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1.  Panitumumab in Japanese Patients with Unresectable Colorectal Cancer: A Post-marketing Surveillance Study of 3085 Patients† 
Panitumumab was approved in Japan in April 2010 for the treatment of Kirsten rat sarcoma-2 virus oncogene wild-type unresectable and recurrent colorectal cancer. We conducted a post-marketing surveillance study to evaluate the safety and effectiveness of panitumumab.
After panitumumab was commercially available in Japan, all patients to be treated with panitumumab were enrolled. Data on baseline characteristics, treatment outcome, and incidence and severity of adverse drug reactions were collected.
In total, 3091 patients were registered. In the safety analysis set (n = 3085), panitumumab was administered as monotherapy (40.7%) or combination therapy (59.4%). The median treatment duration was 113 days (range: 1–559 days), and 451 (14.6%) patients received panitumumab for ≥10 months. The overall incidence rate of adverse drug reactions was 84.1%, and the most common adverse drug reaction was skin disorders (78.4%). The incidence rates (all grades) of interstitial lung disease, infusion reaction, electrolyte abnormalities and cardiac disorders were 1.3% (mortality rate: 0.6%), 1.5, 19.3 and 0.2%, respectively. The median survival time of patients treated with panitumumab monotherapy as the third-line, or later, therapy was 10.3 months.
This post-marketing survey in clinical practice confirmed the safety and effectiveness of panitumumab. The benefit/risk balance for panitumumab in Japanese patients with unresectable colorectal cancer remains favorable.
PMCID: PMC3941645  PMID: 24526771
colorectal cancer; panitumumab; post-marketing surveillance; safety
2.  EphA4 is a prognostic factor in gastric cancer 
Erythropoietin-producing hepatocellular (Eph) receptor, consisting of a family of receptor tyrosine kinases, plays critical roles in tumour development and is considered an attractive target for cancer therapy.
Tumour samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy. The expressions of EphA2, EphA4, and ephrinA1 were evaluated immunohistochemically.
High expressions of EphA2, EphA4, and ephrinA1 significantly correlated with variables related to tumour progression, including the depth of invasion, metastatic lymph nodes, pathological stage, and distant metastasis or recurrent disease. High expressions of EphA2, EphA4, and ephrinA1 were significantly associated with poorer disease-specific survival (DSS; p < 0.001, p < 0.001, p = 0.026). On multivariate analysis, EphA4 was an independent prognostic factor of DSS (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.1-4.8; p = 0.028), and EphA2 tended to be a prognostic factor (HR, 2.4; 95% CI, 1.0-5.8; p = 0.050). In stage II and III cancer, EphA4 and EphA2 were both significantly associated with shorter survival (p = 0.007 and 0.019), but only EphA2 was an independent prognostic factor (HR, 2.6; 95% CI, 1.1-6.3; p = 0.039).
EphA4 may play important roles in tumor progression and outcomes in patients with gastric cancer.
PMCID: PMC3720259  PMID: 23738943
EphA4; EphA2; ephrinA1; Gastric cancer
3.  Female Longitudinal Anal Muscles or Conjoint Longitudinal Coats Extend into the Subcutaneous Tissue along the Vaginal Vestibule: A Histological Study Using Human Fetuses 
Yonsei Medical Journal  2013;54(3):778-784.
It is still unclear whether the longitudinal anal muscles or conjoint longitudinal coats (CLCs) are attached to the vagina, although such an attachment, if present, would appear to make an important contribution to the integrated supportive system of the female pelvic floor.
Materials and Methods
Using immunohistochemistry for smooth muscle actin, we examined semiserial frontal sections of 1) eleven female late-stage fetuses at 28-37 weeks of gestation, 2) two female middle-stage fetus (2 specimens at 13 weeks), and, 3) six male fetuses at 12 and 37 weeks as a comparison of the morphology.
In late-stage female fetuses, the CLCs consistently (11/11) extended into the subcutaneous tissue along the vaginal vestibule on the anterior side of the external anal sphincter. Lateral to the CLCs, the external anal sphincter also extended anteriorly toward the vaginal side walls. The anterior part of the CLCs originated from the perimysium of the levator ani muscle without any contribution of the rectal longitudinal muscle layer. However, in 2 female middle-stage fetuses, smooth muscles along the vestibulum extended superiorly toward the levetor ani sling. In male fetuses, the CLCs were separated from another subcutaneous smooth muscle along the scrotal raphe (posterior parts of the dartos layer) by fatty tissue.
In terms of topographical anatomy, the female anterior CLCs are likely to correspond to the lateral extension of the perineal body (a bulky subcutaneous smooth muscle mass present in adult women), supporting the vaginal vestibule by transmission of force from the levator ani.
PMCID: PMC3635647  PMID: 23549829
Anal canal; levator ani muscle; longitudinal anal muscle; rectum; smooth muscle; embryology
4.  Study protocol of the B-CAST study: a multicenter, prospective cohort study investigating the tumor biomarkers in adjuvant chemotherapy for stage III colon cancer 
BMC Cancer  2013;13:149.
Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy. Several oral fluorouracil (5-FU) derivatives with different properties are available in Japan, but which drug is the most appropriate for each patient has not been established. Although efficacy prediction of 5-FU derivatives using expression of 5-FU activation/metabolism enzymes in tumors has been studied, it has not been clinically applied.
The B-CAST study is a multicenter, prospective cohort study aimed to identify the patients who benefit from adjuvant chemotherapy with each 5-FU regimen, through evaluating the relationship between tumor biomarker expression and treatment outcome. The frozen tumor specimens of patients with stage III colon cancer who receives postoperative adjuvant chemotherapy are examined. Protein expression of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) are evaluated using enzyme-linked immunosorbent assay (ELISA). mRNA expression of TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyl transferase (OPRT) are evaluated using reverse transcription polymerase chain reaction (RT-PCR). The patients’ clinical data reviewed are as follow: demographic and pathological characteristics, regimen, drug doses and treatment duration of adjuvant therapy, types and severity of adverse events, disease free survival, relapse free survival and overall survival. Then, relationships among the protein/mRNA expression, clinicopathological characteristics and the treatment outcomes are analyzed for each 5-FU derivative.
A total of 2,128 patients from the 217 institutions were enrolled between April 2009 and March 2012. The B-CAST study demonstrated that large-scale, multicenter translational research using frozen samples was feasible when the sample shipment and Web-based data collection were well organized. The results of the study will identify the predictors of benefit from each 5-FU derivative, and will contribute to establish the “personalized therapy” in adjuvant chemotherapy for colon cancer.
Trial registration NCT00918827, UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002013
PMCID: PMC3618253  PMID: 23530572
Colon cancer; Adjuvant chemotherapy; 5-FU; Personalized therapy; Cohort study; Translational research; Thymidine phosphorylase (TP); Thymidylate synthase (TS); Dihydropyrimidine dehydrogenase (DPD); Orotate phosphoribosyl transferase (OPRT)
5.  Benefit of the measurement of mesorectal extension in patients with pT3N1-2 rectal cancer without pre-operative chemoradiotherapy: Post-operative treatment strategy 
A treatment strategy based on the distance of mesorectal extension (DME) for pT3N1-2 rectal cancer patients without pre-operative chemoradiotherapy has not yet been defined. The present study aimed to describe the benefit of the measurement of mesorectal extension in stratifying treatment for pT3N1-2 rectal cancer patients. Data from 512 patients with pT3N1-2 rectal cancer undergoing curative surgery at 28 institutes were analyzed in this study. DME was measured histologically, and the optimal prognostic cut-off point of the DME was determined using Cox regression analyses. Survival was calculated using the Kaplan-Meier method. The patients were subdivided into two groups based on the optimal prognostic cut-off point: DME ≤4 mm and DME >4 mm. The DME was found to be a powerful independent risk factor for predicting distant and local recurrences. The recurrence-free 5-year survival rates of patients with DME >4 mm were significantly poorer for Stages IIIB (53.3%; p=0.0015; HR, 1.76; 95% CI, 1.233–2.501) and IIIC (32.9%; p=0.0095; HR, 1.64; 95% CI, 1.119–2.407) than for patients with DME ≤4 mm (69.7 and 50.4%, respectively). The cancer-specific survival rates of patients with DME >4 mm were also significantly worse than those with DME ≤4 mm. A value of 4 mm provides the best cut-off point for subdividing the mesorectal extension to predict oncologic outcomes. Measurement of mesorectal extension appears to be of benefit in stratifying patients for post-operative adjuvant treatments.
PMCID: PMC3570185  PMID: 23407463
rectal cancer; mesorectal extension; TNM staging system; prognosis; adjuvant treatment
6.  A rare case of extensive ductal carcinoma in situ of the breast with secretory features 
Rare Tumors  2012;4(4):e52.
We report a very rare case of extensive ductal carcinoma in situ (DCIS) of the breast with secretory features in a 30-year old Japanese woman. The patient presented with a nodule in the lower inner quadrant of the left breast measuring approximately 2–3 cm, accompanied by an irregular tumor shadow with segmental microcalcification on mammography. These findings suggested malignancy, and excisional biopsy was performed following core needle biopsy. Pathological diagnosis was that of DCIS with secretory features. A treatment plan of simple mastectomy and sentinel lymph node biopsy was chosen. Most previous reports have only described invasive secretory carcinoma of the breast. We have only been able to find 2 case reports of non-invasive secretory lesion in the English literature to date. Because the characteristics of this lesion are not widely known, we thought it important to share our findings.
PMCID: PMC3557566  PMID: 23372916
secretory carcinoma; breast cancer; ductal carcinoma in situ.
7.  Analysis of neurosensory adverse events induced by FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies 
Cancer Medicine  2012;1(2):198-206.
The grades of neurosensory adverse events (NSAEs) induced by FOLFOX4 treatment were compared between Asian and Western colorectal cancer patients and correlated with cumulative oxaliplatin doses. A total of 3359 patients treated with FOLFOX4 were analyzed: 1515 from two Asian studies (Japanese Post Marketing Surveillance [J-PMS] and MASCOT) and 1844 from four Western studies (EFC2962, N9741, EFC4584, and MOSAIC). The onset of NSAEs was analyzed in terms of treatment duration and cumulative dose of oxaliplatin. The incidence of grade ≥3 NSAEs ranged from 2.0% to 4.4% in Asian studies and 9.3% to 19% in Western studies. The cumulative doses of oxaliplatin that induced grade ≥3 NSAEs in 10% of patients were higher in Asian studies (1526 mg/m2 or not reached) than in Western studies (805–832 mg/m2). No significant correlations were noted between occurrence of grade ≥3 NSAEs and demographic/baseline characteristics. The frequency of escalation from grade 0 to 1 in J-PMS was statistically significantly lower than that in EFC4584, and that from grade 0 to 1 and from grade 1 to 2 in MASCOT lower than that in MOSAIC. The cumulative oxaliplatin doses administered during grade escalation in J-PMS were similar to those in EFC2962 or EFC4584. All grade-3 NSAEs in MASCOT and 96% of those in MOSAIC improved to grade 2 or less within 12 months of follow-up. The Asian populations accrued to these studies appear to be less susceptible to the neurotoxicity of oxaliplatin than the mainly Caucasian populations in the Western studies.
PMCID: PMC3544454  PMID: 23342269
Colorectal cancer; ethnic difference; FOLFOX4; neurotoxicity; oxaliplatin
8.  Study protocol of the SACURA trial: a randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer 
BMC Cancer  2012;12:281.
Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy, but the usefulness of adjuvant chemotherapy for stage II colon cancer remains controversial. The major Western guidelines recommend adjuvant chemotherapy for “high-risk stage II” cancer, but this is not clearly defined and the efficacy has not been confirmed.
SACURA trial is a multicenter randomized phase III study which aims to evaluate the superiority of 1-year adjuvant treatment with UFT to observation without any adjuvant treatment after surgery for stage II colon cancer in a large population, and to identify “high-risk factors of recurrence/death” in stage II colon cancer and predictors of efficacy and adverse events of the chemotherapy. Patients aged between 20 and 80 years with curatively resected stage II colon cancer are randomly assigned to a observation group or UFT adjuvant therapy group (UFT at 500–600 mg/day as tegafur in 2 divided doses after meals for 5 days, followed by 2-day rest. This 1-week treatment cycle is repeated for 1 year). The patients are followed up for 5 years until recurrence or death. Treatment delivery and adverse events are entered into a web-based case report form system every 3 months. The target sample size is 2,000 patients. The primary endpoint is disease-free survival, and the secondary endpoints are overall survival, recurrence-free survival, and incidence and severity of adverse events. In an additional translational study, the mRNA expression of 5-FU-related enzymes, microsatellite instability and chromosomal instability, and histopathological factors including tumor budding are assessed to evaluate correlation with recurrences, survivals and adverse events.
A total of 2,024 patients were enrolled from October 2006 to July 2010. The results of this study will provide important information that help to improve the therapeutic strategy for stage II colon cancer.
Trial registration NCT00392899.
PMCID: PMC3459783  PMID: 22769569
Colon cancer; Stage II; Adjuvant chemotherapy; UFT; Risk factor; Predictive factor; Prognostic factor; Surgery-alone; Randomized controlled trial; Japan
9.  Anococcygeal Raphe Revisited: A Histological Study Using Mid-Term Human Fetuses and Elderly Cadavers 
Yonsei Medical Journal  2012;53(4):849-855.
We recently demonstrated the morphology of the anococcygeal ligament. As the anococcygeal ligament and raphe are often confused, the concept of the anococcygeal raphe needs to be re-examined from the perspective of fetal development, as well as in terms of adult morphology.
Materials and Methods
We examined the horizontal sections of 15 fetuses as well as adult histology. From cadavers, we obtained an almost cubic tissue mass containing the dorsal wall of the anorectum, the coccyx and the covering skin. Most sections were stained with hematoxylin and eosin or Masson-trichrome solution.
The adult ligament contained both smooth and striated muscle fibers. A similar band-like structure was seen in fetuses, containing: 1) smooth muscle fibers originating from the longitudinal muscle coat of the anal canal and 2) striated muscle fibers from the external anal sphincter (EAS). However, in fetuses, the levator ani muscle did not attach to either the band or the coccyx. Along and around the anococcygeal ligament, we did not find any aponeurotic tissue with transversely oriented fibers connecting bilateral levator ani slings. Instead, in adults, a fibrous tissue mass was located at a gap between bilateral levator ani slings; this site corresponded to the dorsal side of the ligament and the EAS in the immediately deep side of the natal skin cleft.
We hypothesize that a classically described raphe corresponds to the specific subcutaneous tissue on the superficial or dorsal side of the anococcygeal ligament.
PMCID: PMC3381476  PMID: 22665356
Anal canal; rectum; smooth muscle; embryology; anatomy; histology
10.  Laparoscopic-assisted colectomy in a patient with colon cancer after percutaneous endoscopic gastrostomy 
A number of patients undergo percutaneous endoscopic gastrostomy (PEG) under various conditions. Open colectomy is usually performed for colon cancer in patients with PEG because the safety of the laparoscopic approach for such patients has not been established. However, if the laparoscopic approach is possible in patients with PEG, it will be less invasive and more helpful in rehabilitation into society.
Case presentation
We describe the case of a 64-year-old male with a T1 adenocarcinoma of the ascending colon 2 years after surgery for nasal cancer and PEG for dysphagia. The patient did not have any distant metastases or malignant tumors on preoperative computed tomography and positron-emission tomography. He underwent laparoscopic-assisted colectomy (LAC) with lymph node dissection. No complications developed during or after the surgery.
LAC could be a potential option for the treatment of colon cancer in patients who have undergone PEG. To our knowledge, this is the first recorded case of an ascending colon cancer treated with LAC under the condition of gastrostoma.
PMCID: PMC3468391  PMID: 22726364
Colon cancer; Laparoscopic colectomy; Percutaneous endoscopic gastrostomy
11.  Prognostic value of RKIP and p-ERK in gastric cancer 
The mitogen-activated protein kinase (MAPK) signaling pathway participates in several steps of tumour development and is considered a prominent therapeutic target for the design of chemotherapeutic agents. We evaluated the expressions of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MEK), an upstream regulator of ERK, and Raf kinase inhibitor protein (RKIP), and investigated correlations of these expressions with clinicopathological features and outcomes in gastric cancer.
Tumour samples were obtained from 105 patients with gastric adenocarcinomas who underwent radical gastrectomy. The expressions of phosphorylated ERK (p-ERK), phosphorylated MEK (p-MEK), and RKIP were analysed by immunohistochemical staining.
Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively. RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007). RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79). Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054). Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001). The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008).
Our results demonstrated that loss of RKIP was associated with tumour progression and poor survival. Negative RKIP expression combined with positive p-ERK expression was an independent predictor of poor outcomes in patients with gastric cancer.
PMCID: PMC3351370  PMID: 22463874
12.  A Japanese Post-marketing Surveillance of Cetuximab (Erbitux®) in Patients with Metastatic Colorectal Cancer 
Cetuximab (Erbitux®) was approved for the treatment of metastatic colorectal cancer in Japan in 2008. To verify information on the safety in practical use of cetuximab, we conducted post-marketing surveillance in accordance with the conditions for approval.
All patients to be treated with cetuximab were enrolled by the central enrolment method. Data on treatment status, and incidence and severity of adverse drug reactions were collected. The target number of patients was 1800.
A total of 2126 patients were enrolled from 637 institutions. Among 2006 patients analysed, 93.2% received cetuximab as third-line or later treatment. The median duration of treatment was 15.3 weeks, and 11.1% of patients received treatment for >48 weeks. The incidence of adverse drug reactions was 89.6%, of which ≥grade 3 was 21.5%. The incidence of infusion reactions was 5.7% (any grade), with 83.3% of them occurring at the first administration. The incidence of skin disorders was 83.7% (any grade), and the time to event varied for each skin disorder. The incidence of interstitial lung diseases was 1.2% (any grade). Diarrhoea and haematotoxicity scarcely occurred with cetuximab alone.
In this surveillance, the incidence and categories of adverse drug reactions are not distinct from previous reports. Although most patients received cetuximab as third-line or later treatment, treatment was maintained with a median duration of 15 weeks. Cetuximab treatment in practical use is considered to be well tolerated and clinically useful in Japanese patients with metastatic colorectal cancer.
PMCID: PMC3314322  PMID: 22327124
colorectal cancer; cetuximab; post-marketing surveillance
13.  PIK3CA mutation and methylation influences the outcome of colorectal cancer 
Oncology Letters  2011;3(3):565-570.
Colorectal cancer (CRC) occurs through the accumulation of genetic and epigenetic alterations. The epigenetic abnormalities, in cooperation with genetic alterations, are capable of causing aberrant gene function that results in cancer. In the present study, we examined mutations and methylation status in 164 CRCs to determine whether the combination of genetic and epigenetic alterations may be used to classify CRC patients in relation to their clinicopathological characteristics and outcomes. Mutation analyses for the KRAS and PIK3CA genes were performed using direct sequencing, and the MethyLight method was used to determine the methylation status of BNIP3, p16 and hMLH1. The combination of the KRAS mutation with methylation status did not have any association with clinicopathological characteristics and outcomes. However, patients with the PIK3CA mutation and/or high methylation (2 or 3 methylated genes) had significantly poorer outcomes in disease-specific survival (DSS) compared with those with wild-type PIK3CA and 0 or 1 methylated genes (P=0.0059). Additionally, multivariate analysis revealed that the PIK3CA mutation and/or a high level of methylation predicts a poor DSS independently of clinicopathological characteristics. Our results suggest that a combination of genetic and epigenetic alterations is a potent biomarker for predicting the prognosis of CRC.
PMCID: PMC3362351  PMID: 22740953
PIK3CA; BNIP3; methylation; mutation; colorectal cancer
14.  Prognostic value of co-expression of STAT3, mTOR and EGFR in gastric cancer 
Signal transducer and activator of transcription 3 (STAT3), the mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR), proteins that mediate intracellular signaling related to cell growth, proliferation and differentiation, have received considerable interest as possible targets for cancer treatment. We examined whether the expression of STAT3, mTOR and EGFR correlates with clinicopathological features and patient outcome in gastric cancer. Tumor samples were obtained from 126 patients with gastric adenocarcinomas who underwent a radical gastrectomy between 1999 and 2002. The expression of phosphorylated STAT3 (p-STAT3), p-mTOR and EGFR was analyzed by immunohistochemical staining. The relations of these to clinicopathological factors and outcomes were assessed. The expression of p-STAT3 p-mTOR and EGFR positively correlated with the following variables related to tumor progression: the depth of tumor invasion (T1 vs. T2–4; p<0.001, p=0.036 and p<0.001, respectively), lymph node involvement (p=0.008, p=0.027 and p=0.007) and tumor stage (I vs. II–IV; p<0.001, p=0.041 and p<0.001). The expression of p-STAT3 and EGFR was significantly related to distant metastasis and recurrence (p=0.001 and p=0.039), as well as significantly poorer disease-specific survival (DSS; p=0.0018 and p=0.026). The expression of p-STAT3 was a marginally non-significant prognostic factor for DSS (hazard ratio=2.0, 95% CI 0.91–4.5, p=0.082). Increasing expression of p-STAT3, p-mTOR and EGFR was associated with progressively worse DSS. Interactions among p-STAT3, p-mTOR and EGFR may play an important role in tumor progression and outcomes in patients with gastric cancer.
PMCID: PMC3440663  PMID: 22977493
signal transducer and activator of transcription 3; mammalian target of rapamycin; epidermal growth factor receptor; gastric cancer
15.  Genome-wide integrative analysis revealed a correlation between lengths of copy number segments and corresponding gene expression profile 
Bioinformation  2011;7(6):280-284.
Microarray analysis has been applied to comprehensively reveal the abnormalities of DNA copy number (CN) and gene expression in human cancer research during the last decade. These analyses have individually contributed to identify the genes associated with carcinogenesis, progression, metastasis of tumor cells and poor prognosis of cancer patients. However, it is known that the correlation between profiles of CN and gene expression does not highly correlate. Factors which determine the degree of correlation remain largely unexplained. To investigate one such factor, we performed trend analyses between the lengths of CN segments and corresponding gene expression profiles from microarray data in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC). Significant correlations were observed in CN gain of HCC and CRC (p<0.05). The trend of the CN loss showed a significant correlation in HCC although there was no correlation between the length of CN loss segments and gene expression in CRC. Our findings suggest that the influence of CN on gene expression highly depends on the length of CN region, especially in the case of CN gain. To the best of our knowledge, this is the first study describing the correlation between lengths of CNA segments and expression profiles of corresponding genes.
PMCID: PMC3280495  PMID: 22355221
copy number alteration; gene expression; microarray; hepatocellular carcinoma; colorectal carcinoma
16.  Methylated BNIP3 gene in colorectal cancer prognosis 
Oncology Letters  2010;1(5):865-872.
The DNA methylation of apoptosis-related genes in various cancers contributes to the disruption of the apoptotic pathway and results in resistance to chemotherapeutic agents. Irinotecan (CPT-11) is one of the key chemotherapy drugs used to treat metastatic colorectal cancer (CRC). However, a number of metastatic CRC patients do not benefit from this drug. Thus, the identification of molecular genetic parameters associated with the response to CPT-11 is of interest. To identify apoptosis-related genes that may contribute to CPT-11 resistance, microarray analysis was conducted using colon cancer cells in which 5-aza-2′deoxycytidine (DAC) enhanced sensitivity to CPT-11. Microarray analysis identified 10 apoptosis-related genes that were up-regulated following treatment with DAC. Among the genes, Bcl-2/adenovirus E1B 19 kDa protein interacting protein 3 (BNIP3), a Bcl-2 family pro-apoptotic protein, was identified as being involved in CPT-11 resistance following methylation of its promoter. An analysis of 112 primary CRC cases revealed that approximately 58% of cases showed BNIP3 methylation, and that patients with methylation exhibited a poorer outcome compared to those without methylation. In addition, in 30 patients who received first-line CPT-11 chemotherapy, patients with methylation exhibited resistance to chemotherapy compared to patients with no methylation. The results suggest that methylation of BNIP3 is a predictive factor in the prognosis and response to CPT-11 treatment in CRC patients.
PMCID: PMC3436434  PMID: 22966396
methylation; colorectal cancer; prognosis; apoptosis; irinotecan
17.  Clinical Omics Analysis of Colorectal Cancer Incorporating Copy Number Aberrations and Gene Expression Data 
Cancer Informatics  2010;9:147-161.
Colorectal cancer (CRC) is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC) and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an “omics” study by integrating many kinds of analysis into a single comprehensive investigation.
In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers.
Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC.
This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC.
Materials and methods:
Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro-dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language.
We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene expression analysis, together with the clinical information, suggested UGT2B28, LOC440995, CXCL6, SULT1B1, RALBP1, TYMS, RAB12, RNMT, ARHGDIB, S1000A2, ABHD2, OIT3 and ABHD12 as genes that are possibly associated with CRC. Some of these genes have already been reported as being related to CRC. TYMS has been reported as being associated with resistance to the anti-cancer drug 5-fluorouracil, and we observed a copy number increase for this gene. RALBP1, ARHGDIB and S100A2 have been reported as oncogenes, and we observed copy number increases in each. ARHGDIB has been reported as a metastasis-related gene, and our data also showed copy number increases of this gene in cases with metastasis.
The combination of CNA analysis and gene expression analysis was a more effective method for finding genes associated with the clinicopathological classification of CRC than either analysis alone. Using this combination of methods, we were able to detect genes that have already been associated with CRC. We also identified additional candidate genes that may be new markers or targets for this form of cancer.
PMCID: PMC2918356  PMID: 20706620
colorectal cancer; clinical omics; microarray; copy number aberration
18.  Colorectal Carcinoma: Local Tumor Staging and Assessment of Lymph Node Metastasis by High-Resolution MR Imaging in Surgical Specimens 
Purpose. To assess the accuracy of high-resolution MR imaging as a means of evaluating mural invasion and lymph node metastasis by colorectal carcinoma in surgical specimens. Materials and Methods. High-resolution T1-weighted and T2-weighted MR images were obtained in 92 surgical specimens containing 96 colorectal carcinomas. Results. T2-weighted MR images clearly depicted the normal colorectal wall as consisting of seven layers. In 90 (94%) of the 96 carcinomas the depth of mural invasion depicted by MR imaging correlated well with the histopathologic stage. Nodal signal intensity on T2-weighted images (93%) and nodal border contour (93%) were more accurate than nodal size (89%) as indicators of lymph node metastasis, and MR imaging provided the highest accuracy (94%–96%) when they were combined. Conclusion. High-resolution MR imaging is a very accurate method for evaluating both mural invasion and lymph node metastasis by colorectal carcinoma in surgical specimens.
PMCID: PMC2817863  PMID: 20150975
19.  Efficacy of laser capture microdissection plus RT-PCR technique in analyzing gene expression levels in human gastric cancer and colon cancer 
BMC Cancer  2008;8:210.
Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase gene expressions are reported to be valid predictive markers for 5-fluorouracil sensitivity to gastrointestinal cancer. For more reliable predictability, their expressions in cancer cells and stromal cells in the cancerous tissue (cancerous stroma) have been separately investigated using laser capture microdissection.
Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase mRNA in cancer cells and cancerous stroma from samples of 47 gastric and 43 colon cancers were separately quantified by reverse transcription polymerase chain reaction after laser capture microdissection.
In both gastric and colon cancers, thymidylate synthase and orotate phosphoribosyltransferase mRNA expressions were higher (p < 0.0001, p <0.0001 respectively in gastric cancer and P = 0.0002, p < 0.0001 respectively in colon cancer) and dihydropyrimidine dehydrogenase mRNA expressions were lower in cancer cells than in cancerous stroma (P = 0.0136 in gastric cancer and p < 0.0001 in colon cancer). In contrast, thymidine phosphorylase mRNA was higher in cancer cells than in cancerous stroma in gastric cancer (p < 0.0001) and lower in cancer cells than in cancerous stroma in colon cancer (P = 0.0055).
By using this method, we could estimate gene expressions separately in cancer cells and stromal cells from colon and gastric cancers, in spite of the amount of stromal tissue. Our method is thought to be useful for accurately evaluating intratumoral gene expressions.
PMCID: PMC2533342  PMID: 18652704
20.  JTE-522, a selective COX-2 inhibitor, inhibits growth of pulmonary metastases of colorectal cancer in rats 
BMC Cancer  2005;5:26.
Epidemiological studies have shown that individuals who regularly consume NSAIDs have lower rates of mortality associated with colorectal cancer. Because COX-2 inhibitors prevent tumor growth through some mechanisms, we assessed the effect of JTE-522, a selective COX-2 inhibitor, on pulmonary metastases of colon cancer in a rat model.
A suspension of 5 × 106 RCN-9 (rat colon cancer cells) was injected into the tail vein of 24 anesthetized male F344/DuCrj rats. Oral JTE-522 (0, 3, 10, or 30 mg/kg/day) was administered from the day before RCN-9 injection until the end of the study. Twenty-four days later, the lungs were removed from sacrificed rats and weighed. Pulmonary metastatic tumors were microscopically evaluated in the largest cross sections. We also performed immunohistochemical staining for both COX-2 and VEGF.
JTE-522 dose-dependently decreased lung weight (p = 0.001) and the size of pulmonary metastatic tumors (p = 0.0002). However, the differences in the number of metastatic tumors among 4 groups were insignificant. Significant adverse effects of JTE-522 were undetectable. Immunohistochemical staining showed high levels of both COX-2 and VEGF in pulmonary metastatic tumors.
JTE-522 dose-dependently decreased the size, but not the number of pulmonary metastases. COX-2 inhibitors might block metastatic tumor growth, but not actual metastasis. Selective COX-2 inhibitors might be useful as therapeutic agents that inhibit the growth of metastatic tumors, as well as the tumorigenesis of colorectal cancer.
PMCID: PMC555553  PMID: 15743541

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