Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation.

BACKGROUND: Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells. METHODS: Here, we characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines. RESULTS: In recipient HNOK cells, we found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). We have also identified CEP55 as a potential cancer exosomal marker. CONCLUSIONS: In conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies.

Post-traumatic stress in head and neck cancer survivors and their partners.

PURPOSE: Head and neck cancer (HNC) diagnosis and treatment are distressing and have immediate detrimental impacts on functioning and quality of life (QoL). Nevertheless, little is known about long-term psychosocial effects. The aim of this study was to determine the prevalence and correlates of clinical post-traumatic stress disorder (PTSD) and subclinical post-traumatic stress symptoms (PTSS) in HNC patients surviving more than 2 years since treatment and in their partners. METHODS: HNC survivors identified from the cancer registry of a London hospital and their partners completed measures of PTSS, depression and anxiety, fear of cancer recurrence, social support, appearance concerns and health-related QoL. Data regarding their clinical and demographic characteristics were also collected. Correlations, as well as linear and logistic regression coefficients, were calculated to estimate associations with PTSS scores. RESULTS: In this analysis of 93 HNC survivors, at a mean of 6 years (SD = 4) after treatment, 33.4% reported PTSS and 11.8% met the criteria for post-traumatic stress disorder (PTSD). Fear of cancer recurrence was independently associated with PTSS (p < .01). In subgroup analyses of patient-partner dyads, 15.4% of patients and 12.8% of partners reported PTSD, with a further 33.3% of patients and 25.7% of partners demonstrating PTSS. Patients' and partners' scores did not differ significantly (p > .05). CONCLUSIONS: This is the first examination of post-traumatic stress in survivors of HNC and shows that high levels of cancer-related PTSS exist for many years after diagnosis in both patients and their partners.

The potential of CD44 as a diagnostic and prognostic tool in oral cancer.

The CD44 family of molecules exists as a wide range of isoforms ubiquitously expressed on the surface of mammalian cells. The variation in patterns of CD44 expression on cancer cells has been widely studied in relation to their behaviour, and further interest has recently arisen in CD44 as a marker of the subfraction tumour cells acting as cancer stem cells in several types of tumours. This review focuses on the patterns of CD44 expression on the stem cell fraction of oral squamous cell carcinoma and on the relationship of detectably different patterns of CD44 expression to the behaviour of tumours.

Survey of United Kingdom oral and maxillofacial surgery (OMFS) specialists and trainees about the reasons that they retain or drop their registration with the General Dental Council (GDC) including a summary of changes in the numbers registered with the GDC 2014-2023.

When dual degree OMFS training was mandated in the UK in 1995, OMFS specialists were required to be registered with both the General Dental Council (GDC) and General Medical Council (GMC). In 2005 this legal requirement for dual registration with both regulators was removed. During 2021 the authors surveyed UK OMFS specialists and trainees asking them why they chose to remain on or leave the Dental Register to give context to the changing numbers of OMFS specialists and trainees holding Dental Registration between 2014 and 2023. In 2014 of 539 OMFS specialists and trainees only 62 (12%) were solely GMC registered, that is, they had let their Dental Registration lapse. In 2023, of 709 OMFS specialists and trainees, 320 (45%) were solely GMC registered. Those whose first qualification was medicine were less likely to be dually registered. Of those who replied to the survey and remained dually registered, most (40%) based this decision on 'worries about the consequences' of dropping their dental registration. Some other reasons were not based on fact at that time. Cost was the most common reason (49%) given for dropping their GDC registration by respondents who were only registered with the GMC. On the positive side, the January 2023 GDC position statement about OMFS who are not on the Dental Register removed the GDC's previous restriction on location of practice and teaching dental students. However the statement does not unambiguously allow OMFS surgeons to practice across the full OMFS curriculum. Will the 2023 GDC position statement alter the trend of OMFS specialists and trainees towards single medical registration?

United Kingdom oral and maxillofacial surgeons support changes to current specialty recruitment process, which could include 'Walport' style local selection and national benchmarking.

Recruitment to oral and maxillofacial Surgical (OMFS) specialty training was centralised in 2010. The 'flexibility' for OMFS to respond to specialty specific recruitment issues is reducing and many Specialty Trainees' (ST) posts are left unfilled. The National Institute for Health and Care Research (NIHR) appointment process designed to address the problem of recruiting and appointing academic surgeons with local selection with national benchmarking has worked. Using a database of all UK OMFS consultants/trainees, an electronic questionnaire was shared by e-mail, WhatsApp, and other social media. Of 306 replies, 125 (41%) were Consultants/post-certificate of completion training (CCT) individuals, 66 (22%) ST, 61 (20%) second degree students, 27 (9%) pre-second degree, 26 (9%) dual degree pre-ST trainees, and one did not indicate their status. A total of 249 (76%) studied dentistry first and 230 (75%) were male. Of those replying, 147 (48%) had no direct experience of national selection. 120 (39%) had experience as a candidate, 20 (7%) as a selector only, 17 (6%) as a candidate and selector, and two did not record their experience. Of 250 expressing an opinion, 156 (62%) supported local selection with 140 (56%) supporting local selection and national benchmarking, which is a process used for research training posts by the NIHR. Geographical continuity was most important for 78% of pre-second-degree trainees, 45% of STs, and 54% of second-degree students. A total of 57 respondents completed free text comments. There is support for changes in OMFS ST selection including creating OMFS posts which include Foundation and second-degree training in NIHR style locally recruited nationally benchmarked posts.

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.

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

BACKGROUND: 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. METHODS: We have recently shown that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a number of FOXM1-induced epigenetic markers. Differential promoter methylation and gene expression in clinical specimens were measured using commercially available bisulfite conversion kits and absolute quantitative PCR, respectively. RESULTS: Here, we investigated 8 FOXM1-induced differentially methylated genes, SPCS1, FLNA, CHPF, GLT8D1, C6orf136, MGAT1, NDUFA10, and PAFAH1B3, using human head and neck tissue specimens donated by 2 geographically independent patient cohorts from Norway and the United Kingdom. Two genes (GLT8D1 and C6orf136) were found to be differentially expressed in head and neck squamous cell carcinomas (HNSCCs). Using methylation-specific quantitative PCR, we confirmed that the promoters of GLT8D1 and C6orf136 were hypo- and hypermethylated, respectively, in HNSCC tissues. CONCLUSIONS: Given that epigenetic change precedes gene expression, methylation status of candidate genes identified from this study may represent a signature of premalignancy, rendering them potentially useful predictive biomarkers for precancer screening and/or therapeutic targets for cancer prevention.

The effects of CD44 down-regulation on stem cell properties of head and neck cancer cell lines.

BACKGROUND: There is now substantial evidence that only a subpopulation of cells in solid cancers is able to sustain tumour growth and to re-initiate new tumours. Various cancers and cancer-derived cell lines, including head and neck squamous cell carcinomas (HNSCC), have a subpopulation of cancer stem cells (CSCs), marked by high levels of expression of the CD44 adhesion molecule. However, it has been unclear whether, in addition to acting as a marker, CD44 has functions that directly influence stem cell properties. The aim of this study was to investigate the role of CD44 in the maintenance of the CSC population in HNSCC cell lines. METHODS: CD44 was down-regulated either by treating cultures with 1 mM sodium butyrate or by the more specific method of knockdown with siRNAs directed against CD44. Changes in CD44 expression levels were assessed at the mRNA and protein levels, and the effects of CD44 down-regulation on cell proliferation and on the fate of the CSC subpopulations were assessed. RESULTS: Reduced CD44 expression resulted in a decreased rate of population expansion, both initially and on repassage, and there was an alteration in colony morphologies indicative of stem cell loss. Down-regulation of CD44 also led to reduced expression of Oct4A, an alternative marker of CSCs. CONCLUSIONS: The results suggest that CD44 has a functional role in maintaining stem cell properties in HNSCC cell lines and provides support for the concept that therapies targeting CD44, or its related signalling pathways, may allow development of more efficient treatment strategies.

Computer guided surgery for implant placement and dental rehabilitation in a patient undergoing sub-total mandibulectomy and microvascular free flap reconstruction.

A 58-year-old patient presented with an extensive, destructive, recurrent pleomorphic adenoma occupying the mandibular body and the soft tissues of the mouth and neck. Resection of the mandible from right ramus to left condylar process, and implant rehabilitation in both jaws with fixed bridgework was planned. Comprehensive presurgical prosthetic work up was carried out to record the existing dental relationship and guide all stages of the reconstruction. The jaw was first grafted with a segmented, fibular microvascular free-flap, which was fixed in place with a fixation plate prebent on a Rapid Prototype Anatomical Model of the jaw. Reconstruction with implant supported fixed partial dentures took place to the dental scheme planned preresection, using a computer guided approach to implant placement in the complex and unfamiliar anatomy of the extensively grafted mandible. This approach facilitated and expedited implant surgery such that treatment could take place using a minimally invasive approach relatively soon after surgery, prior to commencement of radiotherapy, and highlights the importance of a multidisciplinary approach to treatment for patients having extensive surgery to the jaws. The patient's personal assessment 2 years post surgery was recorded using 1999 University of Washington Quality of Life Questionnaire.

Oral and Maxillofacial Surgery (OMFS) Consultant Workforce in the UK: reducing consultant numbers resulting from recruitment issues, pension pressures, changing job-plans, and demographics when combined with the COVID backlog in elective surgery, requires urgent action.

Mean retirement age for UK doctors is 59.6 years, giving the average OMFS consultant approximately 20 years of practice. Current pension tax regulations, new consultant posts typically restricted to a maximum of 10 sessions (40 hours), increasing proportions of consultants working less than full time (LTFT), all combined with the backlog of elective care created by COVID-19 will create a significant gap between workforce capacity and clinical demand. The age of current OMFS consultants was estimated using the date of their primary medical/dental qualification. Changes in job plans were estimated using data from the BAOMS Workforce Census and from recently advertised posts. Reports of unfilled posts were collated by OMFS Regional Specialty Professional Advisors (RSPAs). First degree dates were identified for 476 OMFS substantive consultant posts. Estimated current average age of OMFS consultants was 52.7 years (minimum 35.9, maximum 72.1), 75th centile age 59.0 and 23% of the current consultant workforce above the average retirement age for doctors. The 10 sessions of new OMFS consultants posts is significantly less than existing consultants' average of 12.1 sessions (48.4 hours). Unfilled consultant posts in Great Britain are 13% of the total compared to 20% in Northern Ireland and Ireland. Many (23%) of the OMFS consultant workforce are above average retirement age. Forty-hour contracts; new consultants working LTFT; and early loss of senior colleagues because of pension pressure will reduce NHS' capacity to treat OMFS disorders and injuries. This paper suggests increasing consultant posts, increasing trainee numbers, and actively retaining senior surgeons to maintain capacity.

Molecular Signatures of Tumour and Its Microenvironment for Precise Quantitative Diagnosis of Oral Squamous Cell Carcinoma: An International Multi-Cohort Diagnostic Validation Study.

BACKGROUND: Heterogeneity in oral potentially malignant disorder (OPMD) poses a problem for accurate prognosis that impacts on treatment strategy and patient outcome. A holistic assessment based on gene expression signatures from both the tumour cells and their microenvironment is necessary to provide a more precise prognostic assessment than just tumour cell signatures alone. METHODS: We reformulated our previously established multigene qPCR test, quantitative Malignancy Index Diagnostic System (qMIDS) with new genes involved in matrix/stroma and immune modulation of the tumour microenvironment. An algorithm calculates and converts a panel of 16 gene mRNA expression levels into a qMIDS index to quantify risk of malignancy for each sample. RESULTS: The new qMIDSV2 assay was validated in a UK oral squamous cell carcinoma (OSCC) cohort (n = 282) of margin and tumour core samples demonstrating significantly better diagnostic performance (AUC = 0.945) compared to previous qMIDSV1 (AUC = 0.759). Performance of qMIDSV2 were independently validated in Chinese (n = 35; AUC = 0.928) and Indian (n = 95; AUC = 0.932) OSCC cohorts. Further, 5-year retrospective analysis on an Indian dysplastic lesion cohort (n = 30) showed that qMIDSV2 was able to significantly differentiate between lesions without transformation and those with malignant transformation. CONCLUSIONS: This study validated a novel multi-gene qPCR test on a total of 535 tissue specimens from UK, China and India, demonstrating a rapid minimally invasive method that has a potential application for dysplasia risk stratification. Further study is required to establish if qMIDSV2 could be used to improve OPMD patient management, guide treatment strategy and reduce oral cancer burden.

Institutionalization of mentally-impaired children in Scotland, c. 1855-1914.

This article examines two institutions which were established in Scotland specifically for the accommodation of mentally-impaired children: Baldovan Asylum near Dundee and the 'Scottish National Institution for the Education of Imbecile Children' in Larbert, Stirlingshire. It surveys the aims and agendas of the institutions in the spheres of residential childcare, mental health, and education and training. It compares the admission regimes of these institutions and considers whether they complemented one another in serving an unsatisfied demand for places, or whether they were in competition for admissions, staff and charitable support. The survey covers the period from the opening of both institutions to the implementation of the Mental Deficiency Act of 1913 which required the (re)certification of all children.

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

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.

COVID-19, domestic violence and abuse, and urgent dental and oral and maxillofacial surgery care.

Household isolation measures to reduce coronavirus transmission during the COVID-19 pandemic have resulted in increased risk of domestic violence and abuse (DVA). DVA physical injury most frequently involves the face. Dentists, dental care professionals, oral surgeons and oral and maxillofacial surgeons all have a critical part to play in identifying patients experiencing DVA, who present with dental and facial injury, and in making referrals to specialist agencies. This paper describes how to ask questions about DVA sensitively and how to make an appropriate referral. Early intervention and referral to a DVA advocate can prevent an abusive situation becoming worse with more intense violence. It can save lives.

Management of the clinically N0 neck in early-stage oral squamous cell carcinoma (OSCC). An EACMFS position paper.

Metastasis of oral squamous cell carcinoma (OSCC) to the cervical lymph nodes has a significant impact on prognosis. Accurate staging of the neck is important in order to deliver appropriate treatment for locoregional control of the disease and for prognosis. The management of the neck in early, low volume disease (clinically T1/T2 oral cavity tumours) has long been debated. The risk of occult nodal involvement in cT1/T2 OSCC is estimated around 20-30%. We describe the natural evolutionary history of OSCC and its patterns of spread and metastasis to the local lymphatic basins. We discuss most published literature and studies on management of the clinically negative neck (cN0). Particular focus is given to prospective randomized trials comparing the outcomes of upfront elective neck dissection against the observational stance, and we summarize the results of the sentinel node biopsy studies. The paper discusses the significance of the primary tumour histological characteristics and specifically the tumour's depth of invasion (DOI) and its impact on predicting nodal metastasis. The DOI has been incorporated in the TNM staging highlighting its significance in aiding the treatment decision making and this is reflected in world-wide oncological guidelines. The critical analysis of all available literature amalgamates the existing evidence in early OSCC and provides recommendations in the management of the clinically N0 neck.