Mizutomo Azuma

Kitasato University, Edo, Tōkyō, Japan

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Publications (51)181.26 Total impact

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    ABSTRACT: NF-κB and CCL2/CCR2 chemokine axis play a central role in tumor progression such as stimulation of angiogenesis, acceleration of tumor invasion and migration, and suppression of innate immunosurveillance in the macrophage-related functions. There have been few reports regarding association of the macrophage function-related genes with clinical outcome in gastric cancer. We hypothesized that variants in genes encoding for NF-κB and CCL2/CCR2 axis may predict prognosis in gastric cancer and tested whether the functional single-nucleotide polymorphisms (SNPs) will be associated with clinical outcome in patients with gastric cancer across two independent groups. This study enrolled two cohorts which consisted of 160 Japanese patients and 104 U.S. patients with loco-regional gastric cancer. Genomic DNA was analyzed for association of 11 SNPs in NFKB1, RELA, CCL2, and CCR2 with clinical outcome using PCR-based direct DNA sequencing. The univariable analysis showed 4 SNPs had significant association with clinical outcome in the Japanese cohort, NFKB1 rs230510 remained significant upon multivariable analysis. The patients with the A allele of the NFKB1 rs230510 had significantly longer overall survival (OS) compared to those with the T/T genotype in both the Japanese and U.S. cohort in the univariable analysis. In contrast, genotypes with the T allele of CCL2 rs4586 were significantly associated with shorter OS compared to the C/C genotype in the U.S. cohort (HR: 2.43; P=0.015) but longer OS in the Japanese cohort (HR: 0.58; P=0.021), resulting in the statistically significantly opposite impact on OS (P=0.001). Our study provides the first evidence that the NFKB1 rs230510 and CCL2 rs4586 are significantly associated with clinical outcome in patients with loco-regional gastric cancer. These results also suggest that the genetic predisposition of the host may dictate the immune-related component of the tumor for progression in gastric cancer. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 11/2014; · 6.58 Impact Factor
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    ABSTRACT: Amphiregulin (AREG) and epiregulin (EREG) are important ligands to the epithelial growth factor receptor, which is involved in the regulation of progression and stemness in gastric cancer (GC). This study investigated whether frequent single nucleotide polymorphisms (SNPs) in genes of AREG and EREG are associated with recurrence-free survival and overall survival in patients with locally advanced GC.
    Pharmacogenetics and Genomics 09/2014; · 3.45 Impact Factor
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    ABSTRACT: Dysregulation of the c-MET signaling pathway results from various molecular mechanisms including mutation, amplification, and overexpression. Overexpression and amplification of c-MET have been correlated with poor clinical outcome in gastric cancer, whereas the associations between c-MET polymorphisms and prognosis have not been well defined. We examined the prognostic impact of functional polymorphisms of the MET gene on clinical outcome in gastric cancer.
    Pharmacogenetics and Genomics 09/2014; · 3.45 Impact Factor
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    ABSTRACT: Purpose A previous phase 1 study suggested that definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) is tolerable and active in patients with advanced esophageal cancer (AEC). This phase 2 study was designed to confirm the efficacy and toxicity of DCF-R in AEC. Methods and Materials Patients with previously untreated thoracic AEC who had T4 tumors or M1 lymph node metastasis (M1 LYM), or both, received intravenous infusions of docetaxel (35 mg/m2) and cisplatin (40 mg/m2) on day 1 and a continuous intravenous infusion of 5-fluorouracil (400 mg/m2/day) on days 1 to 5, every 2 weeks, plus concurrent radiation. The total radiation dose was initially 61.2 Gy but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during radiation therapy was reduced from 4 to 3. The primary endpoint was the clinical complete response (cCR) rate. Results Characteristics of the 42 subjects were: median age, 62 years; performance status, 0 in 14, 1 in 25, 2 in 3; TNM classification, T4M0 in 20, non-T4M1LYM in 12, T4M1LYM in 10; total scheduled radiation dose: 61.2 Gy in 12, 50.4 Gy in 30. The cCR rate was 52.4% (95% confidence interval [CI]: 37.3%-67.5%) overall, 33.3% in the 61.2-Gy group, and 60.0% in the 50.4-Gy group. The median progression-free survival was 11.1 months, and the median survival was 29.0 months with a survival rate of 43.9% at 3 years. Grade 3 or higher major toxicity consisted of leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). Conclusions DCF-R frequently caused myelosuppression and esophagitis but was highly active and suggested to be a promising regimen in AEC. On the basis of efficacy and safety, a radiation dose of 50.4 Gy is recommended for further studies of DCF-R.
    International journal of radiation oncology, biology, physics 07/2014; · 4.59 Impact Factor
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    ABSTRACT: Purpose We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC). Methods Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60 mg/m2 plus cisplatin 30 mg/m2, every 2 weeks) or irinotecan alone (irinotecan 150 mg/m2, every 2 weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS). Results 130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8 months [95% confidence interval (CI) 3.0–4.7]) than in the irinotecan group (2.8 months and ; hazard ratio 0.68, 95% CI 0.47–0.98; P = 0.0398). Median overall survival was 10.7 months in the BIRIP group and 10.1 months in the irinotecan group (HR 1.00, 95% CI 0.69–1.44, P = 0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P = 0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P = 0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P = 0.009), but any grade diarrhoea (17% versus 42%, P = 0.002) was more common in the irinotecan group. Conclusion BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial.
    European journal of cancer (Oxford, England: 1990) 05/2014; · 4.12 Impact Factor
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    ABSTRACT: Many malignant tumors consist of heterogeneous subpopulations of cells. This heterogeneity is associated with genetic characteristics. However, it remains unclear whether gene expression levels differ among specific sites of tumors in gastric cancer. We studied differences in gene expression levels among specific sites of primary tumors and synchronous lymph node metastases, using formalin-fixed, paraffin-embedded specimens resected surgically from 48 patients with previously untreated advanced gastric cancer. Specimens were obtained by laser-captured microdissection from five regions: (1) nonneoplastic mucosa, (2) surface layer (mucosa) of the primary tumor (surface sections), (3) middle layer (submucosa) of the primary tumor (middle sections), (4) the deepest layer of the primary tumor (muscularis propria or deeper) at the site of deepest invasion (deep sections), and (5) level 1 synchronous lymph node metastasis (lymph node metastases). Expression levels of the following target genes were determined by quantitative real-time polymerase chain reaction: thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF1α). TP, DPD, EGFR, and HIF1α gene expression levels were significantly higher in deep sections than in surface sections. TP, EGFR, VEGF, and HIF1α gene expression levels were significantly higher in lymph node metastases than in surface sections. TP, DPD, EGFR, VEGF, and HIF1α gene expression levels were positively correlated with the specific samples harvested from the tumors. Our results show that the expression levels of some genes in tumor cells can change in specific sites of tumors and can become higher in association with tumor progression.
    Gastric Cancer 03/2014; · 4.83 Impact Factor
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    ABSTRACT: Background Combined chemotherapy with cisplatin, 5-fluorouracil, and docetaxel (DCF) is a promising regimen for the treatment of esophageal squamous cell carcinoma (ESCC). However, careful attention must be paid to severe neutropenia. Methods A total of 17 patients with ESCC who received DCF therapy (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and 5-fluorouracil 750 mg/m2 on days 1–5) were studied from December 2010 through May 2012. We assessed the relation between neutropenia and the plasma concentration of each anticancer drug during the first course of DCF therapy. Results The maximum plasma concentration (C max) (mean ± SD) of docetaxel was 1,929 ± 458 ng/mL, while that of cisplatin was 2,870 ± 410 ng/mL, and that of 5-fluorouracil was 448 ± 121 ng/mL. The area under the plasma concentration–time curve (AUC) (mean ± SD) as calculated by MOMENT analysis was 2,428 ± 513 ng/mL h for docetaxel and 135,950 ± 22,330 ng/mL h for cisplatin. The AUC of 5-fluorouracil was not calculated. Higher C max and AUC values for docetaxel were associated with trends toward lower nadir absolute neutrophil counts (ANCs). The C max of docetaxel reflected the AUC of docetaxel. Neither the C max nor AUC of docetaxel was related to the occurrence of febrile neutropenia. Conclusions Higher C max or AUC values of docetaxel are associated with a trend toward lower nadir ANCs in patients with ESCC who receive DCF therapy. The C max of docetaxel, which is assessable immediately after starting treatment, might be useful for predicting the severity of the nadir ANC or for selecting the management method.
    Esophagus 01/2014; · 0.74 Impact Factor
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    ABSTRACT: Approximately 80%-95% of gastrointestinal stromal tumors (GISTs) show positive staining for KIT, while the other 5%-20% show negative staining. If the tumor is negative for KIT, but is positive for CD34, a histological diagnosis is possible. However, if the tumor is negative for KIT, CD34, S-100, and SMA, a definitive diagnosis is often challenging. Recently, Discovered on GIST-1 (DOG1) has received considerable attention as a useful molecule for the diagnosis of GIST. DOG1, a membrane channel protein, is known to be overexpressed in GIST. Because the sensitivity and specificity of DOG1 are higher than those of KIT, positive staining for DOG1 has been reported, even in KIT-negative GISTs. KIT-negative GISTs most commonly arise in the stomach and are mainly characterized by epithelioid features histologically. We describe our experience with a rare case of a KIT-negative GIST of the stomach that was diagnosed by positive immunohistochemical staining for DOG1 in a patient who presented with severe anemia. Our findings suggest that immunohistochemical staining for DOG1, in addition to gene analysis, is useful for the diagnosis of KIT-negative tumors that are suspected to be GISTs.
    World Journal of Gastroenterology 12/2013; 19(47):9133-6. · 2.43 Impact Factor
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    ABSTRACT: Lemur tyrosine kinase-3 (LMTK3) was recently identified as estrogen receptor (ER) -α modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotype predicted improved outcomes in breast cancer. Since different predominant ERs distributions link to breast and gastric cancer and little is known of the prognostic role of LMTK3 in gastric cancer, this study was conducted to clarify the prognostic role of these polymorphisms in gastric cancer. One-hundred and sixty-nine Japanese and one-hundred and thirty-seven United States (US) patients with localized gastric adenocarcinoma were enrolled. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Overall, these polymorphisms were not associated with survival in both cohorts. When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival (HR 4.37; 95% CI, 2.08-9.18; p<0.0001) and overall survival (OS) (HR 3.69; 95% CI, 1.65-8.24; p=0.0014) in the Japanese males and time to recurrence (HR 7.29; 95% CI, 1.07-49.80; p=0.043) in the US females. Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR 3.04; 95% CI, 1.08-8.56; p=0.035) and the US males (HR 3.39; 95% CI, 1.31-8.80; p=0.012). The prognostic role of these polymorphisms may be negative in gastric cancer. These findings suggest that the estrogen pathway may play a prognostic role in patient with gastric cancer but this may be dependent on the regional differences both in physiology and genetic alterations of gastric cancer.
    Molecular Cancer Therapeutics 08/2013; · 5.60 Impact Factor
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    ABSTRACT: BACKGROUND: Most previous studies of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms were retrospective; prospective studies are scant. OBJECTIVE: To prospectively assess the efficacy and safety of ESD for superficial esophageal neoplasms. DESIGN: Phase II study. SETTING: University hospital. PATIENTS: Fifty-two patients (median age 68 years; 48 men) who had a histologic diagnosis of superficial esophageal cancer without metastasis on CT or high-grade intraepithelial neoplasia (HGIN) were enrolled from April 2009 through November 2011. INTERVENTION: ESD was used to treat 56 lesions. All procedures were done by 4 endoscopists who each had previously performed ESD in more than 100 patients with gastric tumors. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the R0 resection rate, and secondary endpoints were the safety and the rate of accurately diagnosing tumor depth on endoscopic examination. RESULTS: The median treatment time was 69 minutes (24-168 minutes). The histopathologic diagnosis was squamous cell carcinoma in 49 lesions, HGIN in 5, and tubular adenocarcinoma in 2. The en bloc resection rate and R0 resection rate were 100% and 94.6%, respectively. The rates of adverse events during ESD and after ESD were 22.2% and 53.8%, respectively, but most events were mild. One patient (1.9%) had mediastinal emphysema without perforation. The rate of accurately diagnosing tumor depth on endoscopic examination was 76.8%. LIMITATIONS: Single-center, nonrandomized study. CONCLUSION: Our study showed that ESD was an effective and relatively safe treatment for superficial esophageal neoplasms. ESD may be a useful treatment option for superficial esophageal neoplasms in hospitals with endoscopists who are experts in performing ESD for gastric tumors. (Clinical trial registration number: UMIN000002047.).
    Gastrointestinal endoscopy 05/2013; · 4.90 Impact Factor
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    ABSTRACT: BACKGROUND: Percutaneous transesophageal gastrotubing (PTEG) was developed as an alternative route to access the gastrointestinal tract when percutaneous endoscopic gastrostomy is contraindicated. PTEG was originally performed without endoscopy. However, endoscopy may enhance safety. MATERIALS AND METHODS: A percutaneous rupture-free balloon is inserted under ultrasonographic control into an upper esophageal puncture site with a specialized needle. A guidewire is inserted through the needle into the rupture-free balloon, followed by a dilator and sheath. A placement tube is then inserted through the sheath. PTEG was performed in 85 patients (56 men and 29 women, mean age 70.5 years), 30 under fluoroscopic guidance and 55 under endoscopic guidance. These groups were subdivided into the nutrition subgroup (fluoroscopy, 20 patients; endoscopy, 23) and the decompression subgroup (fluoroscopy, 10 patients; endoscopy, 32) according to the purpose of PTEG. RESULTS: Nine (30%) of the 30 patients in the fluoroscopy group required endoscopic assistance to complete the procedure. None of the patients in the endoscopy group required fluoroscopy (P<0.05). The overall complication rate of PTEG was 16.4%. Complication rates in the nutrition and decompression subgroups were, respectively, 20.0 and 20.0% in the fluoroscopy group and 17.4 and 12.5% in the endoscopy group (NS). No patient required surgery or died because of the procedure. Survival rates did not differ significantly between the groups. CONCLUSION: Endoscopically assisted PTEG is a feasible, safe, and useful procedure. The use of endoscopy enhances visual information, may increase the safety of the procedure, and allows better confirmation of each step involved, without radiation exposure.
    European journal of gastroenterology & hepatology 05/2013; · 1.66 Impact Factor
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    ABSTRACT: BACKGROUND: Few studies have compared the outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in patients with early gastric cancer. METHODS: We studied 780 lesions for which endoscopic treatment was indicated according to the Japanese Gastric Cancer Association (JGCA) criteria or the extended National Cancer Center (NCC) criteria from April 1995 to December 2007. A total of 359 lesions were treated by endoscopic aspiration mucosectomy (EAM) between April 1995 and March 2003 (EAM group), and 421 lesions were treated by ESD between April 2003 and December 2007 (ESD group). Long-term outcomes (local recurrence rate, overall survival) were compared between the groups. RESULTS: The median follow-up was 73 months in the EAM group and 65 months in the ESD group. Overall, the local recurrence rate was significantly lower in the ESD group (0.2 %, 1/421) than in the EAM group (4.2 %, 15/359) (p < 0.05). For lesions meeting the JGCA criteria, the local recurrence rate was 2.9 % in the EAM group and 0 % in the ESD group (p < 0.05). For lesions meeting the NCC criteria, the local recurrence rate was 12.5 % in the EAM group and 0.6 % in the ESD group (p < 0.05). There was no significant difference between the groups in overall survival. CONCLUSIONS: On long-term follow-up, ESD was associated with a lower rate of local recurrence than EAM for lesions that met the JGCA or the NCC criteria. From the point of view of radical curability, ESD can be recommended for the management of lesions that meet either set of criteria.
    Gastric Cancer 04/2013; · 4.83 Impact Factor
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    ABSTRACT: BACKGROUND: Endoscopic submucosal dissection (ESD) for early gastric cancer accompanied by an ulcer scar remains challenging. Several counter-traction techniques have been attempted to facilitate ESD, but a standard procedure remains to be established. OBJECTIVE: To evaluate the efficacy and safety of double-endoscope ESD by using a single light source in patients with early gastric cancer accompanied by an ulcer scar. DESIGN: Single center, retrospective study. SETTING: Kitasato University East Hospital. PATIENTS: A total of 30 early gastric cancers with ulcer scars were treated by double-endoscope ESD in 30 patients from October 2008 through May 2012. INTERVENTION: Double-endoscope ESD. MAIN OUTCOME MEASUREMENTS: En bloc resection rate, complete resection rate, treatment time, and adverse events. RESULTS: The use of two endoscopes for ESD provided a good field of vision and allowed counter-traction to be applied to the lesion, clearly facilitating submucosal dissection. Because only a single light source was used, the working space of the endoscope room was not compromised. Moreover, it was unnecessary to prepare another light source or to coordinate image filing. The en bloc resection rate and complete resection rate were 100% and 90%, respectively, and the median treatment time was 80 minutes. As compared with historical control data obtained before the introduction of double-endoscope ESD, the rate of cutting into the specimen was significantly lower (7% vs 35%; P = .01). No serious adverse events occurred during the procedure. Postoperatively, however, 3 patients (10%) had delayed hemorrhage, and 1 (3.3%) had a delayed perforation. LIMITATIONS: Single-center, nonrandomized study. CONCLUSION: Our experience indicates that our procedure for double-endoscope ESD is useful and feasible in patients with early gastric cancer accompanied by an ulcer scar.
    Gastrointestinal endoscopy 03/2013; · 4.90 Impact Factor
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    ABSTRACT: The objectives of surveillance after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma are: (i) early detection and treatment of recurrence; and (ii) early detection and treatment of metachronous esophageal squamous cell carcinoma and second primary cancers. Protocols for follow up after EMR or ESD for esophageal squamous cell carcinoma should be based on the risks of lymph node metastasis and distant metastasis as assessed on the basis of tumor staging at initial treatment. Early detection of recurrence or metachronous carcinomas often allows curative or less invasive treatment. Particular attention should be paid to the development of metachronous esophageal squamous cell carcinomas and second primary cancers (in particular, head and neck cancer and gastric cancer because of their high incidence).
    Digestive Endoscopy 03/2013; 25(S1). · 1.61 Impact Factor
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    ABSTRACT: Endoscopic submucosal dissection is associated with a longer treatment time and a higher risk of patient discomfort than conventional procedures. Adequate, safe sedation is therefore essential. Sedation can cause adverse effects such as hypoxemia and hypotension, requiring continuous intraoperative and postoperative monitoring of blood pressure, use of the electrocardiogram, and arterial blood oxygen saturation by pulse oximetry. A physician and a nurse solely responsible for sedating and monitoring the patient should be present during treatment.A combination of benzodiazepines and analgesics are generally used for sedation, but new sedatives such as propofol and dexmedetomidine hydrochloride are expected to be useful agents. Endoscopists should become more familiar with sedatives, analgesics, and emergency procedures in the future.
    Digestive Endoscopy 02/2013; · 1.61 Impact Factor
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    ABSTRACT: To evaluate the usefulness and safety of argon plasma coagulation (APC) for superficial esophageal squamous-cell carcinoma (SESC) in high-risk patients. We studied 17 patients (15 men and 2 women, 21 lesions) with SESC in whom endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and open surgery were contraindicated from March 1999 through February 2009. None of the patients could tolerate prolonged EMR/ESD or open surgery because of severe concomitant disease (e.g., liver cirrhosis, cerebral infarction, or ischemic heart disease) or scar formation after EMR/ESD and chemoradiotherapy. After conventional endoscopy, an iodine stain was sprayed on the esophageal mucosa to determine the lesion margins. The lesion was then ablated by APC. We retrospectively studied the treatment time, number of APC sessions per site, complications, presence or absence of recurrence, and time to recurrence. The median duration of follow-up was 36 mo (range: 6-120 mo). All of the tumors were macroscopically classified as superficial and slightly depressed type (0-IIc). The preoperative depth of invasion was clinical T1a (mucosal cancer) for 19 lesions and clinical T1b (submucosal cancer) for 2. The median treatment time was 15 min (range: 10-36 min). The median number of treatment sessions per site was 2 (range: 1-4). The median hospital stay was 14 d (range: 5-68 d). Among the 17 patients (21 lesions), 2 (9.5%) had recurrence and underwent additional APC with no subsequent evidence of recurrence. There were no treatment-related complications, such as bleeding or perforation. APC is considered to be safe and effective for the management of SESC that cannot be resected endoscopically because of underlying disease, as well as for the control of recurrence after EMR and local recurrence after chemoradiotherapy.
    World Journal of Gastroenterology 10/2012; 18(38):5412-7. · 2.43 Impact Factor
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    ABSTRACT: Multicentric squamous dysplasia of the esophagus is characterized by multiple Lugol-voiding lesions (LVLs) on Lugol chromoendoscopy. Multiple LVLs are associated with a very high risk of multiple cancers arising in the esophagus as well as the head and neck. To gain insight into the pathogenesis of multiple LVLs of the esophageal mucosa, we studied risk factors for the development of such lesions in 76 patients who had a current or previous diagnosis of esophageal squamous cell carcinoma. All patients underwent Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Polymorphisms of the aldehyde dehydrogenase type 2 (ALDH2) gene were identified by polymerase chain reaction using sequence-specific primers. Clinical factors related to multiple LVLs were analyzed. All patients with multiple LVLs were drinkers. On univariate analysis, male sex (odds ratio [OR] 15, 95% confidence interval [CI] 1.84-122.45: P = 0.011), presence of the ALDH2-2 allele (OR 4.5, 95% CI 1.55-13.24: P = 0.006), and smoking index ≥1000 (OR 2.6, 95% CI 1.02-6.6: P = 0.045) were associated with multiple LVLs. On multivariate analysis, male sex (OR 10.02, 95% CI 1.13-88.44: P = 0.038) and presence of the ALDH2-2 allele (OR 4.56, 95% CI 1.4-14.82: P = 0.012) were associated with multiple LVLs. Among drinkers, a daily alcohol intake of ≥100 g pure ethanol with the ALDH2-2 allele (OR 17.5, 95% CI 1.97-155.59: P = 0.01) and a daily alcohol intake of <100 g pure ethanol with the ALDH2-2 allele (OR 8.85, 95% CI 1.68-46.69: P = 0.01) more strongly correlated with multiple LVLs than did a daily alcohol intake of <100 g pure ethanol without the ALDH2-2 allele, whereas a daily alcohol intake of ≥100 g pure ethanol without the ALDH2-2 allele (OR 4.0, 95% CI 0.54-29.81: P = 0.18) did not. In conclusion, male sex and the ALDH2-2 allele are associated with an increased risk for multiple LVLs of the esophageal mucosa in patients with esophageal squamous cell carcinoma. Among drinkers with the ALDH2-2 allele, the risk of multiple LVLs increased in parallel to the daily alcohol intake.
    Diseases of the Esophagus 09/2012; · 2.06 Impact Factor
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    ABSTRACT: The phase III CONFIRM clinical trials demonstrated that metastatic colorectal cancer patients with elevated serum lactate dehydrogenase (LDH) had improved outcome when the vascular endothelial growth factor receptor (VEGFR) inhibitor PTK/ZK (Vatalanib) was added to FOLFOX4 chemotherapy. We investigated the hypothesis that high intratumoral expression of genes regulated by hypoxia-inducible factor-1 alpha (HIF1α), namely LDHA, glucose transporter-1 (GLUT-1), VEGFA, VEGFR1, and VEGFR2, were predictive of outcome in CONFIRM-1. Tumor tissue was isolated by laser-capture microdissection from 85 CONFIRM-1 tumor specimens; FOLFOX4/placebo n=42, FOLFOX4/PTK/ZK n=43. Gene expression was analyzed using quantitative RT-PCR. In univariate analyses, elevated mRNA expression of LDHA, GLUT-1, and VEGFR1 were associated with response to FOLFOX4/PTK/ZK. In univariate and multivariate analyses, elevated LDHA and VEGFR1 mRNA levels were associated with improved progression-free survival in FOLFOX4/PTK/ZK patients. Furthermore, increased HIF1α and VEGFR2 mRNA levels were associated with decreased survival in FOLFOX/placebo patients but not in patients who received FOLFOX4/PTK/ZK. These are the first data suggesting intratumoral mRNA expression of genes involved in angiogenesis/HIF pathway may predict outcome to VEGFR-inhibitors. Biomarkers that assist in directing VEGFR-inhibitors toward patients with an increased likelihood of benefit will improve the cost-effectiveness of these promising agents.The Pharmacogenomics Journal advance online publication, 5 June 2012; doi:10.1038/tpj.2012.23.
    The Pharmacogenomics Journal 06/2012; · 5.13 Impact Factor
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    ABSTRACT: Endoscopic submucosal dissection (ESD) has become a standard treatment. However, the treatment time tends to be relatively long and insufflation and manipulation of the endoscope can increase pain and discomfort. We aimed to find an optimal method for sedation during ESD. Patients scheduled to undergo ESD for early gastric cancer or adenoma were randomly assigned to sedation with midazolam or propofol, and consciousness level was evaluated by bispectral index (BIS) monitoring. Primary end points of effectiveness (three parameters) and secondary end points of safety during ESD and after return to the ward were compared between the groups. Study registration was in the UMIN Clinical Trial Registry (UMIN 000001497), and the institutional trial number was KDOG 0801. From June 2008 through June 2009, we enrolled 178 patients (90 midazolam, 88 propofol). Regarding safety after ESD, recovery was significantly better in the propofol group immediately after and at 1 hour and 2 hours after return to the ward (P < 0.001). The number of patients who required a continuous supply of oxygen 2 hours after returning to the ward was significantly lower in the propofol group (midazolam 18; propofol 6; P = 0.010). Though propofol seemed to be better for effectiveness and safety, there were no statistically significant differences for all three primary end points and the safety parameters (hypotension, hypoxia, bradycardia). Propofol with BIS monitoring improved recovery of patients after ESD, though this study was underpowered to prove the effectiveness and safety of propofol.
    Endoscopy 06/2012; 44(6):584-9. · 5.20 Impact Factor
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    ABSTRACT: Multicentric squamous dysplasia in the esophagus can be visualized by Lugol chromoendoscopy as multiple Lugol-voiding lesions (LVLs). Narrow-band imaging combined with magnifying endoscopy (NBI-ME) facilitates the detection of superficial squamous cell carcinoma within the head and neck region (HNSCC). We investigated risk factors for superficial HNSCC in patients with esophageal squamous cell carcinoma (ESCC). Case-control study. We studied 71 patients with synchronous or former ESCC. All patients underwent screening of the head and neck by NBI-ME and Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Genetic polymorphisms of aldehyde dehydrogenase type 2 (ALDH2) were identified by the sequence-specific primer polymerase chain reaction. Clinical factors related to superficial HNSCC were analyzed. All patients with superficial HNSCC were drinkers. On univariate analysis, multiple LVLs (odds ratio [OR], 56.92; 95% confidence interval [CI] 6.93-467.38; P < .001), ALDH2-2 allele (OR, 14.48; 95% CI, 1.8-116.56; P = .01), current smoker (OR, 4.25; 95% CI, 1.44-12.57; P = .009), and smoking index ≥ 1,000 (OR, 3.45; 95% CI, 1.19-9.99; P = .02) were associated with superficial HNSCC. On multivariate analysis, multiple LVLs (OR, 61.12; 95% CI, 5.4-691.64; P = .001), ALDH2-2 allele (OR, 16.19; 95% CI, 1.15-228.06; P = .04), and current smoker (OR, 8.02; 95% CI, 1.09-59.22; P = .04) were associated with superficial HNSCC. Patients with ESCC, particularly drinkers, current smokers, and those with the ALDH2-2 allele and multiple LVLs, have an increased risk of superficial HNSCC.
    The Laryngoscope 06/2012; 122(6):1291-6. · 2.03 Impact Factor

Publication Stats

453 Citations
181.26 Total Impact Points

Institutions

  • 2003–2014
    • Kitasato University
      • Department of Gastroenterology
      Edo, Tōkyō, Japan
  • 2006–2013
    • University of Southern California
      • • Keck School of Medicine
      • • Department of Pathology
      • • Department of Biochemistry and Molecular Biology
      Los Angeles, California, United States
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2006–2011
    • University of California, Los Angeles
      • Division of Hematology and Medical Oncology
      Los Angeles, CA, United States
  • 2009
    • Tokyo Medical and Dental University
      • Department of Surgical Oncology
      Edo, Tōkyō, Japan