Carcinogenicity of smokeless tobacco: Evidence from studies in humans & experimental animals.

A Working Group of the Monographs programme of the International Agency for Research on Cancer has classified smokeless tobacco as carcinogenic to humans (Group 1). This review article summarizes the data that support the evaluations of sufficient evidence in humans and in experimental animals for the carcinogenicity of smokeless tobacco whether used alone or with betel quid. It also identifies compounds of smokeless tobacco relevant to carcinogenicity (prominently tobacco-specific nitrosamines) and addiction (nicotine). The epidemiological evidence is summarized for oral cancer, other cancers associated with smokeless tobacco and oral potentially malignant lesions with a focus on analytical studies from the SEARO Region. Studies on cancer in experimental animals are summarized with a focus on studies applying smokeless tobacco products typical for the regions, such as mishri and naswar.

Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers.

Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer.

Combined Genetic Biomarkers and Betel Quid Chewing for Identifying High-Risk Group for Oral Cancer Occurrence.

We integrated genetic risk scores (GRS) and environmental factors for identifying high-risk subjects for oral squamous cell carcinoma (OSCC) occurrence by using case-control study. A total of 447 patients diagnosed with OSCC and 580 unrelated subjects were recruited from two medical centers in Taiwan. A multinomial logistic regression model was conducted to access interaction between GRS and betel quid (BQ) chewing. We employed ROC curve to compare the accuracy of OSCC occurrence. Four tag SNPs were found in NOTCH1, BRCA1, COL9A1, and HSPA13 genes that were significantly associated with OSCC occurrence. GRS was calculated by the four tag SNP risk alleles. The higher GRS (scores = 4) remained independently associated with risk of OSCC after adjustment for age, the use of alcohol, BQ, and cigarette: adjusted OR = 4.42 [95% confidence interval (95% CI), 1.34-14.55]. The GRS and BQ chewing interaction showed an increased risk for OSCC occurrence with adjusting for other substance use and age (OR = 70.77; 95% CI, 8.70-575.73). The synergy index was 16.58 (95% CI, 2.27-70.56), suggesting a positive additive interaction between GRS and BQ chewing. The areas under the ROC curves (AUROC) were 0.91 for combined GRS and BQ chewing with sensitivity of 88.6% and specificity of 86.7%. The AUROC of GRS and BQ chewing is above 90%, which may be valuable in identifying high-risk subjects. Early screening can allow the clinician to provide the appropriate intervention and to reduce the OSCC occurrence. Cancer Prev Res; 10(6); 355-62. ©2017 AACR.

Adverse Health Effects of Betel Quid and the Risk of Oral and Pharyngeal Cancers.

Global reports estimate 600 million betel quid (BQ) chewers. BQ chewing has been demonstrated not only to be a risk factor for cancers of the oral cavity and pharynx and oral potentially malignant disorders (OPMD) but also to cause other cancers and adverse health effects. Herein, we summarized the international comparison data to aid in the understanding of the close relationship between the prevalence of BQ chewing, the occurrence of oral and pharyngeal cancers, and adverse health effects. Potential biomarkers of BQ carcinogens, such as areca nut, alkaloids, and 3-methylnitrosaminopropionitrile (MNPN), are closely associated with human health toxicology. Molecular mechanisms or pathways involving autophagy, hypoxia, COX-2, NF-κB activity, and stemness are known to be induced by BQ ingredients and are very closely related to the carcinogenesis of cancers of oral and pharynx. BQ abuse-related monoamine oxidase (MAO) gene was associated with the occurrence and progress of oral and pharyngeal cancers. In summary, our review article provides important insights into the potential roles of environmental BQ (specific alkaloid biomarkers and nitrosamine products MNPN) and genetic factors (MAO) and offers a basis for studies aiming to reduce or eliminate BQ-related OPMD and oral/pharyngeal cancer incidences in the future.

A Comprehensive Analysis on the Association between Tobacco-Free Betel Quid and Risk of Head and Neck Cancer in Taiwanese Men.

OBJECTIVES: Although betel quid (BQ) is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature regarding the dose-response, BQ types, HNC sites, and BQ cessation. The current study was conducted to fill these insufficiencies. MATERIALS AND METHODS: A hospital-based case-control study was conducted to evaluate the association between BQ and HNC. In-person interview was conducted to collect data on BQ chewing. The current analysis included 487 men newly diagnosed with HNC and 617 male controls who were frequency-matched to the cases by age. The association between BQ and HNC was assessed using multivariable unconditional logistic regression. RESULTS: Ever BQ chewing was associated with an increased HNC risk regardless of the BQ types. A non-linear positive association between BQ and HNC was observed, with a steep rise in HNC risk for the first 5 pack-years or 200,000 minutes of BQ consumption. Every year of BQ cessation was associated with a 2.9% reduction in HNC risk; however, the risk did not reduce to the level of non-BQ chewers even after 20 years of BQ cessation. Eliminating BQ chewing may prevent 51.6% of HNCs, 62.6% of oral cancers, and 41.3% of pharyngeal cancers in Taiwan. CONCLUSION: Our results supported the positive association between BQ and HNC. BQ cessation is effective in reducing HNC risk and should be encouraged. Because BQ cessation may not reduce the HNC risk to the level of non-BQ chewers, it is important to prevent the initiation of BQ chewing.

[Betel - the fourth most popular substance in the world]. / Betel - czwarta najpopularniejsza uzywka na swiecie.

Betel is a kind of substance for chewing, that is made from piper betle, areca nuts and other, additional constituents. It is the fourth most popular psychoactive substance in the world, right after caffeine, nicotine and alcohol. It is particularly famous in Asia. Betel chewing induces euphoria and it is addictive. Similarly like in other substances such as nicotine or alcohol, betel also has detrimental effects. It causes e.g. oral cancer and cancer of the oesophagus, it contributes to the development of metabolic syndrome, liver cirrhosis and chronic kidney disease. There are also positive effects of chewing betel, because is has antioxidant, anti-inflammatory, antyparasitic and antiseptic properties. The aim of this paper was to expand knowledge about betel and its both: positive and negative influence on human health. In this article original and review papers associated with the topic were used.

Betel nut chewing and its deleterious effects on oral cavity.

The habit of chewing betel nut has a long history of use. Betel nut and products derived from it are widely used as a masticatory product among various communities and in several countries across the world. Over a long period, several additives have been added to a simple betel nut preparation; thus, creating the betel quid (BQ) and encompassing chewing tobacco in the preparation. Betel nut has deleterious effects on oral soft tissues. Its effects on dental caries and periodontal diseases, two major oral diseases are less well-documented. Betel-induced lichenoid lesions mainly on buccal mucosa have been reported at quid retained sites. In chronic chewers, a condition called betel chewers mucosa is often found where the quid is placed. Betel nut chewing is implicated in oral submucous fibrosis (OSF) and its use along with tobacco can cause leukoplakia, both of which are potentially malignant in the oral cavity. Oral cancer often arises from such precancerous changes. Thus, public health measures to quit betel use are recommended to control disabling conditions such as OSF and oral cancer.

Cross-sectional and longitudinal associations of lifestyle factors with depressive symptoms in ≥ 53-year old Taiwanese - results of an 8-year cohort study.

OBJECTIVE: The objective of this study is to determine the concurrent and longitudinal associations of lifestyle factors including smoking, alcohol drinking, betel quid chewing, tea (Camellia sinensis) drinking and physical activity with depressive symptoms in older Taiwanese. METHODS: The study analyzed Taiwan Longitudinal Study on Aging (TLSA) datasets to determine the association of lifestyle variables with concurrent depressive symptoms in 4122 ≥ 50-year-old Taiwanese at baseline (1999) and with the new development of depressive symptoms 8 years later. RESULTS: Heavy/problem alcohol drinking increased the association with concurrent depressive symptoms (OR=1.85, 95%CI=1.02-3.36); frequent tea drinking (OR=0.63, 95%CI=0.50-0.79) and frequent physical activity (OR=0.59, 95%CI=0.48-0.71) reduced the association; whereas smoking and betel quid chewing showed no significant associations. Smoking (OR=1.56, 95%CI=1.06-2.30) increased the development of depressive symptoms 8 years later; past smoking and current betel quid chewing showed similar trends (OR=1.47, 95%CI=0.93-2.31); exercising ≥ 3 times/wk reduced the development (OR=0.77, 95%CI=0.60-0.99) while alcohol drinking showed no impact. CONCLUSION: Lifestyle variables can impact the mental wellbeing of older Taiwanese. Interventions to reduce the risk of depressive symptoms in older adults should include strategies aimed at improving these modifiable risk factors.

Cheilitis granulomatosa associated with allergic contact dermatitis to betel quid.

Cheilitis granulomatosa (CG) is a rare disorder of unknown origin, which is characterized clinically by painless, recurrent or persistent swelling of 1 or both lips. Betel quids, composed of betel nuts (seeds of the Areca catechu), slake lime, and Piper betel leaf/or Piper betel inflorescence, are widely used in Asia and strongly associated with oral mucosal disease. It has also been found to be a cause of contact leukomelanosis because of its ingredients of various chemicals. We describe a case of CG induced by betel quid chewing.

Chewing of betel, areca and tobacco: perceptions and knowledge regarding their role in head and neck cancers in an urban squatter settlement in Pakistan.

The link of betel, areca and chewable tobacco with head and neck cancers is clearly established. Fifty eight percent of the global head and neck cancers occur in South and Southeast Asia, where chewing of betel, areca and tobacco are common. This study was carried out to establish the pattern of use of Paan, Chaalia, Gutka, Niswar, Tumbaku and Naas among population of squatter settlement of Karachi and to determine the perceptions and knowledge regarding their role in the etiology of head and neck cancers. It was a cross-sectional study, performed at Bilal colony in Karachi. Through systematic sampling, 425 subjects [a male and female from a household] were interviewed with a structured questionnaire. Knowledge regarding etiology of head and neck cancers was classified in ordinals of "good", "some" and "poor", for each substance separately, while practices were classified into "daily user", "occasional user" and "never user". About 40% of the participants were chewing at least one item [betel, areca or tobacco products] on daily basis. This prevalence was 2.46 times higher among males than females and 1.39 times higher among adolescents than adults. At least 79% of the participants were classified as having poor knowledge about the carcinogenicity of each of these items. Knowledge increased with age and level of education. Health hazards of these items were poorly recognized and about 20% perceived at least one of these items to be beneficial. Positive attitudes were seen regarding the steps to curb the production, business and consumption of these substances. In conclusion, prevalence of chewing of betel, areca and tobacco among adults and adolescents is high. Deficiency in knowledge and wrong perception of favorable effect of chewing products is common. Besides curtailing the availability of chewing products, correct knowledge regarding its ill-effects should be inculcated among population to decrease the burden of head and neck cancers.

Alterations of the p14ARF-p53-MDM2 pathway in oral squamous cell carcinoma: MDM2 overexpression is a common event.

The majority of global incidences of oral cancer occur in Asia, and the aetiology of oral cancer is different in Asia as it is in the West. However, whereas there is a growing understanding of the molecular mechanisms of oral cancer progression in the West, there is little progress in this understanding in Asia. In particular, the role of the p53 pathway in modulating cancer progression in Asian oral cancer remains unclear. In this study, we micro-dissected and analysed 20 well-differentiated oral squamous cell carcinoma specimens for alterations in the p53 pathway. We found that 6/20 samples contained mutations in the p53 gene which occurred in three hotspots, at codon 203, 218 and 296. Furthermore, 6/20 samples had a homozygous deletion of p14ARF, but notably p14ARF deletion and p53 mutation events were often independent and mutually exclusive. Strikingly, MDM2 was upregulated in 20/20 samples, but not in 3/3 normal tissue specimens. Taken together, these data suggest that inactivation of the p53 pathway is a frequent event in oral squamous cell carcinoma, which occurs by an aberration in one of a number of players in the p53 pathway.

Allelic alterations at the STR markers in the buccal tissue cells of oral cancer patients and the oral epithelial cells of healthy betel quid-chewers: an evaluation of forensic applicability.

Although cancerous specimens are usually not used in forensic DNA typing, they might be forcibly employed under certain instances. On the other hand, though the oral epithelial samples have been applied to forensic identification, the great popularity of betel quid (BQ)-chewing in Taiwan, which is known to be a risk factor leading to an oral cancer, makes this application questionable. The DNA stability of nine short tandem repeat (STR) markers (the AmpFlSTR kit) was first investigated and then used to evaluate the forensic appropriateness of the oral samples of both healthy BQ-chewers and the archived clinical specimens from oral cancer patients. The analyses were performed on buccal samples from 100 BQ-chewers and 100 oral cancer patients, as well as their paired peripheral blood samples, and a group of 100 non-BQ-chewers were used for the control. In the group of 100 oral cancer patients, two types of DNA instability were found. They were major allelic imbalance, and allelic alterations including the expansion, the contraction and the un-classified type (i.e. can not be confirmed as the expansion or the contraction). The overall percentage of the cancerous subjects demonstrating DNA instability was 33% (five patients possessing both types of DNA instability). Both types of DNA instability showed a tendency of increasing with the severity of the pathological stage of oral cancer. Forty-four occurrences of major allelic imbalance were found from 21 cancer patients. The statistical result revealed that there was no significant difference in the allelic imbalanced occurrence among the nine STR loci. Allelic alterations were found in 17 patients, within which 12 individuals had the expansion, five had the contraction, and three were the un-classified type. Further, among these 17 patients, three were found to acquire multiple allelic alterations at multiple loci. In the group of 100 unrelated healthy BQ-chewers, two loci with major allelic imbalance were detected. However, the two imbalanced alleles were virtually half lost, and could still be recognized as heterozygous alleles. The statistical results of ANOVA, chi(2), and Scheffe tests indicated that the means of allelic imbalance at the nine STR loci of the oral cancerous group revealed a significant difference from those in the control group. Our results suggest that oral cancer tissues cannot be used as references for forensic purposes using the PCR-based STR systems, whereas the oral swabs from healthy BQ-chewers can be employed, but should be done with caution.