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1.  Successful management of rectovaginal fistula treated by endorectal advancement flap: report of two cases and literature review 
SpringerPlus  2015;4:21.
Rectovaginal fistula (RVF) sometimes has a difficulty in treatment. This report describes two patients who suffered from RVF.
Case descriptions
One patient was a 76-year-old woman who had a RVF over 30 years after the 3rd childbirth. She underwent endorectal advancement flap (ERAF). She had a nighttime soiling after ERAF once a month, which disappeared one year after surgery. Second patient was a 23-year-old woman who had a RVF one month after the first childbirth. She underwent ERAF, and did not have any complications.
Discussion and evaluation
Both patients did not develop recurrence for four years. Quality of life after ERAF was satisfactory in both patients. ERAF is a safe procedure in terms of both short and long outcomes. We also present a review of the literature concerning ERAF for RVF.
ERAF can be a potential option as a treatment for RVF.
PMCID: PMC4325007
Rectovaginal fistula; Endorectal advancement flap
2.  Periostin suppression induces decorin secretion leading to reduced breast cancer cell motility and invasion 
Scientific Reports  2014;4:7069.
The ability of cancer cells to metastasize is dependent on the interactions between their cell-surface molecules and the microenvironment. However, the tumor microenvironment, especially the cancer-associated stroma, is poorly understood. To identify proteins present in the stroma, we focused on phyllodes tumors, rare breast tumors that contain breast stromal cells. We compared the expression of proteins between phyllodes tumor and normal tissues using an iTRAQ-based quantitative proteomic approach. Decorin was expressed at reduced levels in phyllodes tumor tissues, whereas periostin was upregulated; this result was validated by immunohistochemical analysis of phyllodes tumors from 35 patients. Additionally, by immunoprecipitation and mass spectrometry, we confirmed that decorin forms a complex with periostin in both phyllodes tumors and BT-20 breast cancer cells. Following siRNA-mediated knockdown of periostin in T-47D cells, secreted decorin in the culture medium could be detected by multiple reaction monitoring (MRM). Furthermore, periostin knockdown in BT-20 cells and overexpression of decorin in MDA-MB-231 cells inhibited cell motility and invasion. Our results reveal the molecular details of the periostin–decorin complex in both phyllodes tumor tissues and breast cancer cells; this interaction may represent a novel target for anti-cancer therapy.
PMCID: PMC4233340  PMID: 25400079
3.  Incidence and Clinical Features of Drug-induced Lung Injury in Patients with Advanced Colorectal Cancer Receiving Cetuximab: Results of a Prospective Multicenter Registry 
Japanese Journal of Clinical Oncology  2014;44(11):1032-1039.
We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system.
We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy.
Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days).
The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients.
PMCID: PMC4214246  PMID: 25210144
biological therapy; cetuximab; chemotherapy; colorectal cancer; drug-induced lung injury
4.  Safety Analysis of FOLFOX4 Treatment in Colorectal Cancer Patients: A Comparison Between Two Asian Studies and Four Western Studies 
Clinical colorectal cancer  2011;11(2):127-137.
FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) is a standard regimen for the treatment of advanced colorectal cancer. Its dose intensity and safety profile were compared between 2 Asian and 4 Western studies by analyzing 3359 patients. There was no evidence that Asian patients experienced worse toxicity than Western patients, and trends toward reduced neurotoxicity and diarrhea among Asian patients were observed.
Oxaliplatin-based therapy, notably FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin), is a standard regimen approved globally for the treatment of metastatic colorectal cancer, and as adjuvant treatment of colon cancer. As part of the Japanese submission for the adjuvant indication, the safety profile of FOLFOX4 regimen was compared in Asian and Western patients.
Patients and Methods
A total of 3359 patients with colorectal cancer treated with the FOLFOX4 regimen were included in the analyses: 1515 from 2 Asian studies (Japanese Post Marketing Surveillance and Multicenter Asia Study in Adjuvant Treatment of Colon Cancer with Oxaliplatin/5-FU/LV), and 1844 from 4 Western studies (EFC2962, N9741, EFC4584, and Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer). Doses administered and safety parameters were analyzed by using common definitions and programs.
Demographic and baseline characteristics were comparable between Asian and Western patients. Patients received FOLFOX4 for a median of 6-12 cycles, which ranged from 16 to 28 weeks. Median dose intensities of oxaliplatin and of 5-fluorouracil, bolus and infusion, were within the ranges of 33 to 36 mg/m2/week, 297 to 338 mg/m2/week, and 467 to 510 mg/m2/week, respectively. Most frequently reported adverse events (AE) included hematologic, gastrointestinal, and neurosensory adverse events (NSAE). The incidence of grade ≥3 neutropenia ranged from 37% (422 of 1134) to 52% (83 of 159) in Asian and 41% (455 of 1108) to 56% (144 of 259) in Western studies; of diarrhea, ranged from 1.4% (3 of 222) to 6.3% (10 of 159) and 11% (30 of 268 or 120 of 1108) to 14% (36 of 259); of NSAEs, from 1.9% (21 of 1134) to 4.4% (7 of 159) and 9.3% (25 of 268) to 19% (39 of 209); and of allergic reactions, from 0.6% (7 of 1134) to 3.1% (5 of 159) and 1.1% (3 of 268) to 3.0% (33 of 1108), respectively. The probability of grade ≥3 NSAEs and diarrhea was statistically significantly lower in Asian than in Western studies by using a log-rank test.
There was no evidence that Asian patients experienced worse toxicity than did Western patients when treated with FOLFOX4, and trends toward reduced neurotoxicity and diarrhea among Asian patients were observed.
PMCID: PMC4127629  PMID: 22099928
Colorectal cancer; Ethnic difference; FOLFOX4; Oxaliplatin; Safety
5.  Over-the-scope-clipping system for anastomotic leak after colorectal surgery: Report of two cases 
An anastomotic leak is one of the major complications following colorectal surgery. Standard treatments for anastomotic leak are total parenteral nutrition or temporary ileostomy. The over-the-scope-clipping (OTSC) system was originally developed to treat intestinal perforation or to close the tissue after natural orifice transluminal endoscopic surgery. Two cases of successful management of an anastomotic leak after colorectal surgery using the OTSC system are reported. One patient avoided a temporary ileostomy. In the other, hospitalization was shortened by the use of the OTSC system. The OTSC system can be a potential option in the management of anastomotic leaks after colorectal surgery.
PMCID: PMC4069327  PMID: 24976736
Over-the-scope-clipping; Colorectal cancer; Anastomotic leak; Colorectal surgery; Double stapling technique
6.  Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer 
Molecular and Clinical Oncology  2014;2(4):509-517.
The overexpression of fibroblast growth factor receptor (FGFR) 2 is an established prognostic factor and treatment target in gastric cancer. However, the roles of other FGFRs have not been fully elucidated. In this study, we investigated the correlations of the expression of FGFR1-4 with clinicopathological characteristics and outcomes in gastric cancer. Tumor samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy between 2003 and 2007. The expression of each FGFR was measured in the tumors by immunohistochemical analysis. The overexpression of FGFR1, FGFR2 or FGFR4 was found to be significantly associated with tumor progression, including depth of invasion, lymph node metastasis, pathological stage and distant metastasis or recurrent disease. Patients exhibiting overexpression of FGFR1, FGFR2 or FGFR4 had a significantly poorer disease-specific survival (DSS; P<0.001, P=0.008 and P<0.001, respectively). Moreover, the co-overexpression of all three FGFRs was significantly associated with a poorer DSS compared to the expression of none or only one of the FGFRs (P<0.001 and P=0.001, respectively) and it was found to be an independent prognostic factor (HR=1.71, 95% CI: 1.02–2.85, P=0.041). In conclusion, high expression of FGFR1, FGFR2 or FGFR4 was associated with tumor progression and poor survival in patients with gastric cancer. Similar to FGFR2, FGFR1 and FGFR4 may be considered as prognostic factors and treatment targets in gastric cancer.
PMCID: PMC4051553  PMID: 24940486
fibroblast growth factor receptor; gastric cancer; immunohistochemical analysis
7.  Severe Infusion Reactions to Cetuximab Occur within 1 h in Patients with Metastatic Colorectal Cancer: Results of a Nationwide, Multicenter, Prospective Registry Study of 2126 Patients in Japan 
Infusion reactions are common adverse reactions associated with antibody preparations. However, no studies have examined the time to onset of serious infusion reactions after administering cetuximab. We aimed to investigate the timing and severity of IRs affecting Japanese patients after administration of cetuximab.
Study subjects were identified from a nationwide prospective registry of 2126 metastatic colorectal cancer patients scheduled to receive cetuximab. Infusion reactions were examined in 2006 patients with adequate safety data.
Infusion reactions of any grade occurred in 114 patients (5.7%), including Grade 3–4 infusion reactions in 22 patients (1.1%). Premedications were antihistamine plus corticosteroid (88.9% of patients with infusion reactions), antihistamine alone (9.2%) or corticosteroid alone (1.1%). In 95 patients (83.3%), infusion reactions occurred after the first dose. Twenty of the 22 Grade 3–4 infusion reactions occurred within 1 h of the first dose (the timing of the infusion reaction was unknown in one patient while another infusion reaction occurred after the fourth dose). Infusion reactions resolved in 111/114 patients (97.4%) while one patient recovered with sequelae, one patient died and one patient failed to recover within the follow-up period. Thirteen patients (15.7% of patients with infusion reactions) with Grade 1–2 infusion reactions showed recurrence after readministration of cetuximab; the recurrent infusion reactions were less severe than the initial reactions.
Grade 3–4 infusion reactions occurred in 1.1% of colorectal cancer patients, and most occurred within 1 h of receiving the first dose of cetuximab. Therefore, patients should be carefully observed following cetuximab infusion, especially during the first hour after the first infusion.
PMCID: PMC4033604  PMID: 24771864
cetuximab; chemotherapy; colorectal cancer; infusion reaction
8.  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
9.  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
10.  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
11.  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)
12.  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
13.  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.
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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