Survival In Oral Cancer Patients Research Articles

Significance of mild and moderate margin dysplasia in disease free survival of oral cancer patients

Significance of mild and moderate margin dysplasia in disease free survival of oral cancer patients

The negative regulators of Wnt pathway-DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival.

The deregulation of Wnt signaling has recently emerged as one of the drivers of head and neck cancers. This is frequently related to the methylation of several antagonists of this pathway. This study aimed at the assessment of the profile of methylation of Wnt pathway antagonists and the determination of the prognostic value of the methylation of selected genes in oral carcinomas. The methylation of DACH1, DKK1, LKB1, PPP2R2B, RUNX3, SFRP2, and WIF-1 was analyzed in 16 oral squamous cell carcinoma cell lines using the methylation-specific polymerase chain reaction. The methylation of selected genes was further analyzed in tumor sections from 43 primary oral carcinoma patients. The analysis of oral carcinoma cell lines showed very frequent methylation of SFRP2 and WIF-1 and also a less frequent methylation of DACH1 and DKK1. On the other hand, RUNX3 was methylated only in one cell line, while LKB1 and PPP2R2B were not methylated in any of the cell lines. The biallelic methylation of DKK1 correlated with the low level of expression of this gene. Further evaluation of the methylation of DACH1, DKK1, and WIF1 in a clinical patient group confirmed the frequent methylation of WIF1 and intermediate or low frequency of methylation of DACH1 or DKK1, respectively. Importantly, the methylation of WIF-1 correlated with shorter survival in oral cancer patients. Overall, the methylation of the antagonists of Wnt pathway is frequently detected in oral squamous cell carcinomas. The methylation of WIF1 may be considered a prognostic marker in oral cancers.

Disparities between Populations with Oral Cancer in Low and Middle Income and High Income Countries

Cancer affects people worldwide, but there are stark differences in prevalence, survival, etiologic risk factors, and type of cancers between the populations in the developed and less developed regions of the world. These differences affect the treatment outcomes, survival, morbidity, disability and quality of life of Individuals diagnosed with cancer. Recently, there has been a significant thrust in the development of technologies in HIC and transfer of these technologies to LMIC. In order to understand whether the technologies for screening, detection and treatment of cancer are appropriate for a particular population it is essential to evaluate the disease burden, the health care delivery model, and the economic resources of that region. Therefore, we proposed to review the literature to identify the disparities between individuals with oral cancer in High Income Countries (HIC) and Low and Middle Income Countries (LMIC). For this review, we used the United States of America (USA) as our representative HIC, and India as our LMIC. The Gross domestic Product (GDP), Human Development Index (HDI) and literacy rate for the two countries vary significantly. According to the United Nations Human Development Report, USA has a very high HDI and is ranked 3rd, in contrast India is ranked 136th with a medium HDI. The average population literacy rates in the US are 99% in comparison to average literacy rates in 78%. The results of our review showed that, for India, the annual incidence of new cases Lip and Oral Cavity Cancer (C00-08) was 77,003 with Age Standardized Rate (ASR) of 10.1 for males and 4.3 for females and 51,797 individuals diagnosed with oral cancer die each year. In comparison, the incidence of new cases in USA is 26, 000 and mortality is 4620 and 5-year prevalence data are 85,000. The Age standardized rates for males in USA is 7.5/100, 000 and females is 3.2/ 100,000 population. The 5-year prevalence for lip and oral cavity cancer is 118,902 for India in comparison to 85, 000 for USA (GLOBOCAN 2012). Oral cancer was diagnosed in a greater proportion of younger males between the ages of 30-69 years as opposed to 45-65 years in USA. Studies among tobacco users have shown the relative risk of developing oral cancer is 5.1 for Indian males, where as, it is slightly lower at 2.6 for males in the USA. In addition, there are differences in the type of tobacco used smokeless versus smoked tobacco between the populations in two regions. The overall observed survival of oral cancer patients (all stages) in USA is 55% in comparison to Indian patients, which is 30-35%. Lower survival in LMIC is mainly due to advanced stage at diagnosis, low health literacy and lack of awareness and limited access to healthcare. The data strongly suggests that for both HIC and LMIC that rural geographic areas, low health literacy, lack of access to healthcare and low socioeconomic status are risk factors for oral cancer. Our future direction is to propose health technological solutions for screening, and early detection of oral cancer appropriate for the populations in LMIC.

Activation of Toll-like receptor-9 promotes cellular migration via up-regulating MMP-2 expression in oral squamous cell carcinoma.

PurposeActivation of Toll like receptors (TLRs) signaling has been implicated in promoting malignant cell invasion and metastatic potential. Previously we demonstrated that increased TLR-9 expression predicted poor survival in oral cancer patients. The objective of this study is to further investigate the roles and potential molecular mechanisms of TLR-9 signaling in human oral cancer cell invasion.MethodsCell migration, invasion and protein expression were detected by wound healing assay, Transwell chambers model and western blot. The secretion and activity levels of metalloproteinases-2/9 were quantified by ELISA and Gelatin zymography. EMSA and ChIP assays were employed to detect the activity of AP-1signal pathway. TLR-9 siRNA transfection was used to regulate the expression and activity of TLR-9 in oral cancer cell line HB cells.ResultThe results of both wound healing assay and in vitro Transwell assay revealed that activation of TLR-9 induced dose- and time- dependent migration and invasion of HB cells. An increased expression, secretion and activity of MMP-2 were observed upon the treatment of CpG-ODN. The TLR-9 signaling-mediated MMP-2 expression appeared to be a consequence of AP-1 activation, because that their DNA binding activity was enhanced by CpG-ODN treatment. All these influences were efficiently repressed by the knockdown of TLR-9 through siRNA or pretreatment of an AP-1 inhibitor.ConclusionActivation of TLR-9 signaling could promote human oral cancer HB cells invasion with the induction of MMP-2 presentation by attenuating AP-1 binding activity, suggesting a novel anti-metastatic application for TLR-9 targeted therapy in oral cancer in the future.

Association between GSTM1 and CYP1A1 polymorphisms and survival in oral cancer patients

Cancer patient's inherited genotype may influence his or her survival, but evidence for the role of these genetic differences in oral cancer survival has not yet been explored. The authors evaluated polymorphisms in the GSTM1 and CYP1A1 genes for associations with overall survival in 100 oral squamous cell carcinoma (OSCC) treated patients and 100 controls who were followed up for survival within 2 years of the date of completion of their treatment. Overall survival was evaluated in Kaplan-Meier survival functions and Cox proportional hazards models. After adjustment for stage and histology, GSTM1null genotype was associated with shorter survival among OSCC patients, compared with GSTM1 present genotype. There was no association between CYP1A1 C genotype and survival in the overall study population. The study indicated a potential role for GSTM1 polymorphism in predicting the clinical outcomes of treated oral carcinoma patients.

The effect of CCND1 +870A>G and VEGF +936C>T polymorphisms on oral cancer development and disease-free survival in a Taiwan population

The association between polymorphisms in vascular endothelial growth factor (VEGF) +936C>T and cyclin D1 (CCND1) +870A>G genes, oral cancer risk, and disease-free survival remains controversial. We found no association between polymorphisms in the CCND1 and VEGF genes and oral cancer development using multivariate logistic regression analysis. Clinical data indicated that the VEGF +936C>T polymorphisms were associated with larger tumor size and advanced cancer stage, but the χ(2) test did not show that CCND1 polymorphisms were associated with larger tumor size and advanced cancer stage. However, Cox proportional hazards model analysis showed no correlation between the VEGF +936C>T polymorphisms and poor disease-free survival. The CCND1 +870A>G polymorphisms (hazard ratio (HR)=1.62, 95% CI=1.10-2.46; adjusted HR=1.63, 95% CI=1.08-2.54) and larger tumor size were associated with poor 5-year disease-free survival by the log rank test and multivariate Cox proportional hazards model analysis. We hypothesized that polymorphisms in CCND1 +870A>G and VEGF +936C>T genes are not correlated with the development of oral cancer. We found the CCND1 +870G allele to be an independent risk factor for poor 5-year disease-free survival in oral cancer patients. VEGF +936C>T polymorphisms were not directly correlated with poor survival, but they might be associated with increased tumor size, which affected our disease-free survival results.

Abstract 3949: Micro-RNA regulated EGFR expression in head and neck squamous cell carcinoma

Abstract Purpose: Each year in the United States there are more than 65,000 Americans diagnosed with head and neck cancer and 25,000 die from this disease. Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with complex molecular abnormalities, including overexpression of epidermal growth factor receptor (EGFR). The overexpression of EGFR is seen in 80-90% of HNSCC cases and has been shown to be an indicator of poor prognosis and survival in oral cancer patients. The molecular mechanism of EGFR gene expression is poorly understood in HNSCC. MicroRNAs are a new class of posttranslational regulators of gene expression and are a useful target in understanding EGFR gene expression in HNSCC. We hypothesize that microRNAs may play an important role in EGFR gene overexpression during HNSCC processes. Design Methods: We generated stably expressing exogenous miRNA-7 or miRNA-128 in cell lines (JHU-06,-011,-013,-019, -022, and -029 using lentivirus infection, performed colony formation assays to determine cell growth and proliferation, QRT-PCR to analyze gene expression, and Western blot analysis to evaluate protein expression. Results: We found that the miR-7 and -128 transfection efficiency were quite different in these six cell lines. The transfected cell lines stably expressed exogenous miR-7 or -128. Compared with the control cells, the levels of EGFR protein and cell viability were significantly lower in miR-7, -128 transfected HNSCC cell lines. CONCLUSION: We successfully constructed the stably expressing exogenous miR-7, -128 HNSCC cell lines and validated that miR-7,-128 can down-regulate EGFR expression by specifically targeting the EGFR mRNA 3’UTR. MiR-7 and miR-128 have potential to serve as a therapeutic approach to specifically target EGFR in HNSCC. This work was supported in part by grants P20 CA118770 from National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3949. doi:10.1158/1538-7445.AM2011-3949

Value of HIF-1α as an independent prognostic indicator in oral squamous cell carcinoma

Evaluation of: Eckert AW, Schutze A, Lautner MHW, Taubert H, Schubert J, Bilkenroth U. HIF-1α is a prognostic marker in OSCC. Int. J. Biol. Markers 25(2), 87–92 (2010).Oral squamous cell carcinoma is the most common cancer in the oral cavity, accounting for 95% of all malignancies. Predicting prognosis and survival of oral cancer patients has been challenging. To date, there are no molecular markers that can be used reliably in routine clinical practice, other than clinical and histological parameters. Numerous molecules have been tested in order to achieve the above objective. Hypoxia-inducible factor (HIF)-1α is a molecule that is mainly activated under hypoxic conditions. According to the article under evaluation, tumors negatively or weakly expressing HIF-1α had a 5-year disease-specific survival of 80% or more, whereas the disease-specific survival in cases with moderate or strong HIF-1α expression was only 49.4 and 33.6%, respectively. The mean disease-specific survival time was 54 months for patients whose tumors showed negative or weak HIF-1α expression, whereas patients with moderate or strong HIF-1α expression survived on average only 38 months (p = 0.001). HIF-1α may have a role to play in diagnostic and clinical practice to predict prognosis of oral cancer, provided the findings are confirmed by more reliable investigations in addition to immunohistochemistry analysis.

PCNA and anti-apoptotic Mcl-1 proteins predict disease-free survival in oral cancer patients treated with definitive radiotherapy

At our laboratory, we recently observed cell cycle and apoptosis-related proteins Myeloid Cell Leukemia-1 (Mcl-1) and Proliferating Cell Nuclear Antigen (PCNA) to be altered in oral tumours/cell lines. The present study aimed to evaluate the above proteins for predicting response and outcome in oral cancer patients treated with definitive radiotherapy. Pre-treatment oral cancer biopsy samples from 39 patients were examined for Mcl-1 and PCNA proteins using immunohistochemistry and correlated with clinico-pathological variables using disease-free survival (DFS) as the primary endpoint. We observed high expression of Mcl-1 in older versus younger patients (p=0.013) and in tobacco chewers+/-alcohol versus smokers+/-alcohol (p=0.037); and PCNA in node-positive versus node-negative tumours (p=0.037). On univariate analysis, high PCNA (p=0.007), Mcl-1 (p=0.050), node positivity (p=0.040) and co-expression of PCNA and Mcl-1 (p=0.008), had a significant impact on DFS. On multivariate analysis, low PCNA/Mcl-1 (p=0.006) co-expressing tumours were associated with improved DFS. Thus our study suggests that in patients undergoing primary radiotherapy, PCNA could be of potential predictive value to identify patients with risk of nodal metastases and in combination with Mcl-1 may have potential prognostic value to differentiate patients with poor DFS. These markers may be used for future trial patients requiring radiotherapy for their treatment.

Cytoplasmic accumulation of activated leukocyte cell adhesion molecule is a predictor of disease progression and reduced survival in oral cancer patients

Activated leukocyte cell adhesion molecule (ALCAM) has been proposed to function as a cell surface sensor for cell density, controlling the transition between local cell proliferation and tissue invasion in cancer progression. Herein, we determined ALCAM expression in 107 oral squamous cell carcinomas (OSCCs), 78 oral lesions (58 hyperplasias and 20 dysplasias) and 30 histologically normal oral tissues using immunohistochemistry and correlated with clinicopathological parameters. Significant increase in ALCAM immunopositivity was observed from normal oral mucosa, hyperplasia, dysplasia to OSCCs (p(trend) < 0.001). Increased ALCAM expression was observed in cytoplasm of epithelial cells as early as in hyperplasia (p = 0.001, OR = 3.8). Sixty-five of 107 (61%) OSCCs showed significant overexpression of ALCAM protein in cytoplasm/membrane of tumor cells (p = 0.043; OR = 3.3) in comparison with the normal oral tissues. Among OSCCs, cytoplasmic ALCAM was associated with advanced tumor size, tumor stage and tobacco consumption. Importantly, cytoplasmic ALCAM was an independent predictor of poor prognosis of OSCCs in multivariate analysis (p = 0.012, OR = 6.2). In an attempt to understand the molecular basis of cytoplasmic localization of ALCAM, 14-3-3 zeta and 14-3-3 sigma were identified as its novel binding partners in oral cancer cells. In conclusion, increased expression of ALCAM is an early event in oral tumorigenesis; its cytoplasmic accumulation in tumor cells is a predictor of poor prognosis of OSCCs, underscoring its potential as a candidate prognostic marker for oral cancer.

The association of smoking, alcoholic consumption, betel quid chewing and oral cavity cancer: a cohort study

We aimed to analyze the relationship between smoking, alcoholic consumption and betel quid chewing with oral cavity cancer. All male patients age > or =18 years who visited our clinic received an oral mucosal inspection. Basic data including personal habits were also obtained. A multivariate logistic regression model was utilized to determine relevant risk factors for developing oral cavity cancer. A total of 8,356 patients were enrolled in this study. Abnormal findings were found in 382 patients (4.6%). Two hundred and ninety-seven patients received biopsy and 191 patients were proven to have oral cavity cancer. The results of multivariate logistic regression showed that those who smoked, consumed alcohol and chewed betel quid on a regular basis were most likely to contract oral cancer (odds ratio: 39.66, 95% confidence interval: 26.04-60.38). Therefore, habitual cigarette smokers, alcohol consumers, and betel quid chewers have a higher risk of contracting oral cavity cancer and should receive oral mucosal screening regularly so potential oral cavity cancer can be detected as early as possible, which may result in better and improved survival of oral cancer patients.

Lipid Peroxidation, Total Antioxidant Status, and Total Thiol Levels Predict Overall Survival in Patients With Oral Squamous Cell Carcinoma

Tobacco is the major etiological factor for oral cancer development through the generation of oxidative stress. Therefore, markers of oxidative stress such as total antioxidant status, lipid peroxidation, and total thiol levels might be useful to monitor oxidative stress and predict overall survival in oral cancer patients. The study included 140 oral cancer patients and 50 healthy controls, who were classified as with the habit of tobacco and no habit of tobacco. Adjacent normal and malignant tissue samples were collected from oral cancer patients. Plasma and tissue levels of lipid peroxidation, thiol, and total antioxidant status were assayed by spectrophotometric methods. Thiol levels were significantly lower in controls with the habit of tobacco (P= .033), oral cancer patients (P= .0001), and malignant tissues (P= .015) as compared to controls with no habit of tobacco, controls with the habit of tobacco, and adjacent normal tissues, respectively. Tobacco exposure was higher in oral cancer patients than controls with the habit of tobacco. Controls with the habit of tobacco who had lower thiol (odds ratio [OR]=10.58, P= .008) and high tobacco exposure (OR=0.251, P= .05) showed an elevated risk of oral cancer development. Patients showing a lipid peroxidation level above the cutoff level as compared to patients below the cutoff level showed poor overall survival, whereas those with thiol and total antioxidant status levels below the cutoff level as compared to their respective counterparts showed poor overall survival. In conclusion, lipid peroxidation and thiol could be useful for predicting the risk of oral carcinogenesis in healthy tobacco consumers and predicting overall survival of oral cancer patients.

Nuclear fractal dimension as a prognostic factor in oral squamous cell carcinoma

Strong theoretical reasons exist for using fractal geometry in measurements of natural objects, including most objects studied in pathology. Indeed, fractal dimension provides a more precise and theoretically more appropriate approximation of their structure properties and especially their shape complexity. The aim of our study was to evaluate the nuclear fractal dimension (FD) in tissue specimens from patients with oral cavity carcinomas in order to assess its potential value as prognostic factor. Relationships between FD and other factors including clinicopathologic characteristics were also investigated. Histological sections from 48 oral squamous cell carcinomas as well as from 17 non-malignant mucosa specimens were stained with Hematoxylin-Eosin for pathological examination and with Feulgen for nuclear complexity evaluation. The sections were evaluated by image analysis using fractal analysis software to quantify nuclear FD by the box-counting method. Carcinomas presented higher mean values of FD compared to normal mucosa. Well differentiated neoplasms had lower FD values than poorly differentiated ones. FD was significantly correlated with the nuclear size. Patients with FD lower than the median value of the sample had statistically significant higher survival rates. Within the sample of patients studied, FD was proved to be an independent prognostic factor of survival in oral cancer patients. In addition this study provides evidence that there are several statistically significant correlations between FD and other morphometric characteristics or clinicopathologic factors in oral squamous cell carcinomas.

Impact of recurrence interval on survival of oral cavity squamous cell carcinoma patients after local relapse

The aim of this study was to investigate whether the recurrence interval influenced the survival of oral cavity squamous cell carcinoma patients after relapse. Retrospective charts were reviewed at a medical center. We retrospectively reviewed 1687 chart records of oral cancer patients. Statistical methods included descriptive statistics, bivariate analyses, Kaplan-Meier survival analyses, and Cox proportional hazard models for investigating the relationship between the recurrence interval and survival of oral cancer patients after relapse. Local recurrence rate was 31.3 percent. Kaplan-Meier survival analyses showed the 5-year overall survival after recurrence was 31.56 percent. Cox proportional hazard model revealed that those with recurrence interval less than 18 months tended to have a higher probability of death than those with recurrence interval greater than or equal to 18 months (relative risk, 1.743; 95% confidence interval, 1.298-2.358). The interval from initial treatment to recurrence is an independent prognostic factor for oral squamous cell carcinoma patients. Those with a shorter disease-free interval tend to have a less favorable outcome.

Socio-demographic factors in the prognosis of oral cancer patients

The aim of this study was to determine the survival rate of oral cancer patients treated in a medical center in central Taiwan and to investigate whether socio-demographic factors influence their survival. We retrospectively reviewed 1010 chart records of oral cancer patients. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model was used for investigating the relationship between socio-demographic factors and survival. The overall 5-year survival rate was 63.24%. Multivariate analysis revealed that those without religious belief tended to have higher probability of death than those who had religious belief (relative risk (RR): 2.057, p<0.001). In addition, those who were single, widow/widower or divorced/separated had a poorer prognosis than those who were married (RR: 1.528, p=0.008). Apart from clinical features, socio-demographic factors also significantly influenced the survival of oral cancer patients. Therefore, care providers should take socio-demographic issues into consideration aside from ordinary clinical health care.

Identification of differentially expressed genes in oral squamous cell carcinoma

Rapid advances in multimodality therapy have not significantly improved the overall 5-yr survival of oral cancer patients in the past two decades, thereby underscoring the need for molecular therapeutics. The development of new treatment strategies for more effective management of oral cancer requires identification of novel biological targets. Therefore, the aim of this study was to identify novel genes associated with oral tumorigenesis by comparing gene expression profile of oral squamous cell carcinomas (OSCCs) and matched nonmalignant oral epithelial tissues with differential display. Of the 180 differentially expressed cDNAs isolated, reamplified, and cloned into pGEMT-Easy Vector, 26 cDNAs were confirmed to be upregulated in OSCCs by reverse Northern blot analysis. The differentially expressed genes included components of immune system, signaling pathways, angiogenesis, cell structure, proliferation, apoptosis, cell-adhesion, and cellular metabolism. Reverse transcription (RT)-polymerase chain reaction (PCR) analysis of 15 OSCCs and matched nonmalignant oral tissues provided the first evidence that 14-3-3-zeta, melanoma metastasizing clone D (MEMD), KIAA0471, sperm protein 17 (SP17), TC21, and anti-TNF alpha antibody are upregulated in OSCCs. Immunohistochemical analysis confirmed overexpression of 14-3-3-zeta and TC21 protein, a member of the Ras family, in OSCCs as compared to histologically normal oral tissues validating the differential display analysis. Identification of six novel differentially expressed genes in oral tumors adds to the repertoire of genes associated with oral carcinogenesis and provides candidate potential biological targets for diagnosis and/or therapy. Further characterization of the 14 unknown differentially expressed cDNAs identified in this study may provide significant clues for understanding the molecular mechanisms underlying oral tumorigenesis.

Survival from oral cancer in Mumbai (Bombay), India.

Cancer survival information is available for only few populations in developing countries. Data on survival of oral cancer patients registered by the Bombay population-based cancer registry, India, during 1992-1994 is presented in this paper. Vital status of the patients was established by matching against death certificates, reply paid postal enquiries, telephone enquiries, scrutiny of hospital records and house visits. Of the 1808 eligible cases for analysis, 1204 (66.6%) were dead; and 604 (33.4%) were alive at last follow-up, of whom 136 were lost to follow-up during the first 5-years after diagnosis. Observed and relative survival rates are presented and hazard ratios and corresponding 95% confidence intervals were estimated using Cox proportional hazard model. The overall 5-year observed and relative survival rates were 30.5% and 39.7%, respectively. Survival steadily declined with advancing age and advanced clinical stages. Five-year observed survival was 59.1% for localised cancer, 15.7% for cancers with regional extension and 1.6% for those with distant metastasis. Those with tongue, buccal mucosa and retromolar trigone cancers had poor survival rates. Our study shows that detecting oral cancer in early stages, when these are amenable to single modality therapies, offers the best chance of long-term survival. However, primary prevention by tobacco/alcohol control measures is important in the long-term perspective.