北山 丈二

Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for patients with ulcerative colitis (UC). The purpose of this study was to investigate the long-term functional outcomes and quality of life (QOL) associated with hand-sewn and stapled IPAA. Ninety-one patients with UC had undergone IPAA using hand-sewn anastomosis with mucosectomy (32 patients) or stapled anastomosis (59 patients) from January 1988 to May 2010. Patients were evaluated according to patient characteristics, postoperative complications, functional outcomes and QOL. The QOL of patients were evaluated using the Medical Outcomes Study Short Form 36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). Numbers of patients with colorectal cancer or dysplasia were significantly greater in the hand-sewn IPAA group (P < 0.01). These patients had longer disease durations and were older (both P < 0.01). There was no difference in the incidence of complications between the groups, except for a greater incidence of postoperative anal fistula in the stapled group (P = 0.03). In the early postsurgery period, both the frequency of bowel movements and the rate of soiling were significantly higher in the hand-sewn group, but in a later period, there was no difference in these events >3 years after surgery. The SF-36 and IBDQ results were similar in the two groups, indicating that hand-sewn and stapled IPAA result in similar QOL in the late postoperative period. Postoperative complications, functional outcomes, and long-term QOL were similar in patients who had received hand-sewn or stapled IPAA.

Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer (CRC) with unresectable metastasis (mCRC). The aim of this study was to investigate the prognostic impact of primary tumor resection in various subgroups of mCRC patients. A total of 1982 patients with mCRC from January 1997 to December 2007 were retrospectively evaluated. The impact of primary tumor resection on cancer-specific survival (CSS) was analyzed using propensity score analysis to mitigate selection bias. Covariates in the models for propensity scores included treatment period, age, gender, tumor location, depth, lymph node metastasis, number of metastatic organs, and carcinoembryonic antigen (CEA) levels. Among the whole patient population, primary tumor resection significantly improved CSS [hazard ratio (HR) 0.46, 95 % confidence interval (CI) 0.32-0.66, p < 0.01]. However, primary tumor resection did not significantly improve CSS in the following subgroups: patients treated in the first 5 years of the study (HR 0.56, 95 % CI 0.28-1.13, p = 0.08), patients aged > 65 years (HR 0.72, 95 % CI 0.36-1.42, p = 0.31), female patients (HR 0.60, 95 % CI 0.31-1.17, p = 0.13), patients with right-sided colon cancer (HR 0.68, 95 % CI 0.39-1.20, p = 0.17), and patients without nodal involvement (HR 0.54, 95 % CI 0.25-1.17, p = 0.09). Our study suggests that primary tumor resection improves the survival of patients with mCRC. However, the prognostic benefit is different among patient subpopulations.

Background: The incidence of anastomotic leakage in rectal surgery is around 10 percent. Poor blood supply to the anastomosis, high anastomotic pressure and tension, increased operative blood loss, long operative time, and male sex are risk factors of anastomotic leakage. In the present study, we examined anastomotic leakage cases in rectal surgery at our institute and tried to ascertain the risk factors. Methods: Three hundred fifty-seven consecutive patients who underwent rectal resection with anastomosis between January 2008 and October 2013 were included in the study. Patients were divided into two groups according to the existence of anastomotic leakage. Clinicopathological features, operative procedures, and intraoperative outcomes were compared between the two groups. Regarding intraoperative procedure, we focused on the ligation level of the inferior mesenteric artery, installing a transanal drainage tube in the rectum, and constructing a diverting stoma. Results: Anastomotic leakage occurred in eight patients. All of them were male (p=0.0284). There were no statistical differences in other characteristics of the patients or tumors, in operative procedures, or in intraoperative outcomes. Conclusions: In the present study, no statistically significant risk factors for anastomotic leakage in rectal surgery were detected, except for male sex. However, the rate of anastomotic leakage at our institute was revealed to be rather low. Our exertion to preserve good blood flow and to prevent high tension and pressure on the anastomosis in operation may have led to this result.

The perioperative immune status of colorectal robotic surgery (RS), laparoscopic surgery (LS), and open surgery (OS) patients has not been compared. Our aim was to evaluate perioperative stress and immune response after RS, LS and OS. This prospective study included 46 colorectal surgery patients from the Department of Surgical Oncology of the University of Tokyo Hospital. Peripheral venous blood samples were obtained preoperatively and on postoperative days 1, 3, and 6. We evaluated expression of HLA-DR (marker of immune competence), C-reactive protein (CRP) levels, and lymphocyte subset counts (natural killers, cytotoxic T cells and helper T cells). Fifteen, 23, and 8 patients underwent RS, LS and OS, respectively. HLA-DR expression was the lowest on day 1 and gradually increased on days 3 and 6 in all the groups. There was no significant difference in postoperative HLA-DR expression between the RS and LS group. However, on day 3, HLA-DR expression in the RS group was significantly higher than in the OS group (p = 0.04). On day 1, CRP levels in the LS group were significantly lower than in the RS group (p = 0.038). There were no significant perioperative changes in the lymphocyte subset cell count between the three groups. Perioperative surgical stress, as evaluated by immunological parameters, was comparable between robotic and laparoscopic surgery and higher with open surgery. Robotic surgery may be an alternative to laparoscopic surgery, as a minimally invasive surgery option for colorectal cancer.

Objective: To construct a predictive model of postoperative colorectal neoplasm development using a nomogram. Background: Although patients with colorectal cancer (CRC) are known to be at high risk of developing metachronous adenoma or CRC, no statistical model for predicting the incidence of postoperative colorectal lesions has been reported. Methods: A total of 309 CRC patients who underwent surgical resection received regular endoscopic follow-up to detect the development of metachronous adenoma or adenocarcinoma. The patients were divided into the derivation set (n = 209) and the validation set (n = 100). The nomogram to predict the 3- and 5-year adenoma-free survival rates was constructed using the derivation set, and a calibration plot and concordance index (c-index) were calculated. The predictive utility of the nomogram was validated in the validation set. Results: Sex, age, and number of synchronous lesions at the time of surgery for primary CRC were adopted as variables for the nomogram. The nomogram showed moderate calibration, with a c-index of 0.709 in the derivation set and 0.712 in the validation set. Conclusions: A nomogram based on sex, age, and number of synchronous lesions at the time of surgery has the ability to predict postoperative adenoma-free survival.

The lymph node ratio (LNR) was proposed as a prognostic indicator in Stage III colorectal cancer (CRC) patients in recent studies. The purpose of this study was to evaluate the prognostic impact of the LNR in Stage IV CRC patients who have undergone curative resection. A retrospective review of 119 Stage IV CRC patients who underwent curative resection in our institute from 1997 to 2009 was performed. Patients were divided into two groups (low LNR and high LNR) by means of their median LNR. A disease-free survival (DFS) and an overall survival (OS) were analyzed using the Kaplan-Meier curve; multivariate analysis was performed using the Cox proportional hazard model. The cutoff value for the LNR was 0.111. For the entire study group, the 5-year DFS was 22 % and the 5-year OS was 65 %. DFS was not significantly different between patients in the low LNR group and the high LNR group (25 and 19 %, respectively; P = 0.317), but OS was significantly higher in the low LNR group patients compared with the high LNR group patients (77 and 54 %, respectively; P < 0.001). Using multivariate analysis, we identified the LNR as an independent prognostic factor for OS, with a hazard ratio of 3.08 (95 % CI 1.38-8.19; P = 0.005). LNR is a potent prognostic indicator for stratification in Stage IV CRC patients who have undergone curative resection.

Background: Although secretory phospholipase A2 (sPLA2) has been shown to be involved in various biological processes, its specific roles in sub-types of cancer development remain to be elucidated. Materials and Methods: We examined the expression of sPLA2 group III (GIII) in 142 patients with colorectal cancer using immunohistochemistry, and its correlation with clinicopathological features and outcomes. In addition, we examined the co-expression of sPLA2GIII and sPLA2GX using serial tissue sections to clarify the roles of both proteins in colorectal carcinogenesis. Results: In 66 cases, diffuse staining of sPLA2GIII was seen; this was defined as the group with high expression. High expression was associated with a significantly higher rate of lymph node metastasis (p=0.02) and poorer survival (p=0.03) compared with low expression. Patients with low sPLA2GIII and high sPLA2GX expression had a significantly higher survival rate than those with high sPLA2GIII and low sPLA2GX expression (p=0.038). Conclusion: sPLA2GIII expression may be used as a risk factor for lymph node metastasis and a prognostic marker in colorectal cancer. In addition, sPLA2GIII and sPLA2GX may play opposing roles in colorectal carcinogenesis.

Purpose: Although stage IV colorectal cancer (CRC) encompasses a wide variety of clinical conditions with diverse prognoses, no statistical model for predicting the postoperative prognosis of stage IV CRC has been established. Thus, we here aimed to construct a predictive model for disease-free survival (DFS) and overall survival (OS) after curative surgery for stage IV CRC using nomograms. Methods: The study included 1133 stage IV CRC patients who underwent curative surgical resection in 19 institutions. Patients were divided into derivation (n = 586) and validation (n = 547) groups. Nomograms to predict the 1- and 3-year DFS rates and the 3- and 5-year OS rates were constructed using the derivation set. Calibration plots were constructed, and concordance indices (c-indices) were calculated. The predictive utility of the nomogram was validated in the validation set. Results: The postoperative carcinoembryonic antigen (CEA) level, depth of tumor invasion (T factor), lymph node metastasis (N factor), and number of metastatic organs were adopted as variables for the DFS-predicting nomogram, whereas the postoperative CEA level, T factor, N factor, and peritoneal dissemination were adopted for the nomogram to predict OS. The nomograms showed moderate calibration, with c-indices of 0.629 and 0.640 in the derivation set and 0.604 and 0.637 in the validation set for DFS and OS, respectively. Conclusions: The nomograms developed were capable of estimating the probability of DFS and OS on the basis of only 4 variables, and may represent useful tools for postoperative surveillance of stage IV CRC patients in routine practice. (C) 2015 Elsevier Ltd. All rights reserved.

The aim of this study was to clarify patient factors contributing to complications after laparoscopic surgery for colorectal cancers. A total of 333 colorectal cancer patients who underwent laparoscopic colorectal resection between January 2007 and December 2012 were enrolled. The association between patient factors and the incidence of complications were analyzed. Postoperative complications were divided into 2 categories: infectious complications and noninfectious complications. The overall complication rate was 13% and mortality rate 0%. Multivariate analysis showed that body mass index > 25 kg/m(2) [odds ratio (OR) = 3.02, P = 0.0254] and tumor location (right colon cancer/rectal cancer: OR = 0.11, P = 0.0083) were risk factors for infectious complications; in addition, male sex (OR = 3.91, P = 0.0102) and cancer stage (stage 2/stage 4: OR = 0.17, P = 0.0247) were risk factors for noninfectious complications. This study shows that different patient factors are associated with the risk of different types of complications.

Solitary fibrous tumors (SFTs) rarely develop in the pelvis. When they do arise, they are usually treated using surgery, although SFTs are often very large by the time of diagnosis, which makes surgical excision difficult. We report a case of a 63-year-old man who was referred to our hospital for the treatment of a giant tumor of the pelvis. Computed tomography (CT) revealed a 30 x 25 x 19 cm sized hypervascular tumor that almost completely filled the pelvic cavity. The diagnosis of SFT was made by CT-assisted needle biopsy. The feeding arteries of the tumor were embolized twice. The first embolization aimed to reduce the tumor volume, while the second one was planned a day prior to the surgery to obtain hematostasis during the operation. Tumor resection was then performed. The blood loss during the operation was 440 ml, and there was no uncontrollable bleeding. The postoperative course was uneventful. No recurrence of SFT was observed during a 2-year follow-up.

Background. A positive cytology of peritoneal lavage fluid (CY1) is a poor prognostic factor in patients with gastric cancer (GC). We have recently reported that CY1 often changes to negative (CY0) following combination chemotherapy including intraperitoneal (IP) paclitaxel (PTX), which results in marked prolongation of survival in GC patients with peritoneal dissemination (P1). Methods. A total of 95 P1 GC patients who received combination chemotherapy with S-1 and intravenous and IP PTX were enrolled. Peritoneal lavage fluid was periodically examined cytologically at the start of every cycle of chemotherapy, and the impact of CY status on patient outcome was retrospectively evaluated. Results. Seventy-three (76.8 %) of 95 patients were diagnosed as CY1 before initial treatment. Median survival time (MST) of the CY1 group was significantly shorter than that of the CY0 group (19.1 vs. 32.5 months, P = 0.033). Cytological status changed from CY1 to CY0 in 68 (93.2 %) of 73 CY1 patients during the whole treatment period and MST of patients who showed a negative change was significantly longer than that of the unchanged group (20.0 vs. 13.0 months, P = 0.0017). In 64 patients who achieved CY0 by IP PTX regimen, the median time to achieve CY0 was 1.4 months, and patients who achieved a negative change within 1 month showed a particularly good outcome (MST = 26.1 months). Conclusions. Periodic cytological examination of peritoneal lavage fluid is clinically useful to evaluate the efficacy of treatment as well as to predict the outcome of patients with P1 GC.

BackgroundRecent studies have proposed the use of log odds of positive lymph nodes (LODDS) as a prognostic indicator in colorectal cancer (CRC) patients without distant synchronous metastasis. In the present study, we aimed to evaluate the prognostic impact of the LODDS in Stage IV CRC patients who have undergone curative resection. MethodsWe performed a retrospective review of 117 Stage IV CRC patients who underwent curative resection at our institute from 1998 to 2011. Patients were categorized into 3 groups (LODDS1-3) according to the ratio of their LODDS. The relationship between the LODDS and disease-free survival (DFS) and overall survival (OS) rates were assessed. ResultsDFS was not significantly different between patients in each LODDS group. The association between the LODDS classification and OS was statistically significant (P=0.021). Multivariate analysis indicated that LODDS classification was an independent prognostic factor for OS, with a hazard ratio of 2.95 for LODDS2 (95% confidence interval [CI]: 1.18-8.35; P=0.021), and 2.98 for LODDS3 (95% CI: 1.20-8.37; P=0.017). ConclusionsThe LODDS is a good prognostic indicator in Stage IV CRC patients who have undergone curative resection. J. Surg. Oncol. 2015 111:465-471. (c) 2015 Wiley Periodicals, Inc.

Background: The function of phosphatidylserine-specific phospholipase A1 (PS-PLA(1)), a phospholipase that acts specifically on phosphatidylserine and produces lysophosphatidylserine, a lysophospholipid mediator, has not been fully elucidated. We evaluated the role of PS-PLA(1) in oncogenesis and metastasis of colorectal cancer (CRC). Materials and Methods: Specimens from 85 patients with CRC were immunostained with a monoclonal antibody against PS-PLA(1). The correlation between PS-PLA(1) expression and the clinicopathological variables was analyzed. Results: Tumor depth and hematogenous metastasis independently positively correlated with PS-PLA(1) expression. High PS-PLA(1) expression was associated with shorter disease-free survival, although it was not an independent predictive factor. Conclusion: PS-PLA(1) expression in CRC is associated with tumor invasion and metastasis.

BACKGROUND: Although neoadjuvant chemoradiotherapy (CRT) has become a standard procedure to downstage locally advanced rectal cancer prior to surgery, markers to predict the response to CRT have not been fully identified. The aim of this study was to identify predictive factors of response to CRT, especially focusing on peripheral blood leukocyte subsets. METHODS: A total of 45 consecutive patients diagnosed with primary rectal cancer were prospectively enrolled and received CRT followed by curative resection. The numbers of each lymphocyte subset in peripheral blood pre- and post-CRT were analyzed using flow cytometry. According to the pathological response to CRT, patients were classified into high (Hi-R) and low (Lo-R) response groups. RESULTS: Hi-R cases had significantly higher numbers of pre-CRT lymphocytes (p = 0.018), T lymphocytes (p = 0.009) and helper T lymphocytes (Th lymphocytes, p = 0.015) compared to the Lo-R cases. With the receiver-operating characteristic curve for numbers of pre-CRT T lymphocytes, the area under the curve (AUC) was 0.733, and the optimal cutoff value was 1196/μl, with 76.5% sensitivity, 67.8% specificity, 59.1% positive and 82.6% negative predictive values. The numbers of pre-CRT Th lymphocytes and cytotoxic lymphocytes were both independent predictors of the high CRT response in the multivariate analysis. CONCLUSIONS: In addition to the direct cytotoxicity of CRT, recent studies have demonstrated the induction of an immunological host response, which also contributed to the tumor regression induced by CRT. Our result suggested the potential role of circulating T lymphocytes in predicting the response to CRT in colorectal cancer patients.

Background. Peritoneal dissemination and positive peritoneal lavage cytology are associated with poor prognosis in colorectal cancer. Carcinoembryonic antigen (CEA) messenger RNA (mRNA) is often used as a marker to detect micrometastases. We aimed to evaluate the prognostic significance of CEA mRNA in the peritoneal lavage of colon cancer patients. Methods. Colon cancer patients (n = 201) who underwent curative operative resection between August 2009 and February 2013 were enrolled. CEA mRNA in peritoneal lavage was measured using the transcription-reverse transcription concerted method, a quantitative RNA amplification method. The correlation between CEA mRNA and overall and peritoneal recurrence-free survival was evaluated. Results. Positive CEA mRNA in peritoneal lavage was an independent risk factor for overall recurrence-free survival in colon cancer (1, < .0001). Positive CEA mRNA was a risk factor for poorer overall recurrence in stage II and III patients (P = .04 and P = .02, respectively). Moreover, among stage III patients with positive CEA mRNA, the postoperative chemotherapy group had significantly lower overall and peritoneal recurrence rates than the no postoperative chemotherapy group (P = .001). Conclusion. Positive cm mRNA in peritoneal lavage was associated with high overall recurrence rates in stage II and III colon cancer Further study is necessary to determinate the efficacy of aggressive postoperative chemotherapy for stage II and III colon cancerpatients with positive CEA mRNA.

BACKGROUND: The branching of the inferior mesenteric artery and vein varies among individuals. Three-dimensional CT angiography is a less invasive modality than traditional angiographic examination to assess the artery and vein. OBJECTIVE: We aimed to demonstrate the clinical applicability of CT angiography by evaluating bifurcations of the inferior mesenteric artery and the positional relationship between the inferior mesenteric artery and vein. DESIGN: This was a prospective observational study of patients undergoing preoperative CT angiography. SETTINGS: This study was conducted at a single tertiary care institution in Japan. PATIENTS: A total of 471 consecutive patients who underwent preoperative CT angiography from April 2012 to December 2013 were prospectively enrolled. MAIN OUTCOME MEASURES: The branching pattern of the inferior mesenteric artery, the positional relationship between the inferior mesenteric artery and vein, and the associations between inferior mesenteric artery length and clinical features were evaluated. RESULTS: The length of the inferior mesenteric artery varied widely, from 10.1 to 82.2 mm. In 41.2% patients, the left colic artery arose independently from the sigmoid artery, and in 44.7% of the patients, the left colic artery and sigmoid artery had a common trunk, whereas the left colic artery did not exist in 5.1%. The left colic artery was located lateral to the inferior mesenteric vein at the level of the origin of the inferior mesenteric artery in 73.0% of the patients. The incidence of a short inferior mesenteric artery was significantly increased in men with high BMIs (75.0%). LIMITATIONS: Three-dimensional reconstruction was performed by the use of a single software, and angiographic examination was not performed. Therefore, accuracy and reliability of the 3-dimensional reconstruction could not be established for each modality. CONCLUSIONS: Using 3-dimensional CT angiography, preoperative understanding of the anatomic vascular variations can be easily obtained, which would help surgeons to safely perform laparoscopic surgery in the left-side colon and rectum.

A 57-year-old woman without any past medical history underwent abdominoperineal resection for rectal cancer in our department. On postoperative day 15, the patient complained of sudden abdominal pain, and high fever was noted in addition to the appearance of erythema around the stoma. The diagnosis of phlegmon was made, and antibiotic infusion was started. However, a few days later, the patient developed hypovolemic shock with hypoalbuminemia and hemoconcentration. Fasciotomy was performed to exclude the necrotizing fasciitis, though all cultures were negative. Upon exclusion of the differential diagnoses, idiopathic systemic capillary leak syndrome (ISCLS) was diagnosed. She was successfully treated with massive fluid infusion under ventilation and continuous hemodiafiltration. Here, we report the first case of ISCLS that occurred during the postoperative period of colorectal surgery.

Background: High-mobility group box 1 (HMGB1) is a nucleoprotein that is related to inflammation. It has been implicated in a variety of biologically important processes, including transcription, DNA repair, differentiation, development, and extracellular signaling. Recently, its important role in the process of tumor invasion, metastasis, and resistance to anti-cancer therapies has been demonstrated. In this study, we aimed to investigate the correlation of HMGB1 expression and resistance of rectal cancer patients to chemoradiotherapy (CRT) prior to curative operation. Methods: We retrospectively reviewed the data of 75 lower rectal cancer patients without complete pathological response who had received preoperative CRT and had undergone curative resection at the University of Tokyo Hospital between May 2003 and June 2010. HMGB1 expression in surgically resected specimens was evaluated using immunohistochemical detection and specimens were classified into high or low HMGB1 expression groups. Clinicopathologic features, degree of tumor reduction, regression of tumor grade, and patient survival were compared between the groups using non-paired Student's t-tests and Kaplan-Meier analysis. Results: A total of 52 (69.3%) patients had high HMGB1 expression, and 23 (30.7%) had low expression. HMGB1 expression was significantly correlated with histologic type (P = 0.02), lymphatic invasion (P = 0.02), and venous invasion (P = 0.05). Compared to patients with low HMGB1 expression, those with high expression had a poorer response to CRT, in terms of tumor reduction ratio (42.2 versus 28.9%, respectively; P < 0.01) and post-CRT histological tumor regression grade (56.5 versus 30.8% grade 2; respectively; P = 0.03). However, no significant correlation was found between HMGB1 expression and recurrence-free and overall survival rates. Conclusions: HMGB1 expression may be one of the key factors regulating the response of rectal cancer to preoperative CRT in terms of tumor invasiveness and resistance to therapy.

We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patient's respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement.

Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular-targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer.

This study reviewed 1059 patients with colorectal cancers (CRCs) to evaluate the age-related changes in the clinicopathologic features, according to the gender. The presence of concomitant adenoma was the only independent age-related factor in men (P = .0044), whereas the presence of right-sided CRC was the only one in women (P < .0001). The results suggest the oncologic background difference between men and women among the elderly. Introduction: Although several reports have documented the increased incidence of right-sided colorectal cancer (CRC) in the elderly, especially in women, the gender-specific, age-related changes in the characteristics of CRCs, especially related to the cancer localization, have not been fully investigated. This study evaluated the age-related changes in the clinicopathologic features of CRCs, according to the gender. Materials and Methods: A total of 1059 consecutive patients with CRCs who were admitted to the authors' surgical department between February 2005 and June 2012 were retrospectively reviewed. The patients were divided into male (n = 632) and female (n = 427) groups and then according to the age group, and the correlation between the age group and the other clinicopathologic features was analyzed by univariate and multivariate analysis. Results: The number of concomitant adenomas found was significantly increased along with increasing age in men, and the presence of concomitant adenoma was the only independent age-related factor of male CRC in the multivariate analysis (P = .0044). In contrast, in women, the location of the CRC progressively shifted to the right side (proximal colon) with increasing age, and the presence of right-sided CRC was the only independent factor of female CRC in the multivariate analysis (P < .0001). Conclusion: There was a significant gender-specific difference in the age-related changes in the characteristics of CRC. Increasing the number of concomitant adenomas and the shift of CRC localization to the proximal colon were the gender-specific characteristics of male and female CRC, respectively.

Background: Either palliative distal gastrectomy or gastrojejunostomy are the initial treatment options for locally advanced gastric cancer with outlet obstruction when curative-intent resection is not feasible. Since chemotherapy is the mainstay for unresectable gastric cancer, the clinical value of palliative distal gastrectomy is controversial. Methods: We retrospectively reviewed the clinical data of patients with gastric cancer with outlet obstruction treated at our institution between January 2002 and December 2012. We compared the clinical outcomes of palliative distal gastrectomy with those of gastrojejunostomy patients and the factors affecting overall survival were evaluated. Results: Elective palliative distal gastrectomy and gastrojejunostomy were performed in 18 and 25 patients, respectively. The median overall survival times in the gastrojejunostomy and palliative distal gastrectomy groups were statistically equivalent at 8.8 and 8.3 months, respectively (P = 0.73), despite the more locally advanced tumors in the gastrojejunostomy as compared with the palliative distal gastrectomy group. A multivariate Cox regression analysis showed absence of postoperative chemotherapy and higher postoperative complication grade to be associated with worse clinical outcomes. Conclusions: Palliative distal gastrectomy offers neither survival nor palliative benefit as compared to gastrojejunostomy. Minimizing the morbidity of intervention for outlet obstruction, followed by chemotherapy, appears to be the optimal initial strategy for incurable gastric cancer with outlet obstruction.

Introduction: We report a rare case of delayed abdominal wall abscess after abdominoperineal resection (APR) for rectal cancer. Case description: A 63-year-old woman was diagnosed with rectal cancer and received chemo-radiotherapy, followed by APR. One year after surgery, the patient complained of pain and skin redness in the lower abdomen. A low-density mass lesion with 5.9-cm diameter was found in the lower abdominal wall by computed tomography, which showed high uptake on positron-emission tomography. These findings suggested the possibilities of either delayed abscess formation or abdominal wall recurrence of rectal cancer with central necrosis. Percutaneous drainage was performed. The content was a purulent exudate, without neoplastic cells in the cytology. The lesion quickly disappeared after the drainage, and no recurrence of the tumor was observed for more than 2 years. Discussion and evaluation: In this case, the un-absorbable yarn, such as silk, has not been used during the operation, no foreign body was retained in the abdominal wall, and there was no associated inflammatory bowel disease. Use of neoadjuvant chemoradiotherapy was the only possible cause of delayed abscess formation in this case. Conclusion: In case local recurrence is suspected by imaging modalities in the postoperative of colorectal cancer, especially those with precedent chemoradiotherapy or radiotherapy, although rare, the possibility of a delayed abscess formation should also be considered.

Background: Lysophosphatidylserine (lysoPS) is a type of lysophospholipid mediator, which is involved in allergic conditions and tumor progression. We investigated the physiological function of lysoPS on colorectal cancer (CRC) cell lines, as well as the involved receptor and signaling pathways. Materials and Methods: Expression of lysoPS receptors on six cell lines was examined by reverse transcription-polymerase chain reaction (RT-PCR). The physiological functions of lysoPS were investigated, and experiments using small interfering RNA (siRNA) or inhibitors of the signaling pathways were conducted. Results: Among the three lysoPS receptors, GPR34 was highly expressed on all cell lines. LysoPS stimulated the chemotactic migratory ability. Wortmannin inhibited the migratory ability, as well as the GPR34 knock-down, strongly suggestive of the involvement of this receptor in the PI3K/Akt pathway. Conclusion: The involved receptor and pathways in the migratory ability in response to lysoPS was demonstrated, which opens premises for targeting as a new strategy for prevention and treatment of colorectal cancer.

Background. Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC. Methods. A total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs. Results. In a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70 years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3 months; p = 0.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7 months; p < 0.0001). Conclusions. It was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC.

The importance of Notch signaling in colorectal cancer (CRC) tumorigenesis has been recently recognized. However, the significance of Notch3 expression and its association with Notch1 expression in CRC is unclear. In the present study, we investigated Notch1 and Notch3 expression in Stage II and III CRC to assess their association with clinicopathological characteristics. The protein expression of Notch1 and Notch3 was examined using immunohistochemistry in 305 CRC specimens. Nuclear expression of Notch1 and Notch3 and their associations with clinicopathological characteristics and distant relapse-free survival (dRFS) were evaluated. Nuclear Notch1 was overexpressed in 37 % of specimen, and nuclear Notch3 in 38 %. Nuclear Notch3 expression correlated with tumor differentiation status (P = 0.0099). Nuclear expression of Notch1 and Notch3 was associated with tumor recurrence (P = 0.0311 and P = 0.0053, respectively). In multivariate analysis, nuclear Notch3 expression [hazard ratio (HR) = 1.71; 95 % confidence interval (CI), 1.06-2.78; P = 0.0271), lymph node metastasis, and venous involvement were independently correlated with dRFS. In subgroup analysis, nuclear Notch3 expression was strongly associated with dRFS in Stage II CRC (HR = 3.47; 95 % CI 1.44-9.22; P = 0.0055). Both nuclear Notch1 and Notch3 were positive in 67 specimens (22 %) and both were negative in 144 specimens (47 %). Coexpression of nuclear Notch1 and Notch3 had an additive effect toward poorer dRFS compared with a negative subtype (HR = 2.48; 95 % CI, 1.41-4.40; P = 0.0019). Nuclear Notch3 expression might be a novel predictive marker for recurrence in Stage II and III CRC.

Surgery is the mainstay of treatment for gastrointestinal stromal tumors (GISTs). However, complete resection of rectal GISTs is sometimes difficult because of bulkiness and/or anatomical reasons. Neoadjuvant imatinib therapy has gained attention as an alternative treatment to increase the chance of en bloc resection of rectal GISTs, although it usually takes several months. In this case report, we first demonstrated that neoadjuvant imatinib therapy can be performed safely not only to downsize tumors, but also to allow adequate time for the effective treatment of major comorbid illnesses. A 74-year-old man was diagnosed with a 45 mm GIST of the lower rectum. He also had severe stenosis in the proximal segment of the left anterior descending coronary artery. Following the implantation of a drug-eluting stent, the patient received imatinib together with dual anti-platelet therapy for 12 months without obvious side effects. Follow-up image studies revealed tumor shrinkage as well as stent patency. En bloc resection of the GIST was performed laparoscopically, which preserved the anus. The patient is currently alive without any evidence of relapse for 12 months after surgery.

Peritoneal carcinomatosis (PC), caused by advanced abdominal malignancies, such as those of the ovarian and gastrointestinal tracts, has an extremely poor prognosis. Intraperitoneal (IP) chemotherapy has been clinically applied for several decades, but its clinical efficacy has not been fully determined. An accumulating body of evidence suggests that cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the optimal treatment for selected patients with ovarian and colorectal cancers with PC. Recent studies suggest that IP administration of taxane with systemic chemotherapy in a neoadjuvant setting improves patient survival in gastric cancer with PC. The pharmacokinetics of IP-administered drugs should be primarily considered in order to optimize IP chemotherapy. Therefore, the development of specific IP drugs using newly emerging molecular targeted reagents or new drug delivery systems, such as nanomedicine or controlled absorption/release methods, is essential to improve the efficacy of IP chemotherapy. (c) 2014 Elsevier Ltd. All rights reserved.

BACKGROUND: Preoperative chemoradiotherapy has been widely used for the prevention of local recurrence of locally advanced rectal cancer, and the effect of chemoradiotherapy is known to be associated with overall survival. OBJECTIVE: We aimed to evaluate the association of the pathologic response grade with tumor recurrence rate after chemoradiotherapy, using radiographic analysis and the Response Evaluation Criteria in Solid Tumors as the parameters. DESIGN: This study was conducted at a single tertiary care institution in Japan. SETTING: This was a retrospective cohort study of patients undergoing preoperative chemoradiotherapy. PATIENTS: A total of 101 low rectal cancer patients receiving preoperative chemoradiotherapy from July 2004 to August 2012 were enrolled. MAIN OUTCOME MEASURES: The tumor reduction rate was measured with the use of traditional Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry, and the correlation between the reduction rate and the pathologic response grade was examined. RESULTS: The tumor reduction rate assessed according to Response Evaluation Criteria in Solid Tumors showed no association with the pathologic response grade (p =0.61). In contrast, the radiographic response rate by both barium enema and CT volumetry strongly correlated with the pathologic response grade (p < 0.0001 and p = 0.001). In terms of local tumor recurrence, those diagnosed as high responders by the pathologic response grade, Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry had a lower recurrence rate (p =0.03, p =0.03, p =0.0002, and p =0.001). The difference between high responders and low responders was especially prominent by barium enema and CT volumetry. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: Double-contrast barium enema and CT volumetry were superior to Response Evaluation Criteria in Solid Tumors in evaluating the effect of chemoradiotherapy and predicting the likelihood of tumor recurrence.

To develop a drug-delivery system for the prolonged retention of intraperitoneally (i.p.) administered cisplatin (CDDP) to deliver intraperitoneal chemotherapy against peritoneal carcinomatosis effectively. CDDP was encapsulated inside an in situ cross-linkable hyaluronic acid (HA)-based hydrogel. The gelation and degradation kinetics of the hydrogel and the release kinetics of CDDP were investigated in vitro, and the antitumor effect was investigated in a mouse model of peritoneal dissemination of human gastric cancer. The gelation time varied according to the concentration of two polymers: HA-adipic dihydrazide and HA-aldehyde. CDDP was released from the hydrogel for more than 4 days. A cell proliferation assay showed that the polymers themselves were not cytotoxic toward MKN45P, a human gastric cancer cell line. By mixing the two polymers in the peritoneum, in situ gelation was achieved. The weight of peritoneal nodules decreased in the hydrogel-conjugated CDDP group, whereas no significant antitumor effect was observed in the free CDDP group. In situ cross-linkable HA hydrogels represent a promising biomaterial to prolong the retention and sustain the release of intraperitoneally administered CDDP in the peritoneal cavity and to enhance its antitumor effects against peritoneal dissemination.

Temsirolimus (TEM) is a novel, water-soluble mammalian target of rapamycin (mTOR) inhibitor that has shown activity against a wide range of cancers in preclinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored. We evaluated the antitumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in vitro and in vivo. In vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Antitumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in vitro and in vivo. In vitro, TEM was effective in inhibiting the growth of two CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1 alpha and VEGF in all three cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. We also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the antitumor activity of TEM in vitro and in vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio. Based on these data, we propose TEM with or without chloroquine as a new treatment option for CRC.

Background: Urethral metastatic adenocarcinoma is extremely rare. Moreover, only 9 previous cases with metastases from colorectal cancer have been reported to date, and not much information on urethral metastases from colorectum is available so far. Case presentation: We report our experience in the diagnosis and the management of the case with urethral metastasis from a sigmoid colon cancer. A 68-year-old man, who underwent laparoscopic sigmoidectomy for sigmoid colon carcinoma four years ago, presented gross hematuria with pain. Urethroscopy identified a papillo-nodular tumor 7 mm in diameter in the bulbar urethra. CT-scan imaging revealed the small mass of bulbous portion of urethra and solitary lung metastasis. Histological examination of the tumor obtained by transurethral resection showed moderately differentiated adenocarcinoma, which was diagnosed as a metastasis of a sigmoid colon carcinoma pathologically by morphological examination. Immunohistochemical analysis of the urethral tumor revealed the positive for cytokertin 20 and CDX2, whereas negative for cytokertin 7. These features were consistent with metastatic adenocarcinoma of the sigmoid colon cancer. As the management of this case with urethral and lung metastasis, 6-cycle of chemotherapy with fluorouracil with leucovorin plus oxaliplatin was administered to the patient, and these metastases were disappeared with no recurrence of disease for 34 months. Conclusion: Urethral metastasis from colorectal cancer is a very rare occurrence. However, in the presence of urinary symptoms, the possibility of the urethral metastasis should be considered.

Published reports concerning internal hernias after extraperitoneal stoma construction are scarce. In our present report, we describe the case of a 56-year-old man who was referred to our hospital for the treatment of rectal cancer. He underwent abdominoperineal resection of the rectum with sigmoidostomy using an extraperitoneal route. On the ninth postoperative day, the patient experienced sudden and intense abdominal pain and was diagnosed with strangulation of the small intestine due to a stoma-associated internal hernia. Therefore, an emergency laparotomy was performed. The surgical findings showed that the small intestine protruded through the space between the sigmoid colon loop and the abdominal wall in a cranial-to-caudal direction. The strangulated portion of the small intestine was recovered, and the orifice of herniation was closed. No recurrence of internal herniation was observed during the follow-up period.

Intraperitoneal (IP) administration of paclitaxel (PTX) can enable direct infiltrate of high amount of PTX into peritoneal nodules and elicit remarkable clinical responses against peritoneal metastases. In this study, we examined the mechanisms leading to tumor shrinkage after IP PTX. We compared the microscopic features of peritoneal metastases before and after IP PTX in surgically removed human samples, as well as in a murine xenograft model using immunohistochemistry. We found that many microvessels exist in the peripheral areas of metastatic nodules in human samples before treatment. However, peripheral vessels were greatly reduced in number, and luminal obstructions were observed in lesions showing complete response after chemotherapy including IP PTX. Similar changes were observed in peripheral vessels of peritoneal tumors in MKN45-inoculated nude mice treated with IP-PTX. Moreover, pimonidazole staining revealed that highly hypoxic regions were produced by IP PTX at the tumor periphery. These findings strongly suggest that the remarkable efficacy of IP PTX in the treatment of peritoneal metastases is, at least in part, dependent on the destruction of peripheral microvessels by exposure to infiltrated PTX.

In this study, we analyzed intraperitoneal cells recovered from human samples and found that CD90(+)CD45(-) cells exist as a minor population but vigorously grow in culture, showing the morphological features of mesothelial cells (MC). Interestingly, the MC highly expressed arginase I and markedly suppressed T cell proliferation with the reduction of CD3 chain expression in T cells stimulated by coated anti-CD3 mAb. The addition of nor-NOHA (500 mu M), or L-arginine (1 mM) mostly restored the inhibitory effect of MC on T cell proliferation as well as the reduced expression of CD3 zeta chain. The expression level of CD3 zeta chain in T cells in the peritoneal cavity was significantly down-regulated from circulating T cells. These results suggest that intraperitoneal free MC have immunomodulatory functions through the control of L-arginine level, and thus may play significant roles in the pathogenesis of various diseases in the peritoneal cavity. (c) 2014 Elsevier Inc. All rights reserved.

Background. Peritoneal metastasis of gastric cancer has extremely poor clinical outcomes. Recently, we developed a combination chemotherapy that used intraperitoneal (IP) paclitaxel (PTX) and produced excellent antitumor effects against peritoneal lesions. However, no information is available about the benefit of gastrectomy in cases with malignant ascites. Methods. A total of 64 patients with severe peritoneal metastasis and ascites received IP PTX at 20 mg/m(2) via implanted subcutaneous peritoneal access ports as well as intravenous (IV) PTX at 50 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2) day for 14 consecutive days, followed by 7 days of rest. In all patients, investigative laparoscopy was performed around the combination chemotherapy, and gastrectomy was performed on patients who showed apparent shrinkage of their peritoneal nodules as well as negative peritoneal cytology at the second laparoscopy. Results. Gastrectomy was performed in 34 patients. The median course of chemotherapy before surgery was 5 courses (range 2-16). R0 operation was achieved in 22 patients (65 %), and grade 2 and 3 histological responses were obtained in 7 (21 %) and 1 (3 %) patient(s), respectively. The median survival time and 1-year overall survival of the gastrectomized patients were 26.4 months and 82 %, and those of the 30 patients who did not receive gastrectomy were 12.1 months and 26 %, respectively. Morbidity was minimal, and there was no mortality. Conclusions. Salvage gastrectomy after chemotherapy of S-1 with IV and IP PTX is promising, even for patients with highly advanced gastric cancer and severe peritoneal metastasis and malignant ascites.

BackgroundPeritoneal metastasis (PM) is the most life-threatening type of metastasis in abdominal malignancy. To improve the diagnostic accuracy of cytologic detection (CY) of free tumor cells (FTC) in the peritoneal cavity, we tried to quantify the FTC to leukocyte ratio using flow cytometry in patients with peritoneal metastasis. MethodsCells were recovered from ascites or peritoneal lavages from 106 patients who underwent abdominal surgery and additional 89 samples which were obtained from peritoneal catheter or access port in patients with PM (+) gastric cancer. The cells were immunostained with monoclonal antibodies to CD45 and to CD326 (EpCAM). Using flow cytometry, CD326 (+) and CD45 (+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated. ResultsIn 106 samples obtained by laparotomy, Median (M) of the TLR of PM (+) patients was 1.39% (0-807.87%) which was significantly higher than PM (-) patients (M=0%, 0-2.14%, P<0.001). In PM (+) patients, 86 CY (+) samples showed higher TLR than 61 CY (-) samples (M=2.81%, 0.02-1868.44% vs. M=0%, 0-3.45%, p<0.0001). In all of the 24 patients who were monitored for TLR before and after intraperitoneal (IP) chemotherapy, the TLR was reduced which was more dramatic than the results of the change in cytology. ConclusionsTLR measured with FACS is an excellent reflection of the tumor spread in the peritoneal cavity and could be a reliable diagnostic biomarker to determine the severity of PM as well as effectiveness of IP chemotherapy. (c) 2013 International Clinical Cytometry Society

In the present study, we aimed to characterize the predictive value of cytokines/chemokines in rectal cancer (RC) patients receiving chemoradiation therapy (CRT). Blood samples were obtained pre- and post-CRT from 35 patients with advanced RC, who received neoadjuvant CRT followed by surgery, and the correlation between plasma levels of cytokines/chemokines and the response to CRT was analyzed. The pre-CRT levels of soluble CD40-ligand (sCD40L) and the post-CRT levels of chemokine ligand-5 (CCL-5) were significantly associated with the depth of tumor invasion and with venous invasion. In addition, a significant decrease in sCD40L and CCL-5, as well as in platelet counts, was associated with a favorable response to CRT. A significant correlation between pre-CRT platelet counts and sCD40L was observed in patients with a favorable response. By contrast, higher post-CRT interleukin (IL)-6 was associated with a poor response. Platelets, immune system and cancer cells, cross-linked through various cytokines/chemokines, appear to play an important role in the response to CRT, and by understanding their roles, new approaches for the improvement of the therapy might be proposed.

Aberrant activation of Wnt signalling results in colorectal tumours. Lgr5 is specifically expressed in stem cells of the intestine and has an essential role in maintaining tissue homeostasis. Lgr5-positive stem cells are responsible for the intestinal adenoma initiated by mutations in adenomatous polyposis coli. Furthermore, Lgr5 interacts with R-spondins and thereby activates Wnt signalling. However, the function of Lgr5 in colorectal tumourigenesis is unclear. Here we show that LGR5 is required for the tumourigenicity of colorectal cancer cells. We show that the transcription factor GATA6 directly enhances the expression of LGR5. We further demonstrate that GATA6 is upregulated in colorectal cancer cells due to the downregulation of miR-363, which directly targets GATA6. Moreover, we show that overexpression of miR-363 suppresses the tumourigenicity of colorectal cancer cells. These results suggest that the miR-363-GATA6-LGR5 pathway is critical for colorectal tumourigenesis and would be a promising target for the treatment of colorectal cancer.

The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(2) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, alpha-smooth muscle actin and fibroblast activated protein-a by the stimulation with TGF-beta, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.