Ryoji Kushima

National Hospital Organization Kyushu Cancer Center, Hukuoka, Fukuoka, Japan

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Publications (175)570.53 Total impact

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    ABSTRACT: We assessed the clinicopathological characteristics of patients with serrated polyposis syndrome (SPS) and the incidence of advanced adenoma/colorectal cancer (CRC). We prospectively enrolled 249 consecutive patients who underwent colonoscopy at the National Cancer Center Hospital over a 6-month period. All the polyps were diagnosed using magnification colonoscopy and resection/biopsy. The enrolled patients were divided into two groups, i) those with ≥5 histologically diagnosed hyperplastic polyps (HPs) proximal to the sigmoid colon, with at least 2 polyps >10 mm in diameter and ii) those with ≥20 HPs distributed throughout the colon. The clinical characteristics of the two groups were compared, including lifestyle, family history of CRC and colonoscopic findings. HPs were identified in 228 patients, of whom 21 (8.4%) had SPS. All 21 patients had ≥20 HPs distributed throughout the colon, with none having >2 HPs ≥1 cm in diameter in the right colon. Synchronous advanced adenoma/CRC was diagnosed in 76/249 (30.5%) patients. The prevalence of advanced adenoma/CRC was higher among patients with compared to those without SPS (P=0.075). SPS was also associated with older age and higher body mass index (BMI). Our results suggested that older age and higher BMI are independent risk factors for SPS. Advanced adenoma/CRC tended to occur more frequently among patients with compared to those without SPS, although the difference was not statistically significant.
    Molecular and clinical oncology. 01/2015; 3(1):69-72.
  • Pathology International 12/2014; · 1.59 Impact Factor
  • Gastrointestinal Endoscopy 11/2014; · 4.90 Impact Factor
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    ABSTRACT: We here report on two rare cases of intrafollicular classical Hodgkin lymphoma (CHL). Case 1 was a 34-year-old man who underwent left supraclavicular lymph node biopsy. Case 2 was a 28-year-old woman who underwent surgical resection of an anterior mediastinal mass. The histology and microenvironment of both specimens resembled those of nodular lymphocyte predominant Hodgkin lymphoma. Nodular architecture was observed, which comprised normal-appearing small lymphocytes and scattered lymphocyte predominant (LP)-like cells. CD23(+) follicular dendritic cell meshworks were present in the nodules, surrounded by a mantle zone containing IgD(+) B cells. The LP-like cells were ringed by CD3(+) and PD-1(+) T cells, and numerous CD20(+) B cells were present in the background. However, the immunophenotypes of the LP-like cells resembled those of Hodgkin/Reed-Sternberg cells of CHL; they were positive for CD15, CD30, and PAX5, and negative for CD20, Bcl6, Oct2, and Bob1. These histopathological findings indicate that CHL can be derived from the germinal center.
    Pathology International 11/2014; · 1.59 Impact Factor
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    ABSTRACT: ABSTRACT This study aimed to indicate the patients' outcomes and pathological characteristics of follicular lymphoma (FL) with peripheral blood (PB) involvement. Of 533 patients with FL, 56 (11%) had PB involvement. Of the patients treated with rituximab, 39 patients with PB involvement had significantly shorter progression-free survival than 107 patients with stage IV disease without PB involvement (P = .021), but the overall survival was not different (P = .804). The histopathology of the primary sites was usually nodal (95%) low-grade (86%) FL with IGH/BCL2 fusion (75%). Flow cytometric and immunohistochemical analyses revealed that the incidence of CD10 positivity was lower in the bone marrow (55% and 58%) and PB (41% and not available) than in the primary site (86% and 93%) (P = .004 and P = .0001, respectively). Therefore, even if small lymphoma cells in the bone marrow and PB are negative for CD10, FL cannot be ruled out.
    Leukemia and Lymphoma 10/2014; · 2.61 Impact Factor
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    ABSTRACT: Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT.
    Journal of Cancer Research and Clinical Oncology 10/2014; · 3.01 Impact Factor
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    ABSTRACT: Background and Objectives The optimal surgical procedure for gastric remnant carcinoma (GRC) remains debatable. The aim of this study was to retrospectively evaluate the surgical treatments for T2-4 GRC developing after distal gastrectomy for gastric cancer.Methods Between 1970 and 2012, a total of 50 patients underwent R0 resection for T2-4 GRC. The clinicopathologic features, therapeutic methods, and follow-up data of these patients were reviewed.ResultsThe tumor was located at a non-anastomotic site of the remnant stomach in 43 of the 50 patients. Total gastrectomy was performed in 48 patients and partial gastrectomy was in two patients. Lymph node metastasis was found in 19 patients. Major postoperative complications occurred in 16 patients. The overall 1-, 3-, and 5-year survival rates of the 50 patients were 90%, 66%, and 44%, respectively. Presence of small intestinal or esophageal infiltration and postoperative complications was independently associated with poorer survival. Dissection of the perigastric and splenic hilar/artery nodes was found to have potential therapeutic benefit.Conclusions Surgical resection for T2-4 GRC developing after distal gastrectomy for gastric cancer can be invasive, but is feasible and effective. Total gastrectomy with splenectomy is one of the recommendable procedures for this disease. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 08/2014; · 2.84 Impact Factor
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    ABSTRACT: We recently reported that the presence of a papillary adenocarcinoma (pap) component was an independent risk factor for lymphatic involvement in endoscopically resected early gastric cancer (EGC). This study aimed to investigate the potential association between the presence of a pap component in EGC and lymph node metastasis (LNM).
    Journal of Gastroenterology 08/2014; · 4.02 Impact Factor
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    ABSTRACT: To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B-cell lymphoma (PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4-year progression free survival (PFS) rate was 78%, and the 4-year overall survival (OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6+ (P = 0.013), MUM1+ (P = 0.091), and pale cytoplasm (P = 0.064) were favorable prognostic indicators of PFS, and Bcl6+ (P = 0.051) and MUM1+ (P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity (n = 11) had 4-year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma (CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6+, MUM1+, Bcl2-, and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL.
    Pathology International 08/2014; 64(8). · 1.59 Impact Factor
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    ABSTRACT: Human epidermal growth factor receptor 2 (HER2) is likely overexpressed and/or amplified in locally advanced gastric cancer with extensive (bulky N2 or paraaortic) lymph node metastasis, and patients may benefit from treatment with anti-HER2 antibodies. This study evaluated the frequency of HER2 overexpression and amplification in The Japanese Gastric Cancer Association (JGCA)-N3 and JGCA-bulky N2 tumors and the correlation between HER2 status and survival.
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    ABSTRACT: Background Lung adenocarcinoma with morule-like components is an unusual variant of lung adenocarcinoma, comprising uniform, tightly packed spindle-shaped cells, which fill the lumen of the glandular structures of the carcinoma. The aim of the study was to outline the clinicopathologic features of this variant. Patients and Methods We examined a series of 904 surgically resected adenocarcinomas. We defined morule like components as small buds of spindle-cell proliferation in the tumor lumen of the glandular structures of the carcinoma and calculated their proportion of total tumor mass. Targeted genotyping was performed for KRAS, EGFR, HER2, BRAF. ALK rearrangements were analyzed immunohistochemically. Immunopositive cases were confirmed using RT-PCR and/or FISH. Results We detected 17 cases of adenocarcinoma with morule-like components. This variant, representing only 1.9% was associated with unfavorable outcomes and a mutation in the EGFR. Histologic examination revealed adenocarcinoma with morule-like components accounting for 5−50% of tumors. Among the morule-like components, 10 (58.8%) of the 17 samples showed intracytoplasmic lumina formation containing eosinophilic mucinous material. The presence of micropapillary components in adenocarcinoma with morule-like components suggests that morule-like components could be merely excessive growth of the micropapillary pattern. However, our results indicated no statistical differences in the MIB-1 indices of the morule-like components and the adjacent tumor components or the micropapillary components. The univariate and multivariate analyses revealed a correlation between the presence of a morule-like components and an unfavorable outcome. Conclusions Our study clearly indicated that adenocarcinoma with morule-like components is distinct unfavorable prognostic and predictor for EGFR mutation.
    Lung cancer (Amsterdam, Netherlands) 07/2014; · 3.14 Impact Factor
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    ABSTRACT: Pathological response rate (pathRR) is a common endpoint used to assess the efficacy of preoperative therapy for gastric cancer. PathRR is estimated based on the percentage of the residual tumor area in the primary tumorous bed. Various cutoff definitions used in previous trials (e.g., 10, 33, 40, 50, 67 %) often impair the comparability of pathRRs between trials.
    Gastric Cancer 06/2014; · 4.83 Impact Factor
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    ABSTRACT: HER2 protein overexpression and gene amplification are important biomarkers for identifying gastric cancer patients who may respond to HER2-targeted therapy using trastuzumab. The aim of this study was to evaluate the concordance between HER2 protein expression and gene amplification in both surgically resected tumors and matched biopsy specimens of gastric cancer. Formalin-fixed, paraffin-embedded sections of 207 surgically resected tumors and 158 biopsy specimens from 207 cases of invasive intestinal-type gastric cancer were analyzed. Protein expression was assessed using immunohistochemistry and graded by the modified scoring criteria for gastric cancer. Gene amplification was evaluated by fluorescence in situ hybridization (FISH). HER2 overexpression was observed in 17 % of both surgically resected tumors (35/207) and biopsy specimens (26/158). HER2 gene amplification was detected in 31 % (61/200) of surgically resected tumors and 32 % (47/147) of biopsy specimens. Except for immunohistochemistry (IHC) equivocal (2+) cases, the concordance rates between IHC and FISH was 90.9 % in surgically resected tumors and 90.2 % in biopsy specimens. In IHC 2+ cases, the rate of HER2 gene amplification was 56 and 38 % in surgically resected tumors and biopsy specimens, respectively. IHC-FISH discordance was mainly due to intratumoral heterogeneity and low-level gene amplification. The concordance rate of IHC results between surgically resected specimens and the corresponding biopsy specimen was 57.0 % (κ = 0.224), and in discordant cases, HER2 positivity in biopsies and HER2 negativity in surgically resected tumors were most common. The concordance rate of FISH results between surgically resected tumors and biopsy specimens was 72.7 % (κ = 0.313). Polysomy 17 was detected in 5.5 and 7.5 % of surgically resected tumors and biopsy specimens and significantly correlated with IHC score, but polysomy 17 could explain one IHC score 3+ and FISH-negative tumor only. Although high concordance rates between HER2-protein expression and gene amplification were observed in both surgically resected tumors and biopsy specimens, the agreement levels were evaluated to be fair. Polysomy 17 was infrequent and seemed to have limited impact on gastric HER2 testing. Further investigations are required for an appropriate biopsy method to reduce false results of HER2 testing and to clarify the clinical significance of intratumoral heterogeneity in HER2 status.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2014; · 2.56 Impact Factor
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    ABSTRACT: AimsMalignant rhabdoid tumours (MRTs) and epithelioid sarcomas (ESs) are distinctive malignant neoplasms with characteristic clinicopathologic features. However, these 2 tumour types share some phenotypes such as epithelioid/rhabdoid cytology, expression of epithelial markers, and immunohistochemical loss of INI1. The distinction can be problematic in atypical clinical settings, and ancillary diagnostic tools are needed. The expression of CD34 is widely cited to favor the diagnosis of ESs, but no formal comparative study has been performed in the post-INI1 era. Here, we evaluated the utility of SALL4 for differentiating MRTs from ESs and compared its performance to that of CD34.Methods and resultsFifteen MRTs and 36 ESs were retrieved. All MRTs and ESs lacked INI1 reactivity, except for 1 MRT that lacked BRG1. A representative slide from each case was stained using antibodies against SALL4 and CD34. Ten (67%) of 15 MRTs expressed SALL4. In contrast, only 1 (3%) of the 36 ES cases was SALL4 positive. CD34 staining was observed in 9 (60%) of 15 MRTs and 29 (81%) of 36 ESs.Conclusions Despite moderate sensitivity, SALL4 expression may aid in distinguishing MRTs from ESs. CD34 was found to have questionable utility in making such distinctions.This article is protected by copyright. All rights reserved.
    Histopathology 05/2014; · 3.30 Impact Factor
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    ABSTRACT: Solitary fibrous tumor (SFT) is an uncommon fibroblastic neoplasm. Although histologic characteristics and frequent CD34 expression allow for an accurate diagnosis in the majority of SFT cases, a wide histologic spectrum and an occasional unexpected immunophenotype may pose diagnostic challenges. Molecular analyses have discovered that almost all SFTs harbor an NAB2-STAT6 fusion gene, which is considered specific to this tumor type. Recent studies have suggested that STAT6 immunohistochemistry is a reliable surrogate for detection of the fusion gene. Our aim was to validate these findings by examining a large number of SFT cases and a broad array of 30 different types of non-SFT tumors. A total of 49 SFTs with a range of histologic characteristics and 159 benign or malignant tumors that can mimic SFTs were retrieved and stained for STAT6. All 49 SFTs (100%) showed STAT6 expression that was restricted in the nucleus, mostly in a diffuse and strong manner, irrespective of the tumor sites and histologic patterns. The staining was uniform in most cases but was heterogenous in about 20% of the cases in which zonal staining attenuation was observed, likely reflecting variability in fixation or tissue ischemia. In contrast, only 4 non-SFT tumors (2.5%) exhibited weak nuclear STAT6 expression, whereas the remaining 155 cases showed no staining or often weak reactivity in both the cytoplasm and the nucleus. Therefore, nuclear STAT6 immunoreactivity is a highly sensitive and specific marker of SFTs and can be helpful when diagnosis is inconclusive by conventional methods.
    The American journal of surgical pathology 04/2014; 38(4):552-9. · 4.59 Impact Factor
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    ABSTRACT: Accurate testing for human epidermal growth factor 2 (HER2)-positive status is now mandatory to identify gastric cancer patients that will respond to trastuzumab treatment. Immunohistochemistry testing is the primary method used in hospitals. We performed a study of diagnostic accuracy by assessing interobserver variability in immunohistochemistry scoring of HER2 and determined the effectiveness of an educational program for general pathologists that used full sections of gastric cancer specimens. A first ring study (Japanese gastric cancer [JGC] ring study) was performed by five expert pathologists, using 50 whole surgical sections selected by a coordinator, to confirm interobserver discrepancies. A second study (quality assurance/quality control program) involved administration of an educational program to 49 general pathologists that consisted of (i) comments and explanation for a set of pre-educational program cases, (ii) a lecture, and (iii) presentation of typical and special cases for discussion. Effectiveness was measured by comparing indices of the difference between scores before and after the program. The JGC ring study demonstrated good agreement in the interpretation of HER2-immunohistochemistry. Kappa coefficients among the five observers were 0.73 (substantial) and 0.84 (almost perfect) in 4 × 4 and 3 × 3 cross tests, respectively. In the second study, the concordance rate and kappa coefficients improved from pre-educational program levels of 78.6 % and 0.68, respectively, to post-educational program levels of 87.1 % and 0.79, respectively. The present results suggest that effective educational programs reduce interobserver differences between pathologists and provide optimal information regarding patient selection for treatment.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2014; · 2.56 Impact Factor
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    ABSTRACT: The prevalence of gastric cancer associated with Lynch syndrome (LS) is highly variable, and the underlying histologic pathway or molecular mechanisms remain unclear. From 1995 to 2012, 15 patients had been treated for both gastric and colonic adenocarcinomas and diagnosed as LS. In all cases, pathologic review, immunohistochemical analysis for mismatch-repair proteins, and microsatellite instability (MSI) tests were performed. To confirm LS, germline mutation tests and multiplex ligation-dependent probe amplification were performed. All gastric and colonic carcinomas were MSI-high and lost expressions of MLH1/PMS2 in 11 (73%) cases and MSH2/MSH6 in 4 (27%) cases. Remarkably, in a patient with LS and germline mutation of MLH1 gene, pyloric gland adenoma (PGA) transformed to adenocarcinoma during follow-up. In 2 additional cases, PGA was found adjacent to advanced gastric cancers. All PGAs in LS patients were MSI-high and lost expression of mismatch-repair proteins (MLH1/PMS2 in 2 cases and MSH2/MSH6 in 1 case), whereas none of the 14 sporadic PGAs was MSI-high or had lost expression of mismatch-repair proteins. On the basis of these observations, although very rare, we suggest the possibility that PGA may be a precursor lesion to gastric adenocarcinoma in LS and that the mismatch-repair deficient pathway of carcinogenesis is involved early in the gastric carcinogenesis pathway.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.
    The American journal of surgical pathology 02/2014; · 4.59 Impact Factor
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    ABSTRACT: The profiles of genetic and epigenetic alterations in cancer-related pathways are considered to be useful for selection of patients likely to respond to specific drugs, including molecular-targeted and epigenetic drugs. In this study, we aimed to characterize such profiles in gastric cancers (GCs). Genetic alterations of 55 cancer-related genes were analyzed by a benchtop next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes. The WNT pathway was activated by mutations of CTNNB1 in 2 GCs and potentially by aberrant methylation of its negative regulators, such as DKK3, NKD1, and SFRP1, in 49 GCs. The AKT/mTOR pathway was activated by mutations of PIK3CA and PTPN11 in 4 GCs. The MAPK pathway was activated by mutations and gene amplifications of ERBB2, FLT3, and KRAS in 11 GCs. Cell-cycle regulation was affected by aberrant methylation of CDKN2A and CHFR in 13 GCs. Mismatch repair was affected by a mutation of MLH1 in 1 GC and by aberrant methylation of MLH1 in 2 GCs. The p53 pathway was inactivated by mutations of TP53 in 19 GCs and potentially by aberrant methylation of its downstream genes in 38 GCs. Cell adhesion was affected by mutations of CDH1 in 2 GCs. Genes involved in cancer-related pathways were more frequently affected by epigenetic alterations than by genetic alterations. The profiles of genetic and epigenetic alterations are expected to be useful for selection of the patients who are likely to benefit from specific drugs.
    Gastric Cancer 02/2014; · 4.83 Impact Factor
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    ABSTRACT: Background:To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors.Methods:We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement.Results:In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001).Conclusions:The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.British Journal of Cancer advance online publication, 6 February 2014; doi:10.1038/bjc.2014.36 www.bjcancer.com.
    British Journal of Cancer 02/2014; · 5.08 Impact Factor
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    ABSTRACT: Background and study aims: After noncurative endoscopic submucosal dissection (ESD) for differentiated-type early gastric cancer (EGC), close observation is often preferred when a cancer-positive lateral margin is the only noncurative factor. However, sometimes recurrence is found during the observation period. This study aimed to examine risk factors for recurrent cancer based on the long-term clinical outcomes after noncurative ESD in which the only noncurative factor was a cancer-positive lateral margin. Patients and methods: Among 3784 EGCs (3316 patients) treated by ESD between 1997 and 2010, 77 noncurative differentiated-type EGCs (75 patients) were retrospectively analyzed after meeting the following inclusion criteria: 1) the only noncurative factor was a cancer-positive lateral margin; 2) close observation was selected after the ESD; and 3) > 1 year follow-up after ESD. Results: Locally recurrent cancer was found in 10 lesions within a median follow-up period of 59.8 months; no metastasis or gastric cancer-related death occurred. The cumulative incidence of local recurrence 5 years after ESD was 11.9 %. All locally recurrent cancers were mucosal differentiated-type adenocarcinomas. Multivariate analysis indicated that a cancer-positive lateral margin length of ≥ 6 mm was significantly associated with local recurrence (hazard ratio 20.8; 95 % confidence interval 5.2 % - 82.9 %; P < 0.001). The cut-off value of 6 mm was determined by the receiver operating characteristic curve; the sensitivity and specificity for 5-year risk of developing local recurrence were 66.7 % and 95.6 %, respectively. Conclusions: A cancer-positive lateral margin length of ≥ 6 mm was an independent risk factor for local recurrence, and this may be a useful criterion for selecting high-risk cases for stricter management.
    Endoscopy 02/2014; · 5.20 Impact Factor

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1k Citations
570.53 Total Impact Points


  • 2010–2014
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
    • University of Bayreuth
      Bayreuth, Bavaria, Germany
  • 2009–2014
    • National Cancer Center, Japan
      • Endoscopy Division
      Edo, Tōkyō, Japan
  • 2013
    • Hangzhou First People's Hospital
      Hang-hsien, Zhejiang Sheng, China
  • 2012
    • Catholic University of Korea
      Sŏul, Seoul, South Korea
  • 2011–2012
    • National Defense Medical College
      • Department of Surgery
      Tokorozawa, Saitama-ken, Japan
    • St. Luke's International Hospital
      Edo, Tōkyō, Japan
  • 1989–2009
    • Shiga University of Medical Science
      • • Department of Clinical Laboratory Medicine
      • • Department of Surgery
      • • Department of Pathology
      • • Department of Urology
      • • Department of Laboratory Medicine
      Ōtu, Shiga, Japan
  • 2008
    • National Hospital Organization Nagoya Medical Center
      • Division of Pathology
      Nagoya, Aichi, Japan
  • 2007
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
  • 2006
    • Kyoto Prefectural University of Medicine
      • Graduate School of Medical Science
      Kioto, Kyōto, Japan