title: Areca nut is associated with younger age of diagnosis, poor chemoradiotherapy response, and shorter overall survival in esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  Areca nut chewing is carcinogenic to humans. However, little is known about the impact of areca nut chewing on esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  We retrospectively reviewed 286 ESCC patients who received surgery or preoperative chemoradiotherapy followed by surgery at our institution. Background characteristics including areca nut chewing history were analyzed. The 4-nitroquinoline 1-oxide (4-NQO)-induced murine ESCC model was used to test the impact of arecoline, a main constituent of areca nut, on ESCC.
  
  
  RESULTS
  Compared to patients without areca nut chewing history, patients with areca nut chewing history had overall a younger age of onset (Mean age: 56.75 versus 52.68 yrs, P<0.001) and significantly worse overall survival than those without areca nut chewing history (P = 0.026). Among patients who received surgery, the overall survival rates were not significantly different between those with or without areca nut chewing history. Among patients who received preoperative chemoradiotherapy followed by surgery, those with areca nut chewing history had a significantly lower pathologic complete response rate (P = 0.002) and lower overall survival rate (P = 0.002) than those without. In the murine ESCC model, the incidence of esophageal invasive squamous cell carcinoma was 40% in mice exposed to concomitant 4-NQO and arecoline treatment for 8 weeks and 6% in mice exposed to 4-NQO only for 8 weeks (P = 0.037).
  
  
  CONCLUSIONS
  Our results indicate that areca nut chewing history is significantly associated with younger age of onset, poor response to chemoradiotherapy, and shorter overall survival in ESCC patients. Arecoline, a main constituent of areca nut, accelerates esophageal tumorigenesis in the 4-NQO-induced murine ESCC model.
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Department of Applied Chemistry, and Graduate Institute of Biomedicine and Biomedical Technology, National Chi-Nan University, Taiwan.
authors.forename: Chang-Han
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yen-Hao
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Huang
authors.affiliation: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001114:Areca / Q000009:adverse effects*; D001115:Arecoline / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009754:Nuts / Q000009:adverse effects*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D001115:Arecoline; D015112:4-Nitroquinoline-1-oxide