Previous studies show that X-ray cross-complementing group 1 (XRCC1) Arg194Trp may result in variations in host's repair efficiency of DNA damage, and this repair deficit may eventually cause individual susceptibility to oral cancer. However, published data regarding the association between XRCC1 Arg194Trp polymorphism and oral cancer risk were contradictory. The aim of this study was to derive a more precise estimation of the association of XRCC1 Arg194Trp polymorphism with oral cancer by performing a meta-analysis. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. Finally, a meta-analysis of nine eligible studies including 1,281 cases and 1,966 controls was performed. Overall, there was a significant association between XRCC1 Arg194Trp polymorphism and oral cancer risk (for Trp versus Arg: OR = 1.41, 95 % CI 1.08-1.83, P = 0.01; for TrpTrp versus ArgArg: OR = 1.50, 95 % CI 1.00-2.30, P = 0.05; for TrpTrp/ArgTrp versus ArgArg: OR = 1.49, 95 % CI 1.14-1.94, P = 0.003). After excluding those studies containing patients with oral leukoplakia, there was still an obvious association between XRCC1 Arg194Trp polymorphism and oral cancer risk (for TrpTrp/ArgTrp versus ArgArg: OR = 1.40, 95 % CI 1.14-1.71, P = 0.001). Subgroup analysis by ethnicity suggested that there was an obvious association between XRCC1 Arg194Trp polymorphism and oral cancer risk in Asians under three genetic models. In conclusion, the results from this meta-analysis suggest that XRCC1 Arg194Trp polymorphism is associated with oral cancer risk, especially in Asians.

Caspase 14 is one of the latter discovered members of the caspase enzyme family and, although sharing sequence homologies with the other caspases, it is not involved in apoptosis. Together with its co-factor filaggrin, it plays an important role in skin barrier formation. It is already known that caspase 14 proteins are reduced during neoplastic dedifferentiation in cervical intraepithelial neoplasms and in invasive cervical carcinomas. Oral squamous carcinoma tissues have not been systematically evaluated for caspase 14 expression yet. Formalin-fixed and paraffin-embedded samples from oral squamous carcinomas (n = 36 tumours from 34 patients), metastases (n = 15) and controls (leukoplakia, n = 10) were analysed by immunohistochemistry. In carcinomas, human papilloma virus (HPV) infection was tested by PCR. Here we demonstrate that, in oral epithelia, caspase 14 is expressed mainly by cells of the intermediate and superficial cell layers while filaggrin is expressed only in keratinising foci in leukoplakia. Caspase 14 and filaggrin are co-localised. In invasive oral carcinomas, reduced expression of caspase 14 was detectable in 47 % of tumours but was not associated with keratinisation, tumour differentiation or HPV infection. Filaggrin was detectable in a subfraction of tumours (56 %) and was restricted to keratinising areas of the carcinomas. In summary, in contrast to cervical carcinomas, partial loss of caspase 14 is not associated with dedifferentiation in neoplastic lesions of the oral mucosa or HPV infection.

Abstract

Background:

The detection of oral cancer at an early stage is an optimal strategy and is the most effective approach for preventing further progression. The rationale of the study was to evaluate the epithelial maturation pattern in oral mucosa exposed to tobacco/alcohol and on dysplastic oral mucosa using the scanning electron microscope.

Methods:

Fifteen subjects were selected based on clinical examination and divided into three groups: group 1-patients with apparently normal oral mucosa; group 2-patients with oral mucosa exposed to tobacco/alcohol; group 3-patients with clinical diagnosis of leukoplakia. An incisional biopsy was performed from the buccal mucosa. One part of the specimen was prepared for light microscopy and the other part was prepared for scanning electron microscopy.

Results:

Light microscopy revealed nonkeratinized stratified squamous epithelium in group 1, while group 2 demonstrated hyperparakeratinized stratified squamous epithelium with mild cytological atypia, and group 3 showed architectural and cytological changes. Scanning electron microscopy demonstrated flat-surfaced cells with equidistant parallel microridges in group 1, while group 2 showed irregular and widened microridges with numerous pits and absence of honeycomb pattern. Group 3 showed irregularly arranged broad and swollen cells with numerous pits and irregular microvilli projecting over the surface.

Conclusion:

The present study establishes the relationship of the surface abnormalities to the tendency of the cells to become malignant and thus serves as a tool in early detection of squamous cell carcinoma. It also emphasizes the need of routine follow-up in these high-risk patients for progression of carcinoma.

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention. Cancer Prev Res; 6(5); 410-8. ©2013 AACR.

Chemoprevention, defined as the use of natural, synthetic, or biologic compounds to halt, reverse, or prevent the initial phases of carcinogenesis or the progression of neoplastic cells to cancer, has produced successes, but progress has been slow. Notably, in the field of oral cancer prevention and despite extensive clinical investigations, a standard systemic therapy for patients with oral premalignant lesions is yet to be developed. In view of safety concerns surrounding the use of pharmaceuticals, the use of phytochemicals derived from the diet has been considered but has not yet translated into clinical success. The Bowman Birk Inhibitor (BBI) is a serine protease inhibitor isolated from soybeans possessing domains with trypsin and chymotrypsin inhibitory activity. Encouraging results were previously reported in a phase IIa trial of BBI complex in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. In this issue of the journal, the less promising results of the randomized, placebo-controlled phase IIb trial are presented. In this commentary, the complexities involved in defining optimal biomarkers and endpoints for oral cancer prevention trials and the development of dietary chemoprevention agents are discussed. Cancer Prev Res; 6(5); 375-8. ©2013 AACR.

Armstrong and colleagues report the result of a large Phase IIb randomized trial evaluating the effectiveness of a preparation of the Bowman Birk Inhibitor compared with an oral placebo in reversing the extent of oral leukoplakia as measured visually by pathology or a battery of intermediate end points. In this editorial, we review the report of this negative clinical trials result to highlight the clinical trial process used in evaluating this previously promising chemoprevention agent. Publishing this report is important to address concerns with publication bias. The challenges in running a chemoprevention trial are reviewed with suggestions to enhance progress going forward. Conceptually, developing drugs to intercept the early stages of carcinogenesis is very attractive, but progress in this area has been slow. Two opportunities to overcome this reality are discussed. These measures include the broader use of neoadjuvant, window-of-opportunity trials with new candidate chemoprevention agents to get more textured information about the mechanistic impact of the drug exposure in previously untreated early tumor tissue. In addition, we discuss the use of new intermediate end point markers such as with optical imaging tools to obtain a more objective and quantitative assessment of drug response. Cancer Prev Res; 6(5); 371-4. ©2013 AACR.

Cancer is one of the most common causes of mortality and morbidity today, with more than 10 million new cases and more than 6 million deaths each year worldwide. Globally Oral Cancer is the sixth most common cause of cancer related death. India accounts for 86% of the world's oral cancer cases. Often it proceeds by pre cancerous conditions and lesions. In search for biological markers with diagnostic value, we investigated serum glycoconjugates like protein bound hexoses, fucose and sialic acid in these diseases.For this Study 27 newly diagnosed Oral leukoplakia, 27 OSMF and 26 Oral Cancer patients, 40 healthy controls who are non tobacco users and 40 healthy controls who are tobacco users were selected. In all these groups we estimated serum glycoconjugates.We observed no difference in serum glycoconjugates levels between tobacco and non tobacco controls (P > 0.05), but very high levels in oral cancer, Leukoplakia and oral sub mucous fibrosis (OSMF) patients (P < 0.001) when compared to control groups. Fucose levels were significant (P < 0.05) of all the glycoconjugates between OSMF and Leukoplakia.The serum glycoconjugates whose levels were very high in OSMF, Leukoplakia and Oral Cancer, do have a significant diagnostic and prognostic value in these diseases.

BACKGROUND:

While the protective role of antioxidant nutrients against cancer is well established, data on Asian diets in patients with oral cancer are meagre.

METHODS:

A total of 1029 subjects over 30 years of age were investigated on their dietary practices in the Sabaragamuwa province (Sri Lanka) in 2006-07. Data collection tools were an interviewer-administered questionnaire, a three-day food diary and an examination of the oral cavity. Subjects identified with Oral Potentially Malignant Disorders (OPMD) and disease-free controls were analysed in a case-control fashion. Among the OPMDs, those with leukoplakia were separately considered. A further subgroup analysis was undertaken for β-carotene-rich foods. The analysis was stratified by portions of fruit/vegetables consumed as five or more portions and two or more portions daily.

RESULTS:

A low BMI (<18.5) was a significant independent risk factor for the development of OPMD. More than half of both cases and controls consumed less than two portions of fruit/vegetables per day and only 20 subjects consumed more than five portions per day. Intake of more than two portions per day of β-carotene-containing fruits/vegetables significantly reduced the risk of having an OPMD and leukoplakia (OR = 0.5; 95% CI, 0.3-0.9). The significant differences observed with BMI and fruits/vegetables were attenuated when adjusted for betel quid chewing, smoking and alcohol use.

CONCLUSIONS:

This study discloses prevailing under-nutrition in this rural population with very low daily consumption of fruit/vegetables. Cancer preventive properties in their diets are limited and are swamped by the known carcinogenic agents associated with use of betel quid, tobacco and alcohol.

This study aimed to investigate the clinical efficacy of using broadband white light (BWL) to observe morphologic appearance, narrow-band imaging (NBI) to observe intraepithelial microvasculature, and both BWL and NBI for the detection of high-grade dysplasia and carcinoma in oral leukoplakia. Among 317 patients (274 males and 43 females; aged 52.4±10.7 years), the odds ratio (95% confidence interval) for detecting high-grade dysplasia and carcinomatous lesions based on morphologic appearances of BWL, and microvasculature patterns of NBI, were 39.12 (9.33-64.10), and 97.16 (38.19-247.21), respectively, which were significantly better than BWL (p<1×10(-15)). The sensitivity, specificity, positive and negative predictive values, and accuracy of use of traditional BWL classification, NBI classification, and combined BWL and NBI classification for detecting high-grade dysplasia and carcinomatous lesions were 96.30, 60.08, 33.12, 98.75, 66.25, 39.92, and 3.70%; 87.04, 93.54, 73.44, 97.23, and 92.43%; and 100.00, 60.08, 33.96, 100.00, and 66.88%, respectively. In conclusion, the diagnostic accuracy by NBI classification of oral leukoplakia based on the intraepithelial microvasculature patterns is significantly better than BWL indicating that NBI is a promising non-invasive tool in detecting high-grade dysplasia and carcinomatous lesions in oral leukoplakia.

Survivin is an inhibitor of apoptosis protein that inhibits caspase 3 function. While cytoplasmic survivin suppresses apoptosis, nuclear survivin regulates cell division. Little is known about the subcellular localization of survivin in oral carcinogenesis. This study examined the subcellular distribution of these 2 proteins in oral squamous cell carcinoma (OSCC) and premalignant lesions including oral leukoplakia (OL) with and without dysplasia. Expression of survivin and caspase 3 were immunohistochemically analyzed in 114 samples including OSCC, OL with and without dysplasia, and normal oral mucosa (NM). Cytoplasmic and nuclear positive cells were counted separately. The results were presented as the frequency of positive cases. The positive expression rates of cytoplasmic and nuclear survivin in OSCC were significantly higher than in NM, OL with and without dysplasia. NM showed a low rate of cytoplasmic survivin expression compared to OL with and without dysplasia. The numbers of cytoplasmic and nuclear expression of caspase 3 in OSCC were significantly higher than that of NM, OL with and without dysplasia. In conclusion, the overexpression of cytoplasmic survivin in OSCC and premalignant lesions suggest that suppression of apoptosis by survivin occurs at early and late stages of oral carcinogenesis. The elevated expression of nuclear survivin and caspase 3 in OSCC indicate that at the late stage survivin increases cell proliferation whereas caspase 3 promotes apoptosis.