Genetic deregulation of the PIK3CA oncogene in oral cancer

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the most commonly deregulated pathways in human cancers. PI3K comprises a catalytic (p110α) and regulatory subunit (p85), and p110α is encoded by the PIK3CA gene. Here, we summarize the known genetic alterations, including amplifications and mutations, of the PIK3CA oncogene in oral cancer. We discuss in detail PIK3CA mutations and their mutual exclusivity with pathway genes in addition to the incidence of PIK3CA mutations in relation to ethnicity. We describe the constitutive activation of PI3K signaling, oncogenicity, and the genetic deregulation of the PIK3CA gene and its association with oral cancer disease stage. We emphasize the importance of therapeutically targeting the genetically deregulated PIK3CA oncogene and its signaling. We also discuss the implications of targeting Akt and/or mTOR, which are the downstream effectors of PI3K that may possibly pave the way for molecular therapeutic targets for PIK3CA-driven oral carcinogenesis. Furthermore, this critical review provides a complete picture of the PIK3CA oncogene and its deregulation in oral cancer, which may facilitate early diagnosis and improve prognosis through personalized molecular targeted therapy in oral cancer.     

MiR-206 inhibits Head and neck squamous cell carcinoma cell progression by targeting HDAC6 via PTEN/AKT/mTOR pathway

As a kind of endogenous noncoding small RNA, microRNA (miRNA) plays important roles of regulation to various physiological functions, while its affections on senescence of human Head and neck squamous cell carcinoma (HNSCC) are still unknown. The objective of this study was to investigate the effect of miR-206 in HNSCC tissues, adjacent normal tissues and cell lines, and explore its biological functions in HNSCC.In our study, the level of miR-206 in HNSCC tissues and adjacent normal tissues was detected via real-time qPCR. The effect of miR-206 on cell proliferation was tested by MTT assay, colony formation and cell cycle assays. In order to explore the effect of miR-206 on HNSCC cell migration and invasion, we performed wound healing assays and transwell assays. Luciferase reporter assays were designed to identify the interaction between 3′UTR of HDAC6 and miR-206. The level of signaling pathway-related proteins was determined by western blot. The expression of miR-206 was found to be observably decreased in HNSCC tissues and cell lines through real time-PCR. Restoration of miR-206 weaked cell proliferation, invasion and migration in HNSCC cells and the cell cycle was arrest in S phase. Further explores have shown that miR-206 could inhibit HNSCC cells proliferation by targeting the HDAC6 via PTEN/AKT/mTOR pathway. Taken together, our results demonstrated that miR-206 plays a critical role in HNSCC progression by targeting HDAC6 via PTEN/AKT/mTOR pathway, which might be a potential target for diagnostic and therapeutic in HNSCC.     

Identification of appropriate outcome indices in head and neck cancer and factors influencing them

Audit of early postoperative outcomes adjusted for patient case mix is still in its infancy in head and neck surgery. Nevertheless the role for audit of early postoperative outcomes is obvious. The primary outcome measure of this study was to identify factors that are associated with early mortality or morbidity after surgery for head and neck squamous cell carcinoma (HNSCC). The secondary outcome measure was to develop a pilot score that allows for risk-adjustment of outcome data to facilitate departmental audit. In this series the mortality rate was low (2.8%), in keeping with other published series. Complications, including those causing death, occurred after 38.1% of operations. Independent risk factors for mortality on logistic regression were shown to be previous HNSCC (P = 0.03), estimated blood loss (l) (P = 0.03), and extracapsular spread (P = 0.05). Age (P = 0.01), tracheostomy (P < 0.01), estimated blood loss (l) (P = 0.05), and duration of anaesthesia (P < 0.01) were independent predictors of complications. Models predicting for risk demonstrated good discrimination (area under the curve statistics) for mortality (0.86) and morbidity (0.81). These pilot scores need external validation and may herald a means of facilitating risk-adjustment in the audit of early outcomes, allowing meaningful comparison of surgeons and their units over time.     

Multivariate analysis of preoperative and postoperative neutrophil-to-lymphocyte ratio as an indicator of head and neck squamous cell carcinoma outcome

Recent publications have highlighted a greater utility of routine blood tests in patients with various cancers than previously assumed. It appears that the neutrophil-to-lymphocyte ratio (NLR) may be a good predictive biomarker for overall survival (OS) and disease-free survival (DFS). Preoperative and postoperative NLR data for patients with head and neck cancers have yet to be established. The aim of this study was to evaluate the preoperative and postoperative NLR in 182 patients with head and neck squamous cell carcinoma and to determine the association of NLR with OS and DFS. The statistical analysis of OS and DFS and their predictors was performed using Kaplan–Meier survival analysis and multivariate Cox proportional hazards regression analysis, with factors including age, sex, alcohol and tobacco use, tumour location, treatment after surgery, and lymphocyte and neutrophil counts. Longer OS was significantly associated with not consuming alcohol, preoperative neutrophil and lymphocyte counts, preoperative NLR, and the difference between the preoperative and postoperative NLR (P = 0.016). Longer DFS was significantly associated with not consuming alcohol, preoperative neutrophil and lymphocyte counts, postoperative NLR, and the difference between preoperative and postoperative NLR (P = 0.028).     

A liquid biopsy for head and neck cancers

Head and neck cancer patients often present with advanced metastatic disease resulting in a poor 5-year survival. Therefore, there is a need for non-invasive diagnostic tools that could complement conventional imaging to inform clinicians of patient outcomes and treatment responses. A liquid biopsy addresses this unmet clinical need; a simple peripheral blood draw could provide information about the disseminated disease in terms of circulating tumor cells and circulating tumor DNA. Moreover, detectable tumor DNA in the saliva of head and neck cancer patients could signify the early signs of the disease and present an opportunity for clinical intervention. This review provides an overview of the current literature with regard to the feasibility of such a test in the head and neck cancer field and highlights the need for such a test.     

Machine learning methods applied to audit of surgical margins after curative surgery for head and neck cancer

Most surgical specialties have attempted to address concerns about the unfair comparison of outcomes by ‘risk-adjusting’ data to benchmark specialty-specific outcomes that are indicative of quality of care. We explore the ability to predict for positive margin status so that effective benchmarking that will account for complexity of case mix is possible. A dataset of care episodes recorded as a clinical audit of margin status after surgery for head and neck squamous cell carcinoma (n=1316) was analysed within the Waikato Environment for Knowledge Analyisis (WEKA) machine learning programme. The outcome was a classification model that can predict for positivity of tumour margins (defined as less than 1mm) using data on preoperative demographics, operations, functional status, and tumour stage. Positive resection margins of less than 1mm were common, and varied considerably between treatment units (19%-29%). Four algorithms were compared to attempt to risk-adjust for case complexity. The 'champion' model was a Naïve Bayes classifier (AUROC 0.72) that suggested acceptable discrimination. Calibration was good (Hosmer-Lemershow goodness-of-fit test p=0.9). Adjusted positive margin rates are presented on a funnel plot. Subspecialty groups within oral and maxillofacial surgery are seeking metrics that will allow for meaningful comparison of the quality of care delivered by surgical units in the UK. To enable metrics to be effective, we argue that they can be modelled so that meaningful benchmarking, which takes account of variation in complexity of patient need or care, is possible.