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In 2020, Fanconi anemia (FA) was classified as a syndrome with insufficient epidemiological evidence in the oral potentially malignant disorder (OPMD) group by the WHO Collaborating Centre. The paucity of case reports on FA-associated OPMD limits evidence-based management, and such cases have not been analyzed collectively in detail. Hence, the objective of this short communication is to summarize the evidence on the onset and progression of OPMD in FA patients, so as to better understand the natural history of oral cancer development in patients affected by FA. A total of 11 eligible papers containing 1332 FA patients are involved in onset and progression of OPMD in FA patients. Of these, 186 (14.0%) were diagnosed with OPMD. With available data from 4 follow-up studies, 30 (41.1%) of 73 FA patients compatible with OPMD further developed into OSCC at young age (10–30 years old). The evidence on FA with malignant potential comprise clinical epidemiology, oral cytology abnormalities, DNA aneuploidy, loss of autofluorescence, loss of heterozygosity, high-risk human papillomavirus infection, DNA mutations in saliva and plasma samples. Collectively, these can consummate the evidence on FA as a syndrome that may potentiate cancer development in oral cavity mentioned by the WHO. Importantly, it highlights close surveillance is instrumental for FA patients with OPMD to early detect oral cancer. [ABSTRACT FROM AUTHOR]

Tobacco and alcohol are the well-known carcinogenic agents of oral cavity health. The purpose of this study was to investigate the scientometric characteristics of alcohol and tobacco use and oral health. The papers on alcohol and tobacco use and oral cavity were published since 1885 and 1895, respectively. All the eligible papers were retrieved on March 20, 2023 from the Scopus database. There are 2529 and 1545 papers on tobacco smoking and alcohol drinking and oral cavity in the Scopus database, respectively. Based on the frequency of keywords in all included papers, both smoking and drinking are involved in mouth neoplasms, oral cancer, leukoplakia, and periodontal diseases. In the papers on tobacco and alcohol use and oral cavity, the same research keywords confirm tobacco and alcohol use associate with oral cancer risk possibly through influencing genetics and gene and protein expression. For the distinctive keywords, nicotine, smoking cessation, and electronic cigarette are unique keywords of tobacco use. Acetaldehyde, alcohol dehydrogenase, and alcohol metabolism are unique ones of alcohol use. This study for the first time reports the scientometric characteristics of tobacco and alcohol use and oral health, which might aid healthcare authorities to promote tobacco and alcohol control measures focused on the necessities of their population. [ABSTRACT FROM AUTHOR]

Oral lichen planus (OLP) is generally considered as an oral potentially malignant disorder (OPMD). Previous studies have shown significantly higher serum carcinoembryonic antigen (CEA), squamous cell carcinoma-antigen (SCC-Ag), and ferritin levels in patients with OPMDs such as oral submucous fibrosis, oral leukoplakia, oral erythroleukoplakia, or oral verrucous hyperplasia. This study aimed to evaluate whether there were significantly higher serum levels and positive rates of CEA, SCC-Ag, and ferritin in OLP patients than in healthy control subjects. The serum CEA, SCC-Ag, and ferritin levels in 106 OLP patients and 187 healthy control subjects were measured and compared. Patients with serum CEA level ≥3 ng/mL, SCC-Ag level ≥2 ng/mL, and ferritin level ≥250 ng/mL were scored as serum positive for CEA, SCC-Ag, and ferritin, respectively. This study found significantly higher mean serum CEA and ferritin levels in 106 OLP patients than in 187 healthy control subjects. Moreover, 106 OLP patients had significantly higher serum positive rates of CEA (12.3%) and ferritin (33.0%) than 187 healthy control subjects. Although the mean serum SCC-Ag level was higher in 106 OLP patients than in 187 healthy control subjects, the difference was not statistically significant. Of the 106 OLP patients, 39 (36.8%), 5 (4.7%), and 0 (0.0%) had serum positivities of one, two, or three tumor biomarkers including CEA, SCC-Ag, and ferritin, respectively. Our findings indicate significantly higher serum levels and positive rates of CEA and ferritin in OLP patients than in healthy control subjects. [ABSTRACT FROM AUTHOR]

Oral mucosal patches striae diseases (OMPSD) represent an important category of oral mucosal disease, most of which may have malignant potential (OMPSD-MP). The differential diagnosis is challenging due to overlap of their clinical and pathological features. 116 OMPSD-MP patients were included in this cross-sectional study from November 2019 to February 2021, including oral lichen planus (OLP), oral lichenoid lesions (OLL), discoid lupus erythematosus (DLE), oral submucous fibrosis (OSF) and oral leukoplakia (OLK). The general information, clinical manifestation, histopathological and direct immunofluorescence (DIF) features were statistically analyzed and compared. OLP was the major type of OMPSD-MP (64.7%), followed by OLL (25.0%), OLK (6.0%), DLE (2.6%) and OSF (1.7%), which were pooled as non-OLP group for further assessment. They shared many clinical and histological features in common. The rate of clinical-pathological diagnosis concordance was 73.5% for OLP, and 76.7% for total OMPSD-MP. DIF positive rate was significantly higher in OLP group than non-OLP group (76.0% vs. 41.5%, P < 0.001), in which the deposition of fibrinogen (Fib) and IgM were most frequently found. A significant overlap in clinical and histopathological features of OMPSD-MP was found, while DIF could be useful in differential diagnosis. Fib and IgM might be important immunopathological factors in OLP, which need further exploration. [ABSTRACT FROM AUTHOR]

• A complete course of PDT can reduce the risk of malignant transformation of OLK. • The protective effect of completing PDT is more significant in high-risk patients. • PDT has considerable application value in the treatment of OLK. Photodynamic therapy (PDT) has shown good short-term efficacy in the treatment of oral leukoplakia (OLK). However, the malignant transformation of OLK was seldom evaluated in most PDT studies. Therefore, this study evaluated the effect of PDT on the risk of malignant transformation of OLK. Kaplan-Meier survival analysis, COX regression, and sensitivity analysis were used to evaluate the effects of PDT on the risk of malignant transformation of OLK. Subgroup analyses were performed to explore the role of PDT in OLK patients with different clinical characteristics. OLK patients with older age (HR=1.032, P = 0.018) and non-homogeneous lesion (HR=2.104, P = 0.044) had higher risk of malignant transformation. Patients who had finished a complete course of PDT (HR=0.305, P = 0.006) had a significant lower risk of malignant transformation, while those who hadn't finished a complete course of PDT (HR=0.692, P = 0.352) cannot be considered to have such a protective effect. In the subgroup analyses, complete PDT course showed a significant protective effect on malignant transformation of OLK in patients with female sex, no smoking or drinking habits, non-homogeneous lesions, lesions on oral mucosa outside the dangerous region, and any grade of epithelial dysplasia. A complete course of PDT could significantly reduce the risk of malignant transformation of OLK, especially in those patients with risk factors of malignant transformation. [ABSTRACT FROM AUTHOR]

• Utilizing deep learning for automated detection of oral lesions. • Detection of Oral Lichen Planus (OLP), Oral Leukoplakia (OLK), and OSCC. • Analysis of clinical photographs to enhance targeted accuracy for OSCC detection. • Accurately identify oral lesions and support healthcare professionals. [ABSTRACT FROM AUTHOR]

Smoking is a well-established risk factor for several oral diseases, including oral cancer, oral leukoplakia and periodontitis, primarily related to reactive oxygen species (ROS). SS-31, a mitochondria-targeting tetrapeptide, has exhibited demonstrable efficacy in medical conditions by attenuating mitochondrial ROS production. However, its potential in the treatment of oral diseases remains underexplored. The aim of this study was to investigate the therapeutic potential of SS-31 in mitigating smoking-induced oral epithelial injury. Through in vitro experiments, our results indicate that SS-31 plays a protective role against cigarette smoke extract (CSE) by reducing oxidative stress, attenuating inflammatory response, and restoring mitochondrial function. Furthermore, we found that mitophagy, regulated by PINK1 (PTEN-induced putative kinase 1)/Parkin (Parkin RBR E3 ubiquitin–protein ligase), was critical for the protective role of SS-31. Our findings offer valuable insights into SS-31's therapeutic potential in mitigating CSE-induced oxidative stress, inflammatory response, and mitochondrial dysfunction in oral epithelial cells. This study provides novel intervention targets for smoking-related oral diseases. [Display omitted] • Smoking-induced ROS and oxidative stress contribute to several oral diseases. • SS-31 attenuated smoking-induced oxidative stress, inflammatory response, and mitochondrial dysfunction. • SS-31 promoted PINK1-mediated mitophagy in oral epithelial cells. • SS-31 may have therapeutic potential for smoking-related oral diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the risk factors associated with developing oral squamous cell carcinoma (OSCC) from surgically excised oral leukoplakia (OL) in patients with previous oral cavity cancer. Clinicopathological data of 84 patients who were treated for OL between July 2002 and July 2020 and who had previously received treatment for OSCC were reviewed retrospectively. The follow-up time ranged from 0.69 to 17.99 years (mean 6.78 ± 4.25 years). The overall cumulative malignant transformation rate was 25% and the annual transformation rate was 5.73%. Kaplan–Meier survival analysis and the log-rank test showed that Candida infection (P = 0.010) was a risk factor associated with malignant transformation. In the multivariate Cox regression analysis, tongue and floor of the mouth as the location of the leukoplakia (P = 0.039), multifocal lesions of OL (P = 0.047), and Candida infection (P = 0.018) were the three independent prognostic factors related to the development of OSCC from the treated OL. A cautious approach to OL of the tongue with Candida infection or multifocal disease in this group of patients would be appropriate. [ABSTRACT FROM AUTHOR]

• Our model outperforms experienced experts in detecting oral cancer-related diseases. • Our model improved oral lesion diagnosis accuracy of general dentists and specialists. • It brought general dentists and specialists comparable to experienced experts. • Our app integrates our model for timely detection of oral cancer in smartphone photos. We aim to develop a YOLOX-based convolutional neural network model for the precise detection of multiple oral lesions, including OLP, OLK, and OSCC, in patient photos. We collected 1419 photos for model development and evaluation, conducting both a comparative analysis to gauge the model's capabilities and a multicenter evaluation to assess its diagnostic aid, where 24 participants from 14 centers across the nation were invited. We further integrated this model into a mobile application for rapid and accurate diagnostics. In the comparative analysis, our model overperformed the senior group (comprising three most experienced experts with more than 10 years of experience) in macro-average recall (85 % vs 77.5 %), precision (87.02 % vs 80.29 %), and specificity (95 % vs 92.5 %). In the multicenter model-assisted diagnosis evaluation, the dental, general, and community hospital groups showed significant improvement when aided by the model, reaching a level comparable to the senior group, with all macro-average metrics closely aligning or even surpassing with those of the latter (recall of 78.67 %, 74.72 %, 83.54 % vs 77.5 %, precision of 80.56 %, 76.42 %, 85.15 % vs 80.29 %, specificity of 92.89 %, 91.57 %, 94.51 % vs 92.5 %). Our model exhibited a high proficiency in detection of oral lesions, surpassing the performance of highly experienced specialists. The model can also help specialists and general dentists from dental and community hospitals in diagnosing oral lesions, reaching the level of highly experienced specialists. Moreover, our model's integration into a mobile application facilitated swift and precise diagnostic procedures. [ABSTRACT FROM AUTHOR]

Oral leukoplakia (OLK) is the most common oral potentially malignant disorder (OPMD), which can be malignantly transformed into oral squamous cell carcinoma (OSCC). Peroxiredoxin1(Prx1) has been predicted to bind to Prohibitin2 (PHB2), which confers to affect OLK progression; however, the mechanism of Prx1/PHB2 mediated mitophagy involved in OLK remains unclear. This study aimed to explore the mechanism of the Prx1/PHB2 axis on senescence in OLK through mediating mitophagy. The positive rate of Ki67 and the expression of p21, p16, PHB2, and LC3 in human normal, OLK, and OSCC tissues were detected by immunohistochemical staining. The mitophagy and mitochondrial function changes were then analyzed in Prx1 knockdown and Prx1C52S mutations in dysplastic oral keratinocyte (DOK) cells treated with H 2 O 2. In situ Proximity Ligation Assay combined with co-immunoprecipitation was used to detect the interaction between Prx1 and PHB2. Clinically, the positive rate of Ki67 progressively increased from normal to OLK, OLK with dysplasia, and OSCC. Higher p21, p16, PHB2, and LC3 expression levels were observed in OLK with dysplasia than in normal and OSCC tissues. In vitro , PHB2 and LC3II expression gradually increased with the degree of DOK cell senescence. Prx1/PHB2 regulated mitophagy and affected senescence in H 2 O 2 -induced DOK cells. Furthermore, Prx1C52S mutation specifically reduced interaction between Prx1 and PHB2. Prx1Cys52 is associated with mitochondrial reactive oxygen species (ROS) accumulated and cell cycle arrest. Prx1Cys52 functions as a redox sensor that binds to PHB2 and regulates mitophagy in the senescence of OLK, suggesting its potential as a clinical target. [ABSTRACT FROM AUTHOR]

• PDT has considerable application value in the treatment of OLK. • Using deep learning and multimodal data to build predictive models. • Inflammatory cell infiltration into lamina propria may be associated with relapse after PDT. • PDT has good efficacy in homogeneous and moderate-severe epithelial dysplasia OLK. The treatment of oral leukoplakia (OLK) with aminolaevulinic acid photodynamic therapy (ALA-PDT) is widespread. Nonetheless, there is variation in efficacy. Therefore, this study constructed a model for predicting the short-term efficacy and recurrence of OLK after ALA-PDT. The short-term efficacy and recurrence of ALA-PDT were calculated by statistical analysis, and the relevant influencing factors were analyzed by Logistic regression and COX regression model. Finally, prediction models for total response (TR) rate, complete response (CR) rate and recurrence in OLK patients after ALA-PDT treatment were established. Features from pathology sections were extracted using deep learning autoencoder and combined with clinical variables to improve prediction performance of the model. The logistic regression analysis showed that the non-homogeneous (OR: 4.911, P : 0.023) OLK and lesions with moderate to severe epithelial dysplasia (OR: 4.288, P : 0.042) had better short-term efficacy. The area under receiver operating characteristic curve (AUC) of CR, TR and recurrence predict models after the ALA-PDT treatment of OLK patients is 0.872, 0.718, and 0.564, respectively. Feature extraction revealed an association between inflammatory cell infiltration in the lamina propria and recurrence after PDT. Combining clinical variables and deep learning improved the performance of recurrence model by more than 30 %. ALA-PDT has excellent short-term efficacy in the management of OLK but the recurrence rate was high. Prediction model based on clinicopathological characteristics has excellent predictive effect for short-term efficacy but limited effect for recurrence. The use of deep learning and pathology images greatly improves predictive value of the models. [ABSTRACT FROM AUTHOR]

• CuB inhibits the proliferation of DOK cells (oral leukoplakia cells) through ferroptosis. • The expression of SLC7A11 may play a key role in the malignant progression of oral leukoplakia. SLC7A11 is expressed at low or no levels in normal human oral mucosal epithelium. Additionally, the expression of SLC7A11 in the oral mucosal epithelium with mild dysplasia was significantly lower than that in the oral mucosal epithelium with moderate and severe dysplasia. • CuB can downregulate the expression of SLC7A11 in DOK cells. Moreover, Cub-Mediated ferroptosis and cytotoxicity are dependent on SLC7A11 in DOK cells. • CuB inhibits the malignant progression of oral leukoplakia by down-regulating SLC7A11 and activating ferroptosis in the oral leukoplakia mice situ model, and has good biological safety. Our study reveals the relationship between CuB, oral precancerous lesions, and ferroptosis for the first time and may bring novel therapy options for OLK. Oral leukoplakia (OLK), characterized by abnormal epithelial hyperplasia, is the most common precancerous oral mucosa lesion and is closely related to oxidative stress. Cucurbitacin B (CuB), a tetracyclic triterpenoid molecule derived from plants, has shown promising anti-proliferative and antioxidant effects in preclinical studies. However, whether CuB can play an antiproliferative role in OLK by regulating oxidative stress remains elusive. To investigate the role of CuB in inhibiting the malignant progression of oral leukoplakia and to further explore its underlying mechanisms of action. In vitro , the effect of CuB on the proliferation, migration, apoptosis, and cell cycle of OLK cells DOK was detected. The core genes and key pathways of OLK and CuB were analyzed in the transcriptome database, by using immunofluorescence, qRT-PCR, and Western blot to evaluate the expression levels of the ferroptosis markers ROS, GSH, MDA, Fe2+, and marker genes SLC7A11, GPX4, and FTH1. Immunohistochemistry of human tissue was performed to investigate the expression of the SLC7A11. In vivo , the model of OLK was established in C57BL/6 mice and the biosafety of CuB treatment for OLK was further evaluated. CuB substantially suppressed the proliferation of DOK cells. Bioinformatics analysis showed that the core targets of OLK crossing with CuB include SLC7A11 and that the essential pathways involve ROS and ferroptosis. In vitro experiments indicated that CuB might promote ferroptosis by down-regulating the expression of SLC7A11. We observed a gradual increase in SLC7A11 expression levels during the progression from normal oral mucosa to oral leukoplakia with varying degrees of epithelial dysplasia. In vivo experiments demonstrated that CuB inhibited the malignant progression of OLK by promoting ferroptosis in OLK mice and exhibited a certain level of biosafety. This study demonstrated for the first time that CuB could effectively inhibit the malignant progression of OLK by inducing ferroptosis via activating the SLC7A11/ mitochondrial oxidative stress pathway. These findings indicate that CuB could serve as the lead compound for the future development of anti-oral leukoplakia drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

The objective of this study is to investigate the variances in transcriptome gene expression of normal oral mucosa-derived mesenchymal stem cell (OM-MSC), oral leukoplakia-derived MSC (OLK-MSC) and oral squamous cell carcinoma-derived MSC(OSCC-MSC). as Additionally, the study aims to compare the in vitro proliferation, migration, invasion ability, and response to photodynamic therapy (PDT) of these three MSC, HOK, DOK, leuk1, and Cal27 cell lines. HOK, DOK, leuk1, Cal27 cells were cultured in vitro. 3 MSC cells were obtained from OM, OLK, OSCC tissue (n = 3) and identified through flow cytometry. They were also cultured in vitro for osteogenic and lipogenic-induced differentiation. Based on the Illumina HiSeq high-throughput sequencing platform, OM-MSC, OLK-MSC, OSCC-MSC (n = 3) were subjected to transcriptome sequencing, functional annotation, and enrichment analysis of differentially expressed genes and related genes. CCK8 assay, wound healing assay, and transwell assay were performed to compare the proliferation, migration, and invasion of the seven types of cells. The 7 cells were incubated with 0, 0.125 mM, 0.25 mM, 0.5 mM, 1 mM, and 2 mM of the photosensitizer (5-aminolevulinic acid, 5-ALA) in vitro. Subsequently, they were irradiated with a 150 mM, 635 nm laser for 1 min, and the cell activity was detected using the CCK8 assay after 24 h. The mitochondrial changes in the 7 cells before and after the treatment of PDT were detected using the JC-10 probe, and the changes in ATP content were measured before and after the PDT treatment. OM-MSC, OLK-MSC, and OSCC-MSC expressed positive MSC surface markers. After osteogenic and lipogenic-induced differentiation culture, stained calcium nodules and lipid droplets were visible, meeting the identification criteria of MSC. Pathway enrichment analysis revealed that the differentially expressed genes (DEGs) of OSCC-MSC compared to OLK-MSC were primarily associated with the PI3K-Akt signaling pathway and tumor-related pathways. OSCC-MSC exhibited stronger migratory and invasive abilities compared to Cal27. The IC50 values required for OM, OLK, and OSCC-derived MSC were lower than those required for epithelial cells treated with PDT, which were 1.396 mM, 0.9063 mM, and 2.924 mM, respectively. Cell membrane and mitochondrial disruption were observed in seven types of cells after 24 h of PDT treatment. However, HOK, DOK, leuk1, and Cal27 cells had an ATP content increased. OLK, OSCC epithelial cells require higher concentrations of 5-ALA for PDT treatment than MSC of the same tissue origin. The concentration of 5-ALA required increases with increasing cell malignancy. Differences in the response of epithelial cells and MSC to PDT treatment may have varying impacts on OLK recurrence and malignancy. • Photodynamic therapy is efficient in oral leukoplakia and early oral squamous cell carcinoma. • Epithelial cell and mesenchymal cell in oral leukoplakia and oral squamous cell carcinoma have different response in photodynamic therapy. • It needs increasing concentration of 5-aminolevulinic acid to treat both epithelial cells and mesenchymal stem cells from oral squamous cell carcinoma than that from oral leukoplakia. [ABSTRACT FROM AUTHOR]

There is a lack of effective clinical management of oral epithelial dysplasias to reduce their risk of malignant transformation and considerable gaps in knowledge regarding the most effective means of treating such lesions. A retrospective cohort of biopsy-confirmed oral epithelial dysplasias consecutively diagnosed in the period 1995–2014 and followed-up until 2017 was identified from pathology department files. Demographic, clinical and follow-up information was collected. Multivariate Cox proportional-hazards models were performed to evaluate sociodemographic, clinical and pathological factors associated with progression to oral squamous cell carcinoma. The study included 144 oral epithelial dysplasias, of which 42% progressed to oral cancer at the end of follow-up (21 years). Clinical aspect of the lesion was described for 77 (53.5%) of the patients. Treatment, age, grade of the lesion and diagnostic period were independent prognostic factors for progression. When considering only patients with described clinical aspect, only treatment and grade of the lesion were independently associated with cancer. The results from this non-selected retrospective cohort of oral epithelial dysplasias underscore the existing limitations of the current standard-of-care of the patients and provide novel insights on the management of these lesions with and without described clinical aspect. Well-designed, robust prospective studies, a homogenized staging system and multidisciplinary treatment guidelines are warranted. [ABSTRACT FROM AUTHOR]

Dyskeratosis congenita is a rare inherited bone marrow failure syndrome with three distinct clinical features: nail dystrophy, reticular skin pigmentation, and oral leukoplakia. The case of a 5-year-old female patient diagnosed with squamous cell carcinoma of the tongue is reported here. An autosomal dominant type 3 TINF2 mutation subsequently confirmed the diagnosis of dyskeratosis congenita. The traditional tongue cancer treatment was adapted for this young patient. While the tongue cancer lesions and leukoplakia were removed, the deep margins were minimized to preserve the tongue muscles and flap surgery was avoided. Additional conservative measures were applied to suppress new leukoplakia lesions. [ABSTRACT FROM AUTHOR]

Background/purpose: Our previous study found significantly lower serum hematinic levels and higher serum homocysteine level as well as higher frequencies of serum hematinic deficiencies and hyperhomocysteinemia in oral leukoplakia (OL) patients than in healthy control subjects. This study evaluated whether carcinoembryonic antigen (CEA)-positive or squamous cell carcinoma-antigen (SCC-Ag)-positive OL patients had significantly lower serum hematinic levels and higher serum homocysteine level as well as significantly higher frequencies of hematinic deficiencies and hyperhomocysteinemia than CEA-negative or SCC-Ag-negative OL patients or healthy control subjects.Methods: The complete blood count, serum iron, vitamin B12, folic acid, and homocysteine levels in 184 OL patients including 85 CEA-positive, 99 CEA-negative, 25 SCC-Ag-positive, and 159 SCC-Ag-negative OL patients and in 184 age- and sex-matched healthy control subjects were measured and compared.Results: We found that the 85 CEA-positive or 25 SCC-Ag-positive OL patients had a significantly lower mean serum folic acid level and a significantly higher mean serum homocysteine level as well as significantly higher frequencies of serum folic acid deficiency and hyperhomocysteinemia than 184 healthy control subjects. Moreover, the 25 SCC-Ag-positive OL patients had a significantly higher mean serum homocysteine level than the 159 SCC-Ag-negative OL patients. The 85 CEA-positive OL patients had a higher mean serum homocysteine level and a higher frequency of hyperhomocysteinemia than 99 CEA-negative OL patients (marginally significant, P = 0.060).Conclusion: CEA-positive or SCC-Ag-positive OL patients tend to have a higher mean serum homocysteine level and a higher frequency of hyperhomocysteinemia than CEA-negative or SCC-Ag-negative OL patients, respectively. [ABSTRACT FROM AUTHOR]

It is clinically challenging to identify oral leukoplakias that have a high risk of undergoing malignant transformation. The aim of this retrospective study was to elucidate the associations between malignant transformation of oral leukoplakias and various clinicopathologic factors. Patients with a diagnosis of clinical oral leukoplakia, verified through histopathologic examination and with access to digital images of the lesion, were retrospectively included for the period 2003–2013. Using the clinical images, all lesions were re-evaluated regarding diagnosis and clinical subtype. Of the 234 included patients, with a median follow-up of 9 years, 27 (11.5%) developed oral squamous cell carcinoma. Among the clinicopathologic factors investigated, non-homogeneous oral leukoplakia (OL), OL with dysplasia, and OL localized to the tongue showed statistically significant increased rates of malignant transformation in the multivariate Cox regression analysis. Non-homogeneous OL showed a 15.2-times higher transformation rate than homogenous OL (P < 0.001). Dysplastic leukoplakias developed into carcinomas 2.4-times more often than did non-dysplastic leukoplakias (P = 0.048). OL located on the tongue showed a 2.8-times higher malignant transformation rate than OLs at other oral locations (P = 0.018), when other locations were combined into one group. Non-homogeneous OL, OL with dysplasia, and OL localized to the tongue have higher transformation rates. [ABSTRACT FROM AUTHOR]

Our previous study showed that carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC–Ag), and ferritin are significantly higher in patients with oral potentially malignant disorders (OPMDs including oral leukoplakia, oral erythroleukoplakia, and oral verrucous hyperplasia) than in healthy controls (HCs). Oral submucous fibrosis (OSF) is also recognized as an OPMD. This study evaluated whether these three serum tumor marker levels were also significantly higher in OSF patients than in HCs. The serum CEA, SCC-Ag, and ferritin levels in 41 OSF patients and 164 HCs were measured and compared. Patients with serum CEA level ≥3 ng/mL, SCC-Ag level ≥2 ng/mL, and ferritin level ≥250 ng/mL were scored as serum positive for CEA, SCC-Ag, and ferritin, respectively. We found significantly higher mean serum CEA, SCC-Ag, and ferritin levels in 41 OSF patients than in 164 HCs (all P -values < 0.05). Moreover, 41 OSF patients had significantly higher serum positive rates of CEA (39.0%), SCC-Ag (19.5%), and ferritin (53.7%) than 164 HCs (all P -values < 0.05). Of the 41 OSF patients, 26 (63.4%), 7 (17.1%), and 2 (4.9%) had serum positivities of one, two, or three tumor markers including CEA, SCC-Ag, and ferritin, respectively. There are significantly higher mean serum CEA, SCC-Ag, and ferritin levels and significantly higher serum positive rates of CEA, SCC-Ag, and ferritin in OSF patients than in HCs. The serum CEA, SCC-Ag, and ferritin levels may be served as tumor markers for evaluation of malignant potential of OSF lesions. [ABSTRACT FROM AUTHOR]

To evaluate the salivary detection of XRCC1 rs25487 single-nucleotide polymorphism (SNP), its relationship with clinicopathological characteristics, and the interactions with demographic/behavioral variables in the etiopathogenesis of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) in a Colombian population. Demographic/behavioral data and saliva samples were obtained from patients with oral leukoplakia (OL, n = 17) and oral lichenoid lesions with epithelial dysplasia (OLL-ED, n = 10), or OSCC (n = 45), along with healthy controls (n = 40). Tissue biopsies were obtained for histological assessment and genetic analysis was performed using polymerase chain reaction-restriction fragment length polymorphism. Descriptive analyses were used to compare the distribution of genotypes/alleles between study groups alongside an analysis of the interaction between genetic findings and demographic/behavioral variables. No association was observed between the genotype and allele frequencies in OPMD or OSCC. The AG genotype was significantly more frequent in OL with high-grade dysplasia, acanthotic epithelial lining, moderate-to-severe mitotic count, and negative-to-mild apoptotic count; and in OSCC cases with stage III/IV, poorly differentiated, perineural/lymphovascular invasion, severe cellular atypia, moderate-to-severe mitotic count, and negative-to-mild apoptotic counts. Significant interaction effects were detected in the AG genotype with regard to ageing, smoking habits, and alcohol consumption in both OL and OSCC. Although rs25487 SNP appeared to not modulate the risk of OPMD/OSCC independently, its significant association with clinicopathological characteristics in OL and OSCC, and the synergistic interaction between ageing and smoking/alcohol consumption, might play a role in these two diseases. • Genetic factors might be critical in the etiopathogenesis of OPMD and OSCC. • XRCC1 rs25487 SNP was genotyped in a Colombian population. • XRCC1 rs25487 SNP appears not to modulate the risk of the OPMD/OSCC independently. • Significant associations with clinicopathological parameters of OL and OSCC could be linked to AG genotype. • Ageing, smoking, and alcohol consumption showed synergistic interactions with AG genotype. [ABSTRACT FROM AUTHOR]

Background/purpose: Several previous studies have reported higher serum tumor marker levels in patients with oral or head and neck squamous cell carcinomas. This study evaluated whether 232 patients with oral precancerous lesions (oral precancer patients) had significantly higher serum carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), and ferritin levels than healthy control subjects.Methods: The serum CEA, SCC-Ag, and ferritin levels in 232 oral precancer patients and 187 healthy control subjects were measured and compared. Patients with serum CEA level ≥3 ng/mL, SCC-Ag level ≥2 ng/mL, and ferritin level ≥250 ng/mL were scored as serum positive for CEA, SCC-Ag, and ferritin, respectively.Results: We found significantly higher mean serum CEA, SCC-Ag, and ferritin levels in 232 oral precancer patients than in 187 healthy control subjects (all P-values < 0.05). Moreover, 232 oral precancer patients had significantly higher serum positive rates of CEA (47.4%), SCC-Ag (13.8%), and ferritin (52.2%) than 187 healthy control subjects (all P-values < 0.05). Of the 232 oral precancer patients, 121 (52.1%), 56 (24.1%), and 10 (4.3%) had serum positivities of one, two, or three tumor markers including CEA, SCC-Ag, and ferritin, respectively.Conclusion: There are significantly higher mean serum CEA, SCC-Ag, and ferritin levels and significantly higher serum positive rates of CEA, SCC-Ag, and ferritin in oral precancer patients than in healthy control subjects. The serum CEA, SCC-Ag, and ferritin levels are of diagnostic value and may be potential tumor markers for the screening of oral precancer patients. [ABSTRACT FROM AUTHOR]

• Significant gene expression differences between PVL and non-PVL oral lesions. • HOX and keratin-associated protein gene families upregulated in PVL. • Connective tissue pathways and fibroblast signatures lower in PVL. • Classifying biomarker models discriminated PVL from non-PVL lesions. Proliferative verrucous leukoplakia (PVL) is a rare and enigmatic oral potentially malignant disorder which almost invariably results in oral squamous cell carcinoma (OSCC). The aims of this project were to use transcriptome profiling to characterise PVL gene expression patterns for biomarker identification and gain insight into the molecular aetiopathogenesis of PVL. Forty-three oral cavity mucosal biopsies from 32 patients with oral lesions clinically compatible with either PVL or non-PVL conventional oral leukoplakia (OLK) underwent transcriptome profiling by RNA sequencing. Data was analysed by hierarchical clustering, differential gene expression, functional enrichment and network analysis, sparse partial least squares discriminant analysis sPLS-DA, and immune cell phenotypic estimation. We found 464 genes significantly differentially expressed at least 2-fold between PVL and non-PVL OLK (193 up and 271 down). HOX genes, including HOXA1 and HOXB7, keratin-associated proteins (KRTAPs) and olfactory receptor G proteins (OR) were significantly upregulated in PVL. Other upregulated genes in PVL included FOS , WNT16 and IFNA1. Pathway analysis showed that there was a significant downregulation of connective tissue signalling in PVL. Classifying multivariate models based upon 22 genes discriminated PVL from non-PVL OLK. Bioinformatic profiling showed that immune cell profiles in PVL and OLK were similar except that fibroblast markers were reduced in PVL. These results demonstrate that PVL and conventional OLK are molecularly distinct with upregulation of many cancer-associated genes. They provide insight into the pathogenesis of PVL and show that biomarker based molecular diagnostics is feasible to discriminate and inform diagnosis and management. [ABSTRACT FROM AUTHOR]

Periodontal bacteria can infiltrate the epithelium, activate signaling pathways, induce inflammation, and block natural killer and cytotoxic cells, all of which contribute to the vicious circle of carcinogenesis. It is unknown whether oral dysbiosis has an impact on the etiology or prognosis of OPMD. Within this paradigm, this work systemically investigated and reported on the composition of oral microbiota in patients with oral potentially malignant disorders (OPMD) versus healthy controls. Observational studies that reported next generation sequencing analysis of oral tissue or salivary samples and found at least three bacterial species were included. Identification, screening, citation analysis, and graphical synthesis were carried out. For oral lichen planus (OLP), the bacteria with the highest abundance were Fusobacterium , Capnocytophaga , Gemella , Granulicatella , Porphyromonas , and Rothia ; for oral leukoplakia (OLK), Prevotella. Streptococci levels in OLK and OLP were lower. The usage of alcohol or smoke had no effect on the outcomes. An increase in periodontal pathogenic bacteria could promote the development and exacerbation of lichen. Effective bacteriome-based biomarkers are worthy of further investigation and application, as are bacteriome-based treatments. • Oral bacteriome composition is altered in patients with OPMD and is changing as the disease progresses. • Oral brushing should be preferred to saliva sampling or biopsies because it is a site-specific and noninvasive procedure. • Samples should be analyzed by second- and third-generation and unified sequencing techniques (e.g. MetaSquare). • Possible biomarkers exist for OLP (P. melaninogenica , S. moorei) and lesion-to-cancer transition (M. micronuciformis). • Increased Fusobacterium, Capnocytophaga, Gemella, Granulicatella, Porphyromonas, Rothia may promote oral lichen planus. [ABSTRACT FROM AUTHOR]

• PDT shows promising clinical efficacy in the treatment of OPMD. • Among the 60 OPMD patients receiving PDT, overall effective rate of 86.67 %. • OPMD still have certain recurrence and malignant transformation rate after PDT. • Fifteen out of the 60 patients relapsed at a rate of 25.00 %. • Nine out of the 60 patients developed MT at a rate of 15.00 %. To investigate the clinical efficacy of aminovalerate hydrochloride photodynamic therapy (PDT) for oral potentially malignant disorder (OPMD),oral leukoplakia (OLK), along with identifying the influencing factors.Additionally, the study aims to detect the rates of recurrence and malignancy after PDT. 60 patients with OPMD who received PDT at our hospital from 2006 to 2021 were included in this study. Relevant patient medical data were collected and analyzed using SAS 9.4 software.The Mann-Whitney U test was used to retrospectively analyze the factors influencing clinical efficacy, as well as recurrence rate and malignant transformation rate (MTR) after treatment. Among the 60 OPMD patients receiving PDT, complete remission in 13 (21.67 %), partial remission in 39 (65.00 %), and no remission in eight (13.33 %), resulting in an overall effective rate of 86.67 %.Fifteen patients experienced relapse, leading to a recurrence rate of 25.00 %. Among these relapses,11 patients occurred within one year after treatment, corresponding to an 18.33 % recurrence rate during that period. Moreover, nine patients developed malignant transformation (MT), resulting in an MTR of 15.00 %. Out of these patients, six individuals developed MT within one year after treatment, resulting in a one-year MTR of 10.00 %. The study findings indicate that PDT shows promising clinical efficacy in the treatment of OPMD, with relatively limited and tolerable postoperative adverse reactions. However, there remains a certain rate of recurrence and malignancy after treatment. Therefore, close attention should be paid to postoperative monitoring, regular follow-up, and further expansion of the sample size to observe its long-term efficacy. [ABSTRACT FROM AUTHOR]

• The review summarizes the available published data on OSCC/OPMD in FA patients. • May provide useful information for clinicians. • Lesions occur more frequently in young adult women. • Most OSCC/OPMD are treated with surgical resection. • High death rates are observed within a short period time. The purpose of the present study was to perform a systematic review focusing on oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD) in Fanconi anemia (FA) individuals. Electronic searches were undertaken in five databases supplemented by manual scrutiny and gray literature. Case reports and/or cases series were included. The searches yielded 55 studies describing 112 cases of OSCC (n = 107) and/or OPMD (n = 5) in FA individuals. The mean age at diagnosis of OSCC/OPMD was 27.1 (±9.6) years, and females (51.8 %) were slightly more affected. Ulcer (n = 37) or mass (n = 25) were described as clinical presentations for OSCC and OPMD. White lesions (n = 4) were the most common manifestation in OPMD. Tongue (47.2 %) was the most frequent location. Sixty-one (54.5 %) individuals underwent HSCT. Surgical resection (n = 75) was the main treatment adopted. The estimated rate of OPMD malignant transformation was 1.8 % and recurrences following OSCC excision occurred in 26.8 % of individuals. Overall, at 60 months of follow-up, the probability of survival fell to 25.5 % and at 64 months the probability of recurrence increased to 63.2 %. The present data support the need for strict surveillance of patients with FA, even in the absence of OPMD, for early OSCC detection and reduction of mortality. [ABSTRACT FROM AUTHOR]

To determine the association of Candida phenotypes, virulence factors, antifungal sensitivity and clinical response to Fluconazole in Oral leukoplakia (OL). Sterile swabs were obtained from oral lesions in immunocompetent subjects [30 Homogenous (HOL), 31 Non- Homogenous (NHOL] and normal buccal mucosa in 30 age and sex-matched healthy controls (C). Candida phenotypes, virulence factors (Secreted Aspartyl Proteinase (SAP), Phospholipase (PL), Biofilm formation (BF) and antifungal sensitivity were determined. Clinical features (Size, Erythema, thickness, oral burning sensation (VAS scores) before and after Fluconazole therapy in OL were recorded by two calibrated observers. Candida was associated with OL (p ​< ​0.01). Candida albicans was the most common phenotype sensitive to Fluconazole. SAP, PL and BF activity was significantly high in NHOL. Strong positive correlation was seen between SAP, and PL activity and pre-treatment VAS scores in NHOL. There was significant reduction in VAS scores, size of lesion [HOL (p ​< ​0.001) NHOL (p ​< ​0.05)], erythematous areas (67.8%) in NHOL and thickness of lesions (42.6%) in both types OL after Fluconazole therapy with substantial inter-observer agreement. Non albicans candida (NAC) species had similar virulence profiles but resistant to Fluconazole and showed minimal clinical improvement. Virulence activity of Candida in OL increases severity of lesions. Fluconazole is effective against virulent Candida albicans , causes clinical improvement and down-staging from high –risk NHOL to low-risk HOL which can reduce risk of malignant transformation. Detection of highly virulent NAC infection and antifungal sensitivity is recommended in OL recalcitrant to Fluconazole therapy. • Oral leukoplakia is associated with highly virulent forms of Candida that can induce inflammation. • Virulence activity of ​ Candida ​is increased in Non- Homogenous lesions and increases severity and oral burning sensation. • Virulence profile of Non albicans ​ Candida ​is similar to ​ Candida albicans ​but resistant to Fluconazole. • Fluconazole causes down- staging from high-risk to low-risk lesions, in ​ Candida albicans associated Oral Leukoplakia. • Identification of Non albicans Candida species and antifungal sensitivity is recommended in recalcitrant lesions. [ABSTRACT FROM AUTHOR]

Proliferative verrucous leukoplakia (PVL) is a rare and refractory form of oral mucosal leukoplakia of unknown origin, characterized by high rates of malignant transformation. Different diagnostic criteria, terminologies, and therapeutic approaches have been proposed since the first report in 1985. There remains no general agreement regarding the clinical and histological diagnosis, prevention, and correct management of this disease. This retrospective study investigated 48 patients affected by PVL showing at least one malignant transformation and followed up at 2-month intervals. Twenty-five were female (52.1%) and 23 (47.9%) were male; their median age was 67 years (range 40–93 years). Follow-up ranged from 18 to 240 months. Clinical examination included the use of Lugol's solution to prevent clinical underestimation of the margins and toluidine blue for suspicious areas. Surgical excision by scalpel was the preferred treatment for suspicious lesions, with only five carcinomas surgically removed by diode laser and two by CO 2 laser. All specimens were accurately mapped after formalin fixation. Fifteen patients (31.3%; 10 female, five male) developed one oral carcinoma, while 33 (68.7%) developed two or more primary tumours (range 3–12). Only four patients (8.3%), who developed between 2 and 8 oral squamous cell carcinomas (OSCCs), died of tumour-related causes. The pre-surgical clinical workup, subsequent surgical treatment, and follow-up are key to success for patients affected by PVL with malignant transformation into stage 1 OSCC and/or verrucous carcinoma, leading to a high overall survival rate. [ABSTRACT FROM AUTHOR]

Oral leukoplakia (OL) is a sign of potentially malignant disorders of the oral mucosa. The risk of malignant transformation of OL is challenging to assess. Furthermore, predictive biomarkers of malignant transformation have not been fully established. We examined the transcriptional status of factor forkhead box P3+ (FOXP3+) lymphocytes, which confer an immune-suppressive microenvironment, in OL and its potential value as a predictor for OL malignant transformation in two independent cohorts of patients. A total of 165 patients who had been histopathologically diagnosed with OL were enrolled in this retrospective study. Patients were divided into derivation and validation cohorts. Cutoff values for the number of FOXP3+ lymphocytes (≥15) were determined using receiver operator characteristic analyses. In the derivation cohort, among FOXP3-high OL patients, FOXP3+ lymphocyte status was the only factor associated with malignant transformation in both univariate and multivariate analyses. There was a similar trend in the validation cohort. Moreover, FOXP3+ lymphocyte expression status was correlated with dysplasia grade. These results suggest that FOXP3+ lymphocyte status is a potential predictive biomarker in patients with OL and may affect multistep carcinogenesis from OL to oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background/purpose: Gastric parietal cell antibody (GPCA), thyroglobulin antibody (TGA), and thyroid microsomal antibody (TMA) may be present in oral mucosal disease patients. This study mainly assessed the frequencies of serum GPCA, TGA, and TMA positivities in 131 oral precancer patients.Methods: Serum GPCA, TGA, and TMA levels were measured in 131 oral precancer patients including 96 oral leukoplakia, 26 oral erythroleukoplakia, and 9 oral verrucous hyperplasia patients and in 131 age- and sex-matched healthy control subjects.Results: We found that 131 oral precancer patients had higher frequencies of serum GPCA (10.7% vs. 2.3%, P = 0.012, statistically significant), TGA (4.6% vs. 2.3%, P = 0.498), and TMA (8.4% vs. 2.3%, P = 0.054, marginal significance) positivities than 131 healthy control subjects. We also found that 1 (0.8%), 6 (4.6%), and 16 (12.2%) oral precancer patients had the presence of three (GPCA + TGA + TMA), two (GPCA + TGA, GPCA + TMA, or TGA + TMA), or one (GPCA only, TGA only, or TMA only) autoantibody in their sera, respectively. Of 10 TGA/TMA-positive oral precancer patients whose serum thyroid-stimulating hormone (TSH) levels were measured, 80%, 10%, and 10% of these 10 TGA/TMA-positive oral precancer patients had normal, lower, and higher serum TSH levels, respectively. We also found a significantly higher GPCA positive rate in 26 smokers consuming >20 cigarettes per day than in 61 smokers consuming ≤20 cigarettes per day (P = 0.008).Conclusion: Approximately 17.6% of 131 oral precancer patients have serum GPCA/TGA/TMA positivity. Only approximately 20% of TGA/TMA-positive oral precancer patients have either hypothyroidism or hyperthyroidism. [ABSTRACT FROM AUTHOR]

Objectives: To map the genomic pathways of patients with oral leukoplakia (OLK) which transformed to cancer (progressive) and those which did not (non-progressive), and to compare their exomic profiles.Materials and Methods: Whole exome sequencing was performed on 42 sequential samples from five progressive and eight non-progressive patients. Association of genomic variant frequencies with progression or lesion severity were analysed by non-parametric tests (Kruskal-Wallis and Mann-Whitney-Wilcoxon) and multivariate sparse partial least squares discriminant analysis (sPLS-DA). Enrichment analysis was used to characterise the effect of mutations upon biological pathways. Confirmatory studies used qPCR and immunohistochemistry.Results: Using sPLS-DA, the variant frequency of a small number of genes could be used to classify the samples based on lesion severity or progressive status. Enrichment analysis showed that DNA damage repair gene related pathways were highly impacted in lesions which progressed to cancer. Multivariate analysis of a set of 148 DNA damage repair genes could be used to classify progressive lesions using mutation frequency. BRCA1, BRCA2 and other double strand break (DSB) repair Fanconi anaemia (FA)/BRCA pathway genes were prominent contributors to this classification.Conclusion: Patients with progressive and non-progressive OLK can be differentiated using the frequency of exomic variants, particularly in DNA damage repair pathway genes. To our knowledge, this is the first report of FA/BRCA (DSB) pathway involvement in malignant transformation of OLK to oral squamous cell carcinoma (OSCC). [ABSTRACT FROM AUTHOR]

Background/purpose: Our previous studies found relatively higher frequencies of anemia, hematinic deficiencies, and hyperhomocysteinemia in patients with different types of oral mucosal diseases. This study evaluated whether patients with oral precancerous lesions (oral precancer patients) had significantly higher frequencies of anemia, hematinic deficiencies, and hyperhomocysteinemia than healthy control subjects.Methods: The complete blood count, serum iron, vitamin B12, folic acid, and homocysteine levels in 131 oral precancer patients including 96 oral leukoplakia, 26 oral erythroleukoplakia, and 9 oral verrucous hyperplasia patients and in 131 age- and sex-matched healthy control subjects were measured and compared.Results: We found significantly lower mean serum iron (for women only), vitamin B12, and folic acid levels and a significantly higher mean serum homocysteine level in oral precancer patients than in healthy control subjects (all P-values < 0.05). Moreover, 131 oral precancer patients had significantly higher frequencies of blood hemoglobin (3.1%), vitamin B12 (43.5%), and folic acid (46.6%) deficiencies and hyperhomocysteinemia (22.1%) than 131 healthy control subjects (all P-values < 0.05). Of 131 oral precancer patients, lower mean serum folic acid levels were found in 87 cigarette smokers than in 44 non-smokers (P = 0.002), in 26 smokers consuming > 20 cigarettes per day than in 61 smokers consuming ≤ 20 cigarettes per day (P = 0.024), and in 52 betel quid chewers than in 79 non-chewers (P = 0.051).Conclusion: There are significantly higher frequencies of anemia, serum vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia in oral precancer patients than in healthy control subjects. [ABSTRACT FROM AUTHOR]

The second article in this continuing medical education series discusses the clinical and histopathologic features of common premalignant and malignant lesions of the oral cavity. It is imperative for dermatologists to be able to appropriately recognize suspicious lesions, determine the need to obtain a biopsy specimen, counsel, and refer patients presenting with premalignant or malignant conditions. Given the higher rates of mortality and morbidity of oral mucosal malignancies because of late diagnosis, appropriate treatment with multidisciplinary care in a timely manner is essential to patients with these neoplasms. [ABSTRACT FROM AUTHOR]

Highlights • Treatment of oral potentially malignant disorder in an elderly patient. • Plum-blossom needle assisted photodynamic therapy was used. • This regimen could be an effective therapeutic strategy. Abstract Oral leukoplakia (OLK) is one of the most common oral potentially‐malignant disorders (OPMD) with complex causes, a long disease course and a high tendency for recrudescence. Although a variety of methods exist for treating this disease, canceration rates remain high. Herein, we described a case of 72-year-old male patient with OLK of the palatine mucous membrane who had achieved complete remission after being treated with five sessions of plum-blossom needle (PBN) assisted 5-aminolevulinic acid-photodynamic therapy (ALA-PDT). The patient had since been subsequently placed under close observation (>12 mo). To date, there has been no recurrence. PBN assisted PDT might be suitable for the treatment of OPMDs in patients presenting with epithelial hyperkeratosis. [ABSTRACT FROM AUTHOR]

Highlights • First and comprehensive systematic review of photodynamic therapy in the treatment of oral leukoplakia. • Effectiveness and advantages of photodynamic therapy are indicated after statistical analysis. • Influencing factors of photodynamic therapy in oral leukoplakia are analyzed and recommended parameters are proposed. Abstract Objective The aim of the present study was to systematically review the efficacy of photodynamic therapy (PDT) in the management of oral leukoplakia (OLK). Methods This systematic review aimed to address the following focused question: "Is photodynamic therapy effective in the management of oral leukoplakia?" PubMed/Medline, EMBASE, ISI Web of Knowledge, OVID, CNKI, and WANFANG DATA were searched up to and including June 2018 using different combinations of the following keywords: photodynamic therapy, leukoplakia, oral dysplasia, oral precancers, and oral premalignant lesions. Results Sixteen studies were included in the present study. A total of 352 patients was included in this review, with age ranging from 20 to 79 years. Photosensitizers used were aminolevulinic acid, Photofrin, methylene blue, and chlorine-e6. Laser wavelength, duration of irradiation, and power density were 420–660 nm, 60–1000 s, and 100–150 mW/cm2, respectively. On the whole, the rates of complete response and partial response were 32.9% and 43.2%, and the sum was 76.1%. The follow-up period ranged from 1 month to 119 months. The recurrence rate of OLK was 0–60%. Conclusion PDT appears to be a useful therapeutic strategy in the management of oral leukoplakia as a non-surgical treatment. Further RCTs with long follow-up period, standardized PDT parameters, and comparing efficacy of PDT with various other therapies are needed to acquire definite conclusions. [ABSTRACT FROM AUTHOR]

Abstract Purpose The aim of this prospective work was to examine oral leukoplakia for their podoplanin expression to determine whether podoplanin expression is associated with the degree of dysplasia. Materials and methods We took biopsy samples from 50 patients with oral leukoplakia in 2013. The preparations studied by immunohistochemistry were analyzed in correlation with the degree of dysplasia and other clinicopathological variables. Results The Chi-square test showed a significant correlation between podoplanin expression and the degree of dysplasia according to the squamous intraepithelial neoplasia (SIN) classification (p = 0.033). Also, a significant association between age grouping and podoplanin expression was found. We were able to show that the distribution is the same for both age groups in relation to the score of podoplanin expression (p = 0.003). Conclusion In a comparable retrospective work of our working group, it could be shown that podoplanin is a reliable predictive marker for the assessment of the risk of malignant transformation. The present work was able to substantiate the assumption that podoplanin not only plays an important role in the context of malignant degeneration but also exerts a major influence in advance. [ABSTRACT FROM AUTHOR]

Recent advances in DNA sequencing technology have facilitated rapid advances in the analysis of the human microbiome and its role in human disease. Several studies have now shown that OSCC and some oral premalignant conditions are associated with alterations in the oral microbiome. These studies raise questions regarding the role of the oral microbiome in the progression of oral malignancies and whether microbiome change is a significant risk factor in the development of oral cancer. This short review summarises current knowledge in the field and highlights questions that require further investigation. [ABSTRACT FROM AUTHOR]

To reveal the mechanisms underlying the epigallocatechin-3-gallate (EGCG)-mediated inhibition of carcinogenesis and the related regulatory signaling pathways. The effect of EGCG on the proliferation of OSCC cells was examined. SuperPred, ChEMBL, Swiss TargetPrediction, DisGeNET, GeneCards, and National Center for Biotechnology Information databases were used to predict the EGCG target genes and oral leukoplakia (OL)-related, oral submucosal fibrosis (OSF)-related, and OSCC-related genes. The binding of EGCG to the target proteins was simulated using AutoDock and PyMOL. The Cancer Genome Atlas (TCGA) dataset was subjected to consensus clustering analysis to predict the downstream molecules associated with these targets, as well as their potential functions and pathways. EGCG significantly inhibited OSCC cell proliferation (p < 0.001). By comparing EGCG target genes with genes linked to oral potentially malignant disorder (OPMD) and OSCC, a total of eleven potential EGCG target genes were identified. Furthermore, EGCG has the capacity to bind to eleven proteins. Based on consensus clustering and enrichment analysis, it is suggested that EGCG may hinder the progression of cancer by altering the cell cycle and invasive properties in precancerous lesions of the oral cavity. Some possible strategies for modifying the cell cycle and invasive properties may include EGCG-mediated suppression of specific genes and proteins, which are associated with cancer development. This study investigated the molecular mechanisms and signaling pathways associated with the EGCG-induced suppression of OSCC. The identification of specific pharmacological targets of EGCG during carcinogenesis is crucial for the development of innovative combination therapies involving EGCG. • Epigallocatechin-3-gallate inhibits the process of oral carcinogenesis. • Eleven direct target proteins for Epigallocatechin-3-gallate were identified. • Targets were enriched in collagen metabolic process and focal adhesion. • Epigallocatechin-3-gallate affected cell function by extra cellular matrix. [ABSTRACT FROM AUTHOR]

Highlights • TGM3 mRNA and protein expressions were frequently downregulated in OL cells and samples. • DNA hypermethylation was a mechanism of TGM3 downregulation in OL cells and samples. • TGM3 overexpression and silencing affected the proliferation, colony formation and apoptosis of OL cells through apoptosis-related protein dysregulations. • Lower TGM3 levels were strongly associated with the grade of epithelial dysplasia and OSCC development. • TGM3 was the independent predictor for malignant transformation of OL. Abstract Oral leukoplakia (OL) is the most common premalignancy in the oral cavity. The objective of this study was to investigate the biological role of transglutaminase 3 (TGM3) in malignant transformation of OL and its clinical value for predicting oral squamous cell carcinoma (OSCC) risk in patients with OL. Immunohistochemistry was used to measure TGM3 expression in OL samples from 98 patients. Patient clinicopathological and follow-up data were analyzed. The TGM3 biological role in OL cells was investigated in gain-of-function and loss-of-function assays, and the TGM3 downregulated mechanism in OLs was characterized. TGM3 mRNA and protein expressions were frequently downregulated in OL cells and samples. DNA hypermethylation was a mechanism of TGM3 downregulation. TGM3 overexpression and silencing affected the proliferation, colony formation, and apoptosis of OL cells through apoptosis-related protein dysregulations. Lower TGM3 levels were strongly associated with the grade of epithelial dysplasia and OSCC development. Multivariate analyses showed that TGM3 was the independent predictor for malignant transformation of OL. Collectively, these data indicated that TGM3 played an important role in OL malignant transformation and may serve as a predictor to identify OL with OSCC development. [ABSTRACT FROM AUTHOR]

The biological process of epithelial-to-mesenchymal transition (EMT) has been studied in oral squamous cell carcinoma (OSCC) metastasis, but it is rarely evaluated at several stages of oral carcinogenesis. This study aimed to analyze the presence of SNAIL and E-cadherin proteins, markers of EMT, in the development and progression of OSCC, evaluating excised specimens of potentially malignant lesions (oral leukoplakia with and without dysplasia-OL and OLD, respectively), tumor tissues (OSCC), metastatic lymph nodes (LN), and normal oral mucosa (NOM) by immunohistochemistry, considering subcellular localization. Additionally, SNAIL and E-cadherin transcripts were evaluated in vitro by qPCR, using SCC-9 cell line in comparison to human keratinocytes (HPEC). There was a significant increase in nuclear expression of SNAIL from NOM to OLD followed by a noticeable decrease in nuclear expression accompanied by increased cytoplasmic expression in OSCC (p<0.05). The E-cadherin cytoplasmic expression was remarkable and statistically significant higher in OSCC and LN, both compared to NOM (p< 0.0001), OL (p<0.01) and OLD (p< 0.0001 and p<0.001, respectively). In vitro , E-cadherin and SNAIL transcripts were lower in SCC-9 compared to HPEC cells, although only the decrease of E-cadherin was statistically significant (p<0.05). Regarding the association of E-cadherin and SNAIL expression with the clinical findings, the analysis revealed an association between the cytoplasmic expression of SNAIL and the invasion pattern (p=0.05) in OSCC. The increased nuclear SNAIL expression may be characteristic of OLD, and the presence of E-cadherin in cell cytoplasm a marker of transformation to malignancy of potentially malignant oral leukoplakias into OSCC. [ABSTRACT FROM AUTHOR]

Purpose Recent studies have emphasized the role of podoplanin in oral lesions at risk of malignant transformation. We investigated a group of oral leukoplakias (OLs) to determine a possible relation between altered podoplanin expression and dysplasia, and to compare the results with those obtained by other, widely used biomarkers. Materials and methods The population consisted of 40 consecutive patients with a clinical and histological diagnosis of OL. Thirty-two OLs did not show dysplasia, whereas eight lesions presented with dysplasia. Immunohistochemical expression of podoplanin, p53 and Ki67 was analyzed in all samples. Results All three biomarkers were positive in seven of eight dysplastic OLs. Among the 32 OLs without dysplasia, Ki67 and p53 showed positive values in 21 and 10 samples respectively, whereas podoplanin was positive in only one case. Multiple logistic regression showed that podoplanin was the most powerful variable (Chi square 9.77; p < .01) statistically related to the presence of dysplasia. In addition, podoplanin showed a higher specificity value (96.87%) than Ki67 (34.37%) and p53 (68.75%). Conclusion Podoplanin seems to be a reliable means of discriminating lesions with epithelial dysplasia and could be introduced in routine practice as a marker to discriminate OLs at risk of developing cancer. [ABSTRACT FROM AUTHOR]

Background/purpose: Oral leukoplakia (OL) is one of the clinically diagnosed oral potentially malignant disorders (OPMDs) with an increased risk of oral cancer development. In this study, we investigated the malignant transformation of OL in Taiwanese population.Methods: A retrospective cohort study was analyzed from Taiwan's National Health Insurance Research Database. A comparison cohort was randomly frequency-matched with the OL cohort according to age, sex, and index year. Oral submucous fibrosis (OSF) and oral lichen planus (OLP) were further stratified to evaluate the possible synergistic effects for OL-associated malignant transformation.Results: In this cohort, 102 (5.374%) of 1898 OL patients were observed to transform into oral cancer. The malignant transformation rate was 26.40-fold in the OL cohort than in the comparison cohort after adjustment (95% confidence intervals 18.46-37.77). To further stratify with OSF and OLP, OL with OSF (58.38; 95% confidence intervals 34.61-98.50) and OL with OLP (36.88; 95% confidence intervals 8.90-152.78) had higher risk of malignant transformation rate than OL alone (27.01; 95% confidence intervals 18.91-38.59). The Kaplan-Meier plot revealed the free of malignant transformation rate was significant over the 13 years follow-up period (log-rank test, p < 0.001).Conclusion: OL patients exhibited a significantly higher risk of malignant transformation than those without OL. In addition, both OSF and OLP could enhance malignant transformation in patients with OL. However, further studies are required to identify the histopathological and clinical parameters in the pathogenesis of malignant transformation among OPMDs. [ABSTRACT FROM AUTHOR]

Objectives: Tobacco usage is the strongest risk factor in the development of oral squamous cell carcinoma (OSCC), which mandates careful screening for oral cancers in smokers. However, there are indications that oral potentially malignant lesions, such as oral epithelial dysplasia (OED), in non-smokers (NS) have a higher cancer risk than those in smokers. Without tobacco as an etiology, the development of these lesions in NS may suggest genetic susceptibility. The increasing incidence of OSCC in NS calls for a better understanding of the natural history of OED in NS as compared to that of smokers.Materials and Methods: Patients from a population-based longitudinal study with more than 10 years of follow up were analyzed. Of the 455 patients with primary OED (233 mild and 212 moderate dysplasia), 139 were NS and 306 were smokers. Demographic and habit information, clinical information (lesion site, size and appearance; toluidine blue and fluorescent visualization), microsatellite analysis for loss of heterozygosity (LOH) and outcome (progression) were compared between the two groups.Results and Conclusions: The majority of patients with OED were smokers. Of these, more were males, non-Caucasians and heavy drinkers. A significantly higher number of OED in NS were in the tongue, whereas a significantly higher number of OED in smokers were in the floor of mouth (FOM). OED in NS showed a greater than 2-fold increase in cancer progression. Strikingly, OED located in the FOM in NS showed a 38-fold increase in cancer progression as compared to those in smokers. [ABSTRACT FROM AUTHOR]

Actinic keratosis, leukoplakia, carcinoma in situ, and superficially invasive carcinomas of the lower lip are caused mainly by the cumulative effects of exposure of the vermilion of the lower lip to ultraviolet radiation. Current treatments all have limitations: cryosurgery or electrosurgery is suitable to treat only focal lesions; topical chemotherapy, which is an option for diffuse actinic damage, yields unreliable results; and laser treatment fails to rejuvenate the vermilion. However, “lip shave”, which involves full-thickness excision of the damaged vermilion and reconstruction with an advancement labial mucosal flap, will produce a fresh mucosal lining to the vermilion border. We describe our experience of the technique and evaluate the functional and aesthetic outcomes in 20 patients treated between January 2011 and January 2016. The follow-up period ranged from 24 to 60 months. Three-quarters of the patients had dysplasia or superficially invasive malignancy. Resected lesions were about 63 mm long, 13.7 mm wide, and 3.9 mm deep. No patients had recurrence or secondary lesions during follow up, functional disturbance was minimal, and the cosmetic outcome pleasing. Lip shave can efficiently reconstruct the vermilion of the lower lip with minimum deformity. [ABSTRACT FROM AUTHOR]

• AI-assisted DNA-ICM was applied to continuously monitor high risk OLK among the long-term follow-ups treated by photodynamic therapy. • Photodynamic therapy showed good clinical efficacy in both primary OLK and recurrent lesions. • AI-assistant DNA-ICM is a promising tool for monitoring the photodynamic prognosis of high-risk OLK. Oral leukoplakia (OLK) is one of the most common potentially malignant disorders. High-risk lesions require early intervention before developing into oral cancer. Photodynamic therapy (PDT) is a noninvasive technique for premalignant lesions. Scalpel biopsy remains a reliable method for monitoring the prognosis of OLK, but it is an invasive procedure with poor reproducibility to suspicious lesions. DNA aneuploidy cytology by oral cytobrush has been proposed as a promising objective and noninvasive tool in screening and diagnosing premalignant and malignant lesions. Here, we discussed the significance of artificial intelligence (AI)-assisted DNA aneuploidy cytology by image cytometry (DNA-ICM) for surveilling non-homogeneous OLK with moderate-to-severe dysplasia that was treated by 5-aminolevulinic acid-mediated PDT (ALA-PDT). The present study provides a scheme of the sequential management and surveillance strategy for OLK. [ABSTRACT FROM AUTHOR]

• Developing new technologies and improved application parameters synergize the treatment efficacy. • Enhanced pretreatment before photodynamic therapy promotes the penetration of photosensitizer and improve treatment efficacy. • Novel surgical instruments, suitable resection, preoperative non-invasive evaluation, intensive follow-up are recommended. • A novel management prescription approach based on the stratification and differential evaluation of "risk groups" is proposed. Oral potentially malignant disorders (OPMDs) are associated with an increased risk of occurrence of cancers of the oral cavity or lips. The unifying theme of OPMDs is their potential risk for cancer development. Therefore, the primary objective of the management should be to prevent carcinogenesis. Beyond diagnosis, current strategies for the management of OPMDs predominantly include non-surgical and surgical interventions and a "watch-and-see" approach, such as disease monitoring or surveillance, and preventive strategies. Though no optimal clinical treatment has gained universal approval for reducing or preventing malignant development of OPMDs. Therefore, an urgent need exits for improved treatment properties and effective predictive markers for OPMDs treatment. This review aims to outline recent synergism regarding to the management of OPMDs. Developing new technologies and improved application parameters to promote the treatment efficacy and a novel management prescription approach to OPMDs are proposed. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infects keratinocytes in the mucosa or skin, and persistent infection with HPV may lead to premalignant lesions and invasive cancer, especially cervical cancer. It has also been hypothesized that HPV infection is an etiological factor of oral squamous cell carcinoma and oral precancerous disorders such as lichen planus, leukoplakia, and erythroplakia. A high percentage of HPV in oral lesions supports the possible viral contribution, but an association of HPV infection with these lesions remains to be established. The current paper will update the latest progress of HPV infection in several oral potentially malignant disorders and oral squamous cell carcinoma and discuss the impact of HPV infection on the progression of oral potentially malignant disorders. [ABSTRACT FROM AUTHOR]

Objectives: Oral leukoplakia (OL) has a well-documented potential risk of malignant transformation into oral squamous cell carcinoma (OSCC), although biomarker(s) predicting malignant potential are limited in capability. The aim of this cross-sectional and retrospective cohort study was to investigate the predictive role of canonical Wnt genes Axin2 and Snail (SNAI1) expression in the malignant transformation of OL lesions.Materials and Methods: The expression of epithelial-mesenchymal transition (EMT) genes Snail and Axin2, which are regulated by the canonical Wnt pathway, were determined using immunohistochemical staining in an OL cohort consisting of 154 samples of patients with long-term follow-up and then evaluated as risk factors for malignant transformation of OL.Results: Increased Axin2 and Snail abundance were found in 107 (69.5%) and 58 (37.7%) of OL patients, respectively. In a multivariate analysis using gender, age, lesion site, Axin2, and Snail as cofactors, both Axin2 and Snail were independent risk factors for malignant transformation with a hazard ratio of 7.47 (95% confidence interval, 2.23-25.02; P=0.001) and 4.41 (95% confidence interval, 1.78-10.93; P=0.001), respectively. A nomogram for predicting 5-, 10-, and 15-year cancer-free survival probability was developed in patients with OL by including gender, age, lesion site, Axin2, and Snail expression with ac-index of 0.760.Conclusion: The increased abundance of Snail and Axin2 is highly correlated to malignant transformation of OL, making them novel biomarker(s) predicting oral cancer development. [ABSTRACT FROM AUTHOR]

Objective: Squamous cell carcinomas (SCC) are the most common malignancies in the oral mucosa; these carcinomas have been preceded by potentially malignant oral disorders (PMODs), mostly oral leukoplakia (OL). No specific biomarker has been widely accepted for predicting the risk of malignant transformation of PMODs. The aim of this study was to develop an accurate prediction model for the malignant transformation of OL using clinical variables and candidate biomarkers.Materials and Methods: To achieve this goal, 10 candidate biomarkers that had previously been reported as useful molecules were investigated: P53, Ki-67, P16, β-catenin, c-jun, c-met, insulin like growth factor II mRNA-binding protein (IMP-3), cyclooxygenase (COX-2), podoplanin (PDPN) and carbonic anhydrase 9 (CA9). For this study, malignant transformed (n=22, median interval of malignant conversion: 3.3years) and untransformed (n=138) OL specimens with median follow-up period of 11.3years (range: 4.6-23.2years) were immunohistochemically stained.Results: Using univariate Cox regression analysis, all biomarkers were proven to be significant for predicting malignant transformation in OL. To reach the highest prediction accuracy, the repeated simulation was performed, revealing that the combination of P53 and CA9 with the clinical factors including age and degree of dysplasia achieved the highest prediction accuracy. We constructed a nomogram with the identified prognostic factors for predicting the 5-, 10-, and 15-year progression free survival of OL.Conclusions: The proposed nomogram may be useful for the accurate and individual prediction of the transformation to SCC in OL patients and may help clinicians offer appropriate treatments and follow up. [ABSTRACT FROM AUTHOR]