Implications of TP-positive CAFs in the Bone Invasion of Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Cancer-associated fibroblasts (CAFs) have recently been suggested as critical cellular components of bone invasion in oral squamous cell carcinoma (OSCC). However, the underlying molecular mechanisms and subtypes related to their bone-invasive function are unclear. This study investigated the implications of thymidine phosphorylase (TP)-positive CAFs (TP+CAFs) in OSCC bone invasion. MATERIALS AND METHODS: TP expression was determined in 116 patients with OSCC using immunohistochemistry. The influence of TP expression on the biological behavior of CAFs was investigated in vitro. The possible impact of TP+CAFs on bone invasion in OSCC was further evaluated using patient-derived xenograft (PDX) mouse models. RESULTS: In bone-invasive OSCC tissues, TP+CAFs were mainly distributed on the surface of resorbed bone tissue rather than on the tumor side. High levels of TP+CAFs were significantly associated with higher T-stage, bone invasion, and worse overall survival and recurrence-free survival in our study cohort. Recombinant human TP promoted the proliferative and invasive abilities of CAFs and increased matrix metalloproteinase-9 mRNA expression in vitro, related to bone resorption. In the PDX mouse models, TP+CAFs were found in early bone resorption on the surface of resorbed bony tissues. Bone resorption occurred more frequently in the PDX models with TP+CAFs than in those without. CONCLUSION: TP+CAFs were significantly associated with bone invasion and the prognosis of OSCC. This study provides insights into cellular and molecular targets for the early diagnosis and treatment of bone-invasive OSCC.

Proteasome Subunit Alpha Type-7 Expression Suppresses Cutaneous Squamous Cell Carcinoma Progression by Inhibiting Cancer-associated Cytokines.

BACKGROUND/AIM: Cutaneous squamous cell carcinoma (cSCC) is a common non-melanoma skin cancer, and its incidence is increasing. Proteasome subunit alpha type-7 (PSMA7) has been found to be aberrantly expressed in several cancers. However, whether it functions as a tumor suppressor or oncogene in the pathogenesis of cancers, particularly cSCC, remains controversial. Here, we aimed to investigate the functions of PSMA7 in cSCC pathogenesis. PATIENTS AND METHODS: Clinicopathological characteristics were evaluated in 131 patients with cSCC using tissue sections. The expression of PSMA7, nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and mitochondrial antiviral signaling protein (MAVS) was determined in cSCC tissue sections using immunohistochemical staining. The effect of PSMA7 expression on the biological behavior of cSCC cells was investigated in vitro. RESULTS: High immunoreactivity of PSMA7 (high-PSMA7) was detected in 53 (40.5%) patients with cSCC and was significantly associated with histologic grade (p=0.008) and favorable recurrence-free survival (p=0.018). The expression of PSMA7 and NOD1 (p=0.026) and MAVS (p=0.032) was negatively correlated in cSCC tissues. Contrary to the results of the cohort study, cell viability and invasiveness significantly decreased after PSMA7 down-regulation in cSCC cells in vitro. mRNA expression of tumor necrosis factor-alpha, interleukin-1 alpha (IL-1α), IL-6, and IL-8 were significantly increased after PSMA7 down-regulation in cSCC cells (all p=0.002). CONCLUSION: PSMA7-mediated degradation of NOD1 and MAVS as well as the subsequent reduction of the cancer-associated cytokine network may be a crucial mechanism of the antitumoral function of PSMA7 in patients with cSCC.

A nomogram combining clinical factors and biomarkers for predicting the recurrence of high-risk cutaneous squamous cell carcinoma.

BACKGROUND: Although determining the recurrence of cutaneous squamous cell carcinoma (cSCC) is important, currently suggested systems and single biomarkers have limited power for predicting recurrence. OBJECTIVE: In this study, combinations of clinical factors and biomarkers were adapted into a nomogram to construct a powerful risk prediction model. METHODS: The study included 145 cSCC patients treated with Mohs micrographic surgery. Clinical factors were reviewed, and immunohistochemistry was performed using tumor tissue samples. A nomogram was constructed by combining meaningful clinical factors and protein markers. RESULTS: Among the various factors, four clinical factors (tumor size, organ transplantation history, poor differentiation, and invasion into subcutaneous fat) and two biomarkers (Axin2 and p53) were selected and combined into a nomogram. The concordance index (C-index) of the nomogram for predicting recurrence was 0.809, which was higher than that for the American Joint Committee on Cancer (AJCC) 7th, AJCC 8th, Brigham and Women's Hospital, and Breuninger staging systems in the patient data set. CONCLUSION: A nomogram model that included both clinical factors and biomarkers was much more powerful than previous systems for predicting cSCC recurrence.

Risk Factors of Microscopically Tumor-Free Surgical Margins for Recurrence and Survival of Oral Squamous Cell Carcinoma Patients.

Objectives: The concept of adequate surgical margins remains controversial in oral squamous cell carcinoma (OSCC) surgery. This study aimed to identify surgical margin-related indicators that might impact recurrence and survival of OSCC patients. Materials and Methods: Histopathological examination was performed using hematoxylin-eosin-stained surgical margin tissue sections in 235 OSCC patients. Axin2 and Snail expression at the surgical margin was detected by immunohistochemistry. The impact of the Axin2-Snail cascade on tumorigenesis of the immortalized human oral keratinocyte (IHOK) line was investigated in vivo. Results: The width and dysplasia of surgical margins were not significantly associated with the outcome of OSCC patients. In a multivariate analysis using variable clinicopathologic factors and with Axin2 and Snail expression as cofactors, higher age (hazard ratio [HR]:1.050; P=0.047), Axin2 (HR:6.883; P=0.014), and Snail abundance (HR:5.663; P=0.009) had independent impacts on worsened overall survival. Similarly, lesion site in retromolar trigone (HR:4.077; P=0.010), upper (HR:4.332; P=0.005) and lower gingiva (HR:3.545; P=0.012), presence of extranodal extension (HR:9.967; P<0.001), perineural invasion (HR:3.627; P=0.024), and Snail abundance (HR:3.587; P<0.001) had independent impacts on worsened recurrence-free survival. Furthermore, Axin2 knockdown induced decreased Snail expression and attenuated tumorigenesis in the IHOK line. Conclusion: Histopathological examination of surgical margins may not be reliable to predict OSCC patient outcome. Molecular analysis may provide a more accurate risk assessment of surgical margins in OSCC. In particular, Axin2 and Snail are potential predictive biomarkers for the risk assessment of surgical margins in OSCC.

Foreign body aspiration and ingestion in dental clinic: a seven-year retrospective study.

Background: This retrospective study investigated the incidence rate of accidental foreign body aspiration and ingestion according to patient sex, age, and dental department. This study aimed to verify whether the incidence rate is higher in geriatric than in younger patients and whether it is different among dental departments. Methods: Accidental foreign body aspiration and ingestion cases were collected from electronic health records and the safety report system of Yonsei University Dental Hospital from January 2011 to December 2017. The collected data included patients' age, sex, medical conditions, treatment procedures, and foreign objects that were accidentally aspirated or ingested. The incidence rate was calculated as the number of accidental foreign body aspirations and ingestions relative to the total number of patient visits. Differences depending on the patients' sex, age, and dental department were statistically identified. Results: There were 2 aspiration and 37 ingestion cases during the 7-year analysis period. The male to female incidence ratio was 2.8:1. The incidence rate increased with age and increased rapidly among those aged 80 years or older. Seven of the 37 patients with accidental foreign body ingestion had intellectual disability, Lou Gehrig's disease, dystonia, or oral and maxillofacial cancer. The incidence rate was highest in the Predoctoral Student Clinic and the Department of Prosthodontics. The most frequently swallowed objects were fixed dental prostheses and dental implant components. Conclusion: The incidence rate of accidental foreign body aspiration and ingestion differed according to patient sex, age, and dental department. Dental practitioners must identify high-risk patients and apply various methods to prevent accidental foreign body aspiration and ingestion in dental clinics. Inexperienced practitioners should be particularly careful.

Identification of combined biomarkers for predicting the risk of osteoporosis using machine learning.

Osteoporosis is a severe chronic skeletal disorder that affects older individuals, especially postmenopausal women. However, molecular biomarkers for predicting the risk of osteoporosis are not well characterized. The aim of this study was to identify combined biomarkers for predicting the risk of osteoporosis using machine learning methods. We merged three publicly available gene expression datasets (GSE56815, GSE13850, and GSE2208) to obtain expression data for 6354 unique genes in postmenopausal women (45 with high bone mineral density and 45 with low bone mineral density). All machine learning methods were implemented in R, with the GEOquery and limma packages, for dataset download and differentially expressed gene identification, and a nomogram for predicting the risk of osteoporosis was constructed. We detected 378 significant differentially expressed genes using the limma package, representing 15 major biological pathways. The performance of the predictive models based on combined biomarkers (two or three genes) was superior to that of models based on a single gene. The best predictive gene set among two-gene sets included PLA2G2A and WRAP73. The best predictive gene set among three-gene sets included LPN1, PFDN6, and DOHH. Overall, we demonstrated the advantages of using combined versus single biomarkers for predicting the risk of osteoporosis. Further, the predictive nomogram constructed using combined biomarkers could be used by clinicians to identify high-risk individuals and in the design of efficient clinical trials to reduce the incidence of osteoporosis.

A 5-year retrospective cohort study of denosumab induced medication related osteonecrosis of the jaw in osteoporosis patients.

Denosumab has been suggested as a first-line therapy for osteoporotic patients. However, a standardized protocol for the prevention of denosumab induced medication-related osteonecrosis of the jaw (MRONJ) has not yet been established. The purpose of this study was to report denosumab induced MRONJ cases, and investigate the factors affecting the occurrence of MRONJ in patients who underwent denosumab and invasive dental treatment (especially tooth extraction) between October 2016 and March 2020. Four of the 98 patients developed MRONJ before and after tooth extraction. The participants were divided into two groups: receiving only denosumab (n = 51) and receiving bisphosphonate as first treatment and denosumab as second treatment (n = 47). There was no significant difference between groups in the occurrence of MRONJ and factors affecting MRONJ. Two out of 4 patients developed MRONJ regardless of invasive treatment after denosumab administration and proceeded with extraction; one patient developed MRONJ after denosumab administration and extraction. The other patient underwent a tooth extraction without osteoporosis treatment, and non-identified MRONJ developed after denosumab administration. MRONJ cases reported in this study show that MRONJ can develop as chronic inflammation without invasive dental treatment; therefore, implementing preventive dental treatment before initiating denosumab treatment is necessary to reduce the occurrence of MRONJ.

Implication of COPB2 Expression on Cutaneous Squamous Cell Carcinoma Pathogenesis.

The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients.

Dental students' perceptions on a simulated practice using patient-based customised typodonts during the transition from preclinical to clinical education.

PURPOSE/OBJECTIVES: Dental students experience difficulties during the transition from preclinical to clinical curriculum. In order to help the students to adapt to the clinical education programme, a simulated practice using patient-based customised models was introduced in this study to prepare for their first clinical practice. METHODS: This study included 45 third-year predoctoral students (D3 students) who were about to perform the preparation of a single crown abutment on their first patient. After practicing abutment preparation using simulated models and providing the actual treatment to their own patient, the students were surveyed to investigate their perceptions on the simulated practice using the 3D-printed customised typodont model. The statistical analysis of the quantitative data and the thematic analysis of the qualitative data were conducted. RESULTS: Regarding this simulation, more than 80% of the students gave positive feedback on their practice of (a) operative positions and postures, (b) finger rest, (c) occlusal reduction, (d) axial reduction and (e) proximal reduction. Student responses on the open-ended questions about how they perceived the usefulness of this simulation were categorised as "First clinical case," "Patient-based model" and "Realistic simulation environment." In addition, a number of improvements of the simulation were also suggested by the students including the typodont and the manikin. CONCLUSIONS: This study gives insights into the significance of simulated practice using patient-based customised typodonts as a transitional education tool and its direction of development in the field of restorative treatments accompanied by irreversible tooth preparations.

Prediction of Chemosensitivity in Multiple Primary Cancer Patients Using Machine Learning.

BACKGROUND/AIM: Many cancer patients face multiple primary cancers. It is challenging to find an anticancer therapy that covers both cancer types in such patients. In personalized medicine, drug response is predicted using genomic information, which makes it possible to choose the most effective therapy for these cancer patients. The aim of this study was to identify chemosensitive gene sets and compare the predictive accuracy of response of cancer cell lines to drug treatment, based on both the genomic features of cell lines and cancer types. MATERIALS AND METHODS: In this study, we identified a gene set that is sensitive to a specific therapeutic drug, and compared the performance of several predictive models using the identified genes and cancer types through machine learning (ML). To this end, publicly available gene expression datasets and drug sensitivity datasets of gastric and pancreatic cancers were used. Five ML algorithms, including linear discriminant analysis, classification and regression tree, k-nearest neighbors, support vector machine and random forest, were implemented. RESULTS: The predictive accuracy of the cancer type models were 0.729 to 0.763 on the training dataset and 0.731 to 0.765 on the testing dataset. The predictive accuracy of the genomic prediction models was 0.818 to 1.0 on the training dataset and 0.759 to 0.896 on the testing dataset. CONCLUSION: Performance of the specific gene models was much better than those of the cancer type models using the ML methods. Therofore, the most effective therapeutic drug can be chosen based on the expression of specific genes in patients with multiple primary cancers, regardless of cancer types.

Clinical Characteristics and Relevance of Oral Candida Biofilm in Tongue Smears.

Dimorphic Candida exist as commensal yeast carriages or infiltrate hyphae in the oral cavity. Here, we investigated the clinical relevance of Candida hyphae in non-pseudomembranous oral candidiasis (OC) by smears of tongue biofilms. We conducted a retrospective study of 2829 patients who had had tongue smears regardless of OC suspicion. Clinical characteristics were evaluated using a novel method of assessing hyphae. Clinical factors (moderate/severe stimulated pain, pain aggravated by stimulation, tongue dorsum appearance and initial topical antifungal use) were highly significant in the high-grade hyphae group but were statistically similar in the low-grade hyphae and non-observed hyphae group, suggesting low-grade hyphae infection as a subclinical OC state. In addition to erythematous candidiasis (EC), a new subtype named "morphologically normal symptomatic candidiasis" (MNSC) with specific pain patterns and normal tongue morphology was identified. MNSC had a significantly higher proportion of moderate and severe stimulated pain cases than EC. Low unstimulated salivary flow rate (<0.1 mL/min) was found to be a common risk factor in MNSC and EC. In non-pseudomembranous OC, pain patterns were dependent on Candida hyphae degree regardless of tongue dorsum morphology. Morphologic differences seen in high-grade hyphae infection were not associated with systemic diseases or nutritional deficiencies.

AXIN2 and SNAIL expression predict the risk of recurrence in cutaneous squamous cell carcinoma after Mohs micrographic surgery.

Recurrence is a common complication observed during cutaneous squamous cell carcinoma (cSCC) treatment; however, biomarkers for predicting recurrence in cSCC remain unknown. The present study aimed to investigate the predictive value of axis inhibition protein 2 (AXIN2) and SNAIL expression in cSCC recurrence. AXIN2 and SNAIL expression was evaluated using immunohistochemistry in 111 cSCC tissue samples obtained from 18 patients who presented recurrence (recurrence interval, 1-91 months) and 93 patients who did not experience recurrence following Mohs micrographic surgery (MMS) during the follow-up period (156 months). Nomogram construction was performed using patients' clinicopathological characteristics and AXIN2 and SNAIL protein expression. The results demonstrated that high AXIN2 (histoscore >100) and SNAIL (histoscore >100) expression was detected in 35 and 44 cSCC tissues, respectively. Furthermore, the expression levels of AXIN2 and SNAIL were significantly associated in patients with cSCC (P=0.001). AXIN2 and SNAIL expression levels were significantly associated with tumor size (P=0.021 and P=0.044, respectively) and recurrence of cSCC (P=0.017 and P=0.042, respectively). In addition, the results of the Kaplan-Meier curve analysis revealed that recurrence-free survival was significantly associated with tumor size (P=0.025), differentiation status (P<0.001), AXIN2 expression (P=0.001) and SNAIL expression (P=0.001). Furthermore, the results of the multivariate analysis demonstrated that age (P=0.043), AXIN2 expression (P=0.001) and SNAIL expression (P=0.045) were independent risk factors for cSCC recurrence in the present cohort. A nomogram for predicting the 1-, 2-, 3-, and 5-year recurrence-free survival was developed for patients with cSCC by including independent risk factors with a concordance index of 0.75. The results suggested that high AXIN2 and SNAIL expression may be considered as potential risk factors for cSCC recurrence. This nomogram may therefore be useful to assess the probability of recurrence in patients with cSCC following MMS.

Effect of Heat and Sonic Vibration on Penetration of a Flowable Resin Composite Used as a Pit and Fissure Sealant.

OBJECTIVE: To evaluate penetration of a flowable resin composite into fissures using three different application methods: (1) conventional, (2) heat, and (3) sonic vibration. STUDY DESIGN: Forty-five sound maxillary third molars were divided randomly into three groups (n=15 per group). The occlusal surfaces of the teeth were etched and flowable resin composites were applied into the fissure using the assigned application method. The crowns were sectioned and examined with an optical microscope to assess penetration. In addition, three-point flexural strength was analyzed. RESULTS: The sonic vibration group exhibited significantly greater penetration into the fissure compared with the other test groups (p<0.001). The heat group exhibited greater penetration into the fissure compared with the conventional group (p=0.003). However, three-point flexural strength was similar among all groups (p>0.05). CONCLUSIONS: Sonic vibration and heat increased penetration into fissures. Notably, sonic vibration exhibited the greatest penetration. We found that the application method did not influence the three-point flexural strength.

Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer.

Valproic acid (2-propylpentanoic acid, VPA) has been widely used as an anticonvulsant drug and is a choice drug for seizure treatment. VPA is also used as a short-chain fatty acid HDAC inhibitor that affects proliferation and differentiation and induces cell apoptosis in both solid and haematologic malignancies. Here, we observed that VPA treatment inhibited HDAC1/2 activity and induced autophagy in gastric cancer cells, leading to apoptosis. VPA-induced apoptosis occurred through inhibition of the HDAC1/PTEN/Akt signalling pathway and involved alterations in Bcl-2 and Beclin-1. The antitumour effects of VPA were verified in vivo using SGC-7901 xenograft models. Moreover, we evaluated the expression of HDAC1/2 in gastric cancer patient samples and revealed a positive correlation between HDAC1/2 overexpression and poor prognosis. These findings indicate that VPA may serve as a potential therapeutic agent for gastric cancer and that HDAC1/2 might be a promising therapeutic biomarker for the disease.

Paip1 Indicated Poor Prognosis in Cervical Cancer and Promoted Cervical Carcinogenesis.

PURPOSE: This study was aimed to investigate the role of poly(A)-binding protein-interacting protein 1 (Paip1) in cervical carcinogenesis. MATERIALS AND METHODS: The expression of Paip1 in normal cervical epithelial tissues and cervical cancer (CC) tissues were detected by immunohistochemistry. In vivo and in vitro assays were performed to validate effect of Paip1 on CC progression. RESULTS: Paip1 was found to be up-regulated in CC, which was linked with shorter survival. Knockdown of Paip1 inhibited cell growth, induced apoptosis and cell cycle arrest in CC cells, whereas its overexpression reversed these effects. The in vivo tumor model confirmed the pro-tumor role of Paip1 in CC growth. CONCLUSION: Altogether, the investigation demonstrated the clinical significance of Paip1 expression, which prompted that the up-regulated of Paip1 can presumably be a potential prognostic and progression marker for CC.

Ataxia-Telangiectasia-Mutated Protein Expression as a Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands.

PURPOSE: Adenoid cystic carcinoma (ACC) is a high-grade malignant tumor of the salivary glands, clinically characterized by multiple recurrences and late distant metastasis. Biological markers for assessing the prognosis of ACC have remained elusive. The purpose of this study was to investigate whether the protein expressions of ataxia telangiectasia mutated (ATM), p53, and ATM-mediated phosphorylated p53 are related to patient survival in ACC. MATERIALS AND METHODS: In this study, 48 surgical samples were used to assess the expressions of ATM and its downstream target p53. Fisher's exact test and Kaplan-Meier analysis were conducted to evaluate the role of ATM, p53, and phospho-p53 (S15) protein expressions in predicting patient survival and distant metastasis. RESULTS: Myb expression was positive in 85.4% of ACCs, but did not reflect patient survival rate. In contrast, low expression of ATM in cancer cells was significantly correlated with poor survival rate (p=0.037). Moreover, under positive p53 expression, low expression of ATM was highly predictive of poor survival in ACC (p=0.017). CONCLUSION: These data indicate that combined assessment of ATM and p53 expression can serve as a useful prognostic marker for assessing survival rate in patients with ACC of the salivary glands.

Predictive Nomogram for Recurrence of Stage I Colorectal Cancer After Curative Resection.

BACKGROUND: Patients with stage I colorectal cancer (CRC) have excellent prognosis after curative surgery. However, approximately 5% to 10% of patients experience recurrence and have a poor prognosis. Because the incidence of stage I CRC is increasing with active screening programs worldwide, a more accurate and easy-to-use predictive tool for recurrence is becoming more important. This study aimed to develop a predictive nomogram for recurrence in stage I CRC. PATIENTS AND METHODS: A total of 1538 patients who underwent curative surgery for stage I CRC were enrolled. Predictive factors for recurrence were determined by multivariate Cox regression model and were used to develop a predictive nomogram. This model was internally validated, and performance was evaluated through calibration plots. RESULTS: The cumulative recurrence rate at 5 years after surgery for stage I CRC was 5.3%. In multivariate Cox analysis, independent predictors of recurrence were tumor location at rectum, pT2 stage, and presence of lymphovascular invasion. The 5-year recurrence rate was significantly different depending on the number of risk factors (0.7% for 0, 5.8% for 1, and 9.7% for ≥ 2 risk factors). On this basis, a nomogram for recurrence-free survival was developed and internally validated. The concordance index of the nomogram was 0.71, and the performance was acceptable. CONCLUSION: We developed and internally validated a nomogram that can predict postoperative recurrence in stage I CRC patients. This nomogram may be used to more accurately stratify the risk of recurrence and to perform personalized postoperative surveillance in stage I CRC patients.

Identifying a combined biomarker for bisphosphonate-related osteonecrosis of the jaw.

BACKGROUND: For this study, the aim was to identify combined biomarkers associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: Microarray data for GSE7116 were downloaded from the Gene Expression Omnibus database, which contains 26 samples, including without ONJ, and 5 healthy volunteers. The combined biomarkers were identified using principal component analysis, and the pathway enrichment analyses were performed using the DAVID online tool. RESULTS: Two hundred differently expressed genes between groups were detected according to the significances. From functional annotation, Y-box binding protein 1 and heterogeneous nuclear ribonucleoprotein C were found to be included in the most significant 10 pathways. Ten combined gene sets were identified that were effective in classifying multiple myeloma (MM) with ONJ and MM without ONJ. CONCLUSION: Identifying combined gene expression profiles is expected to contribute to more personalized management of BRONJ and to improve existing therapies, and it will be helpful in finding new therapies by identifying more predictive biomarkers.

Snail and Axin2 expression predict the malignant transformation of oral leukoplakia.

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.

Nomogram for risk prediction of malignant transformation in oral leukoplakia patients using combined biomarkers.

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, ß-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.