potential of deep learning to assist the pathologist with automatic and reliable classification of HN lesions following the 2022 WHO classification system. We created, for the first time, a large-scale database of histological samples (>2000 slides) intended for developing an automatic diagnostic tool. We developed and trained a weakly supervised model performing classification from whole-slide images (WSI). We evaluated our model on both internal and external test sets and we defined and validated a new confidence score to assess the predictions that can be used to identify difficult cases. RESULTS: Our model demonstrated high classification accuracy across all lesion types on both internal and external test sets (respectively average area under the curve [AUC]: 0.878 (95% confidence interval [CI]: [0.834-0.918]) and 0.886 (95% CI: [0.813-0.947])) and the confidence score allowed for accurate differentiation between reliable and uncertain predictions. CONCLUSION: Our results demonstrate that the model, associated with confidence measurements, can help in the difficult task of classifying HN squamous lesions by limiting variability and detecting ambiguous cases, taking us one step closer to a wider adoption of AI-based assistive tools.
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Carcinoma de Células Escamosas , Aprendizaje Profundo , Humanos , Cuello , Hiperplasia , CabezaRESUMEN
BACKGROUND: ALK, ROS1 and RET rearrangements occur, respectively, in 5%, 2%, and 1% non-small cell lung cancers (NSCLC). ALK and ROS1 fusion proteins detection by immunohistochemistry (IHC) has been validated for rapid patient screening, but ROS1 fusions need to be confirmed by another technique and no RET IHC test is available for clinical use. RESEARCH DESIGN AND METHODS: We report herein the usefulness of the HTG EdgeSeq Assay, an RNA extraction-free test combining a quantitative nuclease protection assay with NGS, for the detection of ALK, ROS1 and RET fusions from 'real-life' small NSCLC samples. A total of 203 FFPE samples were collected from 11 centers. They included 143 rearranged NSCLC (87 ALK, 39 ROS1, 17 RET) and 60 ALK-ROS1-RET negative controls. RESULTS: The assay had a specificity of 98% and a sensitivity for ALK, ROS1 and RET fusions of 80%, 94% and 100% respectively. Among the 19 HTG-assay false negative samples, the preanalytical conditions were identified as the major factors impacting the assay efficiency. CONCLUSIONS: Overall, the HTG EdgeSeq assay offers comparable sensitivities and specificity than other RNA sequencing techniques, with the advantage that it can be used on very small and old samples collected multicentrically.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adhesión en Parafina , Humanos , Quinasa de Linfoma Anaplásico/análisis , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Proteínas de Fusión Oncogénica/análisis , Proteínas Tirosina Quinasas/análisis , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-ret/análisis , Proteínas Proto-Oncogénicas c-ret/metabolismo , ARN , Inmunoquímica/métodosRESUMEN
Pan-Trk immunohistochemistry has been described as a screening test for the detection of NTRK fusions in a broad spectrum of tumor types. However, pan-Trk testing in the clinical setting may be limited by many factors, including analytical parameters such as clones, platforms, and protocols used. This study aimed to harmonize pan-Trk testing using various clones and immunohistochemical (IHC) platforms and to evaluate the level of analytical variability across pathology laboratories. We developed several IHC pan-Trk assays using clones EPR17341 (Abcam) and A7H6R (Cell Signaling Technology) on Ventana/Roche, Agilent, and Leica platforms. To compare them, we sent unstained sections of a tissue microarray containing 9 cases with NTRK3 fusions to participating laboratories, to perform staining on Ventana/Roche (10 centers), Agilent (4 centers), and Leica (3 centers) platforms. A ready-to-use pan-Trk IVD assay (Ventana/Roche) was also performed in 3 centers. All slides were centrally and blindly reviewed for the percentage of stained tumor cells. Laboratory-developed tests with clone EPR17341 were able to detect pan-Trk protein expression in all cases, whereas lower rates of positivity were observed with clone A7H6R. Moderate to strong variability of the positive cases rate was observed with both antibodies in each IHC platforms type and each of the positivity cut points evaluated (≥1%, ≥10%, and ≥50% of stained tumor cells). The rate of false-negative cases was lower when pan-Trk staining was assessed with the lowest positivity threshold (≥1%). In conclusion, most evaluated pan-Trk IHC laboratory-developed tests were able to detect NTRK3-fusion proteins; however, a significant analytical variability was observed between antibodies, platforms, and centers.
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Biomarcadores de Tumor , Receptor trkA , Humanos , Inmunohistoquímica , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/metabolismoRESUMEN
OBJECTIVES: Chatbots, conversational agents that walk medical students (MS) though a clinical case, are serious games that seem to be appreciated by MS. Their impact on MS's performance in exams however was not yet evaluated. Chatprogress is a chatbot-based game developed at Paris Descartes University. It contains 8 pulmonology cases with step-by-step answers delivered with pedagogical comments. The CHATPROGRESS study aimed to evaluate the impact of Chatprogress on students' success rate in their end-term exams. METHODS: We conducted a post-test randomized controlled trial held on all fourth-year MS at Paris Descartes University. All MS were asked to follow the University's regular lectures, and half of them were randomly given access to Chatprogress. At the end of the term, medical students were evaluated on pulmonology, cardiology and critical care medicine. MAIN OUTCOMES MEASURES: The primary aim was to evaluate an increase in scores in the pulmonology sub-test for students who had access to Chatprogress, compared to those who didn't. Secondary aims were to evaluate an increase in scores in the overall test (Pulmonology, Cardiology and Critical care medicine test (PCC)) and to evaluate the correlation between access to Chatprogress and overall test score. Finally, students' satisfaction was assessed using a survey. RESULTS: From 10/2018 to 06/2019, 171 students had access to Chatprogress (the Gamers) and among them, 104 ended up using it (the Users). Gamers and Users were compared to 255 Controls with no access to Chatprogress. Differences in scores on the pulmonology sub-test over the academic year were significantly higher among Gamers and Users vs Controls (mean score: 12.7/20 vs 12.0/20, p = 0.0104 and mean score: 12.7/20 vs 12.0/20, p = 0.0365 respectively). This significant difference was present as well in the overall PCC test scores: (mean score: 12.5/20 vs 12.1/20, p = 0.0285 and 12.6/20 vs 12.1/20, p = 0.0355 respectively). Although no significant correlation was found between the pulmonology sub-test's scores and MS's assiduity parameters (number of finished games among the 8 proposed to Users and number of times a User finished a game), there was a trend to a better correlation when users were evaluated on a subject covered by Chatprogress. MS were also found to be fans of this teaching tool, asking for more pedagogical comments even when they got the questions right. CONCLUSION: This randomised controlled trial is the first to demonstrate a significant improvement in students' results (in both the pulmonology subtest and the overall PCC exam) when they had access to Chatbots, and even more so when they actually used it.
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Educación de Pregrado en Medicina , Estudiantes de Medicina , Juegos de Video , Humanos , Evaluación Educacional , Programas Informáticos , Educación de Pregrado en Medicina/métodosRESUMEN
INTRODUCTION: In early cervical cancer (EEC), 10 to 15% of patients without nodal metastasis (N-) will suffer from recurrences with further similar survival as N+ patients. However, no clinical, imaging or pathological risk-factor is today available to identify them. In the present study, we hypothesized that the N- histologically characterized patients who present a poor prognosis could be patients for whom metastasis are missed by classical procedure. Therefore, we propose to research HPV tumoral DNA (HPVtDNA) in pelvic Sentinel Lymph Nodes (SLN) biopsy using ultrasensitive droplet-based digital PCR (ddPCR) to detect eventual occult metastasis. MATERIALS AND METHODS: Sixty HPV16, HPV18 or HPV33 positive EEC N- patients with available SLN were included. In SLN, HPV16 E6, HPV18 E7 and HPV33 E6 gene were respectively detected using ultrasensitive ddPCR technology. Survival data were analysed using Kaplan-Meier-curves and log-rank-test to compare progression-free survival (PFS) and disease-specific survival (DSS) in two groups according to their HPVtDNA status in SLN. RESULTS: More than half (51.7%) of the patients finally showed HPVtDNA positivity in SLN initially diagnosed as negative by histology. Two patients with negative HPVtDNA SLN and 6 with positive HPVtDNA SLN group presented recurrence. Finally, all of the 4 deaths listed in our study occurred in the positive HPVtDNA SLN group. CONCLUSION: These observations hint that the use of ultrasensitive ddPCR to detect HPVtDNA in SLN could allow the identification of two subgroups of histologically N- patients that may have different prognosis and outcome. To our knowledge, our study is the first one to evaluate the detection of HPVtDNA in SLN in early cervical cancer using ddPCR highlighting its interest as a complementary tool for N- specific early cervical cancer diagnosis.
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Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Virus del Papiloma Humano , Metástasis Linfática/patología , Ganglios Linfáticos , Reacción en Cadena de la Polimerasa , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Estadificación de NeoplasiasRESUMEN
Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.
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Fibroblastos , Pulmón , Animales , Epítopos/metabolismo , Fibroblastos/metabolismo , Fibrosis , Inmunoterapia , Hígado/patología , Pulmón/metabolismo , Ratones , Vacunación , Proteína con Dedos de Zinc GLI1/metabolismoRESUMEN
Medical reports are key elements to guarantee the quality, and continuity of care but their quality remains an issue. Standardization and structuration of reports can increase their quality, but are usually based on expert opinions. Here, we hypothesize that a structured model of medical reports could be learnt using machine learning on retrospective medical reports extracted from clinical data warehouses (CDW). To investigate our hypothesis, we extracted breast cancer operative reports from our CDW. Each document was preprocessed and split into sentences. Clustering was performed using TFIDF, Paraphrase or Universal Sentence Encoder along with K-Means, DBSCAN, or Hierarchical clustering. The best couple was TFIDF/K-Means, providing a sentence coverage of 89 % on our dataset; and allowing to identify 7 main categories of items to include in breast cancer operative reports. These results are encouraging for a document preset creation task and should then be validated and implemented in real life.
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Neoplasias de la Mama , Data Warehousing , Algoritmos , Neoplasias de la Mama/cirugía , Análisis por Conglomerados , Femenino , Humanos , Estudios RetrospectivosRESUMEN
The COVID-19 pandemic has led health schools to cancel many on-site training and exams. Teachers were looking for the best option to carry out online OSCEs, and Zoom was the obvious choice since many schools have used it to pursue education purposes. METHODS: We conducted a feasibility study during the 2020-2021 college year divided into six pilot phases and the large-scale eOSCEs on Zoom on June 30th, 2021. We developed a specific application allowing us to mass create Zoom meetings and built an entire organization, including a technical support system (an SOS room and catching-up rooms) and teachers' training sessions. We assessed satisfaction via an online survey. RESULTS: On June 30th, 531/794 fifth-year medical students (67%) participated in a large-scale mock exam distributed in 135 Zoom meeting rooms with the mobilization of 298 teachers who either participated in the Zoom meetings as standardized patients (N =135, 45%) or examiners (N =135, 45%) or as supervisors in the catching-up rooms (N =16, 6%) or the SOS room (N =12, 4%). In addition, 32/270 teachers (12%) experienced difficulties connecting to their Zoom meetings and sought the help of an SOS room member. Furthermore, 40/531 students (7%) were either late to their station or had technical difficulties and declared those issues online and were welcomed in one of the catching-up rooms to perform their eOSCE stations. Additionally, 518/531 students (98%) completed the entire circuit of three stations, and 225/531 students (42%) answered the online survey. Among them, 194/225 (86%) found eOSCES helpful for training and expressed their satisfaction with this experience. CONCLUSION: Organizing large-scale eOSCEs on Zoom is feasible with the appropriate tools. In addition, eOCSEs should be considered complementary to on-site OSCEs and to train medical students in telemedicine.
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COVID-19 , Estudiantes de Medicina , Estudios de Factibilidad , Humanos , Pandemias , Encuestas y CuestionariosRESUMEN
BACKGROUND: Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD. METHODS: Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan-Meier curves and Cox models. RESULTS: In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4-0.7, Pearson correlation = 0.64-0.86, all P < 10-11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I-III BRCA (interaction test, P < 0.001). CONCLUSIONS: UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.