Iain Hutchison

Mood and malignancy: head and neck cancer and depression.

Head and neck cancer patients have been reported to show high rates of depression. However, it is important to differentiate between depressive symptoms and a depressive disorder. This review critically examines the relationship between head and neck cancer and depression. There appears to be little evidence for depression leading to an increased risk of developing cancer and although depressive symptoms in head and neck cancer patients are common, very few studies have investigated depressive disorders. The studies that investigated the incidence of a comorbid depressive disorder report a prevalence very close to that of the general population, implying that major depression is not a normal response to cancer. Finally, the evidence suggests that comorbidity of depression with cancer has a negative impact on morbidity and mortality. Both psychosocial and biological factors could account for this. Dysregulation of the stress hormone axis and increased inflammation are common in depressive disorders and have been suggested as underlying pathological mechanisms and are both markers of poor prognosis in cancer. This evidence suggests that a relatively small number of patients develop a depressive disorder following a diagnosis of cancer, but for those that do it may have a substantial impact on their prognosis.

Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial.

Summary Background Between 1990 and 2000, we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy. We aimed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy, or both, affected clinical outcome. Here we report survival and recurrence after 10 years of follow-up. Methods Between Jan 15, 1990, and June 20, 2000, 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey. Patients with locally advanced head and neck cancer, and who had not previously undergone surgery, were randomly assigned to one of four groups in a 3:2:2:2 ratio, stratified by centre and chemotherapy regimen: radical radiotherapy alone (n=233); radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy (SIM alone; n=166); or 14 and 28 days after completing radiotherapy (SUB alone, n=160); or both (SIM+SUB; n=154). Chemotherapy was either methotrexate alone, or vincristine, bleomycin, methotrexate, and fluorouracil. Patients who had previously undergone radical surgery to remove their tumour were only randomised to radiotherapy alone (n=135) or SIM alone (n=118), in a 3:2 ratio. The primary endpoints were overall survival (from randomisation), and event-free survival (EFS; recurrence, new tumour, or death; whichever occurred first) among patients who were disease-free 6 months after randomisation. Analyses were by intention to treat. This trial is registered at www.Clinicaltrials.gov, number NCT00002476. Findings All 966 patients were included in the analyses. Among patients who did not undergo surgery, the median overall survival was 2·6 years (99% CI 1·9–4·2) in the radiotherapy alone group, 4·7 (2·6–7·8) years in the SIM alone group, 2·3 (1·6–3·5) years in the SUB alone group, and 2·7 (1·6–4·7) years in the SIM+SUB group (p=0·10). The corresponding median EFS were 1·0 (0·7–1·4), 2·2 (1·1–6·0), 1·0 (0·6–1·5), and 1·0 (0·6–2·0) years (p=0·005), respectively. For every 100 patients given SIM alone, there are 11 fewer EFS events (99% CI 1–21), compared with 100 given radiotherapy, 10 years after treatment. Among the patients who had previously undergone surgery, median overall survival was 5·0 (99% CI 1·8–8·0) and 4·6 (2·2–7·6) years in the radiotherapy alone and SIM alone groups (p=0·70), respectively, with corresponding median EFS of 3·7 (99% CI 1·1–5·9) and 3·0 (1·2–5·6) years (p=0·85), respectively. The percentage of patients who had a significant toxicity during treatment were: 11% (radiotherapy alone, n=25), 28% (SIM alone, n=47), 12% (SUB alone, n=19), and 36% (SIM+SUB, n=55) among patients without previous surgery; and 9% (radiotherapy alone, n=12) and 20% (SIM alone, n=24) among those who had undergone previous surgery. The most common toxicity during treatment was mucositis. The percentage of patients who had a significant toxicity at least 6 months after randomisation were: 6% (radiotherapy alone, n=13), 6% (SIM alone, n=10), 4% (SUB alone, n=7), and 6% (SIM+SUB, n=9) among patients who had no previous surgery; and 7% (radiotherapy alone, n=10) and 11% (SIM alone, n=13) among those who had undergone previous surgery. The most common toxicity 6 months after treatment was xerostomia, but this occurred in 3% or less of patients in each group. Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences, new tumours, and deaths in patients who have not undergone previous surgery, even 10 years after starting treatment. Chemotherapy given after radiotherapy (with or without concurrent chemotherapy) is ineffective. Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy. Funding Cancer Research UK, with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre.

FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma.

The oncogene FOXM1 has been implicated in all major types of human cancer. We recently showed that aberrant FOXM1 expression causes stem cell compartment expansion resulting in the initiation of hyperplasia. We have previously shown that FOXM1 regulates HELLS, a SNF2/helicase involved in DNA methylation, implicating FOXM1 in epigenetic regulation. Here, we have demonstrated using primary normal human oral keratinocytes (NOK) that upregulation of FOXM1 suppressed the tumour suppressor gene p16INK4A (CDKN2A) through promoter hypermethylation. Knockdown of HELLS using siRNA re-activated the mRNA expression of p16INK4A and concomitant downregulation of two DNA methyltransferases DNMT1 and DNMT3B. The dose-dependent upregulation of endogenous FOXM1 (isoform B) expression during tumour progression across a panel of normal primary NOK strains (n = 8), dysplasias (n = 5) and head and neck squamous cell carcinoma (HNSCC) cell lines (n = 11) correlated positively with endogenous expressions of HELLS, BMI1, DNMT1 and DNMT3B and negatively with p16INK4A and involucrin. Bisulfite modification and methylation-specific promoter analysis using absolute quantitative PCR (MS-qPCR) showed that upregulation of FOXM1 significantly induced p16INK4A promoter hypermethylation (10-fold, P<0.05) in primary NOK cells. Using a non-bias genome-wide promoter methylation microarray profiling method, we revealed that aberrant FOXM1 expression in primary NOK induced a global hypomethylation pattern similar to that found in an HNSCC (SCC15) cell line. Following validation experiments using absolute qPCR, we have identified a set of differentially methylated genes, found to be inversely correlated with in vivo mRNA expression levels of clinical HNSCC tumour biopsy samples. This study provided the first evidence, using primary normal human cells and tumour tissues, that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a unique FOXM1-induced epigenetic signature which may have clinical translational potentials as biomarkers for early cancer screening, diagnostic and/or therapeutic interventions.

Barriers to recruitment for surgical trials in head and neck oncology: a survey of trial investigators

Objectives Many randomised trials in surgery suffer from recruitment rates that lag behind projected targets. We aim to identify perceived barriers to recruitment among these pioneering trials in the field of head and neck cancer surgery. Design Recruiting centres to all three trials (Selective Elective Neck Dissection (SEND), Positron Emission Tomography (PET)-Neck and Hyperbaric Oxygen in the Prevention of Osteoradionecrosis (HOPON)) were contacted by email by the chief investigators. Responders were asked to complete a web-based survey in order to identify the barriers to recruitment in their centre and grade each by severity. Setting Secondary care: 44 head and neck oncology regional referral centres. Participants Analysis was based on 85 responses evenly distributed between the three trials. Results The most commonly identified perceived barriers to recruitment (more than 50% of responders identified the item as a barrier in all the three trials) in the order of frequency were: patients consent refusal because of expressed treatment preference, patients consent refusal owing to aversion to randomisation, excess complexity/amount of information provided to patients and lack of time in clinic to accommodate research. The most severely rated of these problems was consent refusal because of the expressed treatment preference and lack of time in the clinic. Conclusions Our findings confirm others’ work in surgery that the most significant barrier to trial recruitment in head and neck cancer surgery is the patients preference for one arm of the trial. It may be that additional training for those taking consent may be helpful in this regard. It is also important to adequately resource busy surgical clinics to support clinical trial recruitment.

Quality of life, psychological wellbeing and treatment needs of trauma and head and neck cancer patients.

There is increasing evidence that patients treated for trauma or cancer of the head and neck may go on to experience psychological distress. We aimed to measure the impact of this on their quality of life (QoL) and to explore their willingness to be referred for psychological support. A total of 96 patients with facial injuries and 124 with cancer of the head and neck completed a self-reported questionnaire to identify psychological distress (Hospital Anxiety and Depression Scale (HADS) and the Acute Stress Disorder (ASD) Scale), quality of life (WHOQoL-BREF), satisfaction with treatment, and willingness to accept psychological support. Thirty-nine percent of patients showed high levels of depressive symptoms and 43% reported high levels of anxiety; 43% in the trauma group and 12% in the cancer group had high ASD scores. Patients with high scores on the HADS reported poorer QoL, and 40% of those with high levels of psychological distress were willing to consider psychological support. Despite the fact that patients report high levels of satisfaction with their medical and surgical care, many have psychological problems and have needs that are not being met. A large proportion would use psychological support services.

Two Mechanisms Regulate Keratin K15 Expression In Keratinocytes: Role of PKC/AP-1 and FOXM1 Mediated Signalling

Background Keratin 15 (K15) is a type I keratin that is used as a marker of stem cells. Its expression is restricted to the basal layer of stratified epithelia, and the bulge in hair follicles. However, in certain clinical situations including oral lichen planus, K15 is induced in suprabasal layers, which is inconsistent with the role of a stem cell marker. This study provides insights into the mechanisms of K15 expression in the basal and differentiating keratinocytes. Methodology/Principal Findings Human keratinocytes were differentiated by three different methods; suspension in methylcellulose, high cell density and treatment with phorbol ester. The expression of mRNA was determined by quantitative PCR and protein by western blotting and immunostaining. Keratinocytes in suspension suppressed β1-integrin expression, induced differentiation-specific markers and K15, whereas FOXM1 (a cell cycle regulated protein) and K14 were downregulated. Rescuing β1-integrin by either fibronectin or the arginine-glycine-aspartate peptide suppressed K15 but induced K14 and FOXM1 expression. Specific inhibition of PKCδ, by siRNA, and AP-1 transcription factor, by TAM67 (dominant negative c-Jun), suppressed K15 expression, suggesting that PKC/AP-1 pathway plays a role in the differentiation-specific expression of K15. The basal cell-specific K15 expression may involve FOXM1 because ectopic expression of the latter is known to induce K15. Using chromatin immunoprecipitation, we have identified a single FOXM1 binding motif in the K15 promoter. Conclusions/Significance The data suggests that K15 is induced during terminal differentiation mediated by the down regulation of β1-integrin. However, this cannot be the mechanism of basal/stem cell-specific K15 expression in stratified epithelia, because basal keratinocytes do not undergo terminal differentiation. We propose that there are two mechanisms regulating K15 expression in stratified epithelia; differentiation-specific involving PKC/AP-1 pathway, and basal-specific mediated by FOXM1, and therefore the use of K15 expression as a marker of stem cells must be viewed with caution.

Exploiting FOXM1-Orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis

Histopathological discordance with molecular phenotype of many human cancers poses clinically challenging tasks for accurate cancer diagnosis, which impacts on treatment strategy and patient outcome. Hence, an objective, accurate and quantitative method is needed. A quantitative Malignancy Index Diagnostic System (qMIDS) was developed based on 14 FOXM1 (isoform B)‐associated genes implicated in the regulation of the cell cycle, differentiation, ageing, genomic stability, epigenetic and stem cell renewal, and two reference genes. Their mRNA expression levels were translated via a prospectively designed algorithm, into a metric scoring system. Subjects from UK and Norway (n = 299) provided 359 head and neck tissue specimens. Diagnostic test performance was assessed using detection rate (DR) and false‐positive rate (FPR). The median qMIDS scores were 1.3, 2.9 and 6.7 in healthy tissue, dysplasia and head and neck squamous cell carcinomas (HNSCC), respectively (UK prospective dataset, p<0.001); 1.4, 2.3 and 7.6 in unaffected, oral lichen planus, or HNSCC, respectively (Norwegian retrospective dataset with up to 19 years survival data, p<0.001). At a qMIDS cut‐off of 4.0, DR was 94% and FPR was 3.2% (Norwegian dataset); and DR was 91% and FPR was 1.3% (UK dataset). We further demonstrated the transferability of qMIDS for diagnosing premalignant human vulva (n = 58) and skin (n = 21) SCCs, illustrating its potential clinical use for other cancer types. This study provided evidence that qMIDS was able to quantitatively diagnose and objectively stratify cancer aggressiveness. With further validation, qMIDS could enable early HNSCC detection and guide appropriate treatment. Early treatment intervention can lead to long‐term reduction in healthcare costs and improve patient outcome.

Temporalis haemangioma presenting as temporomandibular joint pain dysfunction syndrome

Pathology within the infratemporal and temporal fossa is notoriously difficult to diagnose. A rare case of a haemangioma within the temporalis muscle, originally diagnosed as temporomandibular joint dysfunction, illustrates the difficulty of recognising disease within this region when clinical signs are minimal.

Identification of FOXM1‐induced epigenetic markers for head and neck squamous cell carcinomas

Epigenetic reprogramming of the methylome has been implicated in all stages of cancer evolution. It is now well accepted that cancer cells exploit epigenetic reprogramming, a mechanism that regulates stem/progenitor cell renewal and differentiation, to promote cancer initiation and progression. The oncogene FOXM1 has been implicated in all major forms of human cancer.

Synovial sarcoma presenting as a parotid mass: case report and review of literature.

Synovial sarcoma is an unusual neoplasm of mesenchymal derivation, which is uncommon in the head and neck sites. In the parotid gland, it is most likely to be misdiagnosed as a myoepithelial, primary mesenchymal, or metastatic neoplasm.