Nobuhiro Kurita

Sonic hedgehog relates to colorectal carcinogenesis

AimThe activation of Hedgehog signaling, which is critical to normal mammalian gastrointestinal development, is implicated in the development of various tumors, including colorectal cancer. In the pancreas, a precursor lesion overexpresses the Sonic hedgehog (Shh) when compared with normal tissue and cancer. The present study was designed to investigate Shh related protein expression in hyperplastic polyps and the adenoma-carcinoma sequence in the colon and rectum.MethodsSeventeen hyperplastic polyps, 24 adenomas of the colon, 69 adenocarcinomas (31 well-differentiated, 38 moderately-differentiated), and 30 normal colon samples were used in the study. We checked the expression of Shh, both patched (Ptch) and smoothened (Smo), by immunohistochemistry and compared the expression rate of each group.ResultsAlmost all adenomas, 22 of 23 (96%), expressed Shh. In other groups, 4 of 17 hyperplastic polyps (24%), 7 of 31 well-differentiated adenocarcinomas (23%), 13 of 38 moderately-differentiated adenocarcinomas (34%) and none of the 30 normal samples expressed Shh. The rate of expression in Ptch and Smo gradually increased in accordance with tumor progression.ConclusionThis result indicates that Shh-related carcinogenesis and Shh expression may be a trigger for the adenoma-carcinoma sequence. This study suggests a potential therapeutic target of hedgehog blockade in carcinogenesis.

Irinotecan Injures Tight Junction and Causes Bacterial Translocation in Rat

BACKGROUND Tight junctions are an essential component of intestinal epithelial barriers. Claudin-1, occludin, and ZO-1 are the components of tight junction. The purpose of this study was to investigate whether irinotecan induces bacterial translocation in rats, and thus elucidate the relationship between tight junction and bacterial translocation. METHODS Ten rats were divided into two groups: Five were treated with irinotecan and five were not treated with irinotecan, the control group. Irinotecan treated rats were administrated irinotecan 250 mg/kg intraperitoneally on days designated 0 and 1, were then killed at 48 h after treatment, and tissues were collected for analysis. Controls were treated with a saline solution. RESULTS In eighty percent of irinotecan treated rats, bacteria were detected in the mesenteric lymph node or spleen. Large intestinal resistance of the rats was decreased. On the contrary, small intestinal resistance increased. Claudin-1 protein expression of both the small and large intestine decreased (P < 0.05), occludin protein expression of the small intestine decreased (P < 0.05), and occludin protein expression of the large intestine had decreasing tendency (P = 0.07) in irinotecan treated rats. In irinotecan treated rats, claudin-1 mRNA of the small intestine decreased (P < 0.05), claudin-1 mRNA of large intestine had a tendency to decrease (P = 0.05), occludin mRNA of both small and large intestine decreased (P < 0.05). CONCLUSIONS Irinotecan injures claudin-1 and occludin. It causes disorders in the intestinal epithelial barrier and induces bacterial translocation.

Risk model for distal gastrectomy when treating gastric cancer on the basis of data from 33,917 Japanese patients collected using a nationwide web-based data entry system

OBJECTIVE To establish a risk model for distal gastrectomy in Japanese patients with gastric cancer. BACKGROUND Risk stratification for distal gastrectomy in Japanese patients with gastric cancer improves surgical outcomes. METHODS The National Clinical Database was constructed for risk determination in gastric cancer-related gastrectomy among Japanese individuals. Data from 33,917 gastric cancer cases (1737 hospitals) were used. The primary outcomes were 30-day and operative mortalities. Data were randomly assigned to risk model development (27,220 cases) and test validation (6697 cases) subsets. Stepwise selection was used for constructing 30-day and operative mortality logistic models. RESULTS The 30-day, in-hospital, and operative mortality rates were 0.52%, 1.16%, and 1.2%, respectively. The morbidity was 18.3%. The 30-day and operative mortality models included 17 and 21 risk factors, respectively. Thirteen variables overlapped: age, need for total assistance in activities of daily living preoperatively or within 30 days after surgery, cerebrovascular disease history, more than 10% weight loss, uncontrolled ascites, American Society of Anesthesiologists score (≥ class 3), white blood cell count more than 12,000/μL or 11,000/μL, anemia (hemoglobin: males, <13.5 g/dL; females, <12.5 g/dL; or hematocrit: males, <37%; females <32%), serum albumin less than 3.5 or 3.8 g/dL, alkaline phosphatase more than 340 IU/L, serum creatinine more than 1.2 mg/dL, serum Na less than 135 mEq/L, and prothrombin time-international normalized ratio more than 1.25 or 1.1. The C-indices for the 30-day and operative mortalities were 0.785 (95% confidence interval, 0.705-0.865; P < 0.001) and 0.798 (95% confidence interval, 0.746-0.851; P < 0.001), respectively. CONCLUSIONS The risk model developed using nationwide Japanese data on distal gastrectomy in gastric cancer can predict surgical outcomes.

Expression of histone deacetylase 1 and metastasis-associated protein 1 as prognostic factors in colon cancer

Histone deacetylase 1 (HDAC1) and metastasis-associated protein 1 (MTA1) form the nucleosome remodeling and histone deacetylation (NuRD) complex and may possibly play a central role in cancer development. However, limited data has been reported regarding the expression of both HDAC1 and MTA1. The aim of the present study was to clarify the clinical role of HDAC1 and MTA1 expression in colon cancer. Seventy-four patients with colon cancer, who underwent colectomy at our institution, were enrolled in this study. Expression of HDAC1 and MTA1 was examined immunohistochemically. The patients were divided into four groups: HDAC1-positive group (n=58), HDAC1-negative group (n=16), MTA1-positive group (n=38) and MTA1-negative group (n=36). Clinicopathological factors and survival rates were compared between the groups. Regarding the clinicopathological factors, the depth of tumor invasion and stage correlated significantly with HDAC1 expression (p<0.05). Age, depth of tumor invasion and vascular invasion tended to correlate with MTA1 expression. The 5-year survival rate in the HDAC1-positive group (55.1%) was significantly worse compared to the HDAC1-negative group (86.5%) (p<0.05), and the 5-year survival rate of the MTA1-positive group (50.5%) was significantly worse than that of the MTA1-negative group (73.1%) (p=0.05). In patients with stages II-IV and curability A, B, the survival rate in those with HDAC1-positive expression was significantly worse than those with HDAC1-negative expression (p<0.05), and the survival rate of the MTA1-positive group tended to be worse than that of the MTA1-negative group (p=0.07). Overall survival in both the HDAC1 and MTA1-positive groups was significantly worse than overall survival of the other groups (p<0.05). Disease-free survival in both the HDAC1- and MTA1-positive groups, among patients with stages II-IV and curability A, B, was also significantly worse than that of the other groups (p<0.05). HDAC1 and MTA1 expression levels were significantly related to poorer prognosis. Therefore, HDAC1 and MTA1 expression levels are potential prognostic indicators for colon cancer.

Characteristics of internal hernia after gastrectomy with Roux-en-Y reconstruction for gastric cancer.

BackgroundAlthough the internal hernias have been a huge topic in the field of bariatric surgery, there were a few reports in gastric cancer. The purpose of this study was to analyze the incidence, clinical features, and prevention of internal hernia after gastrectomy for gastric cancer.MethodsTwelve patients who underwent surgical treatment for internal hernia in our hospital after gastrectomy were analyzed. Features, including incidence, symptoms, and signs, were investigated in detail.ResultsThe operative procedures for preceding gastrectomies were open distal gastrectomy in three patients, open total gastrectomy in three patients, laparoscopic-assisted distal gastrectomy in two patients, and laparoscopic total gastrectomy in four patients. The most frequent sites of internal hernias were jejunojejunostomy mesenteric defects (five patients) and Petersen’s defect (five patients), mesenterium of transverse colon (one patient), and esophagus hiatus (one patient). There was no significant difference between open and laparoscopic preceding gastrectomies. After closure of the mesenteric defect was introduced, no further internal hernias occurred. On CT examination, the whirl sign was present in ten patients on 3D images.ConclusionsThe present data suggest the importance of early recognition and treatment of internal hernia, as well as its prevention by closure of mesenteric defects.

Platelet-derived endothelial cell growth factor/thymidine phosphorylase inhibitor augments radiotherapeutic efficacy in experimental colorectal cancer

PURPOSES A lot of radiosensitizers have been developed. However, there are few to be available in the clinical setting. Thymidine phosphorylase inhibitor (TPI) regulates the phosphorolysis of thymidine to thymine and 2-deoxy-d-ribose-1-phosphate which is essential for tumor angiogenesis. The aim of this study is to evaluate whether TPI augments the radiotherapy for colorectal cancer in vitro and in vivo studies. MATERIALS AND METHODS The cytotoxicity of TPI with irradiation on HT29 and HCT116 cells was examined using MTT- and colony formation assay. At 10days post-inoculation, HT29 bearing orthotopic model mice (n=28) were divided into four groups and orally treated with TPI- (50mg/kg/day for 2weeks), radiation (RT, 2Gy×4: Total 8Gy), their combination or the vehicle. The mechanisms underlying the efficacy were assessed genomically and immunohistochemically. RESULTS Compared to each single treatment, the combination of TPI and RT synergistically inhibited the cell viability in a time- and dose-dependent manner. In the HT-29 bearing mice, the combination of TPI and RT reduced the tumor growth compared with RT alone. Notably, the mRNA levels of VEGF, TGF-β and, Rad51 and the protein expressions of VEGF and CD34 were significantly lower in the combination than the others. Furthermore, the combination markedly increased the TUNEL-positive cells, suggesting that TPI augments the cancer cell death through inhibition of angiogenesis and DNA repair system in the radiotherapy. CONCLUSIONS Our study first demonstrated that the combination of TPI and irradiation was effective in colon cancer. TPI would provide a promising therapeutic strategy as a radiosensitizer.

Duodenal–jejunal bypass improves diabetes and liver steatosis via enhanced glucagon‐like peptide‐1 elicited by bile acids

Bariatric surgery not only elicits weight loss but also rapidly resolves diabetes. However, the mechanisms remain unclear. The present study investigates how diabetes and liver steatosis are improved after duodenal–jejunal bypass (DJB) compared with a glucagon‐like peptide‐1 (GLP‐1) analog and correlations between bile acids and GLP‐1 secretion.

Squamous Cell Carcinoma of the Descending Colon: Report of a Case and Literature Review

It is very rare that squamous cell carcinoma (SCC) arises from colorectal epithelium. An 89-year-old man was treated in 2001 with chief complaints of anorexia, abdominal pain, and low grade fever. The histological diagnosis as SCC was determined by biopsy during a colonoscopy. We diagnosed primary SCC of the colon because except in the colon no malignant lesions were found by systemic CT. Surgical complete resection was performed. However, he died three months after surgical resection because of hepatic metastasis and cachexia. The prognosis of this disease seems to be worse than that of adenocarcinoma.

Benefits of simultaneous laparoscopic resection of primary colorectal cancer and liver metastases

Recently, consensus on the optimal strategy for resectable synchronous colorectal liver metastases (LM) seems to have shifted toward simultaneous resection. However, there are still relatively few reports about simultaneous laparoscopic resection. The aim of this study is to evaluate the outcomes of patients who underwent simultaneous laparoscopic resection.

Short-term results of laparoscopic surgery after preoperative chemoradiation for clinically staged T3 and T4 rectal cancer

The feasibility of laparoscopic surgery for clinically staged T3 and T4 rectal cancer has not been clearly defined specifically in cases following preoperative chemoradiation therapy (CRT). Our aim was to investigate the feasibility of laparoscopic surgery after preoperative CRT for clinically staged T3 and T4 rectal cancer.