Priyamal Silva

Relation of a Hypoxia Metagene Derived from Head and Neck Cancer to Prognosis of Multiple Cancers

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.

Prognostic Significance of Tumor Hypoxia Inducible Factor–1α Expression for Outcome After Radiotherapy in Oropharyngeal Cancer

PURPOSE Head-and-neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of patients in terms of subsite, treatment, and biology. Currently most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumor biology. We investigated the prognostic significance of clinicopathologic features and tumor hypoxia-inducible factor-1alpha (HIF-1alpha) expression in a homogeneous series of patients who underwent radiotherapy. METHODS AND MATERIALS An audit identified 133 consecutive patients with histologically proven squamous cell carcinoma of the tonsil or tongue base. All patients received primary radiotherapy between 1996 and 2001. Tumor HIF-1alpha expression was examined in 79 patients. RESULTS Features associated with poor locoregional control were low Hb level (p = 0.05) and advancing T (p = 0.008), N (p = 0.03), and disease (p = 0.008) stage. HIF-1alpha expression was a more significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence interval [CI]. 3.04-176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14-7.19) group (p = 0.03, test for interaction). High tumor HIF-1alpha expression was associated with low blood Hb levels (p = 0.03). In a multivariate analysis HIF-1alpha expression retained prognostic significance for locoregional control (HR, 7.10; 95% CI, 3.07-16.43) and cancer-specific survival (HR, 9.19; 95% CI, 3.90-21.6). CONCLUSIONS There are significant differences in radiation therapy outcome within a homogeneous subsite of the oropharynx related to molecular marker expression. The work highlights the importance of studying homogeneous groups of patients in HNSCC, and the complex interrelationships between tumor biology and clinicopathologic factors. The establishment of tumor-type specific markers would represent a major advance in this area.

Clinical and biological factors affecting response to radiotherapy in patients with head and neck cancer: a review.

Objective:  The main aim of this article was to review the clinical and biological factors that have been shown to influence the response of the head and neck squamous cell carcinoma (HNSCC) to primary radiotherapy and briefly discuss how some of these factors could be exploited to improve outcome.

Should FDG-PET scanning be routinely used for patients with an unknown head and neck squamous primary?

BACKGROUND Between 1 and 2 per cent of head and neck squamous cell carcinoma patients will reveal no evidence of a primary malignancy. The management of this group poses many problems, including the morbidity associated with wide field irradiation as well as the difficulty in treatment when a primary does emerge. The aim of this study was to assess the use of fluoro-deoxy-glucose positron emission tomography (FDG-PET) imaging in patients presenting with an unknown head and neck primary and to consider its routine use in such patients. METHODS We enrolled 25 patients into our study over a four year period. They all presented with a histologically proven, metastatic, squamous cell carcinoma of the neck for which no primary could be found despite full clinical, endoscopic and radiological evaluation with computed tomography (CT) and/or magnetic resonance imaging (MRI). Additionally, all the patients underwent imaging using FDG-PET. The images were interpreted by two radiologists experienced in PET imaging. RESULTS A primary was identified in nine of the 25 patients (42 per cent); however, of these patients, six had false positive results and only three patients were true positives with supportive histology. In the remaining 16 patients, no abnormality was identified on CT, MRI or PET. Of these 16 patients, two eventually displayed a primary carcinoma, the other 14 patients remaining without evidence of any primary. CONCLUSION Despite the high number of positive PET scans, the actual true positive rate was 3/9 (33 per cent); conversely, the true negative rate was 14/16 (88 per cent). We conclude from this study that there is a role for FDG-PET in the patient with an unknown head and neck primary, particularly in the context of a negative PET scan.

Nodular fasciitis of the head and neck

Nodular fasciitis is an unusual benign reactive process affecting superficial and deep fascia. Its rapid growth, rich cellularity, high mitotic activity and poorly circumscribed nature result in it being easily misdiagnosed as a sarcomatous lesion. Three cases of nodular fasciitis presenting as neck lumps are reported. They were successfully treated with local excision, with no signs of recurrence following two years of follow up. This paper describes the clinical presentation and microscopic features of this rare benign lesion and it emphasizes the need for accurate histopathology and clinical suspicion, if inappropriate aggressive management is to be avoided.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease.

Use of multiple biological markers in radiotherapy-treated head and neck cancer.

OBJECTIVE Management of patients with head and neck squamous cell carcinoma is often based on clinical parameters, with little appreciation of the underlying tumour biology. Single biological marker studies fail to acknowledge the complexity of these tumours. Our aim was to define a profile of biological markers associated with outcome. DESIGN This retrospective study involved consecutive patients with oropharyngeal squamous cell carcinoma treated with primary radiotherapy between 1996 and 2001. Pre-treatment biopsies were used to study the immunohistochemical expression of nine biological markers. Markers were chosen to reflect biologically relevant pathways. RESULTS Following analysis of nine markers, a profile of two markers was derived (carbonic anhydrase 9 and major vault protein), the co-expression of which conferred a significantly poor probability of locoregional control. The prognostic effect of these biomarkers in combination was greater than their effect individually. CONCLUSION Biomarker profiles can be established which highlight large differences in locoregional control. Identifying tumours that express both carbonic anhydrase 9 and major vault protein may facilitate patient selection for more aggressive treatment.