The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma

Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor-supporting pathways. Using shRNA-mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three-dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated-like phenotype, indicating a context-dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous-type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Head and neck cancer - prediction and modeling of regional progression

Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, is responsible for over 500'000 new cases annually. Despite advances in surgical techniques and radiation therapy protocols, along with the emergence of targeted treatments and immunothérapies, the survival of HNSCC patients has not progressed in the last 20 years1. The presence of lymph node metastasis (LNM) is the most accurate predictor of cancer-related outcome in HNSCC patients2-4. Therefore, correct assessment of the neck is critical for risk stratification and treatment planning. Clinically negative neck (cNO) is defined as the absence of LNM based on pre-treatment clinical and radiological examinations. Currently, the recommended approach to treat cNO patients is to perform an elective neck dissection. As the prevalence of OLNM in only 20-30%, this means that at least 70% of neck dissections are useless. Sentinel node biopsy (SLNB) is a less invasive alternative to elective neck dissection, but SLNB is technically challenging and still requires an opening of the neck. In this work, we developed a différent approach, which enables the prédiction of occult LNM (OLNM) solely based on primary tumor features, thereby reserving neck dissection for high-risk patients. We showed that the lymphatic endothelial marker PROX1 and the pan-endothelial marker CD31, which are both expressed at the level of the primary tumor, were significantly associated with OLNM. We used a machine learning approach to combine CD31 and PROX1 with classical clinicopathological markers. This model reached 95% negative prédictive value while conserving a reasonably good positive prédictive value (PPV). While OLNM is a significant problem regarding the secondary effects of surgery, treatment failures account for a majority of HNSCC related deaths. To better understand how tumors relapse after surgery we had first to create a surgical mouse model. This model is based on the orthotopic implantation of mEERL5 and mEERL95 cells6 which initiate primary tumors in the neck, recapitulate the histology of poorly differentiated aggressive HNSCC and give rise to post-surgical récurrences. This model is the first immune-competent orthotopic mouse model of HNSCC disease progression suitable for pre-clinical studies. Post-surgical local, régional and distant relapses are initiated by cancer cell clones that escaped from the surgical field and subsequently promoted secondary tumor growth. To understand the clonal dynamics of tumor progression, mEERL, and mEERL95 cells were transduced with a highly complex genetic barcoding library. Following implantation of cells in the floor of the mouth of C57BL/6Rj mice, we micro-surgically resected primary tumors and followed mice until they developed local récurrence. Barcodes retrieved by PCR from genomic DNA were analyzed by next-generation sequencing (NGS). Barcoding revealed that HNSCC tumor progression is governed by a successive clonal shift aiong with an exponential enrichment of malignant clones following a stepwise advancement from the primary tumor and nodal métastasés to récurrent tumors, récurrent nodal and distant métastasés. The development of a prédictive model of OLNM now calls for a prospective randomized trial comparing RF model risk stratification versus elective neck dissection, whereas our insights on clonal évolution shall motivate novel approaches for the development of targeted therapies directed at advanced HNSCC cases. -- Les carcinomes épidermoïdes de la tête et du cou représentent la sixième cause de cancer dans le monde. Malgré de nombreuses avancées chirurgicales, radio- et immuno- thérapeutiques , la survie des patients ne s'est pas améliorées depuis près de 20 ans1. La présence de métastases ganglionnaires est le prédicteur le plus précis du pronostic de la maladie2-4. Les patients avec un cou cliniquement négatif (cNO), défini par l'absence de métastases ganglionnaires lors de l'examen initial, sont actuellement traité électivement par un évidement ganglionnaire, en raison du risque de métastases occultes, qui peut atteindre jusqu'à 30% des patients. En contrepartie, cela signifie que 70% des évidements cervicaux n'ont pas de réelle utilité. La biopsie du ganglion sentinelle est une technique alternative de pointe à la dissection ganglionnaire élective mais celle-ci demeure toujours invasive et requiert une collaboration étroite entre de nombreux spécialistes. Dans le présent travail nous avons montré que des marqueurs au niveau de la tumeur primaire, PROX1 et CD31, exprimés par les cellules endothéliales, étaient significativement associés à la présence de métastases ganglionnaires occultes. Nous avons utilisé une approche d'apprentissage automatique pour combiner ces marqueurs à des paramètres clinico- pathologiques classiques. Le modèle prédictif final a atteint une valeur prédictive négative de 95% tout en conservant une bonne valeur prédictive positive. Bien que les métastases ganglionnaires occultes soit un problème significatif, les échecs de traitements représentent la cause majeure de décès liés à cette maladie. Afin de mieux comprendre comment les tumeurs récidivent après la chirurgie, nous avons créé un nouveau modèle chirurgical murin. Ce dernier est basé sur l'implantation des cellules mEERL5 ou mEERL956 qui développent de manière reproductible des tumeurs primaires dans le cou, des récurrences locales, des métastases, et récapitulent bien l'histologie de carcinomes épidermoïdes agressifs et peu différenciés. Les récidives post-chirurgicales sont initiées par des clones cellulaires cancéreux qui ont échappés à la résection chirurgicale et permettent ainsi le développement de tumeurs secondaires. Pour comprendre la dynamique clonale des récurrences et métastases, nous avons transduit les cellules mEERL et mEERL95 avec une librairie hautement complexe de code-barres génétiques. Après l'implantation des cellules, nous avons réséqué micro-chirurgicalement les tumeurs primaires et suivi les animaux jusqu'à ce qu'ils développent des récurrences locales et des métastases. Les codes-barres ont été récoltés par PCR depuis de l'ADN génomique de cinq tissus différents, avant la déconvolution finale des codes- barres par des techniques de séquençage de nouvelle génération. Ceci a permis le suivi des clones à une échelle unicellulaire. En résumé, ceci nous a permis de mettre en valeur que la progression tumorale des carcinomes épidermoïdes de la tête et du cou est gouvernée par une transition clonale successive accompagnée d'un enrichissement exponentiel de clones malins, de la tumeur primaire à la récurrence locale, puis à aux récidives régionales et à distance. Le développement d'un modèle prédictif de métastases ganglionnaires occultes devra être suivi par un essai prospectif randomisé comparant une approche de stratification du risque à la dissection ganglionnaire élective. Quant à nos avancées concernant la description de l'évolution clonale, ces dernières devraient motiver de nouvelles approches pour le développement de thérapies ciblées des carcinomes épidermoïdes de la tête de du cou de stades avancés

Mediastinal abscess revealed by computed tomography after pharyngeal fish-bone impaction

Fishbone impactions in the upper aerodigestive tract are frequent but rarely cause serious complications when recognized and treated early. In this report, we describe the case of a patient that sought medical attention as late as 2 weeks after the fishbone impaction. A 52-year-old male was presented with fever, odynophagia and a toxic appearance. CT scan revealed a large cervicomediastinal abscess. The patient was immediately started on large-spectrum antibiotics, treated by surgical drainage, and recovered uneventfully. This case report highlights the occurrence of severe complications of upper digestive tract fishbone impaction and the usefulness of a preoperative CT scanner in this context

FDG PET-CT for the Detection of Occult Nodal Metastases in Head and Neck Cancer: A Systematic Review and Meta-Analysis

Because of an estimated 20–30% prevalence of occult lymph node (LN) metastases in patients with head and neck squamous cell carcinoma (HNSCC), neck dissection is often proposed, despite its potential morbidity. In this systematic review and meta-analysis, the diagnostic performance of FDG PET-CT in detecting occult LN metastases was evaluated in patients with clinically negative necks (cN0) and in whom histopathology of a neck dissection specimen served as gold standard. Overall, 16 studies out of 2062 screened on PubMed and EMBASE fulfilled the inclusion criteria (n = 1148 patients). Seven of these sixteen studies were split into two or three studies because they contained data that could be processed distinctly in our meta-analysis. For this reason, a total of 25 studies were identified and included in the analysis (n total = 1918 patients). The overall prevalence of metastatic nodes per patient was 22.67%. The pooled sensitivity, specificity, diagnostic odds ratios, and negative predictive value (NPV) were 0.71 (95%CI: 0.66–0.75), 0.90 (95%CI: 0.84–0.93), 20.03 (95%CI: 13.51–29.70), and 0.92 (95%CI: 0.89–0.95), respectively. The main causes of inter-study heterogeneity included different reference standards (evaluation per patient, per neck side, or per neck level). The current meta-analysis showed that FDG PET-CT has a high specificity and NPV for ruling out nodal involvement in cN0 necks, but a limited sensitivity.</p

Distal oesophagus food impaction removal with a rigid endoscope using an inflatable shoulder roll : A technical case report

Background : Rigid esophagoscopy is commonly performed by otolaryngologists, both for the workup of patients with head and neck squamous cell carcinoma and in case of a foreign body or food impaction. Because of the natural S-shaped curve of the spine, one has to elevate the torso to align the oral cavity and the distal third of the oesophagus, thereby allowing the rigid scope to progress in an atraumatic manner. Methods : This paper describes using an inflatable shoulder roll as a straightforward and safe technique to remove a food impaction in the distal third of the oesophagus using a rigid endoscope. Results : Case presentation and step-wise technical explanation are provided Conclusion : By using this technique, rigid oesophagoscopy can be used in the distal third of the oesophagus.</p

Cardiac metastasis from squamous cell carcinoma of the oral cavity: A rare case report

A 58-year-old male with squamous cell carcinoma of the floor of mouth underwent surgical planning for tumor resection and floor of mouth reconstruction. Unexpectedly, preoperative cervico-thoracic computed tomography (CT) indicated possible right ventricular intramural thrombosis, prompting initiation of unfractionated heparin. Follow-up echocardiography revealed no thrombus reduction, raising concerns of intracardiac metastasis. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose with computed tomography (18F-FDG PET/CT) showed a hypermetabolic mass in the right ventricle, raising concern for a distant tumor metastasis. Under anti-coagulation, the patient experienced recurrent tumor-related hemorrhage, necessitating urgent lingual artery embolization. Due to disease progression, surgical options were dismissed in favor of palliative chemo-immunotherapy, which both led to significant regression of both primary and metastatic lesions

A new dimension of success in the management of airway disease in children with neurological deficit

Objectives: Anomalies of the larynx and trachea can cause respiratory distress in infants and older children. Depending on its nature, degree and extent of the disease invasive open surgery is indicated. Non-airway-related co-morbidities increase the challenges in its treatment. Neurological deficit poses a great challenge as it is associated with hypotonia and causes diminished laryngeal coordination. The definition of success in treatment of laryngotracheal disease has always focused on the post-operative functional outcomes: breathing, voice swallowing. The aim of this study is to describe a new dimension of success in the management of laryngotracheal disease in children with moderate neurological deficit, where the expected functional gain is less than in otherwise healthy children. Methods: This retrospective observational study includes all patients who have undergone open reconstructive airway surgery between 2012 and 2017. Control patients without neurological deficit and cases with moderate neurological deficit were included. Functional outcome data was obtained from clinical records and two questionnaires were filled in by the parents of the children: one the pediatric voice-handicap index (pVHI) and a quality of life questionnaire. Results: Thirty-two children were included of which ten had moderate neurological deficit. Both groups revealed post-operatively an improvement in the functional outcomes: breathing, voice and swallowing, however, as expected, a trend was observed towards less functional improvement in children with neurological deficit. Both groups reveal a remarkable gain in quality of life (QoL). Conclusion: Indicating the QoL to be an unidentified, dimension of success in the management of laryngotracheal disease in children with moderate neurological deficit.</p

Pilomatrixoma of the parotid region : A benign tumor mimicking metastatic cutaneous squamous cell carcinoma

Head and neck tumors in adults present a broad differential diagnosis, particularly when considering malignant neoplasms that require prompt diagnosis and intervention. We report the case of a 66-year-old woman with a progressively enlarging mass in the left parotid region. Initial assessments, including fine needle aspiration biopsy and imaging studies from outside institutions, suggested a diagnosis of squamous cell carcinoma. However, final histopathological analysis revealed that the mass was consistent with a pilomatrixoma. This case highlights the critical importance of meticulous radiological interpretation and the role of fine needle aspiration cytology (FNA) in accurately distinguishing between these 2 entities before initiating treatment