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We introduced a reduced-port procedure for laparoscopic restorative proctocolectomy without diverting ileostomy for patients with familial adenomatous polyposis and ulcerative colitis.A multichannel port was inserted through a 2.5-cm umbilical incision. A 12-mm port in the right lower abdomen and a 3- or 5-mm port were also employed. A proctocolectomy was performed intracorporeally, and the entire colon and rectum were delivered through the umbilical incision. An ileal J-pouch was made extracorporeally following division of the mesenteric vessels. Ileal j-pouch-anal anastomosis was performed intracorporeally or transanally after rectal mucosectomy. A drain was inserted through the 12-mm port incision, and a transanal decompression tube was placed in the pouch. Two women and one man underwent this surgery, and their postoperative recovery was uneventful.Laparoscopic restorative proctocolectomy without a diverting stoma by a reduced-port technique is feasible and provides excellent cosmetic outcomes in selected patients.

Much interest has been drawn to possible associations between vitamin D receptor (VDR) gene polymorphisms and colorectal cancer risk in conjunction with potentially protective effects of calcium and vitamin D. In a study of 685 cases of colorectal cancer and 778 community controls in Japan, we examined the associations of the FokI, BsmI, ApaI, and TaqI polymorphisms with colorectal cancer risk and effect modification by dietary calcium and vitamin D. Genotypes were determined by the PCR-RFLP method. The ApaI polymorphism seemed to be associated with a decreased risk of colorectal cancer, particularly of rectal cancer. The adjusted odds ratio of colorectal cancer for the ApaI AA and Aa genotypes combined versus the aa genotype was 0.83 (95% confidence interval [CI] 0.67-1.02), and the corresponding value for rectal cancer was 0.75 (95%CI 0.56-0.99). A decreased risk of colorectal cancer for the ApaI AA and Aa genotypes combined was more evident in individuals with high calcium intake (interaction p=0.055). The FokI polymorphism seemed to be associated with a decreased risk of colon cancer among those with high vitamin D intake (interaction p=0.09). The BsmI and TaqI polymorphisms were unrelated to colorectal cancer risk, and the null associations were not modified by calcium or vitamin D intake. In conclusion, the ApaI polymorphism may be associated with a decreased risk of colorectal cancer in Japanese, dependent on dietary calcium intake.

Laparoscopic lateral pelvic lymph node dissection (LPLD) is a minimally invasive alternative to open surgical therapy for advanced low rectal cancer patients. This study assessed potential risk factors for lateral pelvic lymph node metastasis (LPLM) and evaluated the feasibility and oncological safety of laparoscopic LPLD compared with the conventional open approach. We retrospectively reviewed the clinical records of 90 patients with advanced low rectal cancer who underwent LPLD following total mesorectal excision at Kyushu University Hospital between January 2001 and July 2014. We compared the clinicopathological features between the patients with and without LPLM and the surgical outcomes between patients who underwent laparoscopic LPLD (LL) and open LPLD (OL). Fourteen (15.6 %) patients had LPLM. Univariate analysis revealed that undifferentiated cancer, positive lymphatic invasion, >50 % circumferential cancer extent, mesorectal lymph node metastases (MLM), and distant metastasis were associated with LPLM. In the multivariate analysis, MLM was the only independent risk factor for LPLM. Forty-six (51.1 %) patients underwent LL, and 44 (48.9 %) patients underwent OL. The mean surgical duration was longer in the LL group than in the OL group (641.0 vs. 312.0 min, P

The present paper presents an effective evaluation method for elasto-plastic buckling loads of elliptic paraboloidal lattice domes for roof on a rectangular plan. The roofs are assumed as three way of single layer with a pin-support or a simple-support at all peripheries on a rectangular plan. The buckling loads are evaluated using a simple procedure adopting a linear buckling analysis, a knockdown factor for imperfection sensitivity, and column buckling strength for axial forces in terms of a generalized slenderness proposed in ordinary recommendations.

The present paper discusses buckling strength of elliptic paraboloidal reticular roofs under uniform load with a rectangular plan. The roofs are assumed as three way single layers with a simple support at all peripheries of a rectangular plan. The buckling analyses are performed for linear buckling, elastic buckling, and elastic-plastic buckling. The results of buckling loads are formulated based on two procedures for practical design use. One is an explicit formula for elastic buckling loads using a knock down factor and the other one is an implicit expression for buckling loads interpreted as a column buckling strength in terms of generalized slenderness ratio.

The present paper discusses buckling strength of elliptic paraboloidal reticular roofs under a uniform load on a rectangular plan. The roofs are assumed as three way single layers with a pin-support at all peripheries on a rectangular plan. The buckling analyses are performed for linear buckling, elastic buckling and elastic-plastic buckling. The results of buckling loads are formulated based on two procedures for practical design use. One is an explicit but approximate formula for elastic buckling loads using a knock down factor and the other one is an implicit expression for buckling loads interpreted into a column buckling strength in terms of generalized slenderness ratio.

症例は16歳男性.幼少時より認めていた下痢,下血,排便時間延長の増悪のため近医を受診した.大腸内視鏡,注腸造影で下部直腸に腫瘍性病変を認め,当科紹介入院となった.当院での大腸内視鏡,注腸造影では,下部直腸に結節状,棍棒状の小隆起の集簇を全周性に認めた.生検では直腸粘膜脱症候群(MPS)の診断であった.排便造影では直腸重積と会陰下降度の増加,直腸肛門内圧検査では最大耐容量の低下を認めた.隆起型のMPSによる残便感から排便時間延長をきたしたものと考え,経肛門的腫瘤切除術を行った.術後,残便感は消失し排便障害も改善した.隆起型のMPSで,病変の存在自体が残便感の原因となっている場合は,経肛門的切除術が有効な治療法の一つと考えられた.

The aim of this study was to determine the utility of detecting methylated ppENK and pi6 in pancreatic juice by methylation specific PCR as a marker of pancreatic adeno-carcinoma. Pancreatic juice samples were collected either intraoperatively, from 92 patients undergoing pancreaticoduodenectomy for benign (n=20) and malignant periampullary disease (n = 72) or endoscopically (by duodenal aspiration after secretin infusion), from 13 patients undergoing investigation for pancreatic disease. Methylated ppENK was detected in the pancreatic juice of 30 (66.7%) of 45 patients with pancreatic ductal adenocarcinoma, in 4 (44.4%) of 9 patients with intraductal papillary-mucinous adenocarcinoma, and in 7 (41.2%) of 17 patients with other periampullary carcinomas, using methylation specific PCR. Methylated pi6 was detected in a lower percentage of these patients (11.1%, 11.1% and 23.5%, respectively). In contrast, methylated ppENK and pi6 were not detected in 20 patients with non-malignant periampullary disease including 12 patients with chronic pancreatitis. Methylated ppENK was detected in 30 of 33 (90.9%) primary pancreatic adenocarcinoma and methylated pi6 was in 6/33 (1 8.2%). Despite the absence of ppENKand pi6 methylation in normal pancreas, methylated ppENK and pi6 was present in the duodenum of 90.5% and 28.6%, respectively of patients without cancer. Further, methylated ppENK and pi6 was seen in 88.9% and 11.1%, respectively of pancreatic juice samples obtained by duodenal aspiration from patients without cancer. We conclude that since ppENK and pi6 are not normally methylated in pancreatic secretions, detection of methylated ppENK and pi6 in pure pancreatic juice obtained by direct cannulation of the pancreatic duct to avoid duodenal secretions may suggest the presence of pancreatic adenocarcinoma

Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3, 15 invasive ductal adenocarcinomas, and 6 miscellaneous pancreatic neoplasms) were microdissected from 29 formalin-fixed paraffin-embedded surgically resected pancreata, and were analyzed by methylation-specific polymerase chain reaction. Fourteen of 15 (93.3%) invasive pancreatic ductal adenocarcinomas showed methylation of the ppENK gene and 4 of 15 (26.7%) showed methylation of the p16 gene. Nonneoplastic pancreatic epithelia did not harbor methylation of either gene. The prevalence of methylation of the ppENK gene increased significantly with increasing PanIN grade. A similar nonsignificant trend was noted for p16 methylation. Aberrant methylation of the ppENK gene was found in 7.7% of PanIN-1A, 7.3% of PanIN-1B, 22.7% of PanIN-2, and 46.2% of PanIN-3. Aberrant methylation of the p16 gene was found in 12% of PanIN-1A, 2.6% of PanIN-1B, 4.5% of PanIN-2, and 21.4% of PanIN-3. All but one of the PanINs from the 14 pancreata without pancreatic carcinoma was unmethylated with respect to either the p16 or ppENK gene. Our results suggest that methylation-related inactivation of the ppENK and p16 genes is an intermediate or late event during pancreatic carcinogenesis. Because aberrant methylation of ppENK or p16 was more often detected in similar grade PanINs from patients with pancreatic carcinoma than in those with other pancreatic diseases, it may be a useful indicator of the potential malignancy of epithelial cells of the pancreas.

We herein present a novel technique for laparoscopic en bloc excision involving anteriorly extended intersphincteric resection with partial resection of the posterior lobe of the prostate for large rectal gastrointestinal stromal tumors (GISTs). The sequence of neoadjuvant imatinib therapy and this less invasive surgery for marginally resectable rectal GISTs has the potential to obviate the need for urinary reconstruction and permanent stomas without jeopardizing the tumor margin status.

Background and Aim We aimed to evaluate the long-term risk of cancer in the rectal remnant in patients with familial adenomatous polyposis after ileorectal anastomosis. Methods Cumulative incidence and clinicopathological characteristics of cancer in the rectal remnant were retrospectively investigated in 27 patients with familial adenomatous polyposis who had undergone ileorectal anastomosis. Results During the follow-up period ranging from 3.0 to 35.0 years (median, 21.1 years), cancer in the rectal remnant developed in 10 patients. Cumulative risk of cancer in the rectal remnant 30 years after surgery was 57%. Five patients had metastases and three patients died of cancer in the rectal remnant after proctectomy. There was a trend towards a higher incidence of cancer in the rectal remnant in patients with small-intestinal adenoma and congenital hypertrophy of the retinal pigment epithelium. Multivariate analysis revealed that the ocular lesion was an independent risk factor associated with cancer in the rectal remnant. Conclusion Subtotal colectomy with ileorectal anastomosis does not seem to be an appropriate prophylactic surgery in patients with familial adenomatous polyposis.

Background Early detection of colorectal cancer (CRC) is crucial to reducing tumor-related mortality. Evaluating aberrantly methylated DNA in stool is promising for CRC screening. However, DNA methylation in the colonic epithelium of background mucosa may compromise stool DNA (sDNA) test results. Thus, we compared aberrant methylation of cancer-related genes in preoperative and postoperative sDNA, with the aim of demonstrating that a cancer-specific methylated allele in sDNA originates from CRCs. Methods Patients who were to undergo CRC resection in Kyushu University Hospital during 2003-2010 were prospectively enrolled. Preoperative (pre) stool samples from 54 patients, postoperative (post) samples from 52 of the patients and tumor samples were collected. Aberrant promoter methylation of CDH4 and GATA5 was assessed in the primary tumors by methylation-specific polymerase chain reaction (MSP) and in stool samples by real-time MSP. Results Aberrant methylation of CDH4 and/or GATA5 was detected in 45 of CRC tissue samples (83.3%) and identified in 23 pre sDNA samples (42.3%) from CRC patients. Aberrant methylation was not found in pre sDNA obtained from CRC patients without aberrant methylation of these genes or in post sDNA in any patient. The detection rate of methylated alleles did not correlate with depth of invasion or tumor stage. Conclusion Our findings demonstrate that aberrantly methylated alleles identified in sDNA originate from CRCs. Although tumor-specific aberrant methylation is found in sDNA from patients harboring early and advanced CRC throughout the colon and rectum, the sensitivity of this test needs to be improved for early detection of CRC.

A 70 -year-old female patient with a palpable mass in the left upper abdomen suffered from abdominal pain and fever. Abdominal computed tomography showed a jejunal tumor 11 cm in diameter with ascites, suggesting rupture of the tumor. Histological diagnosis via endoscopic ultrasound-guided fine needle aspiration indicated c-kit-positive gastrointestinal stromal tumor. Diagnostic laparoscopy demonstrated a large jejunal tumor possibly invading the stomach and pancreas. The patient then underwent tube jejunostomy. Thereafter, preoperative induction chemotherapy with imatinib mesylate(400mg/ body/day)via jejunostomy was administered for 6 months, resulting in 20%reduction of the tumor diameter and disappearance of any indication of stomach and pancreas invasion. The patient then underwent radical partial resection of the jejunum without combined resection of either the stomach or pancreas. Postoperative adjuvant chemotherapy with imatinib mesylate (400mg/body/day)was also indicated. No sign of recurrence has been detected to date after 1 year of follow-up.

Objective A diet high in sugars may promote colorectal carcinogenesis, but it remains uncertain whether high intake of sugars or sucrose confers increased risk of colorectal cancer. The authors investigated the associations of sugars and sucrose intake with colorectal cancer risk in a community-based case–control study in Japan. Methods The study subjects comprised 816 incident cases of colorectal cancer and 815 community controls. Consumption frequencies and portion sizes of 148 food and beverage items were ascertained by a computer-assisted interview. The authors used the consumption of 29 food items to estimate sugars and sucrose intake. The odds ratios of colorectal cancer risk according to intake categories were obtained using a logistic regression model with adjustment for potential confounding variables. Results Overall, intakes of sugars and sucrose were not related to colorectal cancer risk either in men or women. The association between sugars intake and colorectal cancer risk differed by smoking status and alcohol use in men, but not in women. In men, sugars intake tended to be associated with colorectal cancer risk inversely among never-smokers and positively among male ever-smokers (interaction p = 0.01). Sugars intake was associated with an increased risk among men with no alcohol consumption, but was unrelated to the risk among male alcohol drinkers (interaction p = 0.02). Body mass index did not modify the association with sugars intake in either men or women. Conclusion Sugars intake was associated with increased risk of colorectal cancer among smokers and non-alcohol drinkers in men selectively.

BACKGROUND Extranodal tumor deposits are involved in TNM classification. However, it is uncertain whether a tumor deposit is a regular lymph node metastasis, and its prognostic significance in patients with stage II or III colorectal cancer remains to be established. OBJECTIVE This study aimed to determine the prognostic significance of tumor deposits for stage II and III colorectal cancer. DESIGN This study is a retrospective review of clinicopathological data. SETTING This study was conducted at a tertiary care hospital/referral center in Japan. PATIENTS We reviewed the clinical course of 171 stage II and 173 stage III consecutive patients between January 1999 and December 2006. MAIN OUTCOME MEASURES We examined the clinicopathological features of colorectal cancers with tumor deposits and calculated overall survival and recurrence-free survival of the patients according to the status of tumor deposits. The primary outcome was the impact of tumor deposits on patient survival. RESULTS Thirty-five (10.2%) patients with colorectal cancers had tumor deposits in the pericolic and/or mesocolic region. Survival rates among the patients with tumor deposits were significantly lower than those without (5-year overall survival: 58.4% vs 81.0%, p < 0.0001; 5-year recurrence-free survival: 47.1% vs 73.4%, p < 0.0001). Tumor deposit was an independent prognostic factor for patients with colorectal cancer in multivariate analysis (overall survival: HR, 2.30; 95% CI, 1.26-4.04; p = 0.04; recurrence-free survival: HR, 2.42; 95% CI, 1.04-4.90; p = 0.04). Tumor deposit was an independent prognostic factor in N0 and N1 colorectal cancer, whereas N2 cancer had poor survival outcome regardless of tumor deposit. LIMITATIONS Our study was a single-institution retrospective study, and the numbers of patients were relatively small to draw firm conclusions. CONCLUSION Tumor deposit may be an independent adverse prognostic factor for stage II and III N1 colorectal cancer.

Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1, a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs.

The present paper investigates the dynamic response characteristics of single layer reticular domes subjected to horizontal earthquake motions from the following view points: (1) how to estimate the statically equivalent seismic forces applied to domes both for high rise and low rise; and (2) how to estimate the collapse accelerations under which the domes collapse dynamically. For these purposes, linear response analyses, linear buckling analyses, geometrically and materially nonlinear static analyses and geometrically and materially nonlinear earthquake response analyses are performed. Based on the results, the collapse accelerations are expressed as a function of the safety factor for domes under self weight. The expression for the collapse accelerations leads to an approximate measure by which structural designers may balance the static resistant capacity under self weight and the dynamic resistant capacity under earthquake motions.

Forty-nine pathologically proven gallbladder lesions were evaluated in 45 patients using dynamic MRI with a spoiled gradient pulse sequence (SPGR), to access the ability of this technique to differentiate benign from malignant gallbladder lesions. The studies were reviewed retrospectively. Signal intensity of the lesions were measured. Twenty-one malignant and 28 benign lesions were classified into three categories: polypoid, diffuse wall thickening, and exophytic. Early and delayed enhancement patterns were evaluated. For the polypoid masses, malignant lesions (n = 9) demonstrated early and prolonged enhancements, whereas benign lesions (n = 14) had early enhancement with subsequent washout (P < .05). For diffuse gallbladder wall thickening, malignant lesions (n = 6) demonstrated early and prolonged enhancement and benign lesions (n = 14) showed relatively slow, prolonged enhancement (P < .05). The exophytic masses (n = 6) all were malignant and demonstrated early and prolonged enhancement. Dynamic MRI can help differentiate benign from malignant gallbladder lesions.

We present a case of carcinoma in adenoma of the gallbladder with anomalous pancreaticobiliary ductal junction (APBDJ) in a 60-year-old Japanese woman. The patient had no abdominal symptoms. Serum levels of carcinoembryonic antigen, carbohydrate antigen 19-9, elastase 1, and α-fetoprotein were all within normal limits. Ultrasonography demonstrated two irregular hyperechoic lesions of the gallbladder. Computed tomography showed two soft-tissue density masses in the gallbladder. Endoscopic retrograde cholangiopancreatography showed APBDJ and two protruding lesions in the gallbladder. Angiography displayed a hypervascular lesion fed by the cystic artery. The patient underwent total cholecystectomy; the diagnosis of the intraoperative frozen section was well differentiated adenocarcinoma with possible mucosal invasion. Amylase level in the gallbladder bile was 90600 IU/l. Macroscopically, there were two polyps in the gallbladder. The larger one, 3.5 cm in diameter, was adenocarcinoma in adenoma, and the smaller one, an inflammatory polyp. We briefly discuss the relationship among adenoma, adenocarcinoma of the gallbladder, and APBDJ.

Nucleolar protein p120 is considered to be associated with cell proliferation and has also been detected in a broad range of human malignant cells and tissues, but not in either normal resting tissue or most benign tumors. To clarify the significance of the expression of p120 in colorectal tumors or to evaluate the contribution of p120 in the development of colorectal carcinoma, the authors developed a monoclonal antibody against p120 and then examined its expression in adenoma, carcinoma, and normal mucosa. In adenomas, p120 expression was shown in none of 13 cases of mild dysplasia (0%), 2 of 15 of moderate dysplasia (13.3%), and in 2 cases of severe dysplasia (100%). p120-positive adenomas of moderate dysplasia tended to be larger and had higher Ki-67 indexes than the negative ones (adenomas of moderate dysplasia). All 27 carcinomas were positive for p120. p120 immunostaining was found in the nuclei and corresponded closely to the prominent nucleoli of tumor cells. In contrast, either weak or the occasional expression of p120 was traced in only one of the nine normal mucosae (11.1%). Three of the transitional mucosae of the carcinoma were also positive for p120. The percentage of p120-positive tumor cells (p120 index) ranged from 3.2% to 86.6%, and the mean p120 indexes of the four adenomas and all carcinomas were 21.3% and 41.5%, respectively. The p120 index was significantly related to the Ki-67 index (P < .001) in the p120-positive tumors, whereas the p120 index of the carcinoma did not significantly correlate to the known prognostic markers, such as tumor size, stage, or the degree of differentiation. These results thus suggest that the expression of p120 serves as a marker for cells with a high proliferative potential and is linked to the late events of colorectal tumor progression.

The treatment of choice for gastroentero-pancreatic neuroendocrine tumor(NET)is resection. Because it is difficult to determine the histological grade of NET before operation, the treatment strategy is usually made based on an imaging study including the tumor's size. Some selected gastrointestinal NETs are indicated for endoscopic resection, while others are resected surgically with lymph node dissection. The types of resections for pancreatic NETs vary from enucleation to pancreatectomy with or without regional lymph node dissection, based on the type of excessive hormone, tumor size, distance from the main pancreatic duct, and the presence of type 1 multiple endocrine neoplasia. Hepatic metastases are also resected, if indicated, and even in patients having unresectable metastatic lesions, multidisciplinary therapy including reduction surgery of over 90% of tumor volume might lead to a favorable prognosis. Postoperative adjuvant therapy is recommended for neuroendocrine carcinoma, while there is no evidence to support adjuvant therapy for curatively resected well-differentiated NET.

放線菌症はActinomyces属の細菌により膿瘍や瘻孔を形成する慢性の化膿性肉芽腫性感染症であり, 近年抗生剤の発達により比較的稀な疾患となっている.今回, 横行結腸に発生した放線菌症の1例を経験した.症例は41歳, 女性.主訴は発熱, 腹痛, 腹部腫瘤.胆嚢摘出, 虫垂切除の既往がある.入院時, 贋左下方に境界不明瞭な手拳大の有痛性腫瘤を触知.便潜血陽性であり, 白血球増多とCRP値の上昇を認めたが, 血液生化学, 凝固系や腫瘍マーカーは正常範囲内.注腸造影で横行結腸に約10cmにわたる鋸歯状の全周性狭窄が認められた.CT, MRIでは, 腹壁に接する6cm大の腫瘤を認めた.抗生剤で炎症を鎮静化した後, 開腹した.大網を巻き込んで腹壁に強固に癒着した横行結腸を中心とした炎症性腫瘤であった.切除標本の病理診断にて特徴的な “菌塊” druse, sulfur granuleを認め, 横行結腸放線菌症と診断した.

The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor (FGFR) mRNA was examined in gastric carcinomas by immunohistochemistry and in situ hybridization, respectively. In the 20 advanced carcinomas examined, bFGF was found in 14 (70.0 per cent) and was confined to the tumour cells, whereas FGFR mRNA was demonstrated in 12 (60.0 per cent) and seen in both tumour cells and endothelial cells. The bFGF and FGFR mRNA-positive carcinomas were larger, were more frequently classified as undifferentiated adenocarcinoma, more frequently invaded the serosal layer, and had a higher rate of lymph node metastases than the bFGF and FGFR mRNA-negative carcinomas. Patients with bFGF and FGFR mRNA-positive carcinomas appear to die earlier than those with bFGF and FGFR mRNA-negative tumours. The values for the carcinomas that were positive for either bFGF or FGFR mRNA fell between these two groups. The findings suggest that the autocrine/paracrine bFGF/FGFR channel is associated with undifferentiated gastric carcinomas and may lead to a poorer prognosis.

Background: EpCAMhigh CD44+colorectal cancer (CRC) cells are thought to be cancer stem cells. Recently CD44- CRC cells are also suggested to acquire a property of cancer stem cells. Epithelial-mesenchymal transition (EMT) is a possible process of acquisition of cancer stem cell (CSC)-like properties. However, it is unclear whether EMT can be induced in primary human CRC cells. Patients and Methods: We obtained surgical specimens from 51 CRC patients, and cultured isolated cancer cells on matrigel-coated dish with medium containing growth factors. For induction of EMT, TGF-beta was added into the culture medium. Otherwise, TWIST1 expression was enforced in the cells by using lentiviral transduction. Immunocytochemical analysis, flow cytometric analysis and single cell PCR analysis using 24-genes set containing embryonic stem cell (ES)-related and EMT-related genes were performed. PCR analysis was carried out by C1 single cell auto prep system. CD44- CRC cells with or without enforced expression of TWIST1 were injected into immunodeficient mice. Results: Fifteen out of 51 samples of cancer cells formed sphere (>50 μm in diameter) after one week culture. The sphere-forming ability was related with clinical stage (Stage 1 and 2;16.7%, Stage 3 and 4;41.3%). Sorted single CD44+ cell had higher sphere-forming ability, compared to CD44- cell. The higher expression of ES- and EMT-related genes was observed in short term culture than in long-term culture, suggesting that differentiation occurred in sphere cells after long-term culture. Single cell PCR analysis revealed that sphere-forming cells were classified into 2 different populations on the basis of primary component analysis. Correlation analysis showed expression of TWIST1 and ES-related genes were correlated. In addition, flow cytometric analysis revealed that sphere forming CD44+ cells gave rise to CD44- cells. These results suggest that CD44+ cells have an ability to reconstruct the heterogeneous population, and EMT is involved in acquisition of CSC-like properties. TGF-beta increased the number of CD44+ cells in CD44- cells, and enhanced sphere-forming ability of CD44- cells. TGF-beta also induced expression of ES-related genes and TWIST1. Enforced expression of TWIST1 induced sphere-forming ability and tumorigenicity in CD44- cells. Conclusions: We established the culture system to observe the differentiation of CSCs and revealed that EMT might be involved in maintenance of CSCs. We firstly demonstrated that primary CD44- CRC cells undergo EMT and become CD44+ cells by TGF-beta treatment or enforced expression of TWIST1. Citation Format: Michitaka Nakano, Mamoru Tanaka, Taichi Isobe, Kohta Miyawaki, Yoshikane Kikushige, Hitoshi Kusaba, Shigeo Takaishi, Takashi Ueki, Eishi Baba, Koichi Akashi. Epithelial mesenchymal transition generates cancer stem cells in CD44- colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1707.

Constipation has been suspected to be linked to colorectal cancer risk, but epidemiological evidence is inconclusive. We described the prevalence of constipation and related lifestyle factors in a community and examined the relation of constipation and other bowel habits to colorectal cancer risk. The prevalence study was based on 833 community controls in the Fukuoka Colorectal Cancer Study, and 212 cases of Dukes' stage A were used in a study on bowel habits and colorectal cancer risk. Bowel habits were assessed by in-person interview. Odds ratio (OR) and 95% confidence interval (CI) of colorectal cancer were estimated with adjustment for dietary and nondietary factors. Constipation was reported by 10.3% of men and 27.7% of women. Individuals with less frequent bowel movements had a lower intake of total energy and were physically less active. The multivariate-adjusted OR (95% CI) of colorectal cancer were 1.51 (1.02-2.25) for self-reported constipation, 1.60 (1.05-2.44) for functional constipation, and 1.24 (0.81-1.90) for infrequent bowel movements (1 stool/day). Self-reported constipation was fairly common in Japanese adults. Constipation was associated with a moderately increased risk of colorectal cancer.

Background. Gastric carcinoma with lymphoid stroma (GCLS) has been reported to have a more favorable prognosis than ordinary gastric carcinoma, however, the precise mechanism of the pathogenesis for GCLS remains unclear. Methods. The authors analyzed 99 GCLS in 94 patients for Epstein-Barr virus (EBV) sequences using polymerase chain reaction (PCR) and in situ hybridization (ISH); these were compared with 42 ordinary gastric carcinomas. Results. Two series of PCR showed 81 (82%) and 46 (47%) of the 99 GCLS to have EBV sequences, which were significantly higher compared with ordinary gastric carcinoma (50% and 9.5%, respectively). With ISH using thymine-thymine dimerized oligonucleotide probes corresponding to EBV-encoded small RNA 1 (EBER1), 82 (83%) of 99 GCLS showed clear, intense hybridization signals localized over the nuclei of the tumor cells, in contrast to only 4 (9.5%) of 42 ordinary carcinomas (P < 0.001). A comparative morphologic analysis of EBER1-positive and negative GCLS revealed that typical features of GCLS, such as mild cellular pleomorphism, rare mitoses, a marked degree of lymphoid stroma, and mild fibrosis, together with a lymphoid infiltration within the cancer cell nests were significantly more frequent in EBER1-positive GCLS. Conclusions. More than 80% of GCLS were associated with EBV. The presence of EBV association in GCLS was characterized by the above morphologic features.

Background: X-ray cross-complementing group 1 (XRCC1) polymorphisms affect DNA repair capacity and may therefore be of importance in colorectal carcinogenesis. Alcohol consumption, an important risk factor for colorectal cancer, may induce carcinogenesis through DNA damage caused by the toxic effects of alcohol or its metabolites. Therefore, we examined the associations of XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms with colorectal cancer and the impact of the association between alcohol consumption and colorectal cancer risk.Methods: This case-control study in Fukuoka, Japan including 685 cases and 778 controls. The cases were incident patients with histologically confirmed colorectal adenocarcinoma. The controls were randomly selected community subjects.Results: The XRCC1 399Gln/Gln genotype was significantly associated with colorectal cancer risk (adjusted odds ratio [OR] 1.57, 95% CI 1.01–2.42; relative to 399Arg/Arg genotype). The association was strongest in individuals with high alcohol consumption. The Arg280His polymorphism modified the association between alcohol consumption and colorectal cancer risk (interaction P = 0.049). The OR of colorectal cancer in individuals with the 280His allele was 0.45 (95% CI 0.26–0.78) as compared with the 280Arg/Arg genotype limited to the 399Gln allele (interaction P = 0.001). The adjusted ORs for 399Gln/Gln-280Arg/Arg-194Arg/Arg and 399Arg/Gln-280Arg/Arg-194Arg/Trp were 1.71 (95% CI 1.02–2.87) and 1.57 (95% CI 1.05–2.33), respectively, with 399Arg/Arg-280Arg/Arg-194Arg/Arg as reference (interaction P = 0.418).Conclusions: The findings are additional evidence that individuals with the XRCC1 399Gln/Gln genotype have an increased risk of colorectal cancer, and that XRCC1 polymorphisms have an important role in colorectal cancer risk associated with alcohol consumption or gene-gene interaction.

Estrogen receptor (ER)-β signaling has generally been implicated in protection against colorectal cancer. The ER-β gene cytosine-adenine (ESR2 CA) repeat polymorphism was reported to be associated with colorectal cancer, although showing contradicting results probably caused by ethnicity or age distribution of the subjects. We investigated the association between this polymorphism and the colorectal cancer risk in a community-based case-control study in Japan (685 cases/778 controls), including only subjects younger than 75. The effect modifications of the body mass index (BMI) and isoflavone intake were also examined. ESR2 CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labeled primers. CA repeat alleles were classified into short (S) allele (

Microsomal epoxide hydrolase (EPHX1) plays an important role in the activation and detoxification of polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Polymorphisms in exon 3 (Y113H) and exon 4 (H139R) of the EPHX1 have been associated with enzyme activity. We investigated the risk of colorectal cancer in relation to the EPHX1 Y113H and H139R polymorphisms and assessed effect modifications of cigarette smoking and the other covariates. The interaction between the EPHX1 polymorphisms and selected genetic polymorphisms was also examined. We used data from Fukuoka Colorectal Cancer Study, a community-based case-control study, including 685 cases and 778 controls. In-person interviews were conducted to assess lifestyle factors. The EPHX1 Y113H and H139R polymorphisms were determined by the TaqMan assay and the polymerase chain reaction-restriction fragment length polymorphism, respectively. Neither of the two polymorphisms nor the imputed EPHX1 phenotype was associated with colorectal cancer risk. Cigarette smoking and alcohol intake showed no effect modification on the association with the EPHX1 polymorphisms or the imputed EPHX1 phenotype. Increased risks of colorectal cancer associated with the 113Y allele and imputed EPHX1 phenotype were observed among individuals with high body mass index (BMI; ≥25.0 kg/m(2)), but not among those with low BMI (25.0 kg/m(2)). The risk decreased with an increasing number of the 139R allele in the null genotypes of GSTM1/GSTT1. It is unlikely that the EPHX1 polymorphisms play an important role in colorectal carcinogenesis. The observed interactions of the EPHX1 polymorphisms with BMI and the GSTM1/GSTT1 genotypes warrant further investigation.

Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced STEAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more STEAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition.

Malignant duodenocolic fistula is a rare complication of gastrointestinal malignancy. We present herein the case of a 34-year-old female in whom a large duodenocolic fistula was caused by advanced transverse colonic carcinoma. Right hemicolectomy combined with pancreaticoduodenectomy enabled en bloc resection of the tumor, and the patient has been free of disease for 1 year and 8 months postoperatively. A review of the international literature, including 33 cases reported in Japan, indicates that if the disease is curable, the treatment of choice is right hemicolectomy with pancreaticoduodenectomy, whereas if it is not curable but locally resectable, the best palliation appears to be right hemicolectomy with partial duodenectomy to include the fistulous tract. Dehiscence of the duodenal wound closure associated with partial duodenectomy can be prevented by using the mucosal or serosal patch techniques with intestinal loops. These therapeutic principles are also applicable for colonic carcinoma which massively involves the duodenum without fistula formation.

Active valve assemblies in important systems to safety are required to maintain the operability during or following earthquakes. Motor operated valve assemblies have been designed to a validated response capacity 60m/s2 at the actuator in accordance with “JEAG4601-supplement 1991” in Japan. The Regulatory Guide for Reviewing Seismic Design of Nuclear Power Reactor Facilities issued in September 2006 defines Design Basis Earthquake Ground Motion and requires that residual risk for large earthquakes should be considered. It is needed to acquire seismic capacity data for a variety of active valve assemblies. JNES has performed fragility tests for motor operated valves: globe valve, gate valve and butterfly valve. An experimental test program is developed to ensure operating requirements for valve assemblies whose safety-related function is to open, close, or regulate fluid flow, and structural requirements for pressure boundary integrity. A series of vibration tests has been performed using shaking tables at varied acceleration levels up to target acceleration levels by sinusoidal waves. As a result of the vibration tests, the operability of valve assemblies for each type of motor operated valve has been verified at the target acceleration levels. The yoke of a motor operated gate valve connecting the actuator and the valve body was identified to be vulnerable for low cycle fatigue depending on the postulated load conditions in terms of intensity and frequency. The resulting seismic capacity data of actual valves will be applied for a fragility analysis of Seismic PSA.Copyright © 2008 by ASME

Background EpCAMhigh CD44+ colorectal cancer (CRC) cells are thought to be cancer stem cells. Recently CD44- CRC cells are also suggested to acquire a character of cancer stem cells, but the molecular mechanisms have not been clarified. Epithelial-mesenchymal transition (EMT) is a possible process of cancer cells to acquire stemness. However, it is unclear whether EMT can be induced in primary human CRC. Patients and Methods We obtained surgical specimens from 51 CRC patients, and cultured isolated cancer cells on matrigel-coated dish with medium containing several growth factors. For induction of EMT, TGF-beta was added into the culture medium. Immunocytochemistry staining, flow cytometric analysis of the spheroid cells and single cell PCR analysis using 48-gene set containing and Embryonic stem cell (ES)-related genes EMT-related genes were performed. Results Cancer cells proliferated and formed sphere (>50 μm in diameter) in 15 out of 51 samples after one week culture. The sphere-forming ability was related with clinical stage (Stage1 and 2:16.7% Stage 3 and 4:41.3%). Sorted single CD44+ cell had higher sphere-forming ability, compared to CD44- cell. The higher expression of ES- and EMT-related genes was observed in sphere-forming cells than in non-sphere forming cells. To confirm the heterogeneity of sphere forming cells derived from sorted single cell, we performed single cell PCR using C1 single cell auto prep system. Cells consisted of a sphere were classified into 2 different population on the basis of primary component analysis. In addition, flow cytometric analysis revealed that sphere forming CD44+ cells gave rise to CD44- cells. These results suggest that CD44+ cells have an ability to reconstruct the heterogeneous population. Next we isolated sphere-forming cells and cultured on the same condition. Isolated sphere-forming CD44+ cells could form sphere with high efficiency. This result suggests that CD44+ cell have a self-renewal ability. Previously, it has been reported that EMT was induced after TGF-beta treatment in cancer cell lines and these cells acquired cancer stem cell properties. In our culture system, we could detect very few CD44+ cells after 8-days culture of CD44- cells, and TGF-beta treatment also increased the number of CD44+ cells. These CD44 expressing cells expressed N-cadherin. Furthermore N-cadherin expressing cells expressed ES-and EMT-related genes. At last, TGF-beta enhanced sphere-forming ability in CD44- cells. Conclusions To our knowledge, this is the first report that CD44- cells from primary CRC samples undergo EMT and induced CD44+ cells by TGF-beta treatment. Investigation whether these induced CD44+ cells have cancer stem cell like properties such as tumorigenic potential in immunosuppressive mouse is underway. Also we are going to identify cancer stem cell specific gene expression in our culture system using DNA microarray. Citation Format: Michitaka Nakano, Hioshi Ariyama, Shingo Tamura, Taichi Isobe, Kohta Miyawaki, Yuta Okumura, Hitoshi Kusaba, Takashi Ueki, Eishi Baba, Koichi Akashi. Plasticity of CD44+ colorectal cancer stem cells depends on TGF-beta-induced epithelial mesenchymal transition (EMT): evidences from ex vivo culture system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1520. doi:10.1158/1538-7445.AM2015-1520

In July 2003, a 59-year-old man underwent a right hemicolectomy for sigmoid colon cancer. Hepatic intraarterial injection therapy with 5-FU/CDDP was not only ineffective against a liver metastasis but a lung metastasis was also found, and therefore systemic chemotherapy with CPT-11/5-FU/l-LV (IFL) was administered. After onetime IFL therapy, the CPT-11 was withheld due to ileus. Although 5-FU/l-LV therapy was administered, it was ineffective. IFL therapy was again performed, with the dose decreased by 20%, as part of ambulatory treatment. Not only the liver metastasis but also the lung metastasis decreased significantly in size after one course. In addition, no severe adverse reactions were observed during the treatment, which enabled the therapy to be continued as part of an ambulatory regimen. The results suggest that IFL therapy is effective against colon cancer with lung/liver metastasis and can be administered as part of ambulatory treatment.

Purpose: Biliary tract cancer is an uncommon malignancy with a poor survival rate. We evaluated p16 gene alteration as a prognostic marker for this disease. Experimental Design: We studied p16 gene alterations by sequencing, methylation, and loss of heterozygosity of chromosome 9p in 118 biliary tract carcinomas, including 68 gallbladder cancers, 33 extrahepatic bile duct cancers, and 17 ampullary cancers. Survival was evaluated in 57 patients with gallbladder carcinomas, 27 with bile duct carcinomas, and 16 with ampullary carcinomas with and without somatic p16 alterations detected by two different methods. Results: p16 gene alterations including silent mutations were present in 61.8% gallbladder cancers, 54.5% bile duct cancers, and 70.6% ampullary cancers. p16 gene nonsilent mutations, p16 methylation, and loss of chromosome 9p21-22 that targets p14, p15, and p16 genes were present in 13 of 53 (24.5%), 8 of 54 (14.8%), and 32 of 44 (72.7%) gallbladder tumors; 5 of 25 (20.0%), 5 of 31 (16.1%), and 12 of 21 (57.1%) bile duct tumors; and 3 of 13 (23.1%), 6 of 15 (40.0%), and 8 of 16 (50.0%) ampullary tumors, respectively. The mean survival of patients with gallbladder cancers without p16 alterations was 21.5 ± 14.8 months compared with 12.1 ± 11.4 months for patients with p16 alterations (P = 0.02). Conclusions: Alteration of p16 gene alone or in combination with alterations of other tumor suppressor genes on chromosome 9p is a prognostic indicator in gallbladder carcinoma, with more favorable survival rates associated with carcinomas lacking p16 gene alterations.

The application of joint contact mechanics requires a precise configuration of the joint surfaces. B-Spline, and NURBS have been widely used to model joint surfaces, but because these formulations use a structured data set provided by a rectangular net first, then a grid, there is a limit to the accuracy of the models they can produce. However new imaging systems such as 3D laser scanners can provide more realistic unstructured data sets. What is needed is a method to manipulate the unstructured data. We created a parametric polynomial function and applied it to unstructured data sets obtained by scanning joint surfaces. We applied our polynomial model to unstructured data sets from an artificial joint, and confirmed that our polynomial produced a smoother and more accurate model than the conventional B-spline method. Next, we applied it to a diarthrodial joint surface containing many ripples, and found that our function's noise filtering characteristics smoothed out existing ripples. Since no formulation was found to be optimal for all applications, we used two formulations to model surfaces with ripples. First, we used our polynomial to describe the global shape of the objective surface. Minute undulations were then specifically approximated with a Fourier series function. Finally, both approximated surfaces were superimposed to reproduce the original surface in a complete fashion.