Keiji Yoshinaga

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (24)49.38 Total impact

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    ABSTRACT: The CXCL12/CXCR4 axis plays a pivotal role in cancer progression and metastases in various epithelial cancer cells. The aim of the present study was to evaluate the localization and correlation between CXCL12/CXCR4 expression and clinicopathological features in gastric cancers.
    Anticancer research 11/2014; 34(11):6397-403. · 1.71 Impact Factor
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    ABSTRACT: Abstract We report a rare case of disseminated carcinomatosis of the bone marrow from rectal cancer with disseminated intravascular coagulation (DIC). A 65-year-old man was admitted with melena and low back pain at rest. X-ray examination showed rectal cancer with multiple bone metastases. Laboratory examination showed severe anemia and DIC. Histologic examination showed disseminated carcinomatosis of the bone marrow. The DIC was considered to be caused by disseminated carcinomatosis of the bone marrow from rectal cancer, and we immediately started treatment with anti-DIC therapy and anticancer chemotherapy with the modified FOLFOX6 regimen (mFOLFOX6). After some response to therapy, the patient's general condition deteriorated, and he died 128 days after admission. This is the first English report showing disseminated carcinomatosis of the bone marrow from colorectal cancer treated with mFOLFOX6.
    International surgery. 09/2014; 99(5):518-522.
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    ABSTRACT: Increased levels of tumor marker in intra-operative peritoneal lavage are associated with an earlier detection of recurrent peritoneal dissemination. Intra-operative peritoneal lavage samples from 193 patients with gastric cancer were obtained to determine the levels of the tumor markers, carcinoembryonic antigen (CEA) and cancer-related antigen 72-4 (CA72-4) using a chemiluminescent enzyme immunoassay. The peritoneal lavage CEA (CY-CEA), CA72-4 (CY-CA72-4) and serosal invasion were independent factors predicting the peritoneal dissemination including CY(+). The patients were divided into four groups on the basis of peritoneal lavage tumor marker status; group A: CY-CEA (-), CY-CA72-4 (-) group (CEA < 0.5 ng/ml, CA72-4 < 1.3 U/ml); group B: CY-CEA (-), CY-CA72-4 (+) group (CEA < 0.5 ng/ml, CA72-4 ≥ 1.3 U/ml); group C: CY-CEA (+), CY-CA72-4 (-) group (CEA ≥ 0.5 ng/ml, CA72-4 < 1.3 U/ml); and group D: CY-CEA (+), CY-CA72-4 (+) group (CEA ≥ 0.5 ng/ml, CA72-4 ≥ 1.3 U/ml). The 5-year survival among the patients in groups A, B, C and D was 87, 68, 38 and 20 %, respectively (p < 0.0001). Combined analysis of these markers is therefore considered to be helpful for accurately determining sites of recurrence and the prognosis in advanced gastric cancer patients.
    Journal of Cancer Research and Clinical Oncology 02/2014; · 2.91 Impact Factor
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    ABSTRACT: We previously reported that PSK-induced lymphocyte blastogenesis reaction (PSK-stimulation index; PSK-SI) may be a prognostic marker for immunochemotherapy using PSK in gastrointestinal cancer patients. In this study we evaluated the usefulness of PSK-SI as a prognostic marker for PSK therapy at higher and lower serum immunosuppressive acidic protein (IAP) levels. 98 gastric and 135 colorectal cancer patients were analyzed. PSK-SI and serum IAP levels were measured preoperatively. After operation, patients received UFT and PSK for two years. There were no differences between patients with higher and those with lower PSK-SI with respect to the clinicopathological factors. In patients with higher serum IAP levels (> or = 500 microg/ml), recurrence-free survival (RFS) and overall survival (OS) were apparently more favorable in the higher PSK-SI group (gastric cancer; > or = 1.75, colorectal cancer; > or = 2.1) than in lower PSK-SI group, although the differences were not significant. Serum IAP levels and PSK-SI may be useful markers for prediction of response to immunochemotherapy using PSK, although further studies are necessary.
    Fukuoka igaku zasshi = Hukuoka acta medica 12/2013; 104(12):549-58.
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    ABSTRACT: Esophagectomy, one of the most invasive of all gastrointestinal operations, is associated with a high frequency of postoperative complications and in-hospital mortality. The purpose of the present study was to determine whether exposure to the atomic bomb explosion at Hiroshima in 1945 might be a preoperative risk factor for in-hospital mortality after esophagectomy in esophageal cancer patients. We thus reviewed the outcomes of esophagectomy in 31 atomic bomb survivors with esophageal cancer and 96 controls (also with cancer but without atomic bomb exposure). We compared the incidences of postoperative complications and in-hospital mortality. Of the clinicopathological features studied, mean patient age was significantly higher in atomic bomb survivors than in controls. Of the postoperative complications noted, atomic bomb survivors experienced a longer mean period of endotracheal intubation and higher incidences of severe pulmonary complications, severe anastomotic leakage, and surgical site infection. The factors associated with in-hospital mortality were exposure to the atomic bomb explosion, pulmonary comorbidities, and electrocardiographic abnormalities. Multivariate analysis revealed that exposure to the atomic bomb explosion was an independent significant preoperative risk factor for in-hospital mortality. Exposure to the atomic bomb explosion is thus a preoperative risk factor for in-hospital death after esophagectomy to treat esophageal cancer.
    Diseases of the Esophagus 11/2013; · 1.64 Impact Factor
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    ABSTRACT: Objective: The study aimed to evaluate the efficacy of surgery after preoperative chemotherapy for unresectable advanced gastric cancer. Method: Twenty patients with disappeared peritoneal dissemination or decreased lymph node metastasis by systemic chemotherapy underwent surgery (group S), while 14 with peritoneal dissemination or lymph nodes >N2 (group C) received continuous systemic chemotherapy. Among group S patients, 15 underwent a curative resection (group R0), while the other 5 did not microscopically undergo a curative resection (group R1). Results: The median survival time for all patients was 535 days. Survival time was significantly dependent on the chemotherapy response (p < 0.002). The survival period in group S was significantly longer than that in group C (median survival time 747 vs. 476 days; p < 0.02). The relapse-free survival was 299 days in group S. In particular, the survival period of patients who underwent R0 surgery by preoperative chemotherapy was significantly longer than that of group R1 patients (median survival time 794 vs. 485 days; p < 0.02). Multivariate analysis revealed that R0 surgery was a significant and independent prognostic factor. Conclusion: Surgery was effective for advanced gastric cancer patients when performed as R0 resection following the disappearance of non-curative factors by preoperative chemotherapy. © 2013 S. Karger AG, Basel.
    Oncology 10/2013; 85(4):241-247. · 2.17 Impact Factor
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    ABSTRACT: The expression of podoplanin is reportedly involved in collective cell invasion, which is independent from the epithelial-mesenchymal transition (EMT). We focused on the expression of podoplanin in esophageal squamous cell carcinomas (ESCC) and investigated the correlation of podoplanin and EMT-related markers, and evaluated its prognostic significance. Five ESCC cell lines were subjected to Western blot analysis for podoplanin and EMT markers. The effects of podoplanin on EMT and carcinoma invasion were evaluated with wound healing assays, invasion assays, and three-dimensional (3D) culture. Transfection of ectopic podoplanin into a podoplanin-negative ESCC cell line (TE-15) induced cell migration and invasive activity (p < 0.001 and p < 0.05, respectively) without downregulation of E-cadherin. In contrast, transfection of si-podoplanin RNA into a podoplanin-positive ESCC cell line (TE-13) reduced cell migration and invasive activity (p < 0.05). We reviewed 101 patients who had undergone esophagectomy for ESCC. Podoplanin expression was observed in 58 patients (57.4%), and positive expression was positively correlated with expression of E-cadherin (p < 0.01), deeper wall invasion (p < 0.01), venous invasion (p < 0.05), and poorer prognosis (p < 0.01). Multivariate Cox analysis revealed that expression of podoplanin was a significant and independent unfavorable predictor of survival (p < 0.05). These data suggest that podoplanin is significantly associated with and likely contributes to ESCC invasion in the absence of EMT. This article is protected by copyright. All rights reserved.
    Cancer Science 09/2013; · 3.48 Impact Factor
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    ABSTRACT: BACKGROUND: In the decade after the 1945 atomic bombing of Hiroshima, a high incidence of leukemia was observed among atomic bomb survivors. However, the incidence of other cancers gradually increased, while that of leukemia decreased after this period. We evaluated the clinical outcome of early gastric cancer and microsatellite stability over a long-term period in atomic bomb survivors. METHODS: The results of surgical treatment for early gastric cancer were reviewed for 117 atomic bomb survivors and 394 control patients between 1995 and 2006. In addition, immunohistochemical staining for hMSH2 and hMLH1 expression was performed to evaluate the status of microsatellite stability in 57 atomic bomb survivors and 82 control patients. RESULTS: The long-term survival rate for early gastric cancer in atomic bomb survivors was significantly lower than that in control patients (p < 0.01). Multivariable analysis revealed that age and sex were significant and independent prognostic factors for early gastric cancer. Defective hMSH2 and/or hMLH1 expression was also significantly higher in survivors than in control patients (p < 0.001). Logistic regression analysis revealed that atomic bomb survivorship was related to defective hMSH2 and/or hMLH1 expression. CONCLUSIONS: The prognosis of early gastric cancer in atomic bomb survivors was poor and was related to age and sex, rather than to being an atomic bomb survivor. Furthermore, a higher rate of defective hMSH2 and/or hMLH1 expression was observed in the survivors.
    Annals of Surgical Oncology 11/2012; · 4.12 Impact Factor
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    ABSTRACT: Plasma D-dimer levels are elevated in patients with a variety of solid tumors. Recently, it has been reported that the level before curative surgery is a prognostic factor for colorectal cancer (CRC). We investigated whether the plasma D-dimer level before systemic chemotherapies is a predictor for advanced or recurrent unresectable CRC. This study included 42 patients treated with systemic chemotherapies for advanced or recurrent unresectable CRC. Variables including clinicopathological factors, plasma D-dimer levels and the modified Glasgow Prognostic Factor Score (mGPS) were evaluated. The plasma D-dimer level was closely related to the mGPS. Survival was shorter for patients with plasma D-dimer levels >5 µg/ml than for those with lower levels. Compared with an mGPS of 0 or 1, an mGPS of 2 was predictive of poor prognosis (p < 0.0001). Old age, advanced stage, plasma D-dimer level and mGPS were significantly associated with mortality, but plasma D-dimer level was the only independent risk factor in multivariate analysis, and was significant related to the clinical response to chemotherapy (p < 0.05). Survival was significantly shorter in patients with elevated plasma D-dimer levels having advanced or recurrent CRC. The plasma D-dimer level before systemic chemotherapies was an independent mortality predictor.
    Oncology 06/2012; 83(1):10-5. · 2.17 Impact Factor
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    ABSTRACT: Systemic chemotherapy is the key treatment for patients presenting with advanced gastric cancer with peritoneal dissemination. In certain cases, adjuvant surgery following systemic chemotherapy may result in improved long-term survival. This study aimed to evaluate the efficacy of adjuvant surgery following response to chemotherapy for advanced gastric cancer with peritoneal dissemination. The study included 13 patients with a diagnosis of advanced gastric cancer with peritoneal dissemination. Of the 13 patients, 5 patients underwent surgery after the peritoneal dissemination was eradicated following systemic chemotherapy (group S), while the remaining 8 patients continued to receive systemic chemotherapy due to persistent peritoneal dissemination (group C). All 13 patients underwent treatment between October 2008 and February 2011. The chemotherapy regimen included cis-diamminedichloride platinum plus S-1 (an oral fluoropyrimidine) or docetaxel plus S-1 for all patients. The median overall survival time of the 13 patients was 660 days. The survival time did not differ with patient response to chemotherapy. The median survival time of the patients in group S was 794 days, which was significantly higher than that of the patients in group C (505 days; p<0.05). One- and 2-year survival was observed in 100 and 60% of patients, respectively, in group S, and 66.7 and 0% of patients in group C. In conclusion, adjuvant surgery led to longer survival in patients having advanced gastric cancer with peritoneal dissemination, which was eradicated following systemic chemotherapy.
    Oncology letters 03/2012; 3(3):662-666. · 0.24 Impact Factor
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    ABSTRACT: 5-Fluorouracil (5-FU) has long been a mainstay antimetabolite chemotherapeutic drug for the treatment of major solid tumors, particularly colorectal cancer. 5-FU is processed intracellularly to yield active metabolites that compromise RNA and DNA metabolism. However, the mechanisms responsible for its cytotoxicity are not fully understood. From the phenotypic analysis of mutant chicken B lymphoma DT40 cells, we found that homologous recombinational repair (HRR), involving Rad54 and BRCA2, and the ATR-Chk1 signaling pathway, involving Rad9 and Rad17, significantly contribute to 5-FU tolerance. 5-FU induced γH2AX nuclear foci, which were colocalized with the key HRR factor Rad51, but not with DNA double-strand breaks (DSBs), in a dose-dependent manner as cells accumulated in the S phase. Inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX and enhanced 5-FU cytotoxicity not only in wild-type cells but also in Rad54- or BRCA2-deficient cells, suggesting that HRR and Chk1 kinase have non-overlapping roles in 5-FU tolerance. 5-FU-induced Chk1 phosphorylation was significantly impaired in Rad9- or Rad17-deficient cells, and severe γH2AX nuclear foci and DSBs were formed, which was followed by apoptosis. Finally, inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX nuclear foci and enhanced 5-FU cytotoxicity in Rad9- or Rad17-deficient cells. These results suggest that Rad9- and Rad17-independent activation of the ATR-Chk1 signaling pathway also significantly contributes to 5-FU tolerance.
    DNA repair 12/2011; 11(3):247-58. · 4.20 Impact Factor
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    ABSTRACT: The mechanism of action of protein-bound polysaccharide K (PSK; KRESTIN(®)) involves the following actions: (1) recovery from immunosuppression induced by humoral factors such as transforming growth factor (TGF)-β or as a result of surgery and chemotherapy; (2) activation of antitumor immune responses including maturation of dendritic cells, correction of Th1/Th2 imbalance, and promotion of interleukin-15 production by monocytes; and (3) enhancement of the antitumor effect of chemotherapy by induction of apoptosis and inhibition of metastasis through direct actions on tumor cells. The clinical effectiveness of PSK has been demonstrated for various cancers. In patients with gastric or colorectal cancer, combined use of PSK with postoperative adjuvant chemotherapy prolongs survival, and this effect has been confirmed in multiple meta-analyses. For small-cell lung carcinoma, PSK in conjunction with chemotherapy prolongs the remission period. In addition, PSK has been shown to be effective against various other cancers, reduce the adverse effects of chemotherapy, and improve quality of life. Future studies should examine the effects of PSK under different host immune conditions and tumor properties, elucidate the mechanism of action exhibited in each situation, and identify biomarkers.
    Surgery Today 12/2011; 42(1):8-28. · 0.96 Impact Factor
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    ABSTRACT: We report three cases of successful surgical removal of a denture with sharp clasps impacted in the cervical esophagus. Patient 1 was a 57-year-old woman institutionalized for over 30 years for schizophrenia, patient 2 was a 62-year-old man hospitalized for brain paralysis, and patient 3 was a 64-year-old man suffering cerebral hemorrhage sequelae. All three patients swallowed a denture accidentally. Chest X-rays showed the denture with sharp clasps in the cervicothoracic region of the esophagus, and endoscopy revealed that it was lodged in the esophageal mucosa. The denture was subsequently removed by cervical esophagotomy. All three patients had a good clinical postoperative course without any complications. Thus, we recommend surgery via a cervical approach to remove a denture with sharp clasps impacted in the cervicothoracic esophagus, with intraoperative endoscopic examination for esophageal injury.
    Surgery Today 09/2011; 41(9):1275-9. · 0.96 Impact Factor
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    ABSTRACT: We herein present the case of a 66-year-old man with both gastric cancer and an infrarenal abdominal aneurysm. The patient's medical history included bladder cancer, chronic renal failure, and ischemic heart disease. We performed a simultaneous endovascular aneurysm repair (EVAR) and total gastrectomy. Following the procedure, the patient remained in the intensive care unit for 3 days. Oral feeding was resumed on postoperative day 7, and the patient was discharged from the hospital on postoperative day 13 with no complications. Despite the patient's medical problems and higher operative risk, he tolerated simultaneous EVAR and total gastrectomy, and had a good outcome after undergoing these simultaneous procedures.
    Surgery Today 05/2011; 41(5):721-5. · 0.96 Impact Factor
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    ABSTRACT: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis. We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism-CGH (SNP-CGH). In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration. LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation.
    Clinical Cancer Research 02/2011; 17(7):1731-40. · 7.84 Impact Factor
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    ABSTRACT: Resections for esophageal cancer are invasive, with high mortality and morbidity rates. The object of this study was to clarify the factors associated with in-hospital death while also evaluating any associated historical changes in the characteristics of such deaths. The factors associated with mortality were examined by logistic regression analysis in 1106 patients who underwent an esophagectomy for esophageal cancer. The historical changes in the characteristics of in-hospital deaths were also evaluated. A multivariate analysis revealed that not only undergoing an esophagectomy before 1979, but also a patient's age (odds ratio 1.070 for every increase in age by year) and an incomplete resection (odds ratio 2.265) were independent factors associated with in-hospital death. The in-hospital mortality rates were 16.1%, 5.8%, 2.5%, and 3.1%, while the 30-day mortality rates were 9.2%, 2.2%, 0.8%, and 0.3% during 1964-1979, the 1980s, the 1990s, and the 2000s, respectively. Eight patients had preoperative comorbidities among 11 patients who died in the hospital after 1997. The mortality rate was 5.5% in patients with any comorbidities, while it was 1.3% in patients without any comorbidities (P = 0.026). The most common direct cause of in-hospital death was previous pulmonary complications; however, cancer progression has recently become the most common cause. To prevent in-hospital mortality after an esophagectomy, strict indications for surgery and careful perioperative management are important, especially in high-risk patients with advanced esophageal cancer.
    Annals of Surgical Oncology 01/2011; 18(6):1757-65. · 4.12 Impact Factor
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    ABSTRACT: Hepatic artery injury is one complication associated with surgery for gastric cancer. This complication does not occur frequently, but it can cause serious problems. Anatomical variations of the hepatic arteries are thought to be a factor in such injuries. Recognizing vascular variations before the operation is thus very important. This report presents a case with a rare variation of the hepatic arteries identified on three-dimensional computed tomography (3D-CT) angiography before gastric cancer surgery. Hepatic artery injury was avoided as a result of the recognition of this extremely rare variation. Preoperative 3D-CT angiography is useful for preventing the complications associated with hepatic artery injury during surgery for gastric cancer.
    Surgery Today 10/2010; 40(10):967-71. · 0.96 Impact Factor
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    ABSTRACT: Prediction of the postoperative course of esophagectomy is an important part of the strict perioperative management of patients undergoing surgery for esophageal cancer. To evaluate their clinical importance, peripheral blood values, including white blood cell count (WBC), lymphocyte count, and the levels of total protein, transferrin, factor XIII, D-dimer, fibrin, and fibrinogen degradation products (FDP) were measured before and after esophagectomy for esophageal cancer in 24 patients. The preoperative WBC and the pre- and postoperative lymphocyte count were decreased remarkably in patients who received preoperative chemoradiotherapy. The values of perioperative serum transferrin were significantly lower in patients with postoperative pneumonia than in those without. The activity of plasma factor XIII was suppressed on postoperative day (POD) 7 in patients with pneumonia and on POD 14 in patients with leakage. These results suggest that patients who receive preoperative chemoradiotherapy are potentially immunosuppressed, the preoperative serum transferrin level is a possible predictive marker of postoperative pneumonia, and suppression of factor XIII activity is related to anastomotic insufficiency.
    Surgery Today 07/2010; 40(7):626-31. · 0.96 Impact Factor
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    ABSTRACT: Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real-time RT-PCR in several gastric cancer cell lines. Ninety-one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN-28 and SNU-1 were transfected with full-length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki-67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer.
    Cancer Science 03/2010; 101(3):639-45. · 3.48 Impact Factor
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    ABSTRACT: Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.
    International Journal of Clinical Oncology 03/2010; 15(2):126-34. · 1.41 Impact Factor