Papers by Keishi Yamashita
Cancer medicine, 2015
Metastatic lymph node density (ND) has been reproducibly proven to be a prognostic factor in gast... more Metastatic lymph node density (ND) has been reproducibly proven to be a prognostic factor in gastric cancer. The molecular mechanisms that underlie this aggressiveness are underexplored. Here, we aimed to identify molecules associated with this unique phenotype. Tumor specimens from patients with stage III gastric cancer with high or low ND (n = 4 for both) were compared at the mRNA level using Affymetrix microarray (harboring 54,675 genes). The expression data were prioritized, and genes that correlated with ND were selected. Ultimately, the EGFR was validated as such a candidate molecule in patients with primary advanced gastric cancer who underwent standard treatment (n = 167). Expression data of the microarray were prioritized based on gene expression ratio and frequency of gene expression. The first priority genes to be selected were genes that are known to be amplified in cancer, which included NKX2.1, CHST9, CTNND2, SLC25A27, FGFR2, EGFR, and PTGER1. Of these genes, the EGFR ...
International journal of radiation oncology, biology, physics, 2014
To assess the long-term outcomes of patients with rectal cancer who received neoadjuvant chemorad... more To assess the long-term outcomes of patients with rectal cancer who received neoadjuvant chemoradiation therapy (NCRT) with concurrent S-1 and irinotecan (S-1/irinotecan) therapy. The study group consisted of 115 patients with clinical stage T3 or T4 rectal cancer. Patients received pelvic radiation therapy (45 Gy) plus concurrent oral S-1/irinotecan. The median follow-up was 60 months. Grade 3 adverse effects occurred in 7 patients (6%), and the completion rate of NCRT was 87%. All 115 patients (100%) were able to undergo R0 surgical resection. Twenty-eight patients (24%) had a pathological complete response (ypCR). At 60 months, the local recurrence-free survival was 93%, disease-free survival (DFS) was 79%, and overall survival (OS) was 80%. On multivariate analysis with a proportional hazards model, ypN2 was the only independent prognostic factor for DFS (P=.0019) and OS (P=.0064) in the study group as a whole. Multivariate analysis was additionally performed for the subgroup of...
International journal of molecular sciences, 2013
The HOP (homeobox only protein) homeobox (HOPX) is most closely related to the homeobox protein t... more The HOP (homeobox only protein) homeobox (HOPX) is most closely related to the homeobox protein that contains a homeobox-like domain but lacks certain conserved residues required for DNA binding. Here, we review the current understanding of HOPX in the progression of colorectal cancer (CRC). HOPX was initially reported as a differentiation marker and is expressed in various normal tissues. In the colon, HOPX is expressed uniquely in the quiescent stem cell, +4, and in differentiated mucosal cells of the colon. HOPX expression is markedly suppressed in a subset of cancers, mainly in an epigenetic manner. CRC may include separate entities which are differentially characterized by HOPX expression from a prognostic point of view. HOPX itself can regulate epigenetics, and defective expression of HOPX can result in loss of tumor suppressive function and differentiation phenotype. These findings indicate that HOPX may be both a central regulator of epigenetic dynamics and a critical determ...
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2014
S-1 is an oral anticancer drug widely used in postoperative adjuvant therapy for patients in Japa... more S-1 is an oral anticancer drug widely used in postoperative adjuvant therapy for patients in Japan with stage II/III gastric cancer. Candidates for more intense adjuvant treatments need to be identified, particularly among patients with stage III cancer. Univariate and multivariate analyses were conducted for patients with stage II/III gastric cancer who underwent surgery and received S-1 postoperatively between 2000 and 2010. Factors indicating poor prognosis identified by univariate analysis include male sex (P = 0.022), age ≥67 years (P = 0.021), intestinal-type histology (P = 0.049), lymph node ratio ≥16.7 % (P < 0.0001), open surgery (P = 0.039), as well as the 13th JGCA stage (P < 0.0001) and the 14th JGCA/7th International Union Against Cancer (UICC) stage (P < 0.0001). Multivariate analysis revealed that lymph node ratio ≥16.7 % and intestinal-type histology were significant as predictors of prognosis, independent from the pathological stages. Based on these and oth...
Neoplasia (New York, N.Y.), 2012
Homeodomain-only protein X (HOPX)-β promoter methylation was recently shown to be frequent in hum... more Homeodomain-only protein X (HOPX)-β promoter methylation was recently shown to be frequent in human cancers and was suggested as tumor suppressor gene in esophageal and gastric cancer. The aim of this study was to investigate the mechanistic roles of HOPX-β promoter methylation and its clinical relevance in colorectal cancer (CRC). HOPX-β promoter methylation was assessed in human CRC cell lines and 294 CRC tissues. HOPX mRNA and protein levels were measured in relation to HOPX-β promoter methylation. The effects of forced HOPX expression on tumorigenesis were studied using in vitro and in vivo assays. The association between HOPX-β promoter methylation and clinical relevance of CRC patients was determined. HOPX-β promoter methylation is cancer-specific and frequently found in CRC cell lines and tissues, resulting in the down-regulation of HOPX mRNA and protein levels. In CRC cell lines, forced expression of HOPX suppressed proliferation, invasion, and anchorage-independent growth. ...
World journal of gastroenterology : WJG, Jan 7, 2011
To investigate the trend in gastric cancer surgery in the context of rapid therapeutic advancemen... more To investigate the trend in gastric cancer surgery in the context of rapid therapeutic advancement in Japan and East Asia. A retrospective analysis was performed on 4163 patients who underwent gastric resection for gastric cancer with histological confirmation between 1971 and 2007 at the surgical unit in Kitasato University Hospital, to determine the trend in gastric cancer requiring surgery. Gastric cancer requiring surgical resection increased in our hospital, but the incidence adjusted for population was constant during the observed period. Interestingly, the ratio of diffuse type/intestinal type gastric cancer was unexpectedly unchanged, and that of advanced/early gastric cancer (EGC) was, however, markedly reduced, while the actual incidence of potentially curative advanced gastric cancer tended to decrease. The incidence of EGC requiring surgery tended to increase as a whole, which is consistent with increased prevalence of endoscopic surveillance. As a result, overall surviv...
Anticancer research, 2011
The aims of the present study were to compare staging between the old (6th edition) and new (7th ... more The aims of the present study were to compare staging between the old (6th edition) and new (7th edition) TNM classifications, and to evaluate the prognostic impact of extended lymph node dissection according to the new nodal staging in advanced gastric cancer. A total of 609 patients with advanced gastric cancer who had undergone curative gastric resection combined with extended lymph node dissection were enrolled in the present study. Survival curves were analyzed according to staging based on the TNM 6th and 7th editions and the Japanese Classification of Gastric Carcinoma (JCGC) 14th edition. The 5-year survival rates and the consecutive stage survival with no significant differences were: IB 88%; II 74%; IIIA 53%; IIIB 39%; and IV 18% (IIIA vs. IIIB, p=0.1307) by the TNM 6th edition; IB 94%; IIA 85%; IIB 71%; IIIA 68%; IIIB 48%; IIIC 23%; and IV 13%; (IIB vs. IIIA, p=0.7665; IIIC vs. IV, p=0.4156) by the TNM 7th and JCGC 14th editions; N0 85%; N1 70%; N2 46%; N3 18%; and M1 13%...
International journal of oncology, 2011
Aberrant methylation of gene promoters and corresponding loss of gene expression plays a critical... more Aberrant methylation of gene promoters and corresponding loss of gene expression plays a critical role in the initiation and progression of colorectal cancer. An IL-6-type cytokine receptor, leukemia inhibitory factor receptor (LIFR), is a component of cell-surface receptor complexes for multifunctional cytokines such as LIF. Herein, we report that LIFR is methylated in human colon cancer. LIFR promoter was methylated in primary tumor tissues with high frequency (65%, 52/80). Quantitative methylation-specific PCR (TaqMan-MSP) demonstrated differential promoter methylation of LIFR in primary colorectal cancer tissues as compared to normal colon tissues (5%, 4/80). LIFR methylation was not detectable in 13 normal colon mucosa samples obtained from patients without cancer. The mRNA expression of LIFR was significantly down-regulated in colon cancer tissues as compared to corresponding normal tissues. A strong expression of LIFR protein was observed in all non-malignant normal and adjac...
Hepato-gastroenterology
Advanced gastric cancer is a disease with dismal prognosis, which is mainly characterized by the ... more Advanced gastric cancer is a disease with dismal prognosis, which is mainly characterized by the emerging intraperitoneal free gastric cancer cells (IFCC). Our interest is to elucidate a causative phenotype linking to IFCC. Two hundred and sixty-nine resected gastric cancer patients examined for IFCC were enrolled at the Kitasato University Hospital to evaluate the clinical significance of the interaction between IFCC and other tumor phenotypes. IFCC was not found in the 22 early gastric cancers, and we were thus restricted to evaluate the remaining gastric cancers beyond the muscuralis propria (MP). Among the 247 advanced gastric cancer patients, IFCC was a potent univariate prognostic factor (p<0.0001) as well as lymph node metastasis (P<0.0001), depth of invasion (P=0.0015), and age (P=0.009). IFCC affects poor prognosis more strongly in the modest node disease (n0/n1) than in the severe node disease (n2/n3/M), even after considering D2 dissection. In the modest node diseas...
Anticancer research
The optimal surgical strategy for proximal gastric cancer (PGC) remains controversial. The princi... more The optimal surgical strategy for proximal gastric cancer (PGC) remains controversial. The principal difference between total gastrectomy (TG) and proximal gastrectomy (PG) is whether lymph node (LN) 4d is dissected by radical lymphadenectomy. The subjects were 243 patients with PGC who had undergone TG between 1990 and 2006. The incidences of metastases to individual LNs were assessed. The 5-year disease-specific survival (DSS) was examined in 179 patients who had undergone TG and an additional 37 patients who had undergone PG between 1990 and 2002. When PGC was confined to the muscularis propria (mp), no patient had LN 4d or 8 metastases although these nodes are considered regional LNs, and the 5-year DSS rate did not significantly differ between TG and PG. When the PGC extended beyond the mp, the patients with LN 4d or 8 metastases in N2 disease had very poor outcomes, similar to those with N3 disease. Multivariate analysis revealed that lymph node metastatic density over 40% (ND...
Anticancer research
Advanced gastric cancer is not controlled by surgery alone, although early gastric cancer can be ... more Advanced gastric cancer is not controlled by surgery alone, although early gastric cancer can be cured by curative gastrectomy. The TNM factor, representing physical tumor spread, accurately predicts patient prognosis in advanced gastric cancer, however, more elaborate prognostic factors reflecting the malignant degree are necessary in order to determine the therapeutic target. The purpose of this study was to select a significant prognostic indicator of gastric cancer with curative intent, independent of TNM stage among daily-feasible clinical parameters. The current study included 382 patients with stage IB to III gastric cancer after curative surgery, in which the robust univariate prognostic predictors were age (p < 0.0001), lymph node metastasis density of 40% or over (ND40) (p < 0.0001), and preoperative high value of carcinoembryonic antigen (CEA) (preCEA) (p = 0.0012), as well as TNM stage, preoperative high value of CA19-9 (preCA19-9), a glyco-chain antigen recognized...
Cancer research, Jan 15, 2003
Trypsin is a serine protease family member with a potential role in cancer invasion. We investiga... more Trypsin is a serine protease family member with a potential role in cancer invasion. We investigated trypsinogen expression at the RNA level in 49 esophageal squamous cell carcinomas (ESCCs) and 72 gastric adenocarcinomas. Almost all primary ESCC tissues (95%) showed reduced expression, and 9 of 13 ESCC cell lines were silenced for trypsinogen expression. Absent expression correlated with promoter hypermethylation of trypsinogen-4 by bisulfite DNA sequence. Moreover, we detected promoter hypermethylation in 50% of primary ESCCs by methylation-specific PCR. A subset of gastric adenocarcinomas (71%) also showed reduced trypsinogen accompanied by reduction in PAR2, a G protein activated by trypsin, and a propensity to penetrate beyond the gastric wall (P = 0.001). Our results support the notion that trypsin plays a tumor-suppressive role in human carcinoma.
Cancer research, Jan 15, 2001
Frequent loss of Fhit expression has been reported in human gastrointestinal tract carcinomas; op... more Frequent loss of Fhit expression has been reported in human gastrointestinal tract carcinomas; opinions remain divergent regarding Fhit expression in colorectal carcinoma (CRC) cases. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins, particularly Msh2. Immunohistochemical analysis of Msh2 and Fhit protein expression in 62 CRC cases was performed. The same CRCs were examined for allelic loss at three loci within or near FHIT and for FHIT mRNA expression by reverse transcription-PCR amplification. Half of the 62 CRC cases were positive for Fhit protein. Fhit protein loss correlated significantly with the progression of carcinoma (P < 0.01) as well as lymph node metastasis (P < 0.05). Loss of Msh2 protein correlated significantly with loss of Fhit protein (P < 0.05) and FHIT locus alteration (P < 0.05). Loss of Fhit protein expression was observed in 50% of sporadic CRCs and was significantly more frequent in m...
World Journal of Gastrointestinal Oncology, 2009
Sakuramoto S, Yamashita K, Watanabe M. Newly emerging standard chemotherapies for gastric cancer ... more Sakuramoto S, Yamashita K, Watanabe M. Newly emerging standard chemotherapies for gastric cancer and clinical potential in elderly patients.
Gastric Cancer, 2014
Little is known about risk factors for recurrence in stage IB gastric cancer without lymph node m... more Little is known about risk factors for recurrence in stage IB gastric cancer without lymph node metastasis. The aims of this study were to determine prognostic factors associated with long-term survival and to clarify patterns of recurrence. We retrospectively reviewed the medical records of 130 patients with primary gastric cancer who underwent gastrectomy at Kitasato University East Hospital from 2001 through 2010 and analyzed clinicopathological characteristics associated with survival and patterns of recurrence. Of the 130 patients, 12 (9.2 %) had recurrence, among whom 10 (83 %) patients died. Four patients (3.1 %) died of other diseases. The 5-year overall survival rate was 89 %. Of the 12 patients with recurrence, 7 (58 %) had liver metastasis, 3 (25 %) had distant lymph-node metastasis, 2 (17 %) had peritoneal dissemination, and 1 (8.3 %) had locoregional recurrence. Patients with tumors more than 5 cm in diameter tended to have recurrence within 1 year. Patients who had recurrence more than 2 years after surgery tended to survive for longer than 5 years after recurrence. Moderate or marked venous invasion (v2 or v3) and age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;65 years were significantly associated with relapse-free and overall survival on univariate analysis. On multivariate analysis, the only independent prognostic factor for relapse-free and overall survival was venous invasion. Moderate or marked venous invasion (v2 or v3) is an independent predictor of relapse-free and overall survival in stage IB node-negative gastric cancer. Postoperative adjuvant chemotherapy, currently not given to this subgroup of patients, may improve the outcomes of patients with stage IB node-negative gastric cancer, particularly when accompanied by venous invasion.
Cancer research, Jan 15, 2003
The detection of urothelial malignancies remains challenging. The majority of patients diagnosed ... more The detection of urothelial malignancies remains challenging. The majority of patients diagnosed with bladder cancer require life-long surveillance for disease recurrence. Monitoring strategies rely predominantly on invasive endoscopic techniques, which are inconvenient and uncomfortable. Multiple in vitro diagnostic technologies have been developed to supplant the contemporary standard of care. The U.S. Food and Drug Administration has approved several assays, but [because of inferior performance characteristics (low sensitivity and specificity)] these tests have not made a significant impact on practice, to date. We sought to develop a test for bladder cancer with better performance characterization detection based on a novel molecular approach. Matched urine and peripheral blood lymphocyte samples were obtained before surgery from 31 patients with bladder cancer (10 pTa, 4 pT1, and 17 pT2>or). DNA from these samples was subjected to allelic imbalance analysis using HuSNP chips...
PloS one, 2014
Cysteine biology is important for the chemosensitivity of cancer cells. Our research has focused ... more Cysteine biology is important for the chemosensitivity of cancer cells. Our research has focused on the epigenetic silencing of cysteine dioxygenase type 1 (CDO1) in colorectal cancer (CRC). In this study, we describe detection of CDO1 methylation in the plasma of CRC patients using methylation specific PCR (Q-MSP) and extensive analysis of the PCR reaction. DNA was extracted from plasma, and analysed for methylation of the CDO1 gene using Q-MSP. The detection rate of CDO1 gene methylation was calculated and compared with that of diluted DNA extracted from "positive control" DLD1 cells. CDO1 gene methylation in the plasma of 40 CRC patients that were clinicopathologically analysed was then determined. (1) The cloned sequence analysis detected 93.3% methylation of the promoter CpG islands of the CDO1 gene of positive control DLD1 cells and 4.7% methylation of the negative control HepG2 CDO1 gene. (2) DLD1 CDO1 DNA could not be detected in this assay if the extracted DNA was...
Molecular and Clinical Oncology, 2015
Systemic abrogation of TGF-β signaling results in tumor reduction through cytotoxic T lymphocytes... more Systemic abrogation of TGF-β signaling results in tumor reduction through cytotoxic T lymphocytes activity in a mouse model. The administration of polysaccharide-Kureha (PSK) into tumor-bearing mice also showed tumor regression with reduced TGF-β. However, there have been no studies regarding the PSK administration to cancer patients and the association with plasma TGF-β. PSK (3 g/day) was administered as a neoadjuvant therapy for 2 weeks before surgery. In total, 31 advanced gastric cancer (AGC) patients were randomly assigned to group A (no neoadjuvant PSK; n=14) or B (neoadjuvant PSK therapy; n=17). Plasma TGF-β was measured pre- and postoperatively. The allocation factors were clinical stage (cStage) and gender. Plasma TGF-β ranged from 1.85-43.5 ng/ml (average, 9.50 ng/ml) in AGC, and 12 patients (38.7%) had a high value, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;7.0 ng/ml. These patients were largely composed of poorly-differentiated adenocarcinoma with pathological stage III/IV. All the six elevated cases in group B showed a significant reduction of plasma TGF-β (from 21.6 to 4.5 ng/ml, on average), whereas this was not exhibited in group A. The cases within the normal limits of TGF-β remained unchanged irrespective of PSK treatment. Analysis of variance showed a statistically significant reduction in the difference of plasma TGF-β between groups A and B (P=0.019). PSK reduced the plasma TGF-β in AGC patients when the levels were initially high. The clinical advantage of PSK may, however, be restricted to specific histological types of AGC. Perioperative suppression of TGF-β by PSK may antagonize cancer immune evasion and improve patient prognosis in cases of AGC.
Hepato-gastroenterology
Macroscopic features and age may be important prognostic factors that discriminate survival among... more Macroscopic features and age may be important prognostic factors that discriminate survival among clinical conditions requiring different therapeutic strategies of advanced gastric cancer (AGC), and this study aimed to identify their clinical relevance.
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Papers by Keishi Yamashita