Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next-generation sequencing.

Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Diclofenac Mouthwash as a potential therapy for reducing pain and discomfort in chemo-radiotherapy-induced oral mucositis.

AIMS: Oral and/or oropharyngeal acute mucositis during and after chemo-radiotherapy (chemo-RT) for head and neck squamous cell carcinoma (HNSCC) can be extremely painful, sometimes requiring nasogastric feeding to enable adequate nutrition. The MASCC/ISOO evidence-based guidelines recommend benzydamine mouthwash for mucositis prevention in RT (recently updated to include chemo-RT), and a Cochrane systematic review found other agents to be effective in prophylaxis. Diclofenac mouthwash is licensed for painful oral mucosal inflammatory conditions but to our knowledge has not been assessed in chemo-RT-associated oral mucositis. METHOD: A clinical observation and service evaluation study in 10 patients undergoing chemo-RT for HNSCC to assess the potential value of diclofenac mouthwash (0.74 mg/mL) in reducing symptoms. Patients used 20ml of mouthwash up to 4 times a day starting in week 3 (of a 6-week course of treatment), recording pain and discomfort scores using a visual analogue scale on days 0, 1,7 and 14 (until the end of week 4). As per our current clinical practice, oral mucositis was not clinically scored as an outcome. Statistical analysis was performed using a one-way ANOVA. RESULTS: Using diclofenac mouthwash, 9/10 patients experienced pain score reduction from day 0 (mean score 6.75 ± SD 1.83) to day 2 (5.05 ± SD 1.62) and day 14 (4.09 ± SD 1.96). CONCLUSIONS: Diclofenac mouthwash may be beneficial for managing chemo-RT-induced oral mucositis. While a prospective randomised clinical trial is needed, it can be prescribed for this condition within its current licence.

A proposal for classification of oropharyngeal squamous cell carcinoma: Morphology and status of HPV by immunohistochemistry and molecular biology.

The current three-tier grading system (well, moderate and poorly differentiated) used to morphologically classify head and neck squamous cell carcinoma (HNSCC) is inadequate for categorisation of oropharyngeal squamous cell carcinoma (OPSCC) owing to the lack of prognostic value. The aim of this study was to assess the validity of a classification system for OPSCC based on morphology and human papilloma virus (HPV) infection status. Haematoxylin and eosin slides of 121 patients (100 M, 21 F, age range 40-89 years) with OPSCC were reviewed and categorised as histological types I, II and III. The presence of HPV was assessed by immunohistochemistry with p16 and RNAscope In situ hybridization (ISH). The follow-up period was 36 months. Ninety-six patients were p16+ and clinical stage I. Patient survival with types I, II and III was 93%, 50% and 96%, respectively. Twenty-five patients were p16-: 10 clinical stage I and 15 stage III. Amongst this group, no type I morphology was identified. At follow-up, 65% of type II and 75% of type III patients were alive. All p16+ cases were also positive for E6/E7 mRNA high-risk HPV by ISH, while 23 p16- cases were negative and two were positive. Cox regression identified three predictors of mortality: older age (HR = 1.14, 95% CI = 1.06-1.23, P = .001); female gender (HR = 0.22.95% CI 0.05-0.88, P = .033); and type II morphology (HR = 13.1, 95% CI = 1.09-157.0, P = .043). OPSCC morphological classification in three sub-types, along with HPV infection status, seems to reflect the outcome of patients with OPSCC.

The E-cigarette ban in India-A step in the right direction?

Electronic cigarettes (e-cigarettes) are a popular method to help quit tobacco smoking. However, there is a paucity of data in the literature on their safety and efficacy. Recently, the Indian Government has called for a ban on all e-cigarettes and taken steps to restrict access to vaping products from the market. This major decision was an attempt to safeguard the younger population from using e-cigarette and their possible longer-term addiction together with its promotions by domestic industries. In this article, we evaluate the role of e-cigarettes to help stop smoking tobacco cessation and consider the factors that have facilitated the ban on e-cigarettes in India.

Circulating tumour cells in head and neck cancers: Biological insights.

Tumour metastasis is one of the leading cause of cancer-related mortality. Circulating tumour cells (CTCs) have been implicated in loco-regional and distant metastasis and its role is being extensively studied in various malignancies, including those from the head and neck region. The main challenge in understanding their significance lies in the rarity of these cells in the blood. However, newer technologies have attempted to overcome these pitfalls. This review explores the evolution of CTC research and other related areas, including its biological significance, sustainability within the circulating vascular environment and possible clinical implications.

Efficacy of scaffold-mediated localized chemotherapy in cancer: A systematic review of current research.

OBJECTIVE: To assess the efficacy of scaffold-mediated localized chemotherapy in cancer. METHODS: Databases including PubMed, Cochrane Library, and SCOPUS were searched for articles reporting the use of scaffold-mediated localized drug delivery in cancer. Essential data including scaffold fabrication material and methods, drug dosage and release duration and its effect on the cancer cells were extracted. RESULTS: 15 articles out of 60 screened, fulfilled the eligibility criteria. Among the 15 studies, 5 studies included only cell lines and 2 studies were on mouse models, while 8 studies involved a combination of cell lines and mouse models. Scaffold materials included both synthetic polymers such as poly-lactide, polycaprolactone and natural materials including d-periosteum and human micro-fragmented adipose tissueA wide number of other variables included the fabrication procedure, drugs used, and the methods used to assess the effects on cancer. As a result, it was not possible to make any direct comparison of the efficacy of the therapeutic strategy used in each of these studies. CONCLUSION: Irrespective of the many variables, a common consensus in all the included studies was that scaffold mediated localized drug delivery effectively reduced cancer cell viability by increasing drug bioavailability to the target tissue, while its localized effect reduced the risk of systemic toxicity.

The relationship of "shisha" (water pipe) smoking to the risk of head and neck cancer.

INTRODUCTION: There has been a recent rise in popularity of waterpipe smoking (WPS) among younger people. While it is a tobacco-related product, research on the possible deleterious effects on health and its relationship with cancer is sparse. In this paper, we evaluated the existing literature and association of WPS with head and neck cancer. MATERIALS AND METHODS: PubMed, EMBASE, Scopus, Web of Science and grey literature from January 1990 up to and including March 2017 were searched. Two independent reviewers performed the study selection according to eligibility criteria. RESULTS: A total of seven studies that met the eligibility criteria were included. In four studies that evaluated the associated risk of oesophageal cancer, the odds ratio (OR) ranged from 1.69 (95% CI = 0.76-3.77) to 21.4 (95% CI = 11.6-39.5). The OR for the association of WPS with nasopharyngeal cancer and oral cancer was reported to be 0.49 (95% CI = 0.20-1.43) and 4.20 (95% CI = 1.32-13.3), respectively. One study that evaluated risk in different head and neck cancers reported 2-fold OR (2.73 [95% CI = 1.65-4.41]). CONCLUSION: On the basis of our evaluation, there is an association of WPS with head and neck cancer. However, larger studies with standardized methods are needed to identify the possible detrimental health effects of WPS more fully.

The relationship of shammah (Arabian snuff) chewing to the risk of oral cancer and oral potentially malignant disorders.

INTRODUCTION: Shammah is a form of smokeless tobacco commonly used in the Arabian Peninsula. The data on the harmful effects of shammah on oral health, particularly oral malignancies, are scarce. The aim of this review was to explore the association between shammah use and development of oral potentially malignant disorders (OPMD) and/or oral cancer. MATERIALS AND METHODS: PubMed, EMBASE, Scopus, Web of Science and grey literature from January 1990 up to and including April 2018 were searched. Two independent reviewers performed the study selection according to eligibility criteria. RESULTS: A total of 10 studies that met the eligibility criteria were included. The odds of developing OPMD and/or oral cancer in relation to shammah use varied, with one study reporting a 39 increased risk (39, 95% CI: 14-105). The associated increased risk was relatively low among those that have stopped using shammah and ranged from threefold (3.65; 95% CI: 1.40-9.50) to 12-fold (12.6; 95% CI: 3.3-48.2). CONCLUSION: Shammah use seems to increase the risk of development of OPMD and/or oral cancer.

A potential new oral mapping (OM) method in the clinical evaluation and documentation of oral submucous fibrosis-A prospective clinical crossover study.

BACKGROUND: Despite much research, there is a lack of a definite protocol or method for documenting oral submucous fibrosis (OSMF) site presentation. In this study, we propose a new potential oral mapping (OM) method and evaluated its use in recording OSMF-affected mucosal sites. METHODS: Fifty OSMF patients were evaluated by 15 primary care dental practitioners using both, a conventional subjective recording method and a new OM method, to document the degree of involvement of affected oral mucosa with a crossover study design. Mann-Whitney test (non-parametric test) was used to make comparison between groups to determine any significant differences between the two identification methods. Wilcoxon tests were used to evaluate any significant differences in the difficulty in identification of two methods. RESULTS: There was a low agreement between the two methods used to detect OSMF in affected mucosal surfaces (P-value < 0.0001). More lesions were identified using the proposed OM method, and less discrepancy was found among dental practitioners. A difference in difficulty of OSMF documentation was found (Wilcoxon z = 3.615, P-value < 0.001), with the proposed OM method found to be easier. CONCLUSION: The proposed OM method appears to be useful for documentation, can easily be adapted in clinical practice, and effectively administered in clinical research. Additionally, it could be a useful tool to helping to maintain an OSMF database.

Odontogenic myxoma: An updated analysis of 1,692 cases reported in the literature.

The aim of the present study was to integrate the available data published on odontogenic myxoma (OM) into a comprehensive analysis of its clinical/radiological features. Electronic search undertaken in January/2018, looking for publications reporting cases of OM. A total of 377 publications were included. We identified 1,692 lesions, and 695 were used for the analysis of recurrence. There is a predominance of OMs in females and in mandibles. OMs usually present with bone expansion, asymptomatic cortical perforation, and a multilocular appearance. Lesion location (maxilla/mandible), bone expansion, cortical bone perforation, locular radiological appearance, tooth resorption, odontogenic epithelial rests, or angular septa are not associated with recurrence. While curettage (31.3%) showed the highest recurrence rate, marginal resection (1.3%) and segmental resection (3.1%) showed the lowest values. Enucleation + peripheral osteotomy (6.7%) showed better results than enucleation (13.1%) or enucleation + curettage (12.7%). In comparison with unilocular lesions, multilocular ones were significantly more prevalent in mandibles, more often presented expansion and cortical bone perforation, had larger mean size, and were more often treated by segmental resection. Conservative surgical procedures are associated with higher probability of recurrence of OM. Taking into consideration the recurrence rate and morbidity associated with different surgical treatments, tumor enucleation followed by peripheral osteotomy should be considered as the first therapeutic choice.

Patient-derived xenografts of a case of ameloblastic fibrodentinoma.

OBJECTIVES: The establishment of animal models of xenotransplantation can contribute to the elucidation of the molecular pathogenesis of ameloblastic fibrodentinomas (AFD) and it also provides an opportunity for drug tests. We aimed to evaluate the possibility of AFD tumour growth in a patient-derived xenograft (PDX) model. In addition, we characterized the human tumour and the PDXs. MATERIALS AND METHODS: A sample of a recurrent AFD was obtained and two fragments were contralaterally implanted subcutaneously in an 8-week old female NUDE mouse. After 250 days, the PDXs were removed and submitted to histopathological and molecular analysis. Immunohistochemical reactions for Ki67 and the phosphorylated form of ERK1/2 were carried out in both, PDXs and human tumour, and the presence of BRAFV600E was assessed. RESULTS: From day 135 onwards, the PDXs presented a growth peak and remained stable until day 250. Histopathologically, the PDXs presented the same features of the patient's tumour. Tumour cells exhibited Ki67 and pERK1/2 immunoexpression in the patient's tumour and PDX. The AFD was wild-type for BRAFV600E. CONCLUSION: The PDX model recapitulated well the human tumour after a long implantation time, representing a possible model to study the AFD and other odontogenic tumours pathobiology.

Current update on the diagnosis and management of head and neck hard tissue sarcomas.

Head and neck hard tissue sarcomas form a rare group of mesenchymal-derived tumours that comprise less than 1% of all head and neck neoplasms. Hard tissue sarcomas account for 20% of head and neck sarcomas and they form a heterogeneous group with a diverse origin. Unlike head and neck soft-tissue sarcomas, they have lower recurrence and mortality rates. In this study, we review the current management of head and neck hard tissue sarcomas.

Association between histopathological features of dysplasia in oral leukoplakia and loss of heterozygosity.

AIMS: Oral leukoplakia (OL) dysplasia is graded on the basis of architectural and cytological features, and grade does not correlate well with malignant transformation. Loss of heterozygosity (LOH) profiles have been validated as risk predictors of OL malignant transformation. We aimed to assess whether the histological parameters used to grade dysplasia show different LOH profiles. METHODS AND RESULTS: Areas of epithelial dysplasia of 29 OL samples were microdissected, and LOH was assessed by use of a panel of 11 microsatellite markers located on chromosomes 3, 9, 11, and 17. Dysplasia was graded, and the cytological and architectural parameters were scored. Dysplasia was graded as mild in 18 samples, moderate in nine, and severe in two. The moderate/severe dysplasias and the mild dysplasias did not show different frequencies of allelic loss. Irregular epithelial stratification was associated with LOH at marker D3S1234 (3p14.2). In addition, the presence of drop-shaped rete ridges and premature keratinization in single cells showed associations with LOH at D9S162 (9p22) and P53 (17p13.1), respectively. CONCLUSIONS: We provide evidence that architectural and cellular changes in OL have different LOH patterns.

Ameloblastic carcinoma: a Brazilian collaborative study of 17 cases.

AIMS: Ameloblastic carcinoma (AMECA) is an odontogenic malignancy that combines the histological features of ameloblastoma and cytological atypia. Because of its rarity, it poses difficulties in diagnosis. The aim of this study was to investigate the socio-demographic data, histopathology, immunohistochemical features, treatment and outcomes of 17 cases. METHODS AND RESULTS: Descriptive statistical analyses were used to portray the clinicopathological data collected, retrospectively. Log-rank tests were performed to determine new prognostic factors. Lesions were immunostained for Ki67, p16, p53, and cytokeratins (CKs), and compared with solid/multicystic ameloblastomas (n = 15). AMECA was mostly diagnosed at a late stage, affecting the posterior mandible of male patients in their fifth decade of life. Recurrence was diagnosed in nearly 90% of treated patients, and metastasis occurred in four patients. The mean number of Ki67-positive cells was 86.4 ± 66 per field. Tumours were focally positive for CK7, CK8, CK14, and CK18, and diffusely positive for CK19, p53, and p16. AMECA showed increased immunoexpression of CK18, CK19, p16, p53 and Ki67 as compared with benign cases. CONCLUSIONS: Our study has contributed to the improved characterization of the epidemiology, prognostic markers, treatment options and outcomes of AMECA. Current criteria must be reviewed to simplify the diagnostic process for these neoplasms.

Hsp27 (HSPB1) differential expression in normal salivary glands and pleomorphic adenomas and association with an increased Bcl2/Bax ratio.

Pleomorphic adenoma (PA) is the most common salivary gland neoplasm. The Hsp27 (HSPB1) is an antiapoptotic protein whose synthesis follows cytotoxic stresses and result in a transient increase in tolerance to subsequent cell injury. Although Hsp27 is expressed in a range of normal tissues and neoplasms, a wide variation in its expression exists among different cells and tissues types. In certain tumours of glandular origin (such as oesophageal adenocarcinomas), the level of Hsp27 is decreased. In the present study, Hsp27 protein levels were evaluated by enzyme-linked immunosorbent assay (ELISA) in a set of 18 fresh PA and 12 normal salivary gland samples. In addition, we tested if Hsp27 protein levels correlated with p53 expression and cell proliferation index, as well as with the transcriptional levels of Bcl-2-associated X protein (BAX), B cell lymphoma 2 (BCL2) and Caspase 3 in PA. We further tested the association between Hsp27 expression and PA tumour size. While all normal salivary gland samples expressed Hsp27 protein, only half of the PA samples expressed it, resulting in a reduced expression of Hsp27 in PA when compared with normal salivary glands (P = 0.003). The expression levels of this protein correlated positively with a higher messenger ribonucleic acid (mRNA) ratio of Bcl2/Bax (R = 0.631; P = 0.01). In conclusion, a decreased Hsp27 protein expression level in PA was found. In addition, Hsp27 levels correlated positively with the Bcl2/Bax mRNA ratio, suggesting an antiapoptotic effect.

Progress towards personalized medicine for ameloblastoma.

Ameloblastoma is a locally infiltrative benign odontogenic neoplasm. Tumours may be large, destructive and recurrent, requiring radical surgery with associated facial deformity and morbidity. The molecular pathogenesis of this tumour has been unclear, retarding the development of non-invasive gene-targeted therapies. In a recent paper in this journal, Kurppa et al. [4] showed that EGFR-targeted therapy blocked cell proliferation in an ameloblastoma primary cell culture. That this therapy was not effective in another primary cell culture led to the discovery of the oncogenic BRAF V600E mutation in a high proportion (63%) of ameloblastoma samples. By defining two separate pathways, both of which can be specifically targeted, these findings are an important step towards personalized medicine of ameloblastoma. We discuss the findings in the broader context of ameloblastoma, as well as the effects of tumour microenvironment and molecular heterogeneity that need to be taken into account when considering the use of personalized therapies based on specific genetic mutations in individual patients.

Relationship between microRNA expression levels and histopathological features of dysplasia in oral leukoplakia.

BACKGROUND: Increased expression of microRNAs (miRNAs), miR-21, miR-345, and miR-181b has been demonstrated in oral leukoplakia (OL) that progresses to oral squamous cell carcinoma (OSCC), suggesting a miRNA signature with potential prognostic value. On the basis of these findings, this pilot study aimed to investigate the cytological and histopathological features that are used to grade oral dysplasia and determine associations with the expression of these 3 potentially cancer-related miRNAs. We also compared the expression levels of these miRNAs in OL with normal oral mucosa and OSCC. METHODS: We evaluated miRNA expression by qPCR in 22 samples of OL demonstrating different grades of dysplasia, as well as 17 cases of OSCC, and 6 samples of normal oral mucosa. We associated the miRNAs expression profiles with cytological and histopathological features of OL. RESULTS: OSCC cases showed increased expression of all 3 miRNAs when compared with OL and normal oral mucosa. Increased expression of miR-21 was also observed in OL when compared with normal oral mucosa. We found a higher expression of miR-21 and miR-181b in OL that presented with an increased number of mitotic figures, increased nuclear/cytoplasmic ratio, or hyperchromasia. Increased expression of miR-21 was also detected in OL with abnormally superficial mitosis. Higher expression of miR-345 was observed in OL with an increased number and size of nucleoli or increased nuclear/cytoplasmic ratio. CONCLUSIONS: In conclusion, the present study shows that some cytological and histopathological parameters used to grade dysplasia are associated with altered miRNA expression.

Loss of heterozygosity (LOH) in tumour suppressor genes in benign and malignant mixed odontogenic tumours.

Although molecular alterations are reported in different types of odontogenic tumours, their pathogenesis remains to be established. Loss of heterozygosity (LOH) studies allow the identification of minimal regions of deletions of known or putative tumour suppressor genes, the losses of which may promote neoplastic growth. The purpose of this study was to investigate LOH in a set of odontogenic mixed tumours. Tumour suppressor gene loci on 3p, 9p, 11p, 11q and 17p chromosomes were analysed in five samples of ameloblastic fibroma (AF), three samples of ameloblastic fibro-odontoma (AFO) and three samples of ameloblastic fibrosarcoma (AFS). The most frequently lost genetic loci were p53 (17p13, 62%) and CHRNB1 (17p13, 55%). LOH at the chromosome regions 3p24.3, 9p22 and 9p22-p21 was identified only in AFS. No sample showed LOH at the chromosomal loci 3p21.2 and 11q13.4. For the region 9p22-p13, LOH occurred in one sample of AFO. The fractional allelic loss (FAL) was calculated for each sample. The mean FAL of the benign lesions (i.e. AF and AFO) was 22%, whereas the mean FAL of the malignant lesions (i.e. AFS) was 74.6%. In conclusion, our results show a higher FAL in AFS compared to its benign counterparts and reveal a different pattern of LOH of tumour suppressor genes in AFS, which may regulate changes in tumour behaviour.

Investigating the Dialysis Treatment Using Hollow Fiber Membrane: A New Approach by CFD.

Due to the increase in the number of people affected by chronic renal failure, the demand for hemodialysis treatment has increased considerably over the years. In this sense, theoretical and experimental studies to improve the equipment (hemodialyzer) are extremely important, due to their potential impact on the patient's life quality undergoing treatment. To contribute to this research line, this work aims to study the fluid behavior inside a hollow fiber dialyzer using computational fluid dynamics. In that new approach, the blood is considered as multiphase fluid and the membrane as an extra flow resistance in the porous region (momentum sink). The numerical study of the hemodialysis process was based on the development of a mathematical model that allowed analyzing the performance of the system using Ansys® Fluent software. The predicted results were compared with results reported in the literature and a good concordance was obtained. The simulation results showed that the proposed model can predict the fluid behavior inside the hollow fiber membrane adequately. In addition, it was found that the clearance decreases with increasing radial viscous resistance, with greater permeations in the vicinity of the lumen inlet region, as well as the emergence of the retrofiltration phenomenon, characteristic of this type of process. Herein, velocity, pressure, and volumetric fraction fields are presented and analyzed.