Although the association and clinical significance of human papillomavirus (HPV) infections with a subset of head and neck cancers, particularly for oropharyngeal carcinoma, has recently been well documented, the involvement of HPV in laryngeal cancer has been inadequately evaluated. Herein we review the currently known associations of HPV infections in diseases of the larynx and their potential for oncogenicity. Using several methods of detection, HPV DNA has been detected in benign (papillomatosis), indolent (verrucous carcinoma), and malignant (squamous cell carcinoma) lesions of the larynx. Consistent with the known oncogenic risk of HPV infections, common HPV types associated with laryngeal papillomatosis include low-risk HPV types 6 and 11, with high-risk HPV types 16 and 18 more commonly present in neoplastic lesions (verrucous carcinoma and squamous cell carcinoma). Although a broad range of prevalence has been noted in individual studies, approximately 25% of laryngeal squamous cell carcinomas harbor HPV infections on meta-analysis, with common involvement of high-risk HPV types 16 (highest frequency) and 18. Preliminary results suggest that these high-risk HPV infections seem to be biologically relevant in laryngeal carcinogenesis, manifested as having viral DNA integration in the cancer cell genome and increased expression of the p16 protein. Despite this knowledge, the clinical significance of these infections and the implications on disease prevention and treatment are unclear and require further investigation.
In medicine, a misdiagnosis or the absence of specialists can affect the patient's health, leading to unnecessary tests and increasing the costs of healthcare. In particular, the lack of specialists in otolaryngology in third world countries forces patients to seek medical attention from general practitioners, whom might not have enough training and experience for making correct diagnosis in this field. To tackle this problem, we propose and test a computer-aided system based on machine learning models and image processing techniques for otoscopic examination, as a support for a more accurate diagnosis of ear conditions at primary care before specialist referral; in particular, for myringosclerosis, earwax plug, and chronic otitis media. To characterize the tympanic membrane and ear canal for each condition, we implemented three different feature extraction methods: color coherence vector, discrete cosine transform, and filter bank. We also considered three machine learning algorithms: support vector machine (SVM), k-nearest neighbor (k-NN) and decision trees to develop the ear condition predictor model. To conduct the research, our database included 160 images as testing set and 720 images as training and validation sets of 180 patients. We repeatedly trained the learning models using the training dataset and evaluated them using the validation dataset to thus obtain the best feature extraction method and learning model that produce the highest validation accuracy. The results showed that the SVM and k-NN presented the best performance followed by decision trees model. Finally, we performed a classification stage-i.e., diagnosis-using testing data, where the SVM model achieved an average classification accuracy of 93.9%, average sensitivity of 87.8%, average specificity of 95.9%, and average positive predictive value of 87.7%. The results show that this system might be used for general practitioners as a reference to make better decisions in the ear pathologies diagnosis.
The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2′deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and hematopoietic malignancy (64% in Burkitt’s lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic-based therapy.
Role of human papillomavirus (HPV) in laryngeal carcinoma remains controversial. The aim of this study is to evaluate the role of HPV in laryngeal squamous cell carcinoma by determining presence of markers of viral infection. HPV DNA and E6*I mRNA status was determined by type-specific E7 PCR bead-based multiplex genotyping and RT-PCR assays in laryngeal squamous cell carcinoma biopsy samples. p16(INK4a) and COX-2 expression was determined by immunohistochemistry. Four cases out of 32 (13%) were HPV DNA+: HPV 11 (n = 1), HPV 31 (n = 3), HPV 59 (n = 1). One double infection: HPV 11 and HPV 31. p16(INK4a) was overexpressed in three cases (9%) and COX-2 in 17 cases (53%). Two of four HPV DNA+ samples had E6*I mRNA for HPV 31 and overexpressed p16(INK4a) and COX-2. HPV appears to play an active role in a small subset of laryngeal squamous cell carcinoma. p16(INK4a) can be used as a surrogate marker of transcriptionally active HPV infection; COX-2 expression had no correlation with HPV DNA and/or RNA positivity.
Human papilloma virus (HPV) has a role in benign and malignant pathology of the larynx. In this review we present the biological and epidemiological aspects related to these issues.
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