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Adenoid ameloblastoma (AA) was recently recognised as a separate tumour type in the most recent World Health Organisation (WHO) classification of head and neck tumours. This decision has been considered controversial by several groups, who have described AA as a subtype of ameloblastoma, a hybrid odontogenic tumour or to fall within the spectrum of other recognised odontogenic tumours, including dentinogenic ghost cell tumour and adenomatoid odontogenic tumour. Here we review the reasons for the WHO decision to classify AA as a separate tumour type. We also critique molecular and histological findings from recent reports published since the WHO classification. While acknowledging that the classification of tumours is constantly evolving, the balance of current evidence suggests that AA should remain a distinct tumour type, and not a subtype of ameloblastoma, pending further molecular characterisation. [ABSTRACT FROM AUTHOR]

High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase in the incidence of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite the favourable prognosis of HPV-HNSCC, the treatment modality, consisting of high dose radiotherapy (RT) in combination with chemotherapy (CT), remains similar to HPV-negative tumours, associated with toxic side effects. Epidermal growth factor receptor (EGFR) is overexpressed in over 80% of HNSCC and correlates with RT resistance. EGFR inhibitor Cetuximab is the only FDA approved targeted therapy for both HNSCC subtypes, however the response varies between HNSCC subtypes. In HPV-negative HNSCC, Cetuximab sensitises HNSCC to RT improving survival rates. To reduce adverse cytotoxicity of CT, Cetuximab has been approved for treatment de-escalation of HPV-positive HNSCC. The results of several recent clinical trials have concluded differing outcome to HPV-negative HNSCC. Here we investigated the role of EGFR in HPV-positive HNSCC response to RT. Remarkably, in HPV-positive HNSCC cell lines and in vivo tumour models, EGFR activation was strongly indicative of increased RT response. In response to RT, EGFR activation induced impairment of DNA damage repair and increased RT response. Furthermore, EGFR was found to downregulate HPV oncoproteinE6 expression and induced p53 activity in response to RT. Collectively, our data uncovers a novel role for EGFR in virally induced HNSCC and highlights the importance of using EGFR-targeted therapies in the context of the genetic makeup of cancer. [ABSTRACT FROM AUTHOR]

Differentiated thyroid cancer (DTC) accounts for over 90 % of thyroid malignancies, and is frequently associated with central neck compartment nodal metastasis that requires a therapeutic central compartment neck dissection (CCND) for clinically evident nodes. Current knowledge on the expected lymph node yield from a CCND is limited, compared with data on the lateral neck. The aim of our study was to accurately quantify nodal yield from the cadaveric central neck compartment. Twenty-eight cadaveric necks were dissected and the central neck compartment was subdivided into four regions: pre-laryngeal (delphian), pre-tracheal, right and left para-tracheal regions. Each cadaver had a thyroid gland, which was also removed, and the CCND tissue in each compartment was processed and examined by a consultant histopathologist. Only lymphoid tissue with a defined microscopic fibrous capsule and subcapsular sinus was included in the node count. The median total lymph node count per cadaver was four (range 1-16), with a median of one node detectable in each para-tracheal region (range 0-7) and the pre-tracheal region (range 0-8). The median pre-laryngeal node count was 0 (range 0- 2). The average lymph node size across all compartments was 2.9 mm. This is the first European study to assess cadaveric central neck lymph nodes and establish baseline counts for nodal yield. If a prophylactic or therapeutic CCND is required during thyroid surgery, those involved in DTC management must recognise that there is a wide range, and low median yield of central neck compartment lymph nodes. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) have a reduced risk of developing second primary upper aerodigestive tract (UADT) tumours compared to patients with HPV-negative primary tumours at the same site. To determine whether this finding might be explained by a lack of viral-induced field cancerisation or multifocal infection, we investigated whether there was epithelial dysplasia and/or evidence of HPV infection at other pharyngeal mucosal sites in patients presenting with the disease. Materials and methods: Sixty-three patients with primary tonsil SCC and 108 pharyngeal endoscopic biopsies, representing at least one pharyngeal subsite from each patient, were included in this study. Tissue samples were tested using HPV PCR (GP5+/6+), p16 immunohistochemistry (IHC) and high risk HPV DNA in situ hybridisation (ISH). Results: There were 46 patients with HPV-related SCC and 17 patients with HPV-negative disease. PCR detected HPV DNA in a fifth of pharyngeal endoscopic biopsies and was equally likely to be from a patient with HPV-related SCC as from a patient with HPV negative disease. All PCR positive cases were tested using p16 IHC and high risk HPV ISH and only three biopsies were positive. Significantly, these three biopsies all showed evidence of epithelial dysplasia and were from patients with an HPV positive index tumour. Conclusion: Our data suggest that virus-induced field cancerisation and/or multifocal oncogenic HPV infection of the pharynx is uncommon in OPSCC and supports the concept that these patients have a lower risk of developing second primary tumours of the UADT. [Copyright &y& Elsevier]

• This is an analysis of stage III-IV oral cancer patients, comparing TNM 8 to TNM 7. • TNM 8 is a better prognosticator for OS, DFS and early disease recurrence. • On MVA, TNM 8 stage, margin status and performance status affect overall survival. • Patients aged < 60 years who smoked less were more likely to recur within 12 months. To assess TNM 8 staging in discriminating overall survival (OS) amongst patients with locally advanced oral cavity squamous cell carcinoma (OCSCC) treated with surgery and post-operative radiotherapy (PORT), compared to TNM 7. Data from OCSCC patients treated with surgery and PORT between January 2010 and December 2018 were reviewed. Demographics, tumour characteristics and treatment response data were collected, and patients staged according to both TNM 7 and TNM 8. OS and disease free survival (DFS) were estimated using the Kaplan Meier method. Univariate and multivariable analyses were conducted for factors affecting OS, DFS and early disease recurrence within 12 months. Overall 172 patients were analyzed. Median follow up was 32 months for all patients and 48 months for surviving patients. TNM 8 staging demonstrated significant stratification of OS and DFS amongst the entire cohort, whereas TNM 7 staging did not. On multivariable analysis, TNM 8 stage, performance status (PS) and a positive surgical margin were prognostic for OS. Looking at disease recurrence within 12 months, TNM 8 stage IVB, presence of lymphovascular invasion (LVSI), younger age and lesser smoking history were predictive factors on multivariable analysis. TNM 8 is a good development of its predecessor in terms of predicting survival for patients with locally advanced OCSCC. We have also identified younger age (<60 years) and a smoking history of <10 pack years as risk factors for early disease recurrence, potentially representing a separate biological cohort within OCSCC patients. [ABSTRACT FROM AUTHOR]

Objectives: This review aims to analyse the recurrence rate in BRAFv600e+ and BRAFv600e− ameloblastomas and explore its association with clinicopathological variables. Methods: A comprehensive search was conducted using databases including PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, Google Scholar and grey literature, without any limitation on start date or language up to 20 June 2023. A random effect meta‐analysis was conducted and Metaregression analyses were performed based on available clinicopathological factors. Results: Fifteen studies met the criteria for meta‐analysis of outcomes. There was no significant difference in overall recurrence rates between the two groups (risk difference = 0.001, p‐value = 0.987). Increasing male:female ratio in the BRAFv600e+ group was associated with a lower reported recurrence, suggesting a higher recurrence rate in females. The odds of having mandibular lesion were four times higher in BRAFv600e+ cases compared to BRAFv600e− cases (confidence interval: 2.121–7.870, p < 0.001, I2 = 28.37%). Conclusion: Within the BRAFv600e+ group, females showed a higher reported recurrence rate. This specific clinical group may benefit from BRAFv600e mutation investigation and potential upscaled surgical treatment and additional BRAF inhibitor therapy, which needs validation in future studies. [ABSTRACT FROM AUTHOR]

• High content image analysis allows single-cell evaluation of HPV + OpSCC H&E slides. • Established and novel prognostic features have been identified. • Neural network model can predict patient outcomes with promising accuracy. • Automated H&E analysis is prognostic without additional diagnostic tests. Routine haematoxylin and eosin (H&E) photomicrographs from human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV + OpSCC) contain a wealth of prognostic information. In this study, we developed a high content image analysis (HCIA) workflow to quantify features of H&E images from HPV + OpSCC patients to identify prognostic features and predict patient outcomes. First, we have developed an open-source HCIA tool for single-cell segmentation and classification of H&E images. Subsequently, we have used our HCIA tool to analyse a set of 889 images from diagnostic H&E slides in a retrospective cohort of HPV + OpSCC patients with favourable (FO, n = 60) or unfavourable (UO, n = 30) outcomes. We have identified and measured 31 prognostic features which were quantified in each sample and used to train a neural network (NN) model to predict patient outcomes. Univariate and multivariate statistical analyses revealed significant differences between FO and UO patients in 31 and 17 variables, respectively (P < 0.05). At the single-image level, the NN model had an overall accuracy of 72.5% and 71.2% in recognising FO and UO patients when applied to test or validation sets, respectively. When considering 10 images per patient, the accuracy of the NN model increased to 86.7% in the test set. Our open-source H&E analysis workflow and predictive models confirm previously reported prognostic features and identifies novel factors which predict HPV + OpSCC outcomes with promising accuracy. Our work supports the use of machine learning in digital pathology to exploit clinically relevant features in routine diagnostic pathology without additional biomarkers. [ABSTRACT FROM AUTHOR]

Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick 'pushing' collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits - no cell-cell junctions and high proteolysis - exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas. [ABSTRACT FROM AUTHOR]

Objectives: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity‐modulated (chemo)radiotherapy [(C)RT]. Materials and methods: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end‐point was post‐failure survival (PFS). Results: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)‐negative; n = 16 HPV‐positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two‐year PFS for the entire population was 30.6%; 20.5% for HPV‐negative and 43.8% for HPV‐positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11). Conclusion: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV‐positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS. [ABSTRACT FROM AUTHOR]

Background: Advanced head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis, and biomarkers that predict response to treatment are highly desirable. The primary aim was to predict progression-free survival (PFS) with a multivariate risk prediction model. Methods: Experimental covariates were derived from blood samples of 56 HNSCC patients which were prospectively obtained within a Phase 2 clinical trial (NCT02633800) at baseline and after the first treatment cycle of combined platinum-based chemotherapy with cetuximab treatment. Clinical and experimental covariates were selected by Bayesian multivariate regression to form risk scores to predict PFS. Results: A ‘baseline’ and a ‘combined’ risk prediction model were generated, each of which featuring clinical and experimental covariates. The baseline risk signature has three covariates and was strongly driven by baseline percentage of CD33+CD14+HLADRhigh monocytes. The combined signature has six covariates, also featuring baseline CD33+CD14+HLADRhigh monocytes but is strongly driven by on-treatment relative change of CD8+ central memory T cells percentages. The combined model has a higher predictive power than the baseline model and was successfully validated to predict therapeutic response in an independent cohort of nine patients from an additional Phase 2 trial (NCT03494322) assessing the addition of avelumab to cetuximab treatment in HNSCC. We identified tissue counterparts for the immune cells driving the models, using imaging mass cytometry, that specifically colocalized at the tissue level and correlated with outcome. Conclusions: This immune-based combined multimodality signature, obtained through longitudinal peripheral blood monitoring and validated in an independent cohort, presents a novel means of predicting response early on during the treatment course. Funding: Daiichi Sankyo Inc, Cancer Research UK, EU IMI2 IMMUCAN, UK Medical Research Council, European Research Council (335326), Merck Serono. Cancer Research Institute, National Institute for Health Research, Guy’s and St Thomas’ NHS Foundation Trust and The Institute of Cancer Research. [ABSTRACT FROM AUTHOR]

Background Oncogenic human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is a subtype of head-and-neck cancer with a distinct clinical and prognostic profile. While there are calls to undertake HPV testing for oropharyngeal SCCs within the diagnostic setting and for clinical trials, there are currently no internationally accepted standards. Methods 142 tonsil SCCs were tested using p16 immunohistochemistry (IHC), high-risk HPV DNA in situ hybridisation (ISH) and HPV DNA polymerase chain reaction (PCR; GP5+/6+ primers). Results There were high levels of agreement between pathologists for p16 IHC and HPV ISH scoring; however, around 10% of HPV ISH cases showed some interobserver discrepancy that was resolved by slide review. The combination of p16 IHC and HPV ISH classified 53% of the samples as HPV-positive, whereas the combination of p16 IHC and HPV PCR classified 61% of the samples as HPV-positive. By employing a three-tiered, staged algorithm (p16 IHC/HPV ISH/HPV PCR), the authors were able to classify 98% of the cases as either HPV-positive (p16 IHC+/HPV DNA+; 62%) or HPV-negative (p16 IHC⇔'/HPV DNA⇔'; 35%). Conclusions The current study suggests that using a combination of p16 IHC/HPV ISH/HPV PCR, in a three-tiered, staged algorithm, in conjunction with consensus reporting of HPV ISH, leads to less equivocal molecular classification. In order to ensure consistent reporting of this emerging disease, it is increasingly important for the head-and-neck oncology community to define the minimum requirements for assigning a diagnosis of 'HPV-related⇔(tm) oropharyngeal SCC in order to inform prognosis and for stratification in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the use of F-FDG PET/CT as the principal investigation to assess tumour response, to determine the need for further surgery and to guide follow-up following radical chemoradiotherapy for stage III/IV oropharyngeal squamous cell carcinoma (OPSCC). Methods: A retrospective analysis was undertaken in 146 patients treated at our centre with radical chemoradiotherapy for OPSCC and who had a PET/CT scan to assess response. According to the PET/CT findings, patients were divided into four groups and recommendations: (1) complete metabolic response (enter clinical follow-up); (2) low-level uptake only (follow-up PET/CT scan in 12 weeks); (3) residual uptake suspicious for residual disease (further investigation with or without neck dissection); and (4) new diagnosis of distant metastatic disease (palliative treatment options). Results: The initial PET/CT scan was performed at a median of 12.4 weeks (range 4.3 - 21.7 weeks) following treatment. Overall sensitivity and specificity rates were 92.0 % (74.0 - 99.0 %) and 85 % (77.5 - 90.9 %). Of the 146 patients, 90 (62 %) had a complete response and had estimated 3-year overall and disease-free survival rates of 91.9 % (85.6 - 98.2 %) and 85.6 % (78.0 - 93.2 %), respectively, 17 (12 %) had residual low-level uptake only (with two having confirmed residual disease on subsequent PET/CT, both surgically salvaged), 30 (21 %) had suspicious residual uptake (12 proceeded to neck dissection; true positive rate at surgery 33 %). HPV-positive patients with reassuring PET/CT findings had an estimated 3-year progression-free survival rate of 91.7 % (85.2 - 98.2 %), compared with 66.2 % (41.5 - 90.9 %) of HPV-negative patients. Conclusion: A strategy of using PET/CT results alongside clinical examination to help select patients for salvage surgery appears successful. Despite a complete response on the 12-week PET/CT scan, HPV-negative patients have a significant risk of disease relapse in the following 2 years and further studies to assess whether surveillance imaging in this group could improve outcomes are warranted. [ABSTRACT FROM AUTHOR]

Background: Sentinel lymph node biopsy is an increasingly recognised option for accurate staging and subsequent management of the clinically negative neck in early stage oral cavity squamous cell carcinoma. However, the technique is currently underused due to several logistic constraints including increased burden on pathology services. Here, we describe the feasibility of an outsourced centralised pathology processing and reporting service for sentinel lymph node biopsies in oral cavity squamous cell carcinoma. Patients and methods: The Southeast England Consortium comprises four surgical centres utilising a central pathology service. Consecutive cases between January 2016 and February 2020 were retrospectively evaluated for survival outcomes and laboratory turnaround times. Results: Twenty‐eight per cent from a cohort of 139 patients had positive sentinel nodes. There was a trend towards greater overall, disease‐free and disease‐specific survival (OS, DFS and DSS, respectively) in sentinel node negative compared to sentinel node positive patients, but these differences were not statistically significant. The sensitivity, negative predictive value and false negative rate were 92.8%, 97.0% and 6.8%, respectively. The mean and mode laboratory TAT were 5 and 4 working days, respectively. Conclusion: An outsourced centralised pathology service is a feasible option to widen the availability of sentinel node biopsy in oral cavity squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral potentially malignant disorders (OPMDs) include a group of oral mucosal diseases with different morphological characteristics that are able to progress to oral squamous cell carcinoma (OSCC). Given OSCC's poor prognosis and high mortality, early diagnosis is a priority step in OSCC. Extrinsic and intrinsic risk factors and etiologies are involved in developing and malignant transformation of oral lesions, and different molecular alterations have been described in early lesions associated with a potential malignant behavior. This review summarizes the information about clinical, morphological and molecular features of OPMDs, with an emphasis on the early detection techniques and an overview of the surgical and systemic therapies' effectiveness. Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs' development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments. [ABSTRACT FROM AUTHOR]

Abstract: We report the creation of a new low-estrogen murine model of concurrent oral and vaginal C. albicans colonization that resembles human candidal carriage at both mucosal sites. Weekly estrogen administration of 5μg intramuscular and subcutaneously was optimal for enhancement of oral colonization and was essential for vaginal colonization. In BALB/c mice, a number of C. albicans clinical isolates (n =3) colonized both oral and/or vaginal sites, but only strain 529L colonized 100% of mice persistently for over 5weeks. Laboratory strains SC5314 and NCPF 3153 did not colonize the model; however, NCPF 3156 showed vaginal colonization up to week 5. Prior passaging through mice enhanced subsequent colonization of SC5314. Intranasal immunization with a C. albicans virulence antigen (secreted aspartyl proteinase 2) significantly reduced or abolished the fungal burden orally and vaginally by week 2 and 7. Our concurrent model of mucosal colonization reduces the numbers of experimental mice by half, can be used to assess potential vaccine candidates, and permits the detailed analysis of host–fungal interactions during the natural state of Candida colonization. [Copyright &y& Elsevier]

Background: The current diagnostic standard for detection of high‐risk human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is via a two‐stage algorithm, namely p16 immunohistochemistry followed by HPV DNA in situ hybridization in p16 positive cases. This study evaluated the feasibility of automated RNA in situ hybridization on a clinical platform as a single‐step alternative to the two‐stage algorithm within a routine diagnostic histopathology setting. Methods: Thirty‐eight cases positive for both p16 and DNA in situ hybridization, 42 p16 negative cases and 20 cases positive for p16 but negative for DNA in situ hybridization were randomly selected. High‐risk HPV RNA in situ hybridization was undertaken on all cases on an automated clinical platform. Manufacturer‐recommended and on‐slide additional p16/HPV positive and negative controls were used. Test quality assurance and diagnostic RNA in situ hybridization were independently assessed by two observers. A consensus diagnosis was reached in the presence of a third observer on discordant cases. All RNA in situ hybridization results were then correlated against p16 and DNA ISH status. Results: Inter‐slide RNA in situ hybridization staining variation was observed in control sections. RNA in situ hybridization demonstrated a high inter‐observer agreement rate (κ =.897, P <.001). Following consensus review, there was full concordance between RNA in situ hybridization and the current standard. Conclusion: Human papillomavirus testing by standalone automated RNA in situ hybridization on a clinical diagnostic platform currently available in routine diagnostic histopathology laboratories is a feasible alternative to the two‐step algorithm of p16 and DNA in situ hybridization. Control tissue staining procedures need to be adapted to achieve the most accurate results. [ABSTRACT FROM AUTHOR]

Objectives: Dental rehabilitation post‐radiotherapy often requires the consideration of dental implants. However, these are tentatively prescribed due to the concern of hypovascularisation and possible osteoradionecrosis. Hence, the current study assessed the microvasculature of the dento‐alveolar bone at implant sites taking into consideration the exact radiotherapy dose received to the region. Materials and methods: Bone cores were taken from nine patients during implant treatment and compared to nine control patients. Specimens were stained using CD31 and digitalised using a high‐resolution scanner for qualitative and quantitative assessment of the microvasculature. Monaco® treatment planning system was used to volume the implant site providing mean dose (Dmean) and maximum dose (Dmax). Results: A total of 23 bone cores were retrieved for analysis. The cohort had a Dmean of 38.4 Gy (59.6‐24.3 Gy). Qualitative analysis identified a clear reduction in the miniscule terminal capillaries and high incidence of obliterated lumens with increasing radiotherapy. Microvasculature density of irradiated patients was markedly reduced (P =.0034) compared to the control group with an inverse correlation to RT doses (P <.0001). Specifically, doses up to 30 Gy appear to preserve sufficient vascularisation (~77% in comparison with control) and tissue architecture. By contrast, exposure to higher doses 40%‐61% of the micro‐vessels were lost. Conclusion: Intensity‐modulated radiotherapy doses above 30 Gy identified reduction in microvasculature which is a lower threshold than previously accepted. In pharyngeal cancer patients' doses to the jaw bones often exceed this threshold. Coupled with favourable survival in certain oropharyngeal and nasopharyngeal cancer, dental rehabilitation via implants provides a significant clinical challenge. [ABSTRACT FROM AUTHOR]

Clinical evaluation of tumour‐infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus‐associated oropharyngeal squamous cell carcinoma Aims: The majority of patients with human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (OpSCC) have favourable survival outcomes, but a significant minority of individuals will die of their disease. There are currently no definitive criteria with which to identify HPV‐associated OpSCC patients with poor outcomes. Recent reports suggest that quantitative evaluation of T‐cell subpopulations in OpSCC may be of prognostic value, but the methods used have limited utility in a clinical diagnostic setting. We therefore sought to determine the clinical prognostic utility of tumour‐infiltrating lymphocyte (TIL) evaluation in patients with HPV‐associated OpSCC within the context of a diagnostic histopathology setting. Methods and results: Representative diagnostic haematoxylin and eosin (H&E)‐stained slides from 232 consecutive HPV‐associated OpSCC patients were classified as containing a high (TILHi; diffuse, lymphocytes in >80% of tumour and stroma), moderate (TILMod; patchy, present in 20–80% of tumour and stroma) or low (TILLo; sparse or absent, present in <20% of tumour and stroma) TILs. Interobserver reliability was assessed, and TIL category was then correlated with overall survival (OS) and disease‐free survival (DFS). Univariate and multivariate analyses showed statistically significant differences in OS and DFS estimates when TILHi and TILMod patients were compared with TILLo patients (P < 0.0001 for TILHi versus TILLo; P < 0.0001 for TILMod versus TILLo). Statistical significance was retained when TILHi and TILMod patients were grouped into a single category (TILHi) and compared with TILLo patients (P < 0.0001). Conclusion: We demonstrate the prognostic utility of TILs in patients with HPV‐associated OpSCC in clinical practice. A binary system classifying HPV‐associated OpSCC into TILHi and TILLo on the basis of routine H&E staining stratifies patients into those with potentially favourable and unfavourable survival outcomes, respectively. [ABSTRACT FROM AUTHOR]

Objectives To identify the most cost-effective treatment strategy in patients with early stage (T1 and T2) cancers of the laryngeal glottis. Design A Markov decision model populated using data from updated systematic reviews and meta-analyses, with attributable costs from NHS sources. Data on local control and mortality were obtained from updates of existing systematic reviews conducted for the NICE guideline on cancer of the upper aerodigestive tract. Procedure costs were sourced from NHS reference costs 2013/14 by applying tariffs associated with the appropriate health resource group code Setting The UK National Health Service. Population Patients with early stage (T1 and T2) cancers of the laryngeal glottis. Interventions Transoral laser microsurgery ( TLM) and radiation therapy ( RT). Main outcome measures Total costs, incremental costs and quality adjusted life years ( QALYs) over a 10-year time horizon. Results Radiation therapy as the initial treatment strategy was found to be more expensive (£2654 versus £623) and less effective ( QALY reduction of 0.141 and 0.04 in T1a and T1b-T2 laryngeal cancers, respectively) than TLM. The dominance of TLM for T1a cancers was unchanged in most scenarios modelled in sensitivity analysis. For T1b-T2 laryngeal cancers, the result changed in numerous scenarios. In probabilistic sensitivity analysis, TLM was found to have a 71% and 58% probability of being cost-effective in T1a and T1b-T2 laryngeal cancers, respectively. Conclusions Transoral laser microsurgery is a cost-effective strategy to adopt in the management of T1a laryngeal cancers. Uncertainty remains over the optimal strategy to adopt in T1b-T2 laryngeal cancers. [ABSTRACT FROM AUTHOR]

Human papillomavirus-associated oropharyngeal squamous cell carcinoma is now recognised as a subtype of head and neck cancer with distinct clinical, molecular and histological characteristics. The majority of these carcinomas are of non-keratinising squamous type but there is a growing number of histomorphologic variants of this disease. Here we describe the clinical, histomorphologic and immunophenotypic features of two cases of human papillomavirus-associated oropharyngeal squamous cell carcinoma demonstrating a clearly delineated biphasic differentiated and undifferentiated phenotype. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC) accounts for 0.6% of all cancers worldwide with the highest prevalence in South East Asia, Southern China and Northern Africa but the disease is uncommon in Europe with an annual incidence in this region of less than 1 per 100 000. Although the Epstein-Barr virus (EBV) is a well known causative agent in NPC, recent reports have implicated oncogenic Human Papillomavirus (HPV) in a subgroup of these tumours. The recent striking rise of oropharyngeal carcinoma has been attributed to HPV, but little is known about the prevalence and clinical significance of the virus in NPC. The aim of this study was to determine the prevalence of oncogenic HPV in NPC from tissue archives of two head and neck cancer centres in the UK. Methods: Samples were available for 67 patients with clinically validated NPC. The detection of high-risk HPV was carried out by screening all cases for p16 using immunohistochemistry and HPV DNA by polymerase chain reaction (PCR) using GP5+/6+ primers. All cases with p16 over-expression or positive for HPV by PCR were then examined by high-risk HPV DNA in-situ hybridisation and genotype analysis by PCR. Results: Eleven cases (11/67, 16.4%) showed concurrent over-expression of p16 and evidence of high-risk HPV DNA by in-situ hybridisation; the majority were HPV16 positive. Of these 11 cases, nine occurred in Whites and two in Blacks. Histologically, there were two keratinising squamous cell carcinoma and nine non-keratinising carcinomas (eight differentiated and one undifferentiated). None of the HPV-positive cases showed any co-infection with EBV. There was no statistically significant difference in overall survival outcome between patients with HPV-positive and HPV-negative NPC. Conclusion: The results of this study show that oncogenic HPV is associated with a subgroup of NPCs and is more likely to occur in Whites. However, unlike oropharyngeal carcinoma there was no significant difference in overall survival between patients with HPV-positive and HPV-negative NPC. [ABSTRACT FROM AUTHOR]

C. albicans is one of the most common fungal pathogen of humans, causing local and superficial mucosal infections in immunocompromised individuals. Given that the key structure mediating host-C. albicans interactions is the fungal cell wall, we aimed to identify features of the cell wall inducing epithelial responses and be associated with fungal pathogenesis. We demonstrate here the importance of cell wall protein glycosylation in epithelial immune activation with a predominant role for the highly branched N-glycosylation residues. Moreover, these glycan moieties induce growth arrest and apoptosis of epithelial cells. Using an in vitro model of oral candidosis we demonstrate, that apoptosis induction by C. albicans wild-type occurs in early stage of infection and strongly depends on intact cell wall protein glycosylation. These novel findings demonstrate that glycosylation of the C. albicans cell wall proteins appears essential for modulation of epithelial immunity and apoptosis induction, both of which may promote fungal pathogenesis in vivo. [ABSTRACT FROM AUTHOR]

The role of human papillomaviruses (HPV) in dysplastic and malignant oral verrucous lesions is controversial since there is a wide range in the incidence of virus detection. This study used a multi-tiered method of HPV detection using DNA in-situ hybridisation (ISH) for lowand high-risk subtypes, consensus PCR, and HPV genotype analysis in archival tissue from 20 cases of dysplastic and malignant oral verrucous lesions. The biological significance of HPV DNA detection was assessed by p16 immunohistochemistry (IHC). While 1/7 carcinomas and 5/13 dysplasias contained HPV DNA by consensus PCR and genotype analysis, all specimens were negative for low- and high-risk HPV ISH and negative for p16 IHC. Results show that although highrisk HPV DNA is detectable in a subset of these lesions, the lack of p16 overexpression suggests that the oncogenic process is not driven by HPV oncoproteins. [ABSTRACT FROM AUTHOR]

We previously reported that a bi-phasic innate immune MAPK response, constituting activation of the mitogen-activated protein kinase (MAPK) phosphatase MKP1 and c-Fos transcription factor, discriminates between the yeast and hyphal forms of Candida albicans in oral epithelial cells (ECs). Since the vast majority of mucosal Candida infections are vaginal, we sought to determine whether a similar bi-phasic MAPK-based immune response was activated by C. albicans in vaginal ECs. Here, we demonstrate that vaginal ECs orchestrate an innate response to C. albicans via NF-κB and MAPK signaling pathways. However, unlike in oral ECs, the first MAPK response, defined by c-Jun transcription factor activation, is delayed until 2 h in vaginal ECs but is still independent of hypha formation. The 'second' or 'late' MAPK response, constituting MKP1 and c-Fos transcription factor activation, is identical to oral ECs and is dependent upon both hypha formation and fungal burdens. NF-κB activation is immediate but independent of morphology. Furthermore, the proinflammatory response in vaginal ECs is different to oral ECs, with an absence of G-CSF and CCL20 and low level IL-6 production. Therefore, differences exist in how C. albicans activates signaling mechanisms in oral and vaginal ECs; however, the activation of MAPK-based pathways that discriminate between yeast and hyphal forms is retained between these mucosal sites. We conclude that this MAPK-based signaling pathway is a common mechanism enabling different human epithelial tissues to orchestrate innate immune responses specifically against C. albicans hyphae. [ABSTRACT FROM AUTHOR]

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising in Western countries and this has been attributed to human papillomavirus (HPV) infection. p16 expression is a marker for HPV infection and p16 positive OPSCC is now recognized as a separate disease entity. There are only limited data available regarding HPV-related OPSCC in Asian countries and no data from Malaysia. Methods: We identified 60 Malaysian patients with OPSCC over a 12-year period (2004–2015) from four different hospitals in two major cities, Kuala Lumpur and Penang. The detection of HPV was carried out using p16 immunohistochemistry and high risk HPV DNA in situ hybridisation. Results: Overall, 15 (25%) tumours were p16 positive by immunohistochemistry, 10 of which were also positive for high risk HPV DNA by in situ hybridisation. By comparison, a matched cohort of UK patients had a p16 positive rate of 49%. However, between 2009 and 2015, where cases were available from all four hospitals, 13 of 37 (35%) cases were p16 positive. In our Malaysian cohort, 53% of patients were of Chinese ethnicity and 80% of the p16 positive cases were found in these patients; no Indian patients had p16 positive disease, despite representing 35% of the total cohort. Conclusion: The proportion of OPSCCs associated with HPV in Malaysia appears to be lower than in European and American cohorts and could possibly be more prevalent amongst Malaysians of Chinese ethnicity. Further, our data suggests that the burden of HPV-related OPSCC could be increasing in Malaysia. Larger cross-sectional studies of Malaysian patients are required to determine the public health implications of these preliminary findings. [ABSTRACT FROM AUTHOR]

In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma. [ABSTRACT FROM AUTHOR]

Background: The incidence of Human Papillomavirus (HPV) associated oropharyngeal cancer (OPC) is increasing. HPV-associated OPC appear to have better prognosis than HPV-negative OPC. The aim of this study was to robustly determine the prevalence of HPV-positive OPC in an unselected UK population and correlate HPV positivity with clinical outcome.Methods: HPV testing by GP5+/6+ PCR, In Situ Hybridisation (ISH) and p16 immunohistochemistry (IHC) was performed on 138 OPCs diagnosed in South Wales (UK) between 2001-06. Kaplan-Meier analysis was used to correlate HPV status with clinical outcome.Results: Using a composite definition of HPV positivity (HPV DNA and p16 overexpression), HPV was detected in 46/83 (55%) samples where DNA quality was assured. Five year overall survival was 75.4% (95% CI: 65.2 to 85.5) in HPV-positives vs 25.3% (95% CI: 14.2 to 36.4) in HPV negatives, corresponding to a 78% reduction in death rate (HR 0.22, p < 0.001). HPV-positives had less locoregional recurrence but second HPV-positive Head and Neck primaries occurred. Poor quality DNA in fixed pathological specimens reduced both HPV prevalence estimates and the prognostic utility of DNA-based HPV testing methods. As a single marker, p16 was least affected by sample quality and correlated well with prognosis, although was not sufficient on its own for accurate HPV prevalence reporting.Conclusions: This study highlights the significant burden of OPC associated with HPV infection. HPV positive cases are clinically distinct from other OPC, and are associated with significantly better clinical outcomes. A composite definition of HPV positivity should be used for accurate prevalence reporting and up-front DNA quality assessment is recommended for any DNA-based HPV detection strategy. [ABSTRACT FROM AUTHOR]