Comparative clinicopathological study of the main anatomic locations of oral squamous cell carcinoma.

OBJECTIVE: To analyze the clinicopathological and evolutionary profile of the main locations of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This is a retrospective study on 133 patients treated for OSCC. The group was composed of 48 women and 85 men, with a mean age 63.9 ± 12.73 years. Most cases involved the lingual border of tongue (63), followed by the gingiva (36) and the floor of mouth (34). A comparative analysis was performed using multinomial regression. RESULTS: There were significant differences regarding age, sex, tobacco and alcohol consumption, liver pathology, oral potentially malignant disorders, and bone and perineural invasion. In multivariate regression, tobacco consumption, and bone invasion remained significant. There were no significant differences in relation to prognosis. CONCLUSION: The location of OSCC is an important factor in the clinicopathological assessment of this neoplasm. The main locations of OSCC show differential etiopathogenic and clinicopathological aspects. Tobacco consumption has a great relevance in the floor of mouth; nonetheless, it is less important in the tongue border and the gum, which suggests other pathogenic factors. It is necessary to consider the anatomical location of OSCC in preventive protocols, with the aim of reducing its high mortality.

Identification of Proteomic Biomarkers in Proliferative Verrucous Leukoplakia through Liquid Chromatography With Tandem Mass Spectrometry.

Proliferative verrucous leukoplakia (PVL) is an oral potentially malignant disorder associated with high risk of malignant transformation. Currently, there is no treatment available, and restrictive follow-up of patients is crucial for a better prognosis. Oral leukoplakia (OL) shares some clinical and microscopic features with PVL but exhibits different clinical manifestations and a lower rate of malignant transformation. This study aimed to investigate the proteomic profile of PVL in tissue and saliva samples to identify potential diagnostic biomarkers with therapeutic implications. Tissue and saliva samples obtained from patients with PVL were compared with those from patients with oral OL and controls. Label-free liquid chromatography with tandem mass spectrometry was employed, followed by qualitative and quantitative analyses, to identify differentially expressed proteins. Potential biomarkers were identified and further validated using immunohistochemistry. Staining intensity scan analyses were performed on tissue samples from patients with PVL, patients with OL, and controls from Brazil, Spain, and Finland. The study revealed differences in the immune system, cell cycle, DNA regulation, apoptosis pathways, and the whole proteome of PVL samples. In addition, liquid chromatography with tandem mass spectrometry analyses showed that calreticulin (CALR), receptor of activated protein C kinase 1 (RACK1), and 14-3-3 Tau-protein (YWHAQ) were highly expressed in PVL samples. Immunohistochemistry validation confirmed increased CARL expression in PVL compared with OL. Conversely, RACK1 and YWHA were highly expressed in oral potentially malignant disorder compared to the control group. Furthermore, significant differences in CALR and RACK1 expression were observed in the OL group when comparing samples with and without oral epithelial dysplasia, unlike the PVL. This research provides insights into the molecular mechanisms underlying these conditions and highlights potential targets for future diagnostic and therapeutic approaches.

Quantitative proteomics in medication-related osteonecrosis of the jaw: A proof-of-concept study.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a paradoxical effect associated with bone-modifying agents (BMAs) and other drugs. Currently, no valuable diagnostic or prognosis biomarkers exist. The goal of this research was to study MRONJ-related salivary proteome. MATERIALS AND METHODS: This case-control aimed to study salivary proteome in MRONJ versus control groups (i) formed from BMAs consumers and (ii) healthy individuals to unravel biomarkers. Thirty-eight samples of unstimulated whole saliva (18 MRONJ patients, 10 BMA consumers, and 10 healthy controls) were collected. Proteomic analysis by SWATH-MS coupled with bioinformatics analysis was executed. RESULTS: A total of 586 proteins were identified, 175 proteins showed significant differences among MRONJ versus controls. SWATH-MS revealed differentially expressed proteins among three groups, which have never been isolated. These proteins had distinct roles including cell envelope organization, positive regulation of vesicle fusion, positive regulation of receptor binding, or regulation of low-density lipoprotein particle clearance. Integrative analysis prioritized 3 proteins (MMP9, AACT, and HBD). Under receiver-operating characteristic analysis, this panel discriminated MRONJ with a sensitivity of 90% and a specificity of 78.9%. CONCLUSION: These findings may inform a novel biomarker panel for MRONJ prediction or diagnosis. Nonetheless, further research is needed to validate this panel.

Genetic linkage analysis of head and neck cancer in a Spanish family.

OBJECTIVES: To describe the genetic variants that may be associated with the development of head and neck cancer (HNC) and functionally validating the molecular implications. MATERIALS AND METHODS: A prospective observational study was carried out on a family of 3 generations in which 3 members had developed HNC. Peripheral blood sample was taken in a routine procedure for exome sequencing in one relative and genotyping in the remaining twelve relatives. For the functional analysis all-trans retinoic acid (atRA) was extracted from saliva and serum and measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The presence of HPV-DNA. RESULTS: None of the patients smoked or consumed alcohol. The presence of HPV DNA was not detected in any of the biopsied samples. A total amount of 6 members out of 13 (46.15%) carried out the same mutation of CYP26B1 (2p13.2; G>T). The mean plasma concentration of atRA was 3.3109 ± 1.4791 pg/mL for the study family and 4.7370 ± 1.5992 pg/mL for the controls (p = 0.042). CONCLUSION: Lower levels of atRA were confirmed in the study family, which may open the way to the possible relationship between the polymorphism CYP26B1 (2p13.2; G>T) and HNC.

Drug use, risk perceptions and attitudes towards drug use amongst medical and dentistry students.

AIMS: To analyse the use of psychoactive substances and the risk perceptions amongst odontology and medical students. To study their perceptions, attitudes and knowledge, and to evaluate their motivation when helping their patients to stop using these substances. METHODS: A cross-sectional study was conducted amongst 962 students in Spain, using validated questionnaires on an anonymous basis. RESULTS: Amongst these students, drug use varies and increases with age as assessed by the DAST and CAST tests, with more problematic use being observed as the academic cycle progresses (p < .001). Participants in the 2nd cycle presented higher consumption than those in the 1st cycle, in the univariate model (OR = 1.77, IC 95% 1.27-2.48, p = .001) and in the adjusted model (OR = 1.86, IC 95% 1.32-2.62, p < .001). Regarding CAST, non-problematic use in the 1st cycle versus the 3rd cycle presented an OR = 8.69 (IC 95% 4.50-16.78, p < .001) and for low risk use it presented an OR = 15.18 (IC 95% 1.83-14.68). Only 46.7% considered using marijuana on a regular basis as a high risk, whilst 60.5% stated that smoking a pack of cigarettes represents a high risk. Alcohol was the substance for which the risk perception was lowest. 66.2% are in the maintenance stage "I provide my regular drug-using patients help to give up," with women being more likely to be in this stage (p = .012). CONCLUSIONS: High risk of drug use increases after the 1st cycle in Dentistry and in Medicine. Training programmes should be implemented in both degrees, focusing on the 1st years in order to simultaneously prevent drug use amongst students.

Critical update, systematic review, and meta-analysis of oral erythroplakia as an oral potentially malignant disorder.

BACKGROUND: Oral erythroplakia has been classically considered as the potentially malignant disorder with the highest rate of malignant development into squamous cell carcinoma. This critical systematic review and meta-analysis aim to estimate the malignant development rate of oral erythroplakia and identify the associated risk factors. METHODS: We performed a bibliographic search in PubMed, Scopus, Web of Science, Embase, and LILACS, with keywords "erythroplakia," "erythroplasia," "malignant transformation," "malignant development," "malignization," "carcinogenesis," "oral cancer," "oral squamous cell carcinoma," "mouth neoplasm," and "prognosis." Meta-analysis was conducted using a random-effects model. RESULTS: Ten observational studies with 441 patients met the inclusion criteria, whose mean malignant development rate was 12.7% and with a mean follow-up period of patients of 6.66 years. In the initial biopsy, 42.8% of oral erythroplakia were already squamous cell carcinoma. The buccal mucosa was the most frequent location of oral erythroplakia, but the floor of the mouth was the most common site of malignant development. All patients who underwent malignant development showed epithelial dysplasia on the initial diagnostic biopsy. CONCLUSION: Overall malignant development rate of OE in the meta-analysis was 19.9%. We could not associate any specific clinicopathological feature with the malignant development. The presence of epithelial dysplasia in the initial biopsy remains the worst prognostic factor. Further observational studies on OE are needed, with well-established diagnostic criteria and good clinical follow-up, in order to identify the true risk of malignant development of oral erythroplakia and the related risk factors.

Caspase 3 and Cleaved Caspase 3 Expression in Tumorogenesis and Its Correlations with Prognosis in Head and Neck Cancer: A Systematic Review and Meta-Analysis.

Head and neck cancer (HNC) is an ascending and agressive disease. The search for new molecular markers is emerging to solve difficulties in diagnosis, risk management, prognosis and effectiveness of treatments. Proteins related to apoptotic machinery have been identified as potential biomarkers. Caspase 3 is the main effector caspase and has a key role in apoptosis. The objective of this systematic review and meta-analysis is to review studies that analyze changes in Caspase 3 and Cleaved Caspase 3 expression both in oral premalignant disorders (OPMD) as well as in head and neck cancer (HNC). This study also proposes to review the prognostic values associated with HNC according to the expression of Caspase 3. Medline (via PubMed), EMBASE, Scopus, Cochrane, Web of Science and Grey Literature Database were screened from inception to june of 2022 and 18 studies were selected and 8 were included in the prognostic meta-analysis. Results related to the comparison of Caspase 3 expression demonstrated similar expression of Caspase 3 in HNC, with an average of 51.9% (9.5-98.1) showing high/moderate expression compared to 45.7% (14.6-84.7) in OPMD. Of interest, Cleaved Caspase 3 resulted incresed in HNC when compared with OPMD, being 73.3% (38.6-88.3) versus 22.9% (7.1-38.7). Pooled Fixed effect of HR values (95% CI) for OS related to Caspase 3 IHC expression in HNC patients was 1.48 (95% CI 0.95-2.28); also, the rate of heterogeneity was low, as revealed by I2 = 31%. For DFS was 1.07 (95% CI 0.79-1.45) with I2 = 0% and DSS showed a HR of 0.88 (95% CI 0.69-1.12) with I2 = 37%. Caspase 3 and Cleaved Caspase 3 expression could be linked with malignancy progression, but the expression of Caspase 3 did not influence the prognosis of patients with HNC.

DNA Methylation by Bisulfite Next-Generation Sequencing for MLH1 and MGMT in Oral Squamous Cell Carcinomas and Potentially Malignant Disorders: An Integrative Analysis towards Field Cancerization.

Background and Objectives: MGMT methylation is a well-described biomarker in several solid tumors and MLH1 seems to occur in the initial stages of oral carcinogenesis. The aims of this study were to evaluate MHL1 and MGMT methylation levels in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs), and to integrate this information with The Cancer Genome Atlas (TCGA) database. Materials and Methods: To determine the percentage of gene methylation in MLH1 and MGMT, pyrosequencing analysis was conducted. Samples were divided as follows: (1) patients diagnosed with OSCC (N = 16); (2) patients with OPDM who developed OSCC in the same location (N = 47); and (3) patients with OPDM who developed OSCC in a different location (N = 22). As a validation cohort in this study, data from The Cancer Genomic Atlas (TCGA) database, particularly regarding Head and Neck Squamous Cell Carcinoma, was used. Results: Overall MLH1 methylation levels of 8.6 ± 11.5% and 8.1 ± 9.2% for MGMT were obtained. With regard to MHL1, the OSCC presented the highest degree of methylation with 9.3 ± 7.3% (95%CI 5.1-13.6), and with regards to MGMT, the simultaneous malignancy group presented the highest degree of methylation with 10 ± 13.5% (95%CI 6-10), although no significant differences were found between the groups (p = 0.934 and p = 0.515, respectively). The estimated survival was higher for MGMT methylated cases (19.1 months, 95%CI 19.1-19.1) than for unmethylated cases (9.4 months, 95%CI 6-12.8), but not statistically significant. Conclusions: Our results did not show a correlation between MGMT and MLH1 methylation and any clinicopathological feature or survival in our institutional cohort. MLH1 methylation was present mainly in OSCC, whilst MGMT in OPMD represented a modest contribution to field cancerization, with an overall consistency with the TCGA database.

Metabolic syndrome and masticatory hypofunction: a cross-sectional study.

The objective of this paper is to clarify the rate of abdominal obesity (AO), waist-to-height ratio (WHtR), metabolic syndrome (MetS) and determine the relationship with the masticatory capacity (MC) in terms of total functional tooth units (t-FTU) in a representative sample of older Spanish adults. This cross-sectional study included 544 adult subjects aged 50 or over, who were prospectively selected and who had participated in a survey conducted in a primary dental care service in a Public Oral Health Service in Spain. Anthropometric, clinical variables and t-FTUs were obtained through a calibrated and well-established protocol. Univariate and multivariate binary and multinomial logistic regression analyses were developed. With regards to the t-FTU or MC, it was poor in 60.3%, good in 17.6%, and complete in 22.1% of the sample. The univariate odss ratio (OR) for MetS and AO increased as the MC decreased and as the age group increased. With regards to gender, women presented with an OR of 5.56 (CI 95% 3.70-8.38). With regards to the WHtR-a3 (WHtR grouped into three categories), the univariate ORs were all significant for morbid obesity compared to the healthy group, with a risk of 6.86 (CI 95% 3.23-14.58) for patients with poor MC compared to those with complete MC. Masticatory hypofunctionality could be associated with the presence of MetS. Clinical relevance: The number of t-FTUs is directly related to AO.

Analysis of the Efficiency and Prognostic Value of the Sentinel Node Technique in Oral Squamous Cell Carcinoma after Seven Years.

Background and objectives: The purpose of this study was to analyse the diagnostic and prognostic efficiency of the sentinel lymph node biopsy technique (SLNB). Materials and Methods: This is a prospective observational study performed by the Hospital Complex in Santiago de Compostela (CHUS) in Spain, between February 2013 and June 2020. The study included 60 patients, who had been diagnosed with OSCC in stage T1/T2N0M0. Results: 10 patients (16.7%) presented with SN+ (sentinel node positive). The majority (80%) only presented subcapsular affection, however one case also presented with extracapsular affection. Using the Kaplan-Meier curves, we determined that the average survival estimation for SN- patients was 74.0 months (CI95% 67.6-80.5) and it was 45.4 months (CI95% 10.9-24.0) for SN+ patients (p = 0.002). SN+ patients presented an OR = 11.000 (CI95% 2.393-50.589, p = 0.002) for cancer-related mortality. In terms of the diagnostic performance of the SN (sentinel node) test, a 55% sensitivity, a 100% specificity, 100% PPV and a 84% NPV were obtained. The analysis using ROC (receiver operating characteristic) curves revealed an AUC = 0.671 (CI95% 0.492-0.850, p = 0.046). Conclusions: SLNB seems to be an adequate technique for the detection of hidden metastases.

Association between periodontitis and medication-related osteonecrosis of the jaw: A systematic review and meta-analysis.

Consensus has yet to be reached about the prevention and treatment of medication-related osteonecrosis of the jaw (MRONJ), which is a treatment sequela of several antiresorptive therapies and other pharmaceutical interventions. Several epidemiologic studies have identified periodontal disease (PD) as a risk factor for this outcome. Thus, the objective of this systematic review and meta-analysis was to investigate this association and its magnitude. A systematic search in MEDLINE via PubMed, Scopus and ISI Web of Science, and a meta-analysis were undertaken. Observational studies that gathered information regarding prefixed definitions for both outcomes were selected, and the relevant information was then extracted, and their risk of bias was evaluated using the Newcastle-Ottawa Scale. The protocol of the study was registered on PROSPERO (CRD42019125646). The initial search yielded 757 eligible records, of which 12 were deemed adequate for inclusion (5 cohort studies and 7 case-control studies). On a random-effects meta-analysis, the risk of PD in MRONJ-affected sites compared with at-risk non-affected patients was significantly greater, with a risk ratio of 2.75 (95% CI: 1.67-4.52). Nonetheless, from a pooled analysis of three standardized periodontal measures (ie plaque index, clinical attachment loss and probing depth) no significant results were obtained. MRONJ appears to be associated with an increase in prevalence of PD. The direction of this association, and the factors influencing it must be investigated using further prospective data, and likewise, the possibility for using periodontal therapy as a prevention strategy must be looked into. Periodontal screening needs to be made an indispensable requisite for clinicians in order to establish a correct multidisciplinary approach in MRONJ.

Prognostic value of CAIX expression in oral squamous cell carcinoma: a systematic review and meta-analysis.

Carbonic anhydrase IX (CAIX) is a hypoxia-related protein considered as a predictor for oral squamous cell carcinoma (OSCC) biological behaviour. Nevertheless, this prognostic value is still yet to be validated. We aim to quantify prognostic significance of CAIX overexpression in OSCC by meta-analysis. We performed searches in MEDLINE, EMBASE, SCOPUS, WOS, WHO'S databases, CPCI, and OATD from inception to August 2019. Overall survival (OS), disease-free survival (DFS), locoregional control (LC), and disease-specific survival (DSS) were considered as outcomes of interest. Overall 18 studies were included. CAIX overexpression was associated with worse OS (hazard ratio [HR] = 1.45 95% confidence interval [CI] 1.17-1.80) and DFS (HR = 1.98 95% CI 1.18-3.32). To the contrary, it was neither associated with LC (HR = 1.01 95% CI 0.50-2.02) nor with DSS (HR = 1.35 95% CI 0.78-2.33). Heterogeneity was negligible in all analyses except for DSS. Small studies effect was not significant for OS and DFS. This study shows that immunohistochemical CAIX assessment is a useful OSCC prognostic biomarker.

Validity, reliability and optimisation of the TOPICOP questionnaire for oral lichen planus.

Objectives: Due to their anti-inflammatory and immunosuppressive effects, topical corticosteroids (TCs) are commonly used for the treatment of patients with oral lichen planus (OLP) with an erosive or ulcerative component. It has been suggested that many of these patients may suffer from fear or anxiety as a result of prolonged treatment with TCs. The objective of this study was twofold: (1) to optimise a patient reported outcome measure (PROM) in order to explore this feature, and (2) to evaluate this PROM in the treatment of OLP patients.Methods: A group of qualitative researchers adapted the TOPICOP questionnaire in order for it to be used as a PROM for OLP via structural equation modelling (SEM) and internal consistency (IC) analysis. Consequently, 34 patients with symptomatic OLP who were undergoing treatment with TCs completed a questionnaire and underwent a clinical assessment.Results: SEM presented an adequate fit (RMSA = 0.07, CFI = 0.94 and WRMR = 1.18), as well as a high IC (α = 0.81). A total of 16 patients (47.1%) reported TCs phobia. The receiver operating characteristic analysis (ROC) revealed that a TOPICOP value ≥50% predicted the presence of TCs phobia with a sensitivity of 93% and a specificity of 100%.Conclusions: The optimised TOPICOP scale proved valuable as a PROM in OLP. TCs phobia can be a real consideration in OLP, nonetheless, it does not appear to be an impediment to treatment adherence.

Identification of Prognosis Associated microRNAs in HNSCC Subtypes Based on TCGA Dataset.

Background and Objectives: Head and Neck Squamous Cell Carcinoma (HNSCC) includes cancers from the oral cavity, larynx, and oropharynx and is the sixth-most common cancer worldwide. MicroRNAs are small non-coding RNAs for which altered expression has been demonstrated in pathological processes, such as cancer. The objective of our study was to evaluate the different expression profile in HNSCC subtypes and the prognostic value that one or several miRNAs may have. Materials and Methods: Data from The Cancer Genome Atlas Program-Head and Neck Squamous Cell Carcinoma (TCGA-HNSCC) patients were collected. Differential expression analysis was conducted by edge R-powered TCGAbiolinks R package specific function. Enrichment analysis was developed with Diana Tool miRPath 3.0. Kaplan-Meier survival estimators were used, followed by log-rank tests to compute significance. Results: A total of 127 miRNAs were identified with differential expression level in HNSCC; 48 of them were site-specific and, surprisingly, only miR-383 showed a similar deregulation in all locations studied (tonsil, mouth, floor of mouth, cheek mucosa, lip, tongue, and base of tongue). The most probable affected pathways based on miRNAs interaction levels were protein processing in endoplasmic reticulum, proteoglycans in cancer (p < 0.01), Hippo signaling pathway (p < 0.01), and Transforming growth factor-beta (TGF-beta) signaling pathway (p < 0.01). The survival analysis highlighted 38 differentially expressed miRNAs as prognostic biomarkers. The miRNAs with a greater association between poor prognosis and altered expression (p < 0.001) were miR-137, miR-125b-2, miR-26c, and miR-1304. Conclusions: In this study we have determined miR-137, miR-125b-2, miR-26c, and miR-1304 as novel powerful prognosis biomarkers. Furthermore, we have depicted the miRNAs expression patterns in tumor patients compared with normal subjects using the TCGA-HNSCC cohort.

Dissecting the Proton Transport Pathway in Oral Squamous Cell Carcinoma: State of the Art and Theranostics Implications.

Cancer cells overexpress proton exchangers at the plasma membrane in order acidify the extracellular matrix and maintain the optimal pH for sustaining cancer growth. Among the families of proton exchangers implicated in carcinogenesis, carbonic anhydrases (CAs), monocarboxylate transporters (MCTs), Na+/H+ exchangers (NHEs), sodium bicarbonate cotransporters (NBCs), and vacuolar ATPases (V-ATPases) are highlighted. Considerable research has been carried out into the utility of the understanding of these machineries in the diagnosis and prognosis of several solid tumors. In addition, as therapeutic targets, the interference of their functions has contributed to the discovery or optimization of cancer therapies. According to recent reports, the study of these mechanisms seems promising in the particular case of oral squamous cell carcinoma (OSCC). In the present review, the latest advances in these fields are summarized, in particular, the usefulness of proton exchangers as potential prognostic biomarkers and therapeutic targets in OSCC.

Differential expression of snoRNAs in oral squamous cell carcinomas: new potential diagnostic markers.

BACKGROUND: Small nucleolar RNAs (snoRNAs) are small non-coding RNA sequences whose most studied function is ribosome biogenesis. The altered expression of snoRNA is observed in tumoral processes such as breast cancer and multiple myeloma. However, we have not found any references to snoRNAs in oral squamous cell carcinomas (OSCC) in the literature at the time this article was written. MATERIAL AND METHODS: We have analyzed snoRNA expression in frozen OSCC tissue samples and have compared them to healthy controls. RNA was extracted from a total of eight OSCC samples and eight control samples, measuring the differential expression of small RNAs with the Affymetrix® miRNA 4.1 Array Plate microarray platform. RESULTS: Results were analyzed using the Transcriptome Analysis Console 3.0 (TAC) software. We obtained a total of 16 deregulated snoRNAs of which one was over expressed and 15 were under expressed. SnoRNAs expression was altered in OSCC and could serve as a diagnostic marker.

Determination and diagnostic value of CA9 mRNA in peripheral blood of patients with oral leukoplakia.

BACKGROUND: Oral leukoplakia is one of the most common oral premalignant disorder. The classical evaluation through tissue biopsy is not always valid to evaluate the risk of malignization. MATERIAL AND METHODS: RT-qPCR was performed on 47 blood samples (21 patients with leukoplakia, 2 with oral squamous cell carcinoma (OSCC), and 24 healthy patients) and on 11 tissue samples (3 leukoplakia, 4 OSCC, and 4 samples of healthy tissue). RESULTS: There are significant differences in expression between the different groups (F = 4.057, p = .006). The Duncan post hoc test shows that the only group that differentiates is the tumour tissue. Using Wilcoxon test, different covariables of patients with leukoplakia were analysed with respect to the group of healthy patients and no significant differences were observed. CONCLUSIONS: The diagnostic route through liquid biopsy has not been conclusive in this study, but there are significant differences in the levels analysed in the different tissue samples.

Tumor budding is a prognostic factor in head and neck squamous cell carcinoma: A comprehensive meta-analysis and trial sequential analysis.

BACKGROUND: Mortality is linked to tumor budding (TB) in certain neoplasms. TB as a relevant histopathological feature is conditioned by tumor site, a specific study on head and neck squamous cell carcinoma (HNSCC) is needed. METHODS: A comprehensive meta-analysis was undertaken to investigate the relationship between TB and HNSCC-related outcomes. RESULTS: Overall 42 studies were included. Patients harboring high TB reported an Overall Survival (OS) Hazard Ratio (HR) of 2.63 (95% confidential interval (CI) 2.04-3.39; p-value < 0.001), Disease-free Survival (DFS) HR of 1.88 (95%CI 1.57-2.24; p-value <0.001) and Disease-specific Survival (DSS) HR of 2.14 (95%CI 1.81-2.52; p-value <0.001). Lymph Node Metastasis (LNM) studies harbored null heterogeneity and marked association with TB (Odds Ratio (OR) = 4.48, 95%CI 2.97-6.76; p-value < 0.001). Trial Sequential Analysis (TSA) supported definitive results for DSS. CONCLUSION: The study has provided compelling evidence that there is a significant association between TB and a worse prognosis for HNSCC.

Protein-based salivary biomarkers for the diagnosis of periodontal diseases: Systematic review and meta-analysis.

Objective: This systematic review and meta-analysis was aimed at determining differentially expressed protein-based biomarkers detectable in the saliva for the diagnosis of major periodontal diseases. Methods: A literature review was conducted through January 31, 2022. The methodological quality and risk of bias were assessed with the Newcastle-Ottawa scale for case-control studies. Heterogeneity among studies was analysed with the Q statistical test and the I2 test. p-values lower than 0.10 and I2 values higher than 50% indicated high heterogeneity among studies; therefore, the random-effects model was used. The analysis of biological pathways associated with the differentially expressed protein markers was performed with the STITCH integration analysis tool and was limited to interactions with high confidence levels (0.7). Results: Of all protein-based biomarkers detected, 12 were suitable for meta-analysis: IL-1ß, MIP-1α, albumin, TNF-α, ICTP, Ig-A, lactoferrin, MMP-8, IL-6, IL-8, IL-17 and PGE2. The salivary markers with high applicability were IL-1ß for differentiating patients with chronic periodontal disease from patients with gingivitis with an OE = 73.5 pg/mL; ICTP for differentiating patients with chronic periodontal disease from healthy control patients with an OE = 0.091 ng/mL; and PGE2 for differentiating patients with chronic periodontal disease from healthy control patients with an OE = 36.3 pg/mL. Conclusions: The biomarkers with the highest differential expression and the greatest potential for clinical applicability are IL-1ß for differentiating periodontitis from gingivitis, and ICTP and PGE2 for differentiating periodontitis from healthy status.

Immunoexpression profile of hypoxia-inducible factor (HIF) targets in potentially malignant and malignant oral lesions: a pilot study.

Oral potentially malignant disorders (OPMD) are associated with an increased risk of oral squamous cell carcinoma (OSCC). OSCC has an aggressive profile and is the most prevalent among different head and neck malignancies. Most OSCC patients are diagnosed with advanced stage tumors and have a poor prognosis. Cancer cells are able to reprogram their metabolism, even in the presence of oxygen, enhancing the conversion of glucose to lactate via the glycolytic pathway, a phenomenon mainly regulated by hypoxia-inducible factor (HIF) signaling. Thus, several glycometabolism-related biomarkers are upregulated. This study aimed to evaluate the immunoexpression of the HIF targets GLUT1, GLUT3, HK2, PFKL, PKM2, pPDH, LDHA, MCT4, and CAIX in OPMD and OSCC samples, in order to identify potential correlations between biomarkers' immunoexpression, clinicopathological features, and prognostic parameters. OSCC and OPMD samples from 21 and 34 patients (respectively) were retrospectively collected and stained for the different biomarkers by immunohistochemistry. CAIX and MCT4 expressions were significantly higher in OSCC samples when compared with OPMD samples, while the rest were also expressed by OPMD. GLUT3 and PKM2 alone, and the concomitant expression of more than four glycometabolism-related biomarkers were significantly correlated with the presence of dysplasia in OPMD. When considering OSCC cases, a trend toward increased expression of biomarkers and poor clinicopathological features was observed, and the differences regarding HK2, PFKL, LDHA and MCT4 expression were significant. Moreover, HK2 and CAIX were correlated with low survival rates. GLUT1 and GLUT3 were significantly associated with poor outcome when their expression was observed in the hypoxic region of malignant lesions. OPMD and OSCC cells overexpress glycolysis-related proteins, which is associated with aggressive features and poor patient outcome. Further research is needed to deeply understand the glycolic phenotype in the process of oral carcinogenesis.