Martin J. Black

Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells.

In order to identify genes involved in head and neck carcinogenesis, we compared the gene expression profile in matched primary normal epithelial cells and primary head and neck cancer cells from the same patients. A cDNA microarray analysis consisting of 12 530 human genes revealed significant changes in the expression of 213 genes, with 91 genes being up-regulated and 122 being down-regulated. This comprehensive list of genes includes those associated with signal transduction (growth factors), cell structure, cell cycle, transcription, apoptosis, and cell–cell adhesion. Further analysis of nine genes involved in cell–cell interaction, using Western blot and/or reverse transcription (RT)–PCR of four paired cell lines supported the reliability of our microarray analysis. More specifically, our study provides the first evidence that claudin-7 and connexin 31.1 are down-regulated in head and neck squamous cell carcinomas (HNSCC) compared to normal cells. These findings provide a large body of information regarding gene expression profiles associated with head and neck carcinogenesis, and also represent a source of potential targets for HNSCC prevention and/or therapeutics.

Familial risks of squamous cell carcinoma of the head and neck: retrospective case-control study

Abstract Objective: To determine the contribution of inheritance to the incidence of squamous cell carcinoma of the head and neck. Design: Historical cohort study. First degree relatives of cases with squamous cell carcinoma of the head and neck made up the exposed cohort and first degree relatives of spouses of cases made up the comparison unexposed cohort. Setting: Ear, nose, and throat clinic in a large metropolitan teaching hospital. Subjects: 1429 first degree relatives of 242 index cases of squamous cell carcinoma of the head and neck; as controls, 934 first degree relatives of the spouses of 156 index cases. Main outcome measures: Relative risk of developing squamous cell carcinoma in first degree relatives of cases compared with risk in first degree relatives of spouses. Results: The adjusted relative risk for developing head and neck cancer if the index case had squamous cell carcinoma of the head and neck was 3.79 (95% confidence interval 1.11 to 13.0). There were no significantly increased risks associated with a family history of cancer at other sites. The adjusted relative risk for squamous cell carcinoma of the head and neck was 7.89 (1.50 to 41.6) in first degree relatives of patients with multiple primary head and neck tumours. Conclusions: These data suggest that genetic factors are important in the aetiology of head and neck cancer, in particular for patients with multiple primary cancers. Given the prolonged exposure of these subjects to carcinogens, these genetic factors may have a role in modifying carcinogen activity or in host resistance to carcinogens. Inherited factors may be important in persons with environmentally induced cancers. Key messages Tobacco and alcohol are established risk factors, but some affected persons are non-smokers and non-drinkers Genetic makeup may determine how individuals respond to carcinogens This study found a significantly increased relative risk of 3.79 for developing head and neck cancer if a first degree relative had squamous cell carcinoma of the head and neck As with other cancers, people with multiple primary cancers of the head and neck may represent a susceptibility group as the familial risks are higher

The role of professional diagnostic delays in the prognosis of upper aerodigestive tract carcinoma

Despite the belief that cancer mortality can be reduced if lesions are detected, diagnosed and treated at an early stage, only one study, among a number concerning cancers of the upper aerodigestive tract (UADT), has found any relationship between such delays and prognosis for this population of cancer patients. The aim of this study was, therefore, to investigate the relationship between patient and professional diagnostic delays and patient prognosis in a group of UADT cancer patients. Patients diagnosed with squamous cell carcinoma of oral cavity sites (ICD-9 141, 143-5)oro-, naso- and hypopharynx (ICD-9 146-8) and larynx (ICD-9 161) were included in the study. Stepwise multiple logistic regression was used to calculate the odds ratio (OR) of late versus early stage disease for selected study variables. The sample comprised 188 subjects. Multivariate analysis found that having a pharyngeal cancer (OR 9.26; 95% CI 4.02-21.32; P: 0.0001) a professional delay > 1 month (OR 2.28; 95% CI 1.13-4.64; P: 0.022) and age > or = 65 years (OR: 0.45; 95% CI: 0.22-0.91; P: 0.024) were predictive of late stage disease. A dose-response relationship between professional delay and OR for late stage disease for the whole sample (P for trend 0.03) and among those with oral cancer (P for trend 0.0001) was found. The results of this study suggest that, among patients with an UADT cancer, professional delays > 1 month are contributing to an increased risk for being diagnosed with late stage disease.

Occult Cervical Metastases: Immunoperoxidase Analysis of the Pathologically Negative Neck:

OBJECTIVES: The purpose of this study is to better estimate the true incidence of occult regional metastases associated with stage I and II squamous cell carcinoma of the oral cavity. The clinical and prognostic significance of micrometastatic disease discovered by cytokeratin immunoperoxidase reactivity in the previously pathologically N0 neck is also evaluated. METHODS: Forty patients treated between 1985 and 1996 with T1 or T2 squamous cell carcinoma of the lip and oral cavity were studied. All had primary surgical treatment including functional neck dissection. No metastases were demonstrated on hematoxylin and eosin microscopy. All specimens were reexamined with immunoperoxidase staining for cytokeratin. RESULTS: Five percent of patients had micrometastatic disease. Retrospective analysis of patients with a minimum follow-up of 2 years has failed to show a statistically significant association between a positive cytokeratin analysis and poor locoregional control or overall survival. CONCLUSIONS: Results suggest that the true incidence of occult metastases with carcinoma of the oral cavity is significantly higher than previously documented. However, the prognostic significance of these findings remains unclear.

Serum Proteomic Approach for the Identification of Serum Biomarkers Contributed by Oral Squamous Cell Carcinoma and Host Tissue Microenvironment

The lack of serum biomarkers for head and neck carcinoma limits early diagnosis, monitoring of advanced disease, and prediction of relapses in patients. We conducted a comprehensive proteomics study on serum from mice bearing orthotopic human oral squamous cell carcinomas (OSCC) with distinct invasive phenotypes. Matched established cell lines were transplanted orthotopically into tongues of RAG-2/gamma(c) mice and mouse serum was analyzed by 2-dimensional-differential gel electrophoresis(2D-DIGE)/liquid chromatography (LC)-MS/MS and by online 2D-LC-MS/MS of iTRAQ labeled samples. We identified several serum proteins as being differentially expressed between control and cancer-bearing mice and between noninvasive and invasive cancer (p<0.05). Differentially expressed proteins of human origin included the epidermal growth factor receptor (EGFR), cytokeratins, G-protein coupled receptor 87, Rab11 GTPase, PDZ-domain containing proteins, and PEST-containing nuclear proteins. Identified proteins of mouse origin included clusterin, titin, vitronectin, vitamin D-binding protein, hemopexin, and kininogen I. The levels of serum and cell secreted EGFR were further validated to match proteomic data regarding the inverse correlation with the invasive phenotype. In summary, we report a comprehensive patient-based proteomics approach for the identification of potential serum biomarkers for OSCC using an orthotopic xenograft mouse model.

No association between P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck.

An initial report suggested that patients homozygous for the arginine allele at codon 72 of P53 were at increased risk for human papillomavirus (HPV)-related cervical cancer, but other groups have not confirmed this finding. Since approximately 18–36% of head and neck cancers are HPV-related, we examined the genotypic frequencies at that locus in 163 cases with squamous cell carcinoma of the head and neck (SCCHN) and 163 ethnically matched controls. We found no significant excess of arginine homozygotes in cases compared to controls (P= 0.50). No significant differences in allele frequencies were observed when the data were stratified by tobacco exposure or by cancer site. These findings suggest a limited role, if any, for this P53 polymorphism in SCCHN.

Phase III randomized study: Oral pilocarpine versus submandibular salivary gland transfer protocol for the management of radiation-induced xerostomia

Xerostomia is a serious morbidity of radiation treatment in head and neck cancer.

Postoperative parathyroid hormone level as a predictor of post-thyroidectomy hypocalcemia.

OBJECTIVES To evaluate levels of parathyroid hormone following total thyroidectomy in order to ascertain its ability to predict postoperative hypocalcemia. To establish standardized criteria permitting the safe discharge of total thyroidectomy patients within 13 hours of surgery. METHODS This is a prospective study in which parathyroid hormone levels were tested in 54 consecutive patients who underwent total thyroidectomy. Levels were measured postoperatively at 6, 12, and 20 hours. Corrected calcium levels were also measured at 6, 12, and 20 hours in accordance with the preexisting protocol. RESULTS Statistical analysis demonstrates that patients with corrected calcium levels greater than or equal to 2.14 mmol/L and parathyroid hormone levels greater than or equal to 28 ng/L at 12 hours post-thyroidectomy can be discharged without further need for calcium monitoring. The analysis also demonstrates that patients with 12-hour parathyroid hormone levels less than or equal to 20 ng/L are at significant risk of developing hypocalcemia. CONCLUSION Parathyroid hormone levels in conjunction with corrected calcium values are accurate predictors of the calcium trends of post-thyroidectomy patients. Implementation of this protocol can result in shorter hospital stays for the majority of post-thyroidectomy patients, which can translate into substantial cost savings for the health care system.

High prevalence of obstructive sleep apnea among patients with head and neck cancer.

OBJECTIVES To determine the prevalence of obstructive sleep apnea (OSA) in patients with cancer of the oral cavity and oropharynx scheduled for primary surgical resection. To correlate the presence of OSA and the occurrence of postoperative morbidities in this patient population. METHODS This was a prospective study involving 17 patients with malignancies of the oral cavity and oropharynx scheduled for primary surgical resection. Consecutive patients were approached to undergo overnight polysomnography to determine the apnea-hypopnea index (AHI). OSA was defined by an AHI value > or = 20 events per hour. Postoperative morbidities were evaluated in a blinded fashion for the patients completing surgery. RESULTS OSA was present in 13 of 17 patients, yielding a striking prevalence of 76% in this patient group. The mean AHI for patients with OSA was 44.7 +/- 3.5 (standard error) events per hour, with a mean nadir oxygen saturation of 88.2 +/- 1.8%, consistent with moderate to severe sleep-disordered breathing. The OSA and non-OSA patients were similar with respect to age and body mass index. The mean size of the primary tumour was 3.3 cm in patients with an AHI < 20 and 3.5 cm in those with an AHI > or = 20 (p = not significant). Overall, postoperative complications, defined as prolonged intensive care unit stay (> 24 hours), need for mechanical ventilation, and cardiopulmonary morbidities, were observed in 67% of OSA and 25% of non-OSA patients. CONCLUSIONS These findings point to a strong association between OSA and malignancies of the oral cavity and oropharynx. This relationship was independent of the size of the primary malignancy in this patient population with tumours ranging from 1 to 7 cm (p = not significant). When comparing the two groups (AHI < 20 and AHI > or = 20), there was a tendency for the group with OSA to have an increase in postoperative morbidities. Further research is warranted to further evaluate the postoperative morbidities and mortalities associated with OSA in this patient population and to determine the potential roles for preoperative treatment with continuous positive airway pressure and tracheotomy.

Sarcomatoid carcinoma of the head and neck

BACKGROUND Sarcomatoid carcinoma (SC) of the upper aerodigestive tract is a rare malignancy of which the diagnosis, optimum treatment, and prognosis remain controversial. A series of 17 patients with SC is presented, along with an analysis of potential prognostic factors, outcome following treatment, and patterns of failure. MATERIALS AND METHODS Hospital charts and pathology material were reviewed in all cases. The end points chosen were overall survival (OS), disease-free survival, and local control above the clavicles. RESULTS There were 15 male and 2 female patients with a median age of 70 years. With a median follow-up length of 29 months, the median survival time was 32 months with an actuarial survival of 72% and 42% at 2 and 5 years, respectively. CONCLUSION All recurrences were detected within 30 months from diagnosis. There was an OS advantage for patients with early-stage disease, patients with extralaryngeal presentations, and patients treated with surgery.