Serum,plasma and saliva biomarkers for head and neck cancer

Introduction: Head and neck squamous cell carcinoma (HNSCC) encompasses tumors arising from several locations (oral and nasal cavities, paranasal sinuses, salivary glands, pharynx, and larynx) and currently stands as the sixth most common cancer worldwide. The most important risk factors identified so far are tobacco and alcohol consumption, and, for a subgroup of HNSCCs, infection with high-risk types of human papillomavirus (HPV). Despite several improvements in the treatment of these tumors in the last decades, overall survival rates have only improved marginally, mainly due to the advanced clinical stage at diagnosis and the high rates of treatment failure associated with this late diagnosis.

Areas covered: This review will focus on the feasibility of evaluating molecular-based biomarkers (mRNA, microRNA, lncRNA, DNA methylation and protein expression) in body fluids (serum, plasma, and saliva) as markers for diagnosis, prognosis, and surveillance.

Expert commentary: The potential use of those markers in the clinical setting would allow for early diagnosis, prediction of treatment response, improvement in treatment selection and provide disease monitoring for early detection of tumor recurrence. It can ultimately be translated into better survival rates and improved quality of life for HNSCC patients.     

Salivary protein biomarkers for head and neck cancer

ABSTRACT

Introduction: Saliva has gained attention as an important diagnostic fluid because it contains biomolecules that have the potential to detect early-stage cancer or to monitor the response to treatment in patients. Several saliva-based proteins have been proposed as potential biomarkers for head and neck cancers (HNC).

Areas covered: This review aims to provide an update on saliva-based protein biomarkers for HNC, often studied in observational research and clinical trials.

Expert opinion: Despite the increasing number of studies relating to salivary proteins as biomarkers for HNC, there is no consensus regarding which proteins have the best clinical utility. Most studies have analyzed individual proteins and not a protein panel approach. It must be considered that combining different proteins as a panel can increase the accuracy and will have the potential to change the current clinical practice for HNC patients.     

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.     

Prevention, detection, and diagnosis of head and neck cancers

Head and neck cancers are a complex group of diseases that result in significantly visible alterations of several vital functions. Ironically, 90% of these tumors are preventable; however, implementing the primary and secondary levels of prevention will require a personal commitment from the patient, in addition to commitments from the community and professionals, such as nurses, physicians, and other members of the health care team.     

Serum biomarkers for Alzheimer's disease: proteomic discovery.

For Alzheimer's disease (AD), the most common neurodegenerative disease, there is no simple, cost-effective biomarker for disease identification. Using novel mass spectrometry (MS)-based techniques, and analysis of the albumin-enriched low molecular weight proteome, minute amounts of human serum were analyzed for the measurement of thousands of peptides and proteins in parallel. The mass spectrograms were then evaluated with a novel computer algorithm to identify spectral peaks that discriminate between samples from patients with and without AD. There are four peaks that distinguish AD from control subjects and AD subjects from those with Parkinson's disease (PD). Additionally, after analyzing data from a recently published study of AD and control subjects, we found three discriminating peaks in common with the four from our patient serum samples. The identification of these peptides/proteins, and their direct measurement in patient serum, may allow the development of a simple, cost-effective test for AD.     

Complications of radiation therapy for head and neck cancers. The patient's perspective

Newer treatments for head and neck cancers, including altered fractionation and the use of concomitant radiotherapy and chemotherapy, may provide better local-regional tumor control rates; however, patients may experience more frequent and more severe acute toxicities that result in considerable suffering. Through this study, we sought a better understanding of patients' experiences when undergoing radiotherapy. Personal interviews were conducted with 33 individuals who had received radiotherapy for head and neck cancers. These individuals described their treatment experiences and identified the most troublesome and debilitating side effects of radiotherapy. Overall, lethargy and weakness, dry mouth, mouth sores and pain, taste changes, and sore throat were the most frequently reported troublesome or debilitating side effects. The single most debilitating side effect was oropharyngeal mucositis that was characterized by patients as sore throat, and mouth sores and pain; both negatively affected the patient's ability to eat and drink, causing many patients to experience significant weight loss. Trends toward more aggressive management of head and neck cancers underscore the need for new and effective therapies for oropharyngeal mucositis occurring in patients receiving radiotherapy.     

Serious soft tissue infections of the head and neck

The head and neck contain a number of spaces that can be invaded by organisms of the mouth or by spread of cervical osteomyelitis. Infection in these spaces may progress from superficial infection to cellulitis to the formation of an abscess requiring immediate drainage. Spread of infection between spaces depends on anatomic location. Most patients require hospitalization and intravenous antibiotic therapy. Because a deep space infection may be occult, a high index of suspicion is required for diagnosis. Early recognition is necessary to avoid tissue damage, bacteremia or airway compromise. The possibility of deep space infection should be considered in any patient who does not respond to the usual treatment of an abscessed tooth or tonsillitis. This type of infection also should be considered in a toxic patient who has a fever of unknown origin, with or without blood cultures that show anaerobic organisms. Computed tomography or magnetic resonance imaging is usually necessary to locate the infection and to detect suppuration that will be amenable to surgical exploration and drainage.     

The role of cetuximab in the management of head and neck cancers

INTRODUCTION: The standard of care for patients with locally-advanced head and neck cancer is chemoradiation or surgical resection followed by radiation treatment with or without chemotherapy and despite aggressive, multimodality therapies with their associated toxicities, attempts are being made to improve efficacy while reducing toxicity. Cetuximab is a chimeric mAb directed against the EGFR that showed clinical activity in squamous cell carcinoma of head and neck (SCCHN). AREAS COVERED: Cetuximab is beneficial in recurrent and metastatic setting, as well as in the definitive setting. In a landmark study by Bonner et al., cetuximab was found to be effective in prolonging survival in conjunction with radiation treatment in locally-advanced tumors versus radiation therapy alone. The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) trial also showed an improvement in conjunction with chemotherapy in recurrent and metastatic tumors. EXPERT OPINION: Cetuximab is an important therapeutic option in SSCHN, and will continue to be used in metastatic and definitive settings. While cetuximab is a valuable tool in the treatment of SCCHN, more studies are needed to maximize the efficacy of this mAb in clinical settings and to identify the subpopulation of patients that truly benefit from its use.     

The role of cetuximab in the management of head and neck cancers

Introduction: There is now accumulating evidence to suggest that intratumoral adaptive immune responses predict patient prognosis. The presence of tumor-infiltrating lymphocytes has been correlated with patients' disease-free and overall survival. Recent exciting studies of human colorectal cancers (CRCs) have underlined the significance of including immunological biomarkers as prognostic markers.

Areas covered: This review covers recent literature which suggests that the type, density and location of immune cells within the colorectal tumors represent a better predictor of patient survival than the histopathological methods currently used to stage CRC.

Expert opinion: Remarkably, the quantity, quality and spatial distribution of immune cells within the tumor has a greater prognostic value than the standard tumor staging based on tumor burden, infiltration of draining and regional lymph nodes by tumor cells, and evidence of metastases. In addition, such an immune classification may also have a predictive value. Thus, by increasing the knowledge of the immune events inside the tumors and by better understanding the immune architecture of these tumors as well as the functional programs of their constituents, there will certainly be a more complete idea of how tumors evade from immunosurveillance. This knowledge will help to identify new targets for the development of therapeutic strategies.     

Promoter methylation of galanin receptors as epigenetic biomarkers for head and neck squamous cell carcinomas

Introduction: While remarkable progress has been made in standard treatments for head and neck squamous cell carcinomas (HNSCCs), the long-term survival remains at an unsatisfactory 40–50%. To improve the survival rate, biomarkers for optimal treatment selection and prognostic prediction, as well as novel, low-toxicity treatment strategies, are required. Galanin receptor (GALR) 1 and GALR2 are well-studied tumor suppressors in HNSCCs. Compared with other clinicopathological factors, the epigenetic variants of GALRs have been found to be the most powerful markers to predict the prognosis of HNSCC patients.

Areas covered: This review outlines the functions and signaling pathways of GALRs and explains the potential of GALR promoter methylation as a biomarker for HNSCC prognosis. We also summarize recent developments in promoter methylation studies in HNSCC and indicate future directions for GALR promoter methylation studies.

Expert commentary: GALR studies have highlighted two major aspects with implications in HNSCC – that G-protein coupled receptors (GPCRs) act as tumor suppressor genes and that GALR promoter methylation is significantly related to the carcinogenesis of HNSCC. The findings of GALR studies can be applied to studies on other GPCRs and further in-depth DNA methylation studies. Deeper insights into GPCR epigenetics are expected to markedly improve HNSCC treatment.     

Long-term oral Candida colonization, mucositis and salivary function after head and neck radiotherapy

The aim of this study was to follow the long-term effects of radiation therapy of head and neck malignancies on oral yeast colonization, mucositis and salivary function. Included in this prospective study were 32 patients with intended radiation therapy of a malignancy of the head and neck. In all patients the salivary glands lay within the radiation field and the patients had at least five teeth. The first examination was performed after oral hygiene instruction and removal of questionable teeth before the start of radiotherapy. The following examinations were conducted after 3, 6, 9 and 12 months. Together with the quantitative determination of Candida colonization, three "mucositis" variables were assessed: (1) examiner-rated mucositis score (LENT/SOMA), (2) patient-rated mucositis symptoms, and (3) scintigraphic salivary excretion fraction. The maximum Candida colonization was found 6 months after radiation therapy and this declined to above normal values after 12 months. Salivary flow was at a minimum 6 months after radiation therapy and had slightly recovered by 12 months. Examiner-rated mucositis and patient-rated xerostomia showed no significant recovery after 6 or 12 months. The results of this study show slight recovery of the oral ecological system. Although the causal role of a single parameter is not clear, persistently elevated Candida colonization should be taken into account therapeutically.     

Serum cystatin C in patients with head and neck carcinoma

BACKGROUND: The balance between proteinases of various classes and their inhibitors was found to be of critical importance for local invasion and metastasizing of tumor cells. The aim of the present study was to determine the changes in the serum cystatin C concentration in patients with squamous cell carcinoma of the head and neck. METHODS: In the sera of 34 patients with squamous cell carcinoma of the head and neck, the concentration of cysteine proteinase inhibitor cystatin C was determined using ELISA. The serum samples were collected at diagnosis (group A) and 7 to 407 days (median, 59 days) after the therapy (group B). The sera of 30 healthy blood donors served as controls (group C). RESULTS: A significant increase in the median concentration of cystatin C was found in the patients' sera (group A: 573 ng/ml, P<0.0001; group B: 551 ng/ml, P<0.0001) compared to control group C (320 ng/ml), whereas no difference was observed between groups A and B (P>0.05). Cystatin C concentrations in the sera of group A correlated with the site of primary tumor (P=0.035), being higher in the patients with non-laryngeal tumors (658 ng/ml) than in those with larynx primaries (529 ng/ml). There was a significant trend (RS=-0.535, P=0.049) towards lower cystatin C concentrations with an increasing time delay in post-treatment serum sampling (group B), which was observed in the patients with no relapse of the disease and a sampling later than 45 days after the completion of therapy. CONCLUSIONS: These results add to the knowledge of the role of cystatin C in invasive behavior of squamous cell carcinoma of the head and neck, and suggest its potential role as a tumor marker in this particular type of cancer.     

Symptom control issues and supportive care of patients with head and neck cancers

Combined-modality treatment of head and neck cancers, though linked to improved outcomes over earlier treatment methods, can be associated with acute and late adverse effects. These toxicities may lead to significant morbidity, increased mortality, and decreased quality of life. It is necessary to provide patients with adequate supportive-care measures in order to lessen suffering while maintaining the ability to deliver necessary doses of anticancer agents. The current review describes the pathology, assessment, and treatment options for cases of mucositis, impaired swallowing, nutritional and metabolic changes, xerostomia, radiation dermatitis, lymphedema, taste alterations, and pain, all of which may be associated with treatment of patients with head and neck cancers. Additionally, the pretreatment and during-treatment evaluation of dental health, as well as posttreatment dental care, are described.     

Clinical analysis of false-negative fine needle aspiration cytology of head and neck cancers

Background: Fine-needle aspiration (FNA) cytology is frequently used for initial and/or preoperative diagnosis of tumors in the head and neck region. However, false-negative results can lead to misdiagnosis. The aim of this study was to investigate the diagnostic results of FNA in the head and neck region and the reasons for false-negative cases.

Methods: The study population comprised 1,341 patients with pathologically confirmed head and neck tumors in whom FNA was performed before surgery or biopsy in the Otolaryngology Department at Numazu City Hospital between 2002 and 2016. We evaluated the false-negative FNA cytology rate as well as the site of the primary nodule, patient age and sex, sensitivity, accuracy, specificity, positive predictive value, negative predictive value, and the pathologic diagnosis after resection.

Results: The rate of false-negative FNA results was 5.9% (78/1,315 cases). The main sites of false-negative cases were the thyroid gland (n = 50), the lymph nodes (n = 16), and the salivary glands (n = 9). The sensitivity of FNA for head and neck tumors was 82.0%, with specificity and accuracy rates of 94% and 92.0%, respectively.

Conclusions: We have assessed the quality of preoperative FNA cytology in head and neck tumors. To avoid misdiagnosis by FNA, it is important that the target tumor is punctured accurately. If the specimen obtained is too small, FNA should be repeated.