Hitoshi Katai

Japanese Foundation for Cancer Research, Edo, Tōkyō, Japan

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Publications (154)545.53 Total impact

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    ABSTRACT: A field for cancerization, or a field defect, is formed by the accumulation of genetic and epigenetic alterations in normal-appearing tissues, and is involved in various cancers, especially multiple cancers. Epigenetic alterations are frequently present in chronic inflammation-exposed tissues, but information on individual genes involved in the formation of a field defect is still fragmental. Here, using non-cancerous gastric tissues of cancer patients, we isolated 16 aberrantly methylated genes, and identified chromatin remodelers ACTL6B and SMARCA1 as novel genes frequently methylated in non-cancerous tissues. SMARCA1 was expressed at high levels in normal gastric tissues, but was frequently silenced by aberrant methylation in gastric cancer cells. Moreover, somatic mutations of additional chromatin remodelers, such as ARID1A, SMARCA2, and SMARCA4, were found in 30% of gastric cancers. Mutant allele frequency suggested that the majority of cancer cells harbored a mutation when present. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, in cancer cell lines promoted their growth. These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis and are frequently involved in the formation of a field defect. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Cancer letters. 11/2014;
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    ABSTRACT: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms of borderline malignancy that generally affect children and young adults.1 IMTs most commonly occur in the lung, mesentery, and retroperitoneum.1 Gastric IMTs are extremely rare, with less than 10 cases reported in English-language literature.2This article is protected by copyright. All rights reserved.
    Histopathology 10/2014; · 2.86 Impact Factor
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    ABSTRACT: Prognostic markers are urgently needed to optimize the postoperative treatment strategies for gastrointestinal stromal tumor (GIST). GISTs of the small intestine (I-GISTs) show more aggressive behavior than those of the stomach (S-GISTs), and the molecular background of the malignancy in I-GISTs may include potential prognostic biomarkers. We conducted integrated proteomic and transcriptomic analysis to identify genes showing differential expressions according to the tumor site. We generated protein expression profiles for 4 cases each of surgically resected I-GISTs and S-GISTs using label-free proteomic analysis. For proteins showing differential expressions, global mRNA expression was compared between 9 I-GISTs and 23 S-GISTs. Among the 2555 genes analyzed, we found that promyelocytic leukemia (PML), a tumor suppressor gene, was significantly down-regulated in I-GISTs at both the protein and mRNA levels (P <0.01; fold difference ≥2.0). Immunohistochemistry of 254 additional cases from multiple clinical facilities showed that PML-negative cases were significantly frequent in the I-GIST group (P <0.001). The 5-year recurrence-free survival rate was significantly lower in the PML-negative than in the PML-positive cases (60.1% versus 91.7%; P <0.001). Multivariate analysis revealed that down-regulation of PML was an independent unfavorable prognostic factor (HR = 2.739; P = 0.001). Our study indicated that prognostication based on PML expression may have potential for optimizing the treatment strategy for GIST patients. Further validation studies of PML for clinical application, and the investigation for the mechanistic significance of PML to clarify the molecular backgrounds of malignancy in GIST seem warranted.This article is protected by copyright. All rights reserved.
    Cancer Science 10/2014; · 3.48 Impact Factor
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    ABSTRACT: The efficacy of 5-fluorouracil (5FU)-based therapy, which remains the cornerstone of gastrointestinal cancer treatment, depends upon the expression of enzymes involved in pyrimidine metabolism, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT). We analyzed the expression of these genes in patients enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) and their possible roles as biomarkers for treatment outcomes.
    08/2014;
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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; · 2.64 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; · 3.79 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.
    07/2014;
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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; · 2.68 Impact Factor
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    ABSTRACT: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). Of 39,859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5,196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3,085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2,111 patients who underwent surgery in 2003 were used as an external validation set. Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 vs. 0.61; p<0.001). Moreover, calibration was accurate. We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.
    Annals of Oncology 03/2014; · 7.38 Impact Factor
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    ABSTRACT: Chromosomal abnormalities are good guideposts when hunting for cancer-related genes. We analyzed copy number alterations of 163 primary gastric cancers using array-based comparative genomic hybridization and simultaneously performed a genome-wide integrated analysis of copy number and gene expression using microarray data for 58 tumors. We showed that chromosome 6p21 amplification frequently occurred secondary to ERBB2 amplification, was associated with poorer prognosis and caused overexpression of half of the genes mapped. A comprehensive small interfering RNA knockdown of 58 genes overexpressed in tumors identified 32 genes that reduced gastric cancer cell growth. Enforced expression of 16 of these genes promoted cell growth in vitro, and six genes showing more than two-fold activity conferred tumor-forming ability in vivo. Among these six candidates, GLO1, encoding a detoxifying enzyme glyoxalase I (GLO1), exhibited the strongest tumor-forming activity. Coexpression of other genes with GLO1 enhanced growth-stimulating activity. A GLO1 inhibitor, S-p-bromobenzyl glutathione cyclopentyl diester, inhibited the growth of two-thirds of 24 gastric cancer cell lines examined. The efficacy was found to be associated with the mRNA expression ratio of GLO1 to GLO2, encoding glyoxalase II (GLO2), another constituent of the glyoxalase system. GLO1 downregulation affected cell growth through inactivating central carbon metabolism and reduced the transcriptional activities of nuclear factor kappa B and activator protein-1. Our study demonstrates that GLO1 is a novel metabolic oncogene of the 6p21 amplicon, which promotes tumor growth and aberrant transcriptional signals via regulating cellular metabolic activities for energy production and could be a potential therapeutic target in gastric cancer.Oncogene advance online publication, 24 March 2014; doi:10.1038/onc.2014.57.
    Oncogene 03/2014; · 8.56 Impact Factor
  • Hiroharu Yamashita, Hitoshi Katai
    Annals of surgery 03/2014; · 7.90 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; · 3.99 Impact Factor
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    ABSTRACT: Currently in Japan, differentiated-type gastric submucosal invasive cancers <500 μm with negative lymphovascular involvement are included in expanded pathological criteria for curative endoscopic treatment. This categorization is based on a retrospective examination of surgical resection cases in which patients suitable for such expanded criteria were determined to have a negligible risk of lymph node metastasis. We performed endoscopic submucosal dissection on a 66-year-old man with early gastric cancer in June 2004, and pathology revealed a well-differentiated adenocarcinoma, 16 × 8 mm in size, minute submucosal invasion depth (100 μm), and negative lymphovascular invasion or ulceration as well as tumor-free margins, so the case was diagnosed as a curative resection. In this case, however, local recurrence and distant metastasis resulted in August 2011. The patient received systemic chemotherapy but died of gastric cancer 23 months after recurrence.
    Gastric Cancer 01/2014; · 3.99 Impact Factor
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    ABSTRACT: To determine the HER2 amplification status and HER2 overexpression status in neuroendocrine carcinomas (NECs) of the stomach. We analyzed 51 gastric NECs, including 15 pure NECs and 36 NECs associated with adenocarcinoma and/or dysplasia, for HER2 amplification by dual-color chromogenic in situ hybridization and for HER2 expression by immunohistochemistry. HER2 amplification was observed in 3 NECs (8%) and in 7 (19%) adenocarcinoma/dysplasia associated with NECs. Immunohistochemically, all the NECs, including those showing HER2 amplification, invariably lacked HER2 expression. On the other hand, 3+/positive and 2+/equivocal HER2 overexpression was observed in 3 (8%) and 6 (17%) adenocarcinoma/dysplasia associated with NEC, respectively. HER2 expression is consistently absent in gastric NECs, regardless of the HER2 amplification status or association with HER2-positive adenocarcinoma/dysplasia components. Accordingly, HER2 is unlikely to be a valid therapeutic target in gastric NECs. Also, the absence of HER2 expression in NECs could be one of the causes of intratumoral heterogeneity of HER2 expression in gastric cancers. This article is protected by copyright. All rights reserved.
    Histopathology 12/2013; · 2.86 Impact Factor
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    ABSTRACT: To evaluate the HER2 status in patients with Siewert type II esophagogastric junction carcinoma. Trastuzumab is now approved for use in the treatment of human epidermal growth factor receptor 2 (HER2)-positive unresectable metastatic gastric or esophagogastric junction (EGJ) carcinoma. Several studies have evaluated HER2 status in EGJ carcinoma, but none has addressed the implication of HER2 positivity in patients with Siewert type II EGJ carcinoma. We retrospectively evaluated the frequency of HER2 positivity in a large single-center cohort of 208 patients with Siewert type II tumors. The relations between HER2 expression and the outcomes and other clinicopathologic features were examined. Overall, 18.2 % (38/208) of patients in our cohort had HER2-positive tumors. HER2 positivity was associated only with differentiated carcinomas. The 5-year overall survival (OS) rate was 58.7 %. The 5-year OS rates in the patient groups with HER2-negative and HER2-positive tumors were 61.2 and 48.5 %, respectively. There was no significant difference between the groups. Recurrence in the liver was observed in 23.7 % patients of the HER2-positive group and 7.6 % patients of the HER2-negative group. Multivariate analysis to identify the risk factors for liver recurrence revealed only HER2 positivity (p = 0.0155) as an independent predictive factor. HER2 positivity is a powerful predictor of liver recurrence in patients with Siewert type II EGJ carcinoma. Use of trastuzumab in combination with chemotherapy in an adjuvant setting can be a potentially useful therapeutic strategy to prevent hepatic recurrence in patients with resectable EGJ adenocarcinoma showing HER2 overexpression.
    World Journal of Surgery 10/2013; · 2.23 Impact Factor
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    ABSTRACT: Hereditary diffuse gastric cancer (HDGC), characterized by susceptibility to gastric signet ring cell carcinomas (SRCCs) and caused by CDH1 germline mutations, is rare in the Japanese. We present here a Japanese family with HDGC identified by comparative genomic hybridization (CGH) analysis. A 55-year-old woman was treated with completion gastrectomy for multiple SRCCs, and pathological examination revealed approximately 200 foci of SRCC with loss of E-cadherin expression. Her 30-year-old son had surveillance endoscopy and was found to have multiple SRCCs. He underwent total gastrectomy, and 32 foci of SRCC with loss of E-cadherin expression were histologically found. Although no point mutations were detected in CDH1 by sequencing, CGH revealed a 275-kb deletion involving exons 7-16 of CDH1 in both patients. While only a few HDGCs have been reported in East Asia, patients with multiple SRCC may need to be offered appropriate genetic counseling and testing in this area.
    Gastric Cancer 09/2013; · 3.99 Impact Factor
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    ABSTRACT: A 67-year-old male underwent endoscopic submucosal dissection (ESD) to treat early gastric cancer (EGC) in 2001. The lesion (50 mm × 25 mm diameter) was histologically diagnosed as poorly differentiated adenocarcinoma, with an ulcer finding. Although the tumor was confined to the mucosa with no evidence of lymphovascular involvement, the ESD was regarded as a non-curative resection due to the histological type, tumor size, and existence of an ulcer finding (as indicated by the 2010 Japanese gastric cancer treatment guidelines, ver. 3). Despite strong recommendation for subsequent gastrectomy, the patient refused surgery. An alternative follow-up routine was designed, which included five years of biannual clinical examinations to detect and measure serum tumor markers and perform visual assessment of recurrence by endoscopy and computed tomography scan after which the examinations were performed annually. The patient's condition remained stable for eight years, until a complaint of back pain in 2010 prompted further clinical investigation. Bone scintigraphy indicated increased uptake. Histological examination of biopsy specimens taken from the lumbar spine revealed adenocarcinoma resembling the carcinoma cells from the EGC that had been treated previously by ESD, and which was consistent with immunohistochemical findings of gastrointestinal tract cancer. Thus, the diagnosis of bone metastasis from EGC was made. The reported rates of EGC recurrence in surgically resected cases range 1.4%-3.4%, but among these bone metastasis is very rare. To our knowledge, this is the first reported case of bone metastasis from EGC following a non-curative ESD and occurring after an eight-year disease-free interval.
    World Journal of Gastroenterology 08/2013; 19(30):5016-20. · 2.55 Impact Factor
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    ABSTRACT: Neuroendocrine carcinoma (NEC) of the stomach has been recognized as a highly malignant tumor; however, because of its rarity, limited information is available regarding its clinicopathologic characteristics. Here, we investigated the morphologic and immunohistochemical features and prognosis of 51 cases of gastric NEC. Histologically, 40 lesions were large cell type, and 11 were small cell type. The large majority of the tumors exhibited a solid growth pattern (94%), with subsets of tumors showing trabecular (18%), scirrhous (10%), or tubular growth patterns (6%). Thirty-six cases (71%) had adenocarcinoma components and/or dysplasia. Among them, 26 cases (51%) were associated with intramucosal adenocarcinoma or dysplasia. Immunohistochemically, synaptophysin, chromogranin A, and CD56 were diffusely expressed in 48 (94%), 44 (86%), and 24 cases (47%), respectively. Two recently reported neuroendocrine markers, ASH1 and NKX2.2, were diffusely positive in 12 (24%) and 17 cases (33%), respectively. The diffuse or focal expression of TTF-1 was observed in 19 cases (37%). Among the 41 patients who underwent a curative resection, 16 patients (39%) developed radiologic recurrences, and the liver was the most frequent site of recurrence (11 patients, 27%). The 3- and 5-year overall survival rates were 57.8% and 44.7%, respectively. Regarding patient outcome, none of the histologic subclassifications, including small cell versus large cell types and the presence versus the absence of adenocarcinoma components and/or dysplasia, were significant. In a multivariate analysis, curative surgery was identified as the sole independent prognostic factor (P=0.03). Although gastric NECs exhibit significant morphologic diversity, their histologic subclassification is unlikely to be of immediate clinical relevance.
    The American journal of surgical pathology 07/2013; 37(7):949-59. · 4.06 Impact Factor
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    ABSTRACT: BACKGROUND: The accurate diagnosis of lymph node (LN) metastasis is important for making treatment decisions for gastric cancer patients. This multicenter study evaluated the clinical performance of the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp.), an automated system that detects cytokeratin 19 (CK19) mRNA, in detecting LN metastases in gastric cancer patients. METHODS: LNs retrieved from patients who had undergone gastric cancer surgery at one of the four Japanese hospitals involved in this study were divided into blocks at 2-mm intervals. Alternate blocks were examined with the OSNA assay and the remaining blocks were assessed histologically. RESULTS: A total of 394 LNs from 61 patients were examined. The concordance rate between the OSNA assay and the histological examination was 0.942 (95 % CI, 0.914-0.963). Sensitivity and specificity of the OSNA assay compared to the histological examination were 0.833 (95 % CI, 0.707-0.921) and 0.959 (95 % CI, 0.932-0.977), respectively. Discordant results were observed in 23 LNs (5.8 %), and these were mainly the result of tissue allocation bias and/or low CK19 protein expression. CONCLUSION: The OSNA assay can detect lymph node metastases in gastric cancer patients as accurately as the histological examination of blocks sectioned at 2-mm intervals. The OSNA assay is a useful tool for the intraoperative diagnosis of LN metastasis in gastric cancer patients.
    Gastric Cancer 06/2013; · 3.99 Impact Factor
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    ABSTRACT: BACKGROUND: We previously reported that S-1 plus cisplatin was feasible as adjuvant chemotherapy for stage III gastric cancer after D2 gastrectomy. Herein we evaluate the recurrence-free survival and overall survival rates as secondary endpoints based on updated follow-up data. METHODS: Patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Treatment consisted of 3 cycles of S-1 (40 mg/m(2) PO) twice daily on days 1-21 and cisplatin (60 mg/m(2) IV) on day 8, and S-1 was given on days 1-28 every 6 weeks until 1 year after surgery. RESULTS: From August 2007 to September 2009, 63 patients were accrued. Overall, 34 and 25 patients had stage IIIA and IIIB disease, respectively. After a median follow-up of 3.9 years, 16 patients experienced recurrence and 11 patients died. The 3-year recurrence-free survival rate was 74.1 % (95 % CI: 60.8-83.5 %, IIIA 81.8 %, IIIB 64.0 %). The 3-year overall survival rate was 84.5 % (95 % CI: 72.3-91.6 %, IIIA 87.9 %, IIIB 80.0 %). Recurrence sites included the peritoneum (n = 8), hematogenous sites (n = 6), and lymph nodes (n = 4). CONCLUSION: The present results indicate that adjuvant therapy with S-1 plus 3 cycles of cisplatin may provide a survival benefit to patients with stage III gastric cancer.
    Gastric Cancer 05/2013; · 3.99 Impact Factor

Publication Stats

3k Citations
545.53 Total Impact Points

Institutions

  • 2013
    • Japanese Foundation for Cancer Research
      Edo, Tōkyō, Japan
  • 2011–2013
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
  • 1996–2013
    • National Cancer Center
      • Endoscopy Division
      Tokyo, Tokyo-to, Japan
  • 2012
    • Catholic University of Korea
      Sŏul, Seoul, South Korea
  • 2010
    • Toranomon Hospital
      Edo, Tōkyō, Japan
  • 2006–2010
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
    • University Hospitals Birmingham NHS Foundation Trust
      Birmingham, England, United Kingdom
  • 2001
    • The University of Tokyo
      Tōkyō, Japan
  • 1994
    • Hospital Dos de Mayo
      Λίμα, Provincia de Lima, Peru