Habitual Betel Quid Chewing and Risk for Hepatocellular Carcinoma Complicating Cirrhosis

Abstract: This case-control study aimed to assess the independent and interactive role of habitual betel quid chewing and known risk factors for hepatocellular carcinoma (HCC). Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients with HCC, patients with cirrhosis alone, and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 5.81; 95% confidence interval [CI], 2.26-14.94); HBsAg (OR, 37.98; 95% CI, 19.65-73.42); and anti-HCV (OR, 47.23; 95% CI, 18.86-118.25) were independent risk factors for HCC when HCC patients were compared with healthy controls. Using patients with cirrhosis alone as a reference group, multivariate analysis indicated that only betel quid chewing (OR, 1.69; 95% CI, 1.04-2.76) and HBsAg (OR, 1.54; 95% CI, l.01-2.37) were independent risk factors for HCC. There was an additive interaction between betel quid chewing and the presence of either HBsAg (synergy index, 5.22) or anti-HCV (synergy index, 1.35). Moreover, a higher risk of HCC was associated with a longer duration of betel quid chewing and a larger amount of betel quid consumed (each pfor trend < 0.0001). In conclusion, betel quid chewing is an independent risk factor for cirrhotic HCC. There is an additive interaction between betel quid chewing and chronic hepatitis B and/or hepatitis C virus infection. Abbreviations: anti-HCV = antibodies to hepatitis C virus, CI = confidence interval, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, OR = odds ratio.

[1]  J. Tsai,et al.  Hepatitis B and C virus infection as risk factors for liver cirrhosis and cirrhotic hepatocellular carcinoma: a case-control study. , 2008, Liver.

[2]  M. Chou,et al.  Cytotoxic and non-genotoxic effects of arecoline on human buccal fibroblasts in vitro. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[3]  J. Jeng,et al.  Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[4]  T. Axéll,et al.  Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: consensus from a workshop held in Kuala Lumpur, Malaysia, November 25-27, 1996. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[5]  M. Kuo,et al.  Expression of cyclin D1 is correlated with poor prognosis in patients with areca quid chewing-related oral squamous cell carcinomas in Taiwan. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[6]  M. Kuo,et al.  Expression of p53 protein correlates with decreased survival in patients with areca quid chewing and smoking-associated oral squamous cell carcinomas in Taiwan. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[7]  M. Kuo,et al.  Expression of CD44s, CD44v5, CD44v6 and CD44v7-8 in betel quid chewing-associated oral premalignant lesions and squamous cell carcinomas in Taiwan. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[8]  K. Chang,et al.  p53 alterations in betel quid- and tobacco-associated oral squamous cell carcinomas from Taiwan. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[9]  N. Johnson,et al.  p53 expression in oral precancer as a marker for malignant potential. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[10]  H. Philipsen,et al.  Betel chewer's mucosa--a review. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[11]  Y. Ko,et al.  Habitual Betel Quid Chewing as a Risk Factor for Cirrhosis: A Case-Control Study , 2003, Medicine.

[12]  L. Hsieh,et al.  Biological Monitoring of Environment Exposure to Safrole and the Taiwanese Betel Quid Chewing , 2002, Archives of environmental contamination and toxicology.

[13]  Lu-Yu Hwang,et al.  Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus , 2002, Hepatology.

[14]  S. Thorgeirsson,et al.  Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China , 2002, Hepatology.

[15]  Chien-Jen Chen,et al.  Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: Multistage hepatocarcinogenesis with multifactorial etiology , 2002, Hepatology.

[16]  H. Asakura,et al.  CASE REPORT: Remote Development of Hepatocellular Carcinoma in Patients with Liver Cirrhosis Type B Serologically Cured for HBs Antigenemia with Long-Standing Normalization of ALT Values , 2002, Digestive Diseases and Sciences.

[17]  Chien-Jen Chen,et al.  Hepatitis B e antigen and the risk of hepatocellular carcinoma. , 2002, The New England journal of medicine.

[18]  K. Eguchi,et al.  Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C , 2002, Cancer.

[19]  C. Pan,et al.  Risk of oral cancer associated with human papillomavirus infection, betel quid chewing, and cigarette smoking in Taiwan--an integrated molecular and epidemiological study of 58 cases. , 2002, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[20]  D. Schuppan,et al.  Cocarcinogenic effects of alcohol in hepatocarcinogenesis , 2002, Gut.

[21]  G. Loss,et al.  Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? , 2002, Hepatology.

[22]  A. de Silvestri,et al.  Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV‐related liver disease , 2002, Hepatology.

[23]  F. Wei,et al.  Squamous Cell Carcinoma of the Oral Mucosa after Release of Submucous Fibrosis and Bilateral Small Radial Forearm Flap Reconstruction , 2002, Plastic and reconstructive surgery.

[24]  G. Krinsky,et al.  Sonographic detection of hepatocellular carcinoma and dysplastic nodules in cirrhosis: correlation of pretransplantation sonography and liver explant pathology in 200 patients. , 2002, AJR. American journal of roentgenology.

[25]  Mauro Salizzoni,et al.  Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. , 2002, Gastroenterology.

[26]  L. Castagnetta,et al.  Epidemiology, Risk Factors, and Natural History of Hepatocellular Carcinoma , 2002, Annals of the New York Academy of Sciences.

[27]  H. Chiou,et al.  Long‐term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B , 2002, Hepatology.

[28]  S. Thung,et al.  Malignant liver tumors. , 2002, Clinics in liver disease.

[29]  P. Berloco,et al.  Serum retinol and risk of hepatocellular carcinoma in patients with child-Pugh class A cirrhosis. , 2002, Cancer letters.

[30]  M. Feitelson,et al.  Genetic mechanisms of hepatocarcinogenesis , 2002, Oncogene.

[31]  M. Nakagawa,et al.  Diabetes Mellitus May Be Associated with Hepatocarcinogenesis in Patients with Chronic Hepatitis C , 2002, Digestive Diseases and Sciences.

[32]  Ding‐Shinn Chen,et al.  Recent research progress in hepatocellular carcinoma. , 2002, Journal of the Formosan Medical Association = Taiwan yi zhi.

[33]  Tien-Yu Shieh,et al.  The incidence of oropharyngeal cancer in Taiwan: an endemic betel quid chewing area. , 2002, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[34]  W. London,et al.  Eight-year follow-up of the 90,000-person Haimen City cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[35]  P. Hytiroglou,et al.  The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation , 2002, European Radiology.

[36]  Ayman Yosry Abdel-Rahim.  Parasitic Infections and Hepatic Neoplasia , 2002, Digestive Diseases.

[37]  S. Franceschi,et al.  Oral cancer in southern India: The influence of smoking, drinking, paan‐chewing and oral hygiene , 2002, International journal of cancer.

[38]  S. Duffy,et al.  Ultrasound screening and risk factors for death from hepatocellular carcinoma in a high risk group in Taiwan , 2002, International journal of cancer.

[39]  S. Porru,et al.  Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. , 2002, American journal of epidemiology.

[40]  J. Zucman‐Rossi,et al.  Specific association between alcohol intake, high grade of differentiation and 4q34-q35 deletions in hepatocellular carcinomas identified by high resolution allelotyping , 2002, Oncogene.

[41]  C. Chi,et al.  HYDROXYL RADICAL FORMATION AND OXIDATIVE DNA DAMAGE INDUCED BY ARECA QUID IN VIVO , 2002, Journal of toxicology and environmental health. Part A.

[42]  E. Tanaka,et al.  Characteristics of Hepatocellular Carcinoma in Japan , 2002, Oncology.

[43]  K. Koike,et al.  Molecular Mechanism of Viral Hepatocarcinogenesis , 2002, Oncology.

[44]  Sheila Sherlock,et al.  Malignant Liver Tumours , 2001 .

[45]  B. McMahon,et al.  Serologic and Clinical Outcomes of 1536 Alaska Natives Chronically Infected with Hepatitis B Virus , 2001, Annals of Internal Medicine.

[46]  H. Asakura,et al.  High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis , 2001, Journal of gastroenterology and hepatology.

[47]  C. Degott,et al.  Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum. , 2001, American journal of clinical pathology.

[48]  E. Bergsland.  Molecular mechanisms underlying the development of hepatocellular carcinoma. , 2001, Seminars in oncology.

[49]  T. Sodeyama,et al.  [Global epidemiology of hepatocellular carcinoma]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[50]  J. Jeng,et al.  Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. , 2001, Oral oncology.

[51]  Hung-Ming Wang,et al.  Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese. , 2001, Carcinogenesis.

[52]  J. Mahanta,et al.  Betel nut and tobacco chewing; potential risk factors of cancer of oesophagus in Assam, India , 2001, British Journal of Cancer.

[53]  H. Hsu,et al.  Risk of betel chewing for oesophageal cancer in Taiwan , 2001, British Journal of Cancer.

[54]  A. Morabito,et al.  High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity , 2001, Hepatology.

[55]  H. El‐Serag,et al.  The role of diabetes in hepatocellular carcinoma: a case-control study among United States veterans , 2001, American Journal of Gastroenterology.

[56]  J. Jang,et al.  Expression of the G1-S modulators in hepatitis B virus-related hepatocellular carcinoma and dysplastic nodule: association of cyclin D1 and p53 proteins with the progression of hepatocellular carcinoma. , 2001, Journal of Korean medical science.

[57]  K. Shiraki,et al.  Impact of hepatitis B and C virus infection on the clinical prognosis of alcoholic liver cirrhosis. , 2001, Anticancer research.

[58]  P. van’t Veer,et al.  Role of genetic polymorphism of glutathione-S-transferase T1 and microsomal epoxide hydrolase in aflatoxin-associated hepatocellular carcinoma. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[59]  H. C. Lee,et al.  Accumulation of mitochondrial DNA deletions in human oral tissues -- effects of betel quid chewing and oral cancer. , 2001, Mutation research.

[60]  G. Thomas,et al.  Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. , 2001, Gastroenterology.

[61]  M. Holmes-McNary.  Impact factors on development of cirrhosis and subsequent hepatocellular carcinoma. , 2001, Compendium of continuing education in dentistry.

[62]  Y. Deugnier,et al.  Iron and hepatocellular carcinoma , 2001, Journal of gastroenterology and hepatology.

[63]  A. Castells,et al.  Hepatocellular carcinoma in primary biliary cirrhosis: similar incidence to that in hepatitis C virus–related cirrhosis , 2001, American Journal of Gastroenterology.

[64]  K. Tsuneyama,et al.  Hepatocellular carcinoma arising in non‐alcoholic steatohepatitis , 2001, Pathology international.

[65]  H. Domínguez-Malagón,et al.  Hepatocellular Carcinoma: An Update , 2001, Ultrastructural pathology.

[66]  T. Tseng,et al.  Synergistic effects of peroxynitrite on arecoline-induced cytotoxicity in human buccal mucosal fibroblasts. , 2000, Toxicology letters.

[67]  M. Srivastava,et al.  Hepatocurative effect of picroliv and silymarin against aflatoxin B1 induced hepatotoxicity in rats. , 2000, Planta medica.

[68]  Y. Joshi,et al.  Nutritional risk factors in esophageal cancer. , 2000, The Journal of the Association of Physicians of India.

[69]  K. Chang,et al.  Safrole in betel quid may be a risk factor for hepatocellular carcinoma: case report. , 2000, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[70]  K. Chang,et al.  Safrole-like DNA adducts in oral tissue from oral cancer patients with a betel quid chewing history. , 1999, Carcinogenesis.

[71]  D. V. van Thiel,et al.  Oxidative DNA damage in circulating leukocytes occurs as an early event in chronic HCV infection. , 1999, Free radical biology & medicine.

[72]  B. Heischober,et al.  Betel nut: a common drug used by naturalized citizens from India, Far East Asia, and the South Pacific Islands. , 1999, Annals of emergency medicine.

[73]  G. Wogan.  Aflatoxin as a human carcinogen , 1999, Hepatology.

[74]  Y. K. Chen,et al.  Primary oral squamous cell carcinoma: an analysis of 703 cases in southern Taiwan. , 1999, Oral oncology.

[75]  C. Lii,et al.  Chemical composition and toxicity of Taiwanese betel quid extract. , 1999, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[76]  Y. Yamazaki,et al.  Characteristics of mutations in the p53 gene of oral squamous‐cell carcinomas associated with betel‐quid chewing in Sri Lanka. Int. J. Cancer 77, 839–842 (1998) , 1999, International journal of cancer.

[77]  S. Patnaik,et al.  Co-overexpression of p53 and c-myc proteins linked with advanced stages of betel- and tobacco-related oral squamous cell carcinomas from eastern India. , 1998, European journal of oral sciences.

[78]  R. Ralhan,et al.  Prognostic significance of p53 protein overexpression in betel‐ and tobacco‐related oral oncogenesis , 1998, International journal of cancer.

[79]  R C Garner,et al.  The role of DNA adducts in chemical carcinogenesis. , 1998, Mutation research.

[80]  A. Borges,et al.  Evaluation of carcinogenic/co‐carcinogenic activity of a common chewing product, pan masala, in mouse skin, stomach and esophagus , 1998, International journal of cancer.

[81]  S. Darby,et al.  Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C , 1997, The Lancet.

[82]  C. J. Chen,et al.  Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1; environmental factors and risk of oral cancer. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[83]  Chien-Jen Chen,et al.  Epidemiological characteristics and risk factors of hepatocellular carcinoma , 1997, Journal of gastroenterology and hepatology.

[84]  M. Sigvardsson,et al.  ORIGINAL PAPERS , 2007 .

[85]  V. Cw.  Oral submucous fibrosis. The South African experience. , 1997 .

[86]  S. Bhide,et al.  Cytogenetic damage in exfoliated oral mucosal cells and circulating lymphocytes of patients suffering from precancerous oral lesions. , 1996, Cancer letters.

[87]  P. Heinzel,et al.  Mutations and polymorphisms in the p53, p21 and p16 genes in oral carcinomas of Indian betel quid chewers , 1996, International journal of cancer.

[88]  C. Ong,et al.  Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis. , 1996, Mutation research.

[89]  Chien-Jen Chen,et al.  Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan , 1996, International journal of cancer.

[90]  C. K. Wang,et al.  The mutagenicities of alkaloids and N-nitrosoguvacoline from betel quid. , 1996, Mutation research.

[91]  Bhatt Rv.  Aflatoxin and liver injury. , 1996 .

[92]  J. Tsai,et al.  Additive effect modification of hepatitis B surface antigen and e antigen on the development of hepatocellular carcinoma. , 1996, British Journal of Cancer.

[93]  Y. Ko,et al.  A case-control study of oral cancer in Changhua County, Taiwan. , 1996, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[94]  J. Tsai,et al.  Independent and additive effect modification of hepatitis C and B viruses infection on the development of chronic hepatitis. , 1996, Journal of hepatology.

[95]  J. W. Chen,et al.  A study on betel quid chewing behavior among Kaohsiung residents aged 15 years and above. , 1996, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[96]  C. Tzeng,et al.  Overexpression of p53 protein in squamous cell carcinoma of buccal mucosa and tongue in Taiwan: an immunohistochemical and clinicopathological study. , 1996, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[97]  I. Su,et al.  Prevalence and related risk factors of betel quid chewing by adolescent students in southern Taiwan. , 1996, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[98]  Y. Ko,et al.  Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. , 1995, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[99]  K. Ogawa,et al.  Wild type p53 and c-myc co-operation in generating apoptosis of a rat hepatocellular carcinoma cell line (FAA-HTC1). , 1995, Oncogene.

[100]  M. Kuo,et al.  Elevated ras p21 expression in oral premalignant lesions and squamous cell carcinoma in Taiwan. , 1995, Journal of Oral Pathology & Medicine.

[101]  A. Singh,et al.  Effect of arecanut, a masticatory, on hepatic drug metabolizing enzymes -SH content and lipid peroxidation in lactating mothers and their suckling neonates. , 1995, Cancer letters.

[102]  M. Rosin,et al.  High prevalence of expression of p53 oncoprotein in oral carcinomas from India associated with betel and tobacco chewing. , 1995, European journal of cancer. Part B, Oral oncology.

[103]  H. Bartsch,et al.  Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing. , 1995, Carcinogenesis.

[104]  M. Colombo,et al.  Epidemiology of hepatocellular carcinoma. , 1995, The Italian journal of gastroenterology.

[105]  B. Ames,et al.  Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[106]  A. Robles,et al.  Induction of cyclin D1 overexpression by activated ras. , 1994, Oncogene.

[107]  Y. Ko,et al.  [Prevalence of smoking, drinking and betel quid chewing and related factors among aborigines in Wufeng District]. , 1994, Gaoxiong yi xue ke xue za zhi = The Kaohsiung journal of medical sciences.

[108]  N. Nishida,et al.  Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. , 1994, Cancer research.

[109]  S. Hirohashi,et al.  Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. , 1994, Cancer research.

[110]  J. Tsai,et al.  Frequency of raised alpha-fetoprotein level among Chinese patients with hepatocellular carcinoma related to hepatitis B and C. , 1994, British Journal of Cancer.

[111]  J. Tsai,et al.  Hepatitis B and C virus infection as risk factors for hepatocellular carcinoma in Chinese: A case‐control study , 1994, International journal of cancer.

[112]  J. Jeng,et al.  Mutations of Ki-ras oncogene codon 12 in betel quid chewing-related human oral squamous cell carcinoma in Taiwan. , 1994, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[113]  Y. Ko,et al.  Prevalence and characteristics of areca nut chewers among junior high school students in Changhua county, Taiwan. , 1993, Community dentistry and oral epidemiology.

[114]  J. Tsai,et al.  Hepatitis C virus infection as a risk factor for non‐alcoholic liver cirrhosis in taiwan , 1993, Journal of medical virology.

[115]  A. Singh,et al.  Effect of arecanut on the black mustard (Brassica niger, L.)-modulated detoxication enzymes and sulfhydryl content in the liver of mice. , 1993, Cancer letters.

[116]  A. Singh,et al.  Modulatory effect of Areca nut on the action of mace (Myristica fragrans, Houtt) on the hepatic detoxification system in mice. , 1993, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[117]  H. Bartsch,et al.  Role of lime in the generation of reactive oxygen species from betel-quid ingredients. , 1992, Environmental health perspectives.

[118]  L. Hwang,et al.  Phenolic compounds of Piper betel flower as flavoring and neuronal activity modulating agents , 1992 .

[119]  S. J. Thomas,et al.  Slaked lime and betel nut cancer in Papua New Guinea , 1992, The Lancet.

[120]  Y. Ko,et al.  Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors. , 1992, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[121]  A. Nishikawa,et al.  A study of betel quid carcinogenesis--VIII. Carcinogenicity of 3-(methylnitrosamino)propionaldehyde in F344 rats. , 1992, Carcinogenesis.

[122]  A. Mukherjee,et al.  Evaluation of pan masala for toxic effects on liver and other organs. , 1992, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[123]  D. Hoffmann,et al.  A study of betel quid carcinogenesis. IX. Comparative carcinogenicity of 3-(methylnitrosamino)propionitrile and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone upon local application to mouse skin and rat oral mucosa. , 1991, Cancer letters.

[124]  S. Raisuddin,et al.  Aflatoxin in betel nut and its control by use of food preservatives. , 1991, Food additives and contaminants.

[125]  N. Day,et al.  Risk factors for cancer of the oesophagus in Kerala, India , 1991, International journal of cancer.

[126]  Chien-Jen Chen,et al.  Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma , 1991, Hepatology.

[127]  H. Bartsch,et al.  Effect of lime composition on the formation of reactive oxygen species from areca nut extract in vitro. , 1990, Carcinogenesis.

[128]  P. Boyle,et al.  Epidemiology of Mouth Cancer in 1989: A Review , 1990, Journal of the Royal Society of Medicine.

[129]  J. Chiu,et al.  The expression of c-myc and c-N-ras in human cirrhotic livers, hepatocellular carcinomas and liver tissue surrounding the tumors. , 1990, Oncogene.

[130]  H. Stich,et al.  The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers. , 1989, Mutation research.

[131]  H. Stich,et al.  Promoting activity of betel quid ingredients and their inhibition by retinol. , 1989, Cancer letters.

[132]  D. Hoffmann,et al.  Cyanoethylation of DNA in vivo by 3-(methylnitrosamino)propionitrile, an Areca-derived carcinogen. , 1988, Cancer research.

[133]  J. Bigby.  Harrison's Principles of Internal Medicine , 1988 .

[134]  G. Talaska,et al.  The correlation between DNA adducts and chromosomal aberrations in the target organ of benzidine exposed, partially-hepatectomized mice. , 1987, Carcinogenesis.

[135]  J. Hoofnagle,et al.  Relation of the hepatitis B virus carrier state to hepatocellular carcinoma , 1987, Hepatology.

[136]  D. Hoffmann,et al.  3-(Methylnitrosamino)propionitrile: occurrence in saliva of betel quid chewers, carcinogenicity, and DNA methylation in F344 rats. , 1987, Cancer research.

[137]  T. Kuniyasu,et al.  Carcinogenicity of betel quid. III. Enhancement of 4-nitroquinoline-1-oxide- and N-2-fluorenylacetamide-induced carcinogenesis in rats by subsequent administration of betel nut. , 1986, Journal of the National Cancer Institute.

[138]  P. Cerutti.  Prooxidant states and tumor promotion. , 1985, Science.

[139]  D. Hoffmann,et al.  A study of betel quid carcinogenesis , 1984, Journal of Cancer Research and Clinical Oncology.

[140]  A. Rao,et al.  Influence of caffeine on arecoline-induced SCE in mouse bone-marrow cells in vivo. , 1983, Mutation research.

[141]  E C Miller,et al.  Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. , 1983, Cancer research.

[142]  A. Rao,et al.  Chromosome-breaking ability of arecoline, a major betel-nut alkaloid, in mouse bone-marrow cells in vivo. , 1982, Mutation research.

[143]  A. Mustafa,et al.  Effect of arecoline on the humoral & cell mediated immune responses in mice. , 1980, Indian journal of experimental biology.

[144]  S. Bhide,et al.  Carcinogenicity of betel quid ingredients: feeding mice with aqueous extract and the polyphenol fraction of betel nut. , 1979, British Journal of Cancer.

[145]  M. F. Laspia,et al.  The detection of various nitrosamines in the hepatocyte primary culture/DNA repair test. , 1979, Cancer Letters.

[146]  N. Breslow,et al.  Cancer of the oral cavity, pharynx/larynx and lung in North Thailand: case-control study and analysis of cigar smoke. , 1977, British Journal of Cancer.

[147]  R. Pugh,et al.  Transection of the oesophagus for bleeding oesophageal varices , 1973, The British journal of surgery.

[148]  C. Uragoda,et al.  Some Observations on Oesophageal Carcinoma in Ceylon, Including its Relationship to Betel Chewing , 1970, British Journal of Cancer.

[149]  J. J. Pindborg,et al.  Oral submucous fibrosis. , 1966, Oral surgery, oral medicine, and oral pathology.

[150]  D. Jussawalla.  Oesophageal cancer in India , 2004, Journal of Cancer Research and Clinical Oncology.

[151]  M. Kuo,et al.  MDM2 expression in areca quid chewing-associated oral squamous cell carcinomas in Taiwan. , 2001, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[152]  H. Bartsch,et al.  Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. , 1999, Cancer detection and prevention.

[153]  E. Zarling,et al.  Immunohistochemical evaluation of bcl-2 gene family expression in liver of hepatitis C and cirrhotic patients: a novel mechanism to explain the high incidence of hepatocarcinoma in cirrhotics , 1999, American Journal of Gastroenterology.

[154]  S. Warnakulasuriya,et al.  Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: Consensus from a workshop held in Kuala Lumpur, Malaysia, , 1999 .

[155]  M. Ozturk.  Genetic Aspects of Hepatocellular Carcinogenesis , 1999, Seminars in liver disease.

[156]  U. M. Moll,et al.  p53--an acrobat in tumorigenesis. , 1998, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[157]  S. Norton.  Betel: consumption and consequences. , 1998, Journal of the American Academy of Dermatology.

[158]  Y. Yamamoto,et al.  Plasma ratio of ubiquinol and ubiquinone as a marker of oxidative stress. , 1997, Molecular aspects of medicine.

[159]  J. Tsai,et al.  Effect of hepatitis C and B virus infection on risk of hepatocellular carcinoma: a prospective study. , 1997, British Journal of Cancer.

[160]  C. vanWyk.  Oral submucous fibrosis. The South African experience. , 1997, Indian journal of dental research : official publication of Indian Society for Dental Research.

[161]  R. V. Bhat.  Aflatoxin and liver injury. , 1996, Tropical gastroenterology : official journal of the Digestive Diseases Foundation.

[162]  H. Bartsch,et al.  Endogenous formation of nitrosamines and oxidative DNA-damaging agents in tobacco users. , 1996, Critical reviews in toxicology.

[163]  C. Chi,et al.  Oxidative damage to DNA induced by areca nut extract. , 1996, Mutation research.

[164]  K. V. Rao,et al.  A comparative clinico-pathological study of oral submucous fibrosis in habitual chewers of pan masala and betelquid. , 1996, Journal of toxicology. Clinical toxicology.

[165]  A. Singh,et al.  Evaluation of the modifying influence of arecanut on the garlic-modulated hepatic detoxication system enzymes, sulfhydryl content, and lipid peroxidation in mice. , 1995, Teratogenesis, carcinogenesis, and mutagenesis.

[166]  F. Chung,et al.  Formation of the acrolein-derived 1,N2-propanodeoxyguanosine adducts in DNA upon reaction with 3-(N-carbethoxy-N-nitrosamino)propionaldehyde. , 1994, Chemical research in toxicology.

[167]  D. Phillips.  DNA adducts derived from safrole, estragole and related compounds, and from benzene and its metabolites. , 1994, IARC scientific publications.

[168]  J. Tsai,et al.  Hepatitis C virus infection among patients with chronic liver disease in an area hyperendemic for hepatitis B. , 1994, Scandinavian journal of gastroenterology.

[169]  H. Vainio,et al.  Identification of carcinogens within the IARC monograph program. , 1992, Scandinavian journal of work, environment & health.

[170]  M. Selvakumaran,et al.  Influence of arecoline on immune system: II. Suppression of thymus-dependent immune responses and parameter of non-specific resistance after short-term exposure. , 1991, Immunopharmacology and immunotoxicology.

[171]  H. Bartsch.  N-nitroso compounds and human cancer: where do we stand? , 1991, IARC scientific publications.

[172]  P. Gupta.  Betel quid and oral cancer: prospects for prevention. , 1991, IARC scientific publications.

[173]  H. Bartsch,et al.  Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients. , 1987, Chemico-biological interactions.

[174]  D. Hoffmann,et al.  The role of N-(nitrosomethylamino)propionitrile in betel-quid carcinogenesis. , 1987, IARC scientific publications.

[175]  D. Woodfield.  Hepatocellular carcinoma. , 1986, The New Zealand medical journal.

[176]  I. Hirono,et al.  Carcinogenicity examination of betel quid. II. Effect of vitamin A deficiency on rats fed semipurified diet containing betel nut and calcium hydroxide. , 1983, Nutrition and cancer.

[177]  M. Graffar.  [Modern epidemiology]. , 1971, Bruxelles medical.

[178]  W. H. Butler,et al.  Acute and chronic effects of aflatoxin on the liver of domestic and laboratory animals: a review. , 1969, Cancer research.