Semaphorin-3F/Neuropilin-2 Transcriptional Expression as a Predictive Biomarker of Occult Lymph Node Metastases in HNSCC

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), A Way to Build Europe; Asociación Española contra el Cáncer (LABAE18025AVIL).The expression of the semaphorin-3F (SEMA3F) and neuropilin-2 (NRP2) is involved in the regulation of lymphangiogenesis. The present study analyzes the relationship between the transcriptional expression of the SEMA3F-NRP2 genes and the presence of occult lymph node metastases in patients with cN0 head and neck squamous cell carcinomas. We analyzed the transcriptional expression of SEMA3F and NRP2 in a cohort of 53 patients with cN0 squamous cell carcinoma treated with an elective neck dissection. Occult lymph node metastases were found in 37.7% of the patients. Patients with occult lymph node metastases (cN0/pN+) had significantly lower SEMA3F expression values than patients without lymph node involvement (cN0/pN0). Considering the expression of the SEMA3F-NRP2 genes, patients were classified into two groups according to the risk of occult nodal metastasis: Group 1 (n = 34), high SEMA3F/low NRP2 expression, with a low risk of occult nodal involvement (14.7% cN0/pN+); Group 2 (n = 19), low SEMA3F or high SEMA3F/high NRP2 expression, with a high risk of occult nodal involvement (78.9% cN0/pN+). Multivariate analysis showed that patients in Group 2 had a 26.2 higher risk of lymph node involvement than patients in Group 1. There was a significant relationship between the transcriptional expression values of the SEMA3F-NRP2 genes and the risk of occult nodal metastases

Semaphorin-3F/Neuropilin-2 Transcriptional Expression as a Predictive Biomarker of Occult Lymph Node Metastases in HNSCC.

The expression of the semaphorin-3F (SEMA3F) and neuropilin-2 (NRP2) is involved in the regulation of lymphangiogenesis. The present study analyzes the relationship between the transcriptional expression of the SEMA3F-NRP2 genes and the presence of occult lymph node metastases in patients with cN0 head and neck squamous cell carcinomas. We analyzed the transcriptional expression of SEMA3F and NRP2 in a cohort of 53 patients with cN0 squamous cell carcinoma treated with an elective neck dissection. Occult lymph node metastases were found in 37.7% of the patients. Patients with occult lymph node metastases (cN0/pN+) had significantly lower SEMA3F expression values than patients without lymph node involvement (cN0/pN0). Considering the expression of the SEMA3F-NRP2 genes, patients were classified into two groups according to the risk of occult nodal metastasis: Group 1 (n = 34), high SEMA3F/low NRP2 expression, with a low risk of occult nodal involvement (14.7% cN0/pN+); Group 2 (n = 19), low SEMA3F or high SEMA3F/high NRP2 expression, with a high risk of occult nodal involvement (78.9% cN0/pN+). Multivariate analysis showed that patients in Group 2 had a 26.2 higher risk of lymph node involvement than patients in Group 1. There was a significant relationship between the transcriptional expression values of the SEMA3F-NRP2 genes and the risk of occult nodal metastases

Facial nerve palsy following parotid gland surgery : A machine learning prediction outcome approach

Machine learning (ML)-based facial nerve injury (FNI) forecasting grounded on multicentric data has not been released up to now. Three distinct ML models, random forest (RF), K-nearest neighbor, and artificial neural network (ANN), for the prediction of FNI were evaluated in this mode. A retrospective, longitudinal, multicentric study was performed, including patients who went through parotid gland surgery for benign tumors at three different university hospitals. Seven hundred and thirty-six patients were included. The most compelling aspects related to risk escalation of FNI were as follows: (1) location, in the mid-portion of the gland, near to or above the main trunk of the facial nerve and at the top part, over the frontal or the orbital branch of the facial nerve; (2) tumor volume in the anteroposterior axis; (3) the necessity to simultaneously dissect more than one level; and (4) the requirement of an extended resection compared to a lesser extended resection. By contrast, in accordance with the ML analysis, the size of the tumor (>3 cm), as well as gender and age did not result in a determining favor in relation to the risk of FNI. The findings of this research conclude that ML models such as RF and ANN may serve evidence-based predictions from multicentric data regarding the risk of FNI. Along with the advent of ML technology, an improvement of the information regarding the potential risks of FNI associated with patients before each procedure may be achieved with the implementation of clinical, radiological, histological, and/or cytological data

Expression of IL-1α correlates with distant metastasis in patients with head and neck squamous cell carcinoma

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER)The presence of IL-1 in human cancers is associated with aggressive tumor biology but its prognostic value is unknown. We studied whether IL-1α expression is a prognostic marker of distant metastasis in patients with head and neck squamous cell carcinoma (HNSCC). IL-1α mRNA and protein levels were determined in tumor samples and cancer cell lines using RT-PCR and ELISA. The effects of constitutive IL-1α expression by tumor lines were characterized. IL-1α mRNA and protein secretion were higher in tumor samples from patients who later developed distant metastasis than in patients who did not. By using distant metastasis as a dependent variable, patients were classified into two categories of IL-1α transcript-levels. The high-IL-1α group had a significantly lower five-year distant metastasis-free survival than the low-IL-1α group [70.0% (CI 95%: 55.9-84.1%) vs 94.7% (CI 95%:90.2-99.2%)]. When IL-1α transcript-levels were combined with clinical factors related to tumor metastasis, the predictive power of the model increased significantly. Additionally, transcript levels of IL-1α correlated significantly with those of the IL-1 family genes and genes related to the metastatic process. IL-1 treatment of microvascular endothelial cells increased adhesion of HNSCC cells but no differences were found based on constitutive IL-1α expression by tumor cells. Nevertheless, IL-1α produced by tumor cells effectively increased their transmigration across the endothelium. We found a significant relationship between IL-1α expression and development of distant metastasis in HNSCC patients. IL-1α expression could help to define a subset of patients at high risk of distant metastasis who could benefit from adjuvant treatment

Epidemiology of human papillomavirus-related oropharyngeal cancer in a classically low-burden region of southern Europe

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16 immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16 double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012-2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe

Papel de la IL-1 en el riesgo de aparición de metástasis a distancia en pacientes con carcinoma escamoso de cabeza y cuello

Uno de los factores responsables del deterioro en la supervivencia de los pacientes con carcinoma escamoso de cabeza y cuello (CECC) con buen control loco-regional, es la aparición de metástasis a distancia. Los marcadores clínico-patológicos contemplados en la práctica clínica tienen una capacidad limitada para predecir el riesgo de metástasis a distancia. Esto ha llevado a la investigación de alteraciones moleculares que puedan dar información sobre el potencial metastásico. La diseminación metastásica del tumor no se deriva del drenaje pasivo de las células tumorales hacia el torrente linfático o vascular, sino que implica un proceso dinámico dependiente de la biología tumoral. En tumores sólidos de páncreas, mama, pulmón, CECC y melanoma, se ha visto que las citoquinas producidas por el tumor y el estroma circundante están implicadas en la patogenicidad y progresión tumoral. Concretamente la IL-1, una citoquina con propiedades proinflamatorias, proangiogénicas e inmunoreguladoras, estimula el crecimiento tumoral y se ha relacionado con un fenotipo agresivo y de peor pronóstico. En el presente estudio se obtuvieron biopsias de tumor de 154 pacientes afectos de CECC tratados en el Hospital Sant Pau entre 2004 y 2010. Se determinaron los niveles de expresión transcripcional de los componentes de la vía de la IL-1 y se relacionaron con el control de la enfermedad a distancia. La IL-1α fue la única molécula de la familia que se relacionó de forma significativa con la aparición de metástasis a distancia. Los niveles elevados de IL-1α tanto a nivel transcripcional como de proteína se relacionaron con mayor riesgo de metástasis a distancia. La supervivencia libre de metástasis a distancia a los 5 años para los pacientes con niveles elevados de IL-1 α fue del 70% mientras que para los pacientes con niveles de expresión bajos fue de 94% (p: 0.0001). Se definió una cohorte de pacientes con factores clínicos de alto riesgo de metástasis (tumores avanzados a nivel loco-regional y extensión extracapsular) y se correlacionó con los niveles de expresión de IL-1α. La supervivencia libre de metástasis a distancia a los 5 años en los pacientes con expresión elevada de IL-1α y factores clínicos de alto riesgo fue del 49%, mientras que en los pacientes con niveles de expresión baja de IL-1α y factores de alto riesgo clínico fue del 93.5% (p: 0.002). Se determinaron los niveles de expresión de un panel de genes relacionados con los procesos de diseminación y metástasis en función de las categorías de expresión de la IL-1α. Se encontró una correlación entre la expresión elevada de IL-1α y la expresión de genes pro-angiogénicos como VEGF, IL-8, COX-2 y mPGES-1. Se realizaron estudios experimentales de adhesión endotelial y transmigración en un panel de líneas de CECC. El tratamiento con IL-1 de células endoteliales microvasculares aumentó la capacidad de adhesión de las células tumorales al endotelio. Adicionalmente las líneas celulares con expresión elevada de IL-1α presentaron mayor transmigración a través del endotelio que las líneas con baja expresión de IL-1α. La conclusión principal de este trabajo es que la IL-1 juega un papel relevante en la diseminación metastásica en pacientes con CECC. La combinación de datos clínicos con los niveles de expresión de IL-1 sería de utilidad en la práctica hospitalaria para detectar a la población con riesgo elevado de metástasis a distancia e instaurar tratamientos adyuvantes de forma oportuna.The development of distant metastasis in patients with head and neck squamous cell carcinoma (HNSSC) that have achieved loco-regional control, is one of the main factors that explain the lack of improvement in overall survival rate. The clinic and pathologic markers used in the clinical practice have shown limited capacity to predict distant metastasis. This has led to the investigation of molecular alterations that can inform about the metastatic potential of the tumor. The appearance of distant metastasis is not the result of the passive drainage of tumor cells into the bloodstream or the lymphatic system; rather than that, it is a dynamic process dictated by the tumor biology. In solid tumors -such as pancreatic, breast or lung tumors, HNSSC and melanoma- the production of cytokines by stromal and malignant cells has been associated with tumor progression. IL-1 is a pro-inflammatory cytokine that promotes angiogenesis and immune responses, and stimulates tumor growth. IL-1 has been linked with aggressive malignant behavior and a decrease in prognosis. In the present study tumor biopsies were obtained from 154 patients with HNSCC treated at Hospital Sant Pau between 2004 and 2010. The transcript levels of IL-1 family members were determined and then related with distance control of the disease. IL-1α was the only variable that was significantly associated to the appearance of distant metastasis. High expression of IL-1α (both transcript and protein) was related with higher risk of distant metastasis. Therefore, five-year distant metastasis free survival was 70% for patients with high IL-1α expression and 94% for patients with low IL-1α (p: 0.0001). The patients with high risk of distant metastasis based on clinical factors (locally and regionally advanced tumors and extracapsular spread) were grouped in a cohort that was then related with levels of IL-1α. The five-year distant metastasis free survival for patients with high expression of IL-1α and clinical risk factors was 49% while for patients with low IL-1α and clinical risk factors was 93.5% (p:0.002). The transcript levels of some genes related with metastatic process were analyzed in association of IL-1α expression levels. Most of these pro-angiogenic genes (VEGF, IL-8, COX-2, mPGES-1) were enhanced in the high IL-1α group. Tumor cell adhesion and trans-endothelial migration assays were performed in a panel of HNSCC lines. When micro-vascular endothelial cells were treated with IL-1, the ability of tumor cells to adhere to the endothelium was enhanced. Additionally, HNSCC cell lines with high expression of IL-1α migrated more through the endothelium than cell lines with low expression of IL-1α. The main conclusion of this thesis is that IL-1 plays an important role in appearance of distant metastasis in patients with HNSSC. The combination of clinical data along with the levels of expression of IL-1 would be useful in the clinical setting to identify the group of patients who are at high risk of development of distant metastasis and to establish adjuvant treatments

uPA/uPAR and SERPINE1 in head and neck cancer : Role in tumor resistance, metastasis, prognosis and therapy

There is strong evidence supporting the role of the plasminogen activator system in head and neck squamous cell carcinoma (HNSCC), particularly of its uPA (urokinase plasminogen activator)/uPAR (urokinase plasminogen activator receptor) and SERPINE1 components. Overexpression of uPA/uPAR and SERPINE1 enhances tumor cell migration and invasion and plays a key role in metastasis development, conferring poor prognosis. The apparent paradox of uPA/uPAR and its inhibitor SERPINE1 producing similar effects is solved by the identification of SERPINE1 activated signaling pathways independent of uPA inhibition. Both uPA/uPAR and SERPINE1 are directly linked to the induction of epithelial-to-mesenchymal transition, the acquisition of stem cell properties and resistance to antitumor agents. The aim of this review is to provide insight on the deregulation of these proteins in all these processes. We also summarize their potential value as prognostic biomarkers or potential drug targets in HNSCC patients. Concomitant overexpression of uPA/uPAR and SERPINE1 is associated with a higher risk of metastasis and could be used to identify patients that would benefit from an adjuvant treatment. In the future, the specific inhibitors of uPA/uPAR and SERPINE1, which are still under development, could be used to design new therapeutic strategies in HNSCCs

Semaphorin-3F/Neuropilin-2 Transcriptional Expression as a Predictive Biomarker of Occult Lymph Node Metastases in HNSCC

The expression of the semaphorin-3F (SEMA3F) and neuropilin-2 (NRP2) is involved in the regulation of lymphangiogenesis. The present study analyzes the relationship between the transcriptional expression of the SEMA3F-NRP2 genes and the presence of occult lymph node metastases in patients with cN0 head and neck squamous cell carcinomas. We analyzed the transcriptional expression of SEMA3F and NRP2 in a cohort of 53 patients with cN0 squamous cell carcinoma treated with an elective neck dissection. Occult lymph node metastases were found in 37.7% of the patients. Patients with occult lymph node metastases (cN0/pN+) had significantly lower SEMA3F expression values than patients without lymph node involvement (cN0/pN0). Considering the expression of the SEMA3F-NRP2 genes, patients were classified into two groups according to the risk of occult nodal metastasis: Group 1 (n = 34), high SEMA3F/low NRP2 expression, with a low risk of occult nodal involvement (14.7% cN0/pN+); Group 2 (n = 19), low SEMA3F or high SEMA3F/high NRP2 expression, with a high risk of occult nodal involvement (78.9% cN0/pN+). Multivariate analysis showed that patients in Group 2 had a 26.2 higher risk of lymph node involvement than patients in Group 1. There was a significant relationship between the transcriptional expression values of the SEMA3F-NRP2 genes and the risk of occult nodal metastases

HPV-relatedness definitions for classifying HPV-related oropharyngeal cancer patient do impact on TNM classification and patients' survival

Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8 edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7 edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16 or HPV-mRNA), p16 positivity alone or the combination of HPV-DNA/p16 positivity as diagnostic tests. A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16 or HPV-mRNA), 83 (10.5%) were p16 positive and 58 (7.4%) were double positive for HPV-DNA/p16. ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria. HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials

Expression of IL-1α correlates with distant metastasis in patients with head and neck squamous cell carcinoma

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER)The presence of IL-1 in human cancers is associated with aggressive tumor biology but its prognostic value is unknown. We studied whether IL-1α expression is a prognostic marker of distant metastasis in patients with head and neck squamous cell carcinoma (HNSCC). IL-1α mRNA and protein levels were determined in tumor samples and cancer cell lines using RT-PCR and ELISA. The effects of constitutive IL-1α expression by tumor lines were characterized. IL-1α mRNA and protein secretion were higher in tumor samples from patients who later developed distant metastasis than in patients who did not. By using distant metastasis as a dependent variable, patients were classified into two categories of IL-1α transcript-levels. The high-IL-1α group had a significantly lower five-year distant metastasis-free survival than the low-IL-1α group [70.0% (CI 95%: 55.9-84.1%) vs 94.7% (CI 95%:90.2-99.2%)]. When IL-1α transcript-levels were combined with clinical factors related to tumor metastasis, the predictive power of the model increased significantly. Additionally, transcript levels of IL-1α correlated significantly with those of the IL-1 family genes and genes related to the metastatic process. IL-1 treatment of microvascular endothelial cells increased adhesion of HNSCC cells but no differences were found based on constitutive IL-1α expression by tumor cells. Nevertheless, IL-1α produced by tumor cells effectively increased their transmigration across the endothelium. We found a significant relationship between IL-1α expression and development of distant metastasis in HNSCC patients. IL-1α expression could help to define a subset of patients at high risk of distant metastasis who could benefit from adjuvant treatment