Dehiscencia de pared anterior de conducto auditivo externo con afectación de articulación temporomandibular tras cirugía de exóstosis. Revisión sistemática / Dehiscence of the anterior wall of the external auditory canal with involvement of the temporomandibular joint after exostosis surgery. Systematic review

Introducción y objetivo: Realizar una revisión sistemática para evaluar la incidencia en la literatura de esta complicación tan infrecuente en cirugía otológica, como es la afectación de la articulación temporomandibular (ATM). Método: Considerando la apertura iatrogénica de la ATM tras cirugía otológica una complicación excepcional, se realiza una revisión de la literatura de dicha patología siguiendo el método PRISMA para revisiones sistemáticas evaluando las bases de datos electrónicas PubMED, Web of Science y Cochrane. Resultados: Se incluyeron 3 artículos con casos publicados de fistulización CAE-ATM y un caso propio. Todos presentaban exploración compatible mediante otoscopia con o sin sintomatología referida por el paciente y que precisasen tratamiento quirúrgico o conservador. Se encontraron un total de 5 casos (4 mujeres y 1 varón), con edades comprendidas entre los 40 y 70 años, con diagnóstico de comunicación CAE-ATM secundaria a canaloplastia. Tres de ellos presentaron enfisema cervical entre los síntomas y signos acompañantes. El tratamiento fue conservador en tres casos mientras que los otros dos precisaron reparación quirúrgica. Discusión/Conclusiones: La canaloplastia es un procedimiento habitual en cirugía otológica que precisa de una técnica de disección meticulosa para evitar daños a estructuras importantes como el nervio facial o la ATM. Presenta baja tasa de complicaciones siendo muy excepcional la fistulización hacia la articulación temporomandibular. No obstante, debemos sospecharla ante dolor persistente, otorrea, bloqueo o chasquido mandibular y, por supuesto, enfisema. (AU)

Introduction and objective: Carry out a systematic review to evaluate the incidence in the literature of this rare complication in otological surgery, such as the involvement of the temporomandibular joint (TMJ). Method: Iatrogenic opening of the TMJ after otological surgery attended is very infrequent, a review of the literature about this pathology was carried out following the PRISMA method for systematic reviews evaluating the electronic databases PubMED, Web of Science and Cochrane. Results: 3 articles with published cases of EAC-TMJ fistulization and one of our own were included. All presented compatible exploration by otoscopy with or without symptoms reported by the patient and requiring surgical or conservative treatment. A total of 5 cases were found (4 women and 1 man), aged between 40 and 70, with a diagnosis of EAC-TMJ communication secondary to canaloplasty. Three of them presented cervical emphysema among the accompanying symptoms and signs. Treatment was conservative in three cases, while the other two required surgical repair. Discussion/Conclusions: Canaloplasty is a common procedure in otological surgery that requires a meticulous dissection technique to avoid damage to important structures such as the facial nerve or the TMJ. It presents a low rate of complications, being fistulization towards the temporomandibular joint very exceptional. However, we must suspect it in the presence of persistent pain, otorrhea, jaw blockage or clicking and, of course, emphysema. (AU)

Dehiscencia de pared anterior de conducto auditivo externo con afectación de articulación temporomandibular tras cirugía de exóstosis. Descripción de un caso clinico. / Dehiscence of the anterior wall of the external auditory canal with involvement of the temporomandibular joint after exostosis surgery. Description of a clinical case

Describir la clínica de presentación y el manejo quirúrgico de una complicación infrecuente en cirugía otológica, como es la afectación de la articulación temporomandibular (ATM). Caso: Presentamos el caso de una paciente de 47 años intervenida de canaloplastia y estapedectomía izquierda en 2017 y dos recambios de prótesis en 2018 en el mismo oído. Enel oído derecho fue intervenida de canaloplastia y posteriormente se le realizó una timpanotomía exploradora a finales de 2018. A principios de 2019, fue remitida a consultas de nuestro hospital por sospecha de otitis externa maligna. Presentaba otorrea derecha de mal manejo, otalgia ocasional y chasquidos que no habían remitido tras tratamiento antibiótico tópico y oral y analgesia. En la otomicroscopia se observó secreciones, así como dehiscencia en suelo y pared anterior del conducto auditivo externo (CAE) derecho. Se le había realizado previamente tomografía computarizada de hueso temporal que confirmaba el defecto óseo de CAE anterior y la comunicación con la articulación temporomanbibular, así como burbujas de aire sugestivas de infección hasta espacio parafaríngeo. Se completó el estudio con una gammagrafía con citrato de galio-67, concordante con la infección en dicha zona, y una resonancia magnética nuclear para valorar más detalladamente la afectación de partes blandas, en particular lo relacionado con la ATM. Tras ingreso para tratamiento antibiótico endovenoso de amplio espectro, fue necesaria reparación quirúrgica del defecto del CAE para tratamiento óptimo. La cirugía consistió en canaloplastia utilizando colgajo pediculado e injerto de cartílago y pericondrio tragal y cerclaje intermaxilar para estabilización de la ATM que se mantuvo durante dos semanas. (AU)

Introduction and objective: To describe the clinical presentation and surgical management of an infrequent complication in ontological surgery such as the involvement of the themporomandibular joint (TMJ). Case: We describe a case of a 47-year-old patient who underwent canaloplasty and left stapedectomy in 2017 and two prosthesis replacements in 2018 in the same ear. She underwent canaloplasty in the right ear and subsequently underwent a exploratory tympanotomy at the end of 2018. At the beginning of 2019, she was referred to our hospital for suspected malignant external otitis. He presented poorly managed right otorrhea, occasional otalgia and clicks that had not remitted after topical and oral antibiotic treatment and analgesia. Otomicroscopy revealed secretions as well as dehiscence in the floor and anterior wall of the right external auditory canal (EAC). A computed tomography scan of the temporal bone had previously been performed, which confirmed the anterior EAC bone defect and communication with the temporomanbibular joint, as well as air bubbles suggestive of infection up to the parapharyngeal space. The study was completed with a gallium-67 citrate scintigraphy, consistent with the infection in that area, and a nuclear magnetic resonance to assess in more detail the involvement of the soft tissues, particularly that related to the TMJ. After admission for broad-spectrum intravenous antibiotic treatment, surgical repair of the EAC defect was necessary for optimal treatment. The surgery consisted of canaloplasty using a pedicled flap and cartilage graft and tragal perichondrium and intermaxillary cerclage for TMJ stabilization that was maintained for two weeks. Results: In our case, two months after surgery the symptoms had disappeared. (AU)

RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination.

RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under- or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS site-specific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness.

ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation.

OBJECTIVE: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-ß (transforming growth factor-ß) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. APPROACH AND RESULTS: In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. CONCLUSIONS: Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.

Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells.

BACKGROUND: Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity. METHODS: We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test. RESULTS: We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03). CONCLUSIONS: Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.