The expression of transglutaminase 2 (TG-2) in oral squamous cell carcinoma and its clinical significance.

BACKGROUND: Glutamine has a very important role in the human body, including pH balance in an acidic environment, as well as supporting the TCA cycle in cancer cell growth. However, the expression of transglutaminase-2 (TG-2) in oral cancer growth related to renal function is unknown. Here we examined TG-2 and its expression as a prognostic tool. METHODS: Fifty-six oral squamous cell carcinoma (OSCC) tissues were collected with the inclusion of tumor in any region of oral area, and patients with creatinine (Cr) and blood urea nitrogen (BUN) results. The tissues were stained using immunohistochemistry (IHC) with a TG-2 antibody [N3C3], then observed under the microscope. The staining were calculated using Adobe Photoshop CS software and statistical analyses using SPSS ver. 21. RESULTS: We found that TG-2 expression showed a significant difference in the expression levels between tumor and the adjacent groups without disease-free survival, disease-specific survival, and recurrence between, with p < 0.05. The average staining intensity with 25th percentile of TG-2 becomes a vital score for the diagnosis. Furthermore, our study demonstrates a good prognosis outcome if the intensity score showed a difference in TG-2 expression between the adjacent and tumor tissue. CONCLUSION: To our knowledge, this is the first clinical study on TG-2 expression in OSCC, and it demonstrates that TG-2 can serve as a predictor of tumorigenesis and prognosis outcome.

Use of panoramic radiography to predict postsurgical sensory impairment following extraction of impacted mandibular third molars.

BACKGROUND: The purpose of this study was to use panoramic radiographic findings to predict postsurgical sensory impairment following the extraction of impacted mandibular third molars. METHODS: There were 120 patients enrolled in this study (55 male and 65 female). A total of 120 impacted mandibular third molars were included due to the proximity between the inferior alveolar nerve (IAN) canal and the roots of the impacted third molar on the panoramic radiograph. Seven radiographic signs were the predictor variables: (1) darkening of the root(s); (2) interruption of the radiopaque line of the inferior alveolar canal; (3) diversion of the inferior alveolar canal; (4) dark and bifid apex; (5) deflection of the root(s); (6) narrowing of the inferior alveolar canal; and (7) narrowing of the root(s). The outcome variable was the postoperative IAN sensory impairment. The retrospective cohort study model was used, and univariable and bivariable statistics was computed with the statistically significant level at p ≤ 0.05. RESULTS: Three of the radiographic signs were statistically associated with IAN sensory impairment (p<0.05). They include: (1) interruption of the radiopaque line [sensitivity = 0.92, specificity = 0.45, positive predictive value (PPV) = 0.17, negative predictive value (NPV) = 0.02]; (2) diversion of the IAN canal (sensitivity = 0.77, specificity = 0.84, PPV = 0.37, NPV = 0.03); and (3) narrowing of the IAN canal (sensitivity = 0.69, specificity = 0.65, PPV = 0.19, NPV = 0.05). However, the other four radiographic signs, namely darkening of the root(s), dark and bifid apex, deflection of the root(s), and narrowing of the root(s), were not statistically associated with IAN sensory impairment (p>0.05). CONCLUSION: There are three radiographic signs: (1) interruption of the radiopaque line; (2) diversion of the IAN canal; and (3) narrowing of the IAN canal. These signs are valuable in presurgical evaluation of the risk of postoperative sensory impairment after surgical removal of impacted mandibular third molar.

Lateral trap-door window approach with maxillary sinus membrane lifting for dental implant placement in atrophied edentulous alveolar ridge.

One of the most challenging and technically sensitive surgical procedures in conjunction with dental implant rehabilitation is sinus membrane lifting to increase the bone height or volume from the maxillary sinus floor. This important preprosthetic surgical technique has been available for >15 years, making possible the creation of bone volume in the edentulous posterior maxilla for the placement of dental implants in surgically compromised cases. Substantial literature exists regarding the most efficacious way to increase the predictability of this surgical procedure, and reduce its associated complications. In this article, we describe the regional anatomy of the maxillary sinus, the evolution of the sinus membrane lifting procedure, the current surgical technique, its survival rate and associated complications, the need for bone graft or bone substitutes, and current advances in the lateral approach through a trap-door window for sinus membrane lifting for dental implants.

miR-196a overexpression and miR-196a2 gene polymorphism are prognostic predictors of oral carcinomas.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is prevalent worldwide, and survival in OSCC has not improved significantly in the last few decades. MicroRNAs have an important regulatory role in oral carcinogenesis. This study investigated the prognostic implications of miR-196 expression and the rs11614913 genotype of the miR-196a2 gene in OSCC. METHODS: The clinicopathologic implications of miR-196 in OSCC were investigated using expression assays and genotyping, and the functional role of miR-196 in OSCC pathogenesis was investigated using exogenous expression and knockdown. RESULTS: miR-196 was up-regulated in OSCC tissue relative to control mucosa. High expression of miR-196a, but not miR-196b, was associated with tumor recurrence, nodal metastasis, and mortality. Plasma miR-196a levels could be used to distinguish patients from controls with a separating power of 0.75. Multivariate analysis showed that both high miR-196a expression and TT genotype were independent predictors for poor survival in OSCC. The risk of mortality was greatest for patients with high miR-196a level and positive node status. Expression of miR-196 enhanced oncogenesis of OSCC cells, while inhibition of miR-196 expression attenuated such effects. CONCLUSIONS: High miR-196a expression in tumor tissue and the presence of the TT variant of miR-196a2 gene indicate worse survival in OSCC.

Predictors and impact of microsurgical complications in patients with locally advanced oral squamous cell carcinoma.

Microvascular free flap transfer for post-oncologic reconstructive surgery in oral cancer is considered to be a challenge due to the complexity of the anatomy and function of the region. We sought to identify possible factors associated with microsurgical complications and to assess the impact of these complications in relation to patient survival. Following the inclusion and exclusion protocol, 142 patients with stage III and IV oral squamous cell carcinoma (OSCC) who underwent immediate free flap reconstruction after tumor ablation were included in the study. Clinical and surgical procedural-related factors were retrieved from a database and analyzed retrospectively; survival data were evaluated using the Kaplan-Meier method. Major complications that required re-anastomosis of the flap vessels occurred in 23 patients (16.2%); total necrosis of the flaps, regardless of salvage treatment, occurred in seven cases, with 95.1% of full flap survival. The American Society of Anesthesiologists classification, types of neck dissection, and number of flaps were regarded as strong predictors for surgical complications. Patients with these complications appeared to have a shortened survival (5-year cancer-specific survival of approximately 60%, both in stage III and IV OSCC). However, the impact of surgical complications on survival was significant only in stage III OSCC (P = 0.037). Strategies to minimize surgical complications should be used to ensure better prognoses for these patients.

Impact of diabetes mellitus on the prognosis of patients with oral squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: Diabetes mellitus (DM) is a prevalent chronic metabolic disease reported to affect the treatment outcomes of malignancies. This study explores the impact of diabetes on the prognosis of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Clinicopathological characteristics and survival in terms of overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) of patients with OSCC who underwent surgical intervention at the Taipei Veterans General Hospital between 2002 and 2005 were stratified by diabetic status and compared. RESULTS: Patients with DM tend to have a lower OS, RFS, and CSS compared with nondiabetics (adjusted hazard ratio [HR] = 2.22, 2.42, and 2.16, respectively) even in less aggressive tumor stages (stage I and II). In advanced tumors, diabetic patients who were not prescribed adjuvant therapy had a significantly higher recurrence rate than nondiabetic patients (HR = 2.66). However, there was no significant difference in treatment outcome in patients with locally advanced tumors amenable to receive adjuvant therapy, even with the delayed initiation of adjuvant therapy in the DM group (49.1 +/- 22.3 days vs. 40.0 +/- 16.6 days, P = .04). DM was also associated with a higher frequency of perineural invasion (adjusted odds ratio [OR] = 2.53). CONCLUSION: DM status could be a prognostic factor for OSCC, particularly for its effect in the survival and perineural invasion. Although diabetes-associated comorbidities may impair decision making toward less aggressive therapeutic modality, adjuvant treatment may be essential for DM patients to improve their survival.

Functional -1562 C-to-T polymorphism in matrix metalloproteinase-9 (MMP-9) promoter is associated with the risk for oral squamous cell carcinoma in younger male areca users.

BACKGROUND: Circulating matrix metalloproteinase-9 (MMP-9) is a prognostic factor for gastric cancer and vascular diseases, and has been associated with head and neck cancers. The -1562 C-to-T polymorphism in MMP-9 promoter (abbreviated MMP-9 -1562 C>T polymorphism) leads to differential transcription, and is associated with increased susceptibility to neoplastic and vascular diseases. Thus, our aim was to determine whether a functional MMP-9 polymorphism might also influence the risk or affect the progression of areca-associated oral cancers. METHODS: Genomic DNAs were obtained from peripheral blood cells of male subjects with areca-associated oral squamous cell carcinoma (OSCC) (n = 192), oral submucosal fibrosis (OSF) (n = 73), and non-diseased areca users (n = 191). The PCR-based restriction fragment length polymorphism analysis was performed for MMP-9 genotyping. RESULTS: MMP-9 -1562 C>T polymorphism was not associated with the risk of OSCC or OSF. However, when subjects were stratified by the median age, an association with the risk of OSCC was found in younger patients (P = 0.029). The T allele frequency was significantly higher in the subset of older patients with buccal mucosa OSCC than older patients with OSCC in counterpart locations. The joint MMP-9 -1562 C>T and MMP-3 -1171 5A>6A functional polymorphisms were not associated with OSCC risk or patient survival. CONCLUSION: Aberrant MMP-9 expression is closely related to tumor invasiveness and the prognosis of head and neck cancers. However, functional MMP-9 -1562 C>T polymorphism is associated with OSCC risk only in younger areca chewers. The impact of aging or areca-related effect on this functional polymorphism should be elucidated.

MICA and MICB overexpression in oral squamous cell carcinoma.

BACKGROUND: The concentration of MICA in serum seems be a good candidate marker in cancer. Previous studies from our laboratory have shown that the polymorphic MIC gene may confer a risk for oral squamous cell carcinoma (OSCC). The study investigated the expression levels of MICA and MICB of OSCC patients and cancer cell lines. MATERIAL AND METHODS: We used RT-PCR to analyze the mRNA expression of MICA and MICB in four oral cancer cell lines compared with three normal human oral keratinocyte (NHOK) cell lines and in tissues from 36 patients with OSCC comparing tumor tissue with non-cancerous matched tissue (NCMT). RESULTS: Endogenous MICB mRNA expression in OSCC cell lines was significantly higher than that in NHOK (1.40 +/- 0.27 vs. 0.40 +/- 0.16; P = 0.04). In 20 of 36 sets of tissue from patients with OSCC, MICB mRNA expression was higher in the cancerous tissue than in the NCMT. The mean MICB mRNA expression in OSCC tissues was significantly higher than in NCMT (0.39 +/- 0.08 vs. 0.14 +/- 0.03, P = 0.009, paired t-test). A significantly lower MICA mRNA was found in patients who chewed areca nut compared with those who did not use areca (P = 0.001) and in patients with well-differentiated tumors compared with those with less well-differentiated tumors (P = 0.02). CONCLUSION: MICA and MICB mRNA expression may be increased in OSCC but there appears to be individual variation.

Use of methylene blue as a diagnostic aid in early detection of oral cancer and precancerous lesions.

We assessed the sensitivity, specificity, and positive and negative predictive value of methylene blue staining in the diagnosis of oral cancer in 58 patients. The sensitivity was 90%, the specificity 69%, positive predictive value 74%, and negative predictive value 87%. Because of the number of false negatives and false positives we recommend that the diagnosis should always be confirmed by histopathological examination of a biopsy specimen. Methylene blue staining may, however, be useful as a screening tool for oral cancer in large, high-risk groups in a similar way to the more expensive toluidine blue.

Functional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewers.

Areca (betel)-chewing is tightly associated with the high prevalence of oral squamous cell carcinoma (OSCC) in Asians. NFKB1 encodes a 105kDa protein that can be processed to produce p50 subunit of nuclear factor-kappaB protein complex. A insertion (ins)/deletion (del) polymorphism (-94ins/delATTG) in NFKB1 promoter, which may drive the ins allele two-fold increase in NFKB1 transcription relative to del allele, was recently found. This study identified that the odds ratio in OSCC carrying ins allelotype were 1.78 relative to controls (56.7 vs 41.8%) in subjects more than 50 years old. L allelotype of Heme oxygenase-1 (HO-1), accounting for a long (GT)(n) repeat in HO-1 promoter, is associated with the risks of areca-related OSCC. Subjects carried both NFKB1 ins and HO-1 L allelotypes had significant risks for various subsets of OSCC. OSCC with lymph node metastasis or advanced stage had significantly higher frequency of NFKB1 ins and HO-1 L allelotypes. This study suggested that the functional NFKB1promoter polymorphism could be valuable for assessment of cancer risk.

A method using vestibulo-sulcoplasty combining a split-thickness skin graft and a palatal keratinized mucosa graft for peri-implant tissue secondary to oral cancer surgery.

Twelve patients presented with oral submucosal fibrosis and loss of keratinized gingiva in a compromised vestibule of a severely deficient mandibular edentulous ridge secondary to oral cancer surgery. They received implant rehabilitation with a total of 49 fixtures without major bone graft augmentation. To overcome vestibular compromise, soft tissue management consisting of simultaneous vestibulo-sulcoplasty, split-thickness skin graft (STSG), and palatal keratinized mucosa graft (KMG) was performed as a second stage when healing abutment was transferred to replace the cover screw of the dental implant. Postoperative follow-up of all patients consisted of clinical and radiographic examinations for an average of 4 years, revealing good stability of implant fixtures with a 91.8% success rate and generally healthy peri-implant tissue, the latter with an average sulcus depth of 2.9 +/- 0.6 mm. Satisfactory results were also demonstrated regarding improved morphology of the vestibule, cosmetics, and prosthetic functionality. Vestibulo-sulcoplasty combining STSG and palatal KMG offers a stable and convenient method for rebuilding peri-implant tissue without need for bone grafting in selected patients who have compromised atrophic ridges secondary to cancer surgery.

Association of GST genotypes with age of onset and lymph node metastasis in oral squamous cell carcinoma.

BACKGROUND: Environment-gene interaction in oral carcinogenesis is well demonstrated by phase I and II enzymes that are involved in the metabolism of carcinogens. This study investigated the association of glutathione S-transferase (GST)T1 and GSTM1 genotypes of phase II enzyme genes with risk for, age of onset, and neck lymph node metastasis (LNM) in areca-associated oral squamous cell carcinoma (OSCC). METHODS: A total of 114 OSCC male patients and 100 male controls were recruited. All subjects were areca users and tobacco smokers. DNA was obtained from peripheral blood samples. Genotyping of GSTT1 (non-null/null) and GSTM1 (non-null/null) was determined by polymerase chain reaction (PCR) analysis using specific primers that only amplify non-null alleles. RESULTS: No association was found between GST genotype and the risk of OSCC based on case-controls. Patients with the GSTT1 null genotype were older at onset (P = 0.03). Those with the GSTM1 null genotype had a higher incidence of neck LNM than those with the GSTM1 non-null genotype (P = 0.01). Patients with the GSTM1/GSTT1 null genotype appeared to have later onset and a higher incidence of neck LNM than those carrying the opposite genotype. CONCLUSION: The GST genotypes may be important markers for the age of onset and risk of metastasis in OSCC. The data also suggest that the various GST isoforms may be differentially involved in development or progression of OSCC.

Rehabilitation of dental implants for the post-irradiated and marginally resected mandible in an oral cancer patient.

We describe a case with severely compromised edentulous ridge in the mandible, which previously received marginal resection and radiotherapy due to oral cancer at the mouth floor. Through careful evaluation, the patient had 30 dives of hyperbaric oxygen therapy (HBO) before implant surgery. The edentulous ridge was rehabilitated with 4 endosteal implant fixtures, and palatal mucosa grafting vestibulosulcoplasty. The case had been followed for 4 years with stability of bone and a satisfactory result of rehabilitation.