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Purpose: A systematic review to establish what evidence is available for swallowing outcomes following IMRT for head and neck cancer., Methods: Online electronic databases were searched to identify papers published in English from January 1998 to December 2009. Papers were independently appraised by two reviewers for methodological quality, method of swallowing evaluation and categorized according to the World Health Organisation's International Classification of Health Functions. The impact of radiation dose to dysphagia aspiration risk structures (DARS) was also evaluated., Results: Sixteen papers met the inclusion criteria. The literature suggests that limiting the radiation dose to certain structures may result in favourable swallowing outcomes. Methodological limitations included variable assessment methods and outcome measures and heterogeneity of patients. There are only limited prospective data, especially where pre-treatment measures have been taken and compared to serial post-treatment assessment., Conclusions: Few studies have investigated the impact of IMRT on swallow function and the impact on everyday life. Initial studies have reported potential benefits but are limited in terms of study design and outcome data. Further well designed, prospective, longitudinal swallowing studies including multidimensional evaluation methods are required to enable a more comprehensive understanding of dysphagia complications and inform pre-treatment counselling and rehabilitation planning., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Secondary tumours of small intestine account for 10% of all small bowel cancers. The most common sites of primary tumour metastasizing to small bowel are uterus, cervix, colon, lung, breast and melanoma. The majority of these metastatic tumours come from adenocarcinoma primaries; squamous cell carcinoma constitutes a very small proportion of all metastatic small intestinal lesions. Metastasis to small bowel by head and neck squamous cell carcinoma is extremely rare and carries an unfavourable prognosis. Owing to the limited number of published studies, its characteristic features, clinical presentation and outcomes are poorly described. This work aims at specifying these characteristics by reviewing, compiling, analysing and reporting all published cases in the published literature on small bowel metastasis secondary to head and neck squamous cell carcinoma. To the best of our knowledge, this is the first comprehensive review article on the small intestinal metastasis from head and neck squamous cell carcinoma., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Impairment of swallowing function is a common multidimensional symptom complex seen in 50-75% of head and neck cancer (HNC) survivors. Although there are a number of validated swallowing-specific questionnaires, much of their focus is on the evaluation of swallowing-related quality of life (QOL) rather than swallowing as a specific function. The aim of this study was to validate the Sydney Swallow Questionnaire (SSQ) as a swallowing-specific instrument in HNC patients. Fifty-four consecutive patients in follow-up for oral and oropharyngeal cancer completed the SSQ and MD Anderson Dysphagia Inventory (MDADI). Thirty-one patients completed both questionnaires again four weeks later to address test-retest reliability. Internal consistency and test-retest reliability was assessed using Cronbach's alpha and Spearman's correlation coefficient, respectively. Construct validity (including group validity) and criterion validity were determined using Spearman's correlation coefficient and Mann-Whitney U-test. Internal consistency, test-retest reliability, construct validity, group validity and criterion validity of the SSQ was found to be significant (P<0.01). We were able to demonstrate the reliability and validity of the SSQ in HNC patients. The SSQ is a precise, reliable and valid tool for assessing swallow in this patient group., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Follow-up in patients treated for head and neck cancer (HNC) is aimed at early detection of recurrence, metastases and second primary tumours. Various modalities for the routine follow-up of patients with HNC have been proposed and studied in the literature. Consequently, practising head and neck surgeons and oncologists all over the world use different guidelines and protocols to follow-up their patients. These guidelines involve follow-up intervals of varying intensity and schedule an assortment of investigations that may be neither logical nor practical. This follow-up process may be difficult to administrate, cause unnecessary discomfort and morbidity to the patient and can have serious cost-implications to the healthcare system. This review summarises strategies for follow-up, imaging modalities and key investigations in the literature published between 1980 and 2009. In this structured review, we have assessed studies in the literature that have addressed follow-up intervals, imaging tests, tumour markers, endoscopy and thyroid function tests as a part of the routine post-treatment surveillance in HNC patients. Studies analysing the cost benefit of such surveillance have also been addressed. Based on the evidence presented, we have compiled definitive recommendations for effective surveillance/post-treatment follow-up in patients with HNC.

Aims: To compare voice quality as defined by formant analysis using a sustained vowel in patients who have undergone a partial glossectomy with a group of normal subjects., Methods & Procedures: The design consisted of a single centre, cross-sectional cohort study. The setting was an Adult Tertiary Referral Unit. A total of 26 patients (19 males) who underwent partial glossectomy and 31 normal volunteers (18 males) participated in the study. Group comparisons using the first three formant frequencies (F1, F2 and F3) using linear predictive coding (Laryngograph Ltd, London, UK) were performed. The existence of any significant difference of F1, F2 and F3 between the two groups using the sustained vowel /i/ and the effects of other factors, namely age, first presentation versus recurrence, site (oral cavity, oropharynx), subsite (anterior two-thirds of the tongue, tongue base), stage, radiation, complication, and neck dissection, were analysed., Outcomes & Results: Formant frequencies F1, F2 and F3 were normally distributed. F1 and F2 were significantly different in normal males versus females. F1, F2 and F3 were not different statistically between male and female glossectomees. Comparison of only women showed significant differences between normal subjects and patients in F2 and F3, but none in F1. This was the opposite in men where F1 was significantly different. Age, tumour presentation, site, subsite, radiation and neck dissection showed no significant difference. Postoperative complications significantly affected the F1 formant frequency., Conclusions: The study found that the formant values in patients following a partial glossectomy were altered significantly as compared with the normal control subjects. Only gender and complications and not the age, site, subsite, radiation and neck dissection were seen to influence the formant scores.

Squamous cell carcinoma of the head and neck (SCCHN) is associated with high morbidity and mortality. Despite significant surgical advances and refinement in the delivery of chemotherapy and radiotherapy, prognosis has improved little in recent decades. Better local control has led to the late presentation of distant metastases and novel therapeutic agents are urgently required to prevent relapse, control disseminated disease and thus improve survival. PIK3CA encodes the p110alpha isoform of phosphoinositide 3-kinase (PI3-K) and is important in SCCHN, aberrations in its activity occurring early in the oncogenic process. PI3-K signalling promotes cell survival, proliferation, invasion and angiogenesis, all contributing to tumour progression. Activation of the PI3-K pathway may also mediate resistance to chemotherapy, radiotherapy and novel therapeutic agents such as epidermal growth factor receptor inhibitors. Elements of this signalling matrix, therefore, offer attractive therapeutic targets in SCCHN as inhibition of many malignant characteristics, as well as sensitisation to multiple treatment modalities, could be anticipated.

The mechanisms by which c-erbB-dependent signaling contribute to the invasive potential of HNSCC remain to be fully elucidated. We have previously shown that c-erbB autocrine and/or paracrine stimulation upregulates MMP-9 but has no effect on the related gelatinase, MMP-2. BTC, a major c-erbB ligand, has the ability to efficiently activate all c-erbB receptors and to bind directly to EGFR and c-erbB-4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in terms of MMP induction relative to other c-erbB ligands so far tested. In the present study, we explored the contribution of major downstream events triggered by BTC/c-erbB receptor signaling to the regulation of MMP-9 and in vitro invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN-006 and Detroit-562, BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors whereas both endogenous MMP-9 and BTC-stimulated MMP-9 were predominantly mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase. The BTC-dependent activation of JNK and PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK-1/ERK pathway occurred via all 4 c-erbB receptors, although again predominantly via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by LY294002 or wortmannin) led to marked reduction of both basal and BTC-induced MMP-9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38 kinase with SB203580 produced no such effects. A specific inhibitor of NF-kappa B, BAY 11-7085, also blocked the stimulatory effect of BTC. No remarkable inhibition of MMP-9 and invasion was observed on targeting other cellular activities, such as PKA, PKC and PLC-gamma. Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells., (Copyright 2004 Wiley-Liss, Inc.)

c-erbB receptor signalling induces pleiotropic responses and influences several biological functions involved in the pathogenesis and progression of HNSCC. Aberrant expression of multiple c-erbB receptors and ligands is frequently observed in tumour cells. EGFR appears to be a dominant factor controlling the malignant phenotype in HNSCC at least in part via regulation of molecules involved in invasive and angio-/lymphangiogenic processes. Although c-erbB-2 is an orphan receptor, the formation of heterodimer complexes appears to be an important mechanism for inter-receptor activation and synergistic signal transduction. The roles of c-erbB-3 and c-erbB-4 in HNSCC progression are less clear. However, their ability to form heterodimers with other c-erbB family members enhances proliferation and invasion in HNSCC cells. At least two major downstream signalling pathways, MAPK and PI3K, are involved in the transcriptional regulation of proteases and cytokines implicated in invasion and angiogenesis. Studies using clinical specimens confirmed experimental data that co-operative signalling of c-erbB receptors may play a significant role in the pathogenesis of HNSCC. Most therapeutic studies in HNSCC so far have focused on the strategies targeting of EGFR. Due to the complexity of the system both at the receptor and ligand levels and the integrated biological functions of the c-erbB family in HNSCC, the effect of combined c-erbB blockade (or their downstream signalling pathways) on HNSCC progression should be explored.

Head and neck squamous cell carcinoma (HNSCC) is characterized by its capacity to invade adjacent tissues and to metastasize locoregionally. Evidence suggests that matrix metalloproteinases (MMPs) may play a causal role in HNSCC progression. While evaluating the role of MMPs in the invasion process, we made the surprising observation that a broad-spectrum MMP inhibitor, (marimastat, BB2516), inhibited the growth in vitro of some HNSCC cell lines. This inhibitory effect was only found in HNSCC cell lines overexpressing epidermal growth factor receptors. The effects of the MMP inhibitor could be reversed by adding exogenous c-erbB ligands, suggesting that the phenomenon may be related to autocrine ligand processing. This hypothesis was supported by the finding that the growth-inhibitory effect of marimastat was directly related to its ability to prevent the release of major c-erbB ligands including transforming growth factor-alpha, betacellulin and heregulin beta1 from HNSCC. Marimastat was also found to potentiate the cytotoxic effects of cisplatin both in vitro and in vivo. Our results indicate that the cleavage of several c-erbB ligands from membrane-anchored precursors requires MMP activity. We conclude that MMP inhibitors could prevent tumor progression not only by inhibiting invasion and angiogenesis, as previously shown, but also by their ability to inhibit autocrine signaling through the c-erbB receptors. Clinical trials to test this hypothesis in HNSCC should be considered., (Copyright 2002 Wiley-Liss, Inc.)