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Accurate tumor stage diagnosis during laparoscopic surgery remains difficult. We clarify the impact of new diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for colorectal cancer compared with other strategies.We defined angiogenesis (Ag) and fibrosis (Fib) grades using NBI laparoscopy (lap-NBI), and assessed the clinicopathological features associated with these grades for 67 patients with colorectal cancer who underwent surgery. We assessed vessel density and gray scale with computer software.NBI-Ag-grade and NBI-Fib-grade of the serosal surface of cancer lesions and peritoneal nodules correlated with vessel density and gray scale of those assessed by Image J computer software. NBI-Fib-grades of liver nodules also correlated with gray scale. NBI-Ag- grade and Fib-grade of the serosal surface of cancer lesions correlated with pathological depth of invasion. These NBI grades of pathological metastatic peritoneal nodules were higher than those of pathologically benign peritoneal nodules. NBI- Fib grades of pathological metastatic liver nodules were higher than those of pathologically benign liver nodules. In multivariate analysis, lap-NBI was associated with different diagnosis for T3, T4 and non-T3, and non-T4. Moreover, lap-NBI was associated with different diagnosis for T4 and non-T4. Predictive value for T4 by lap-NBI showed high sensitivity (85%) specificity (87%), positive predictive value (74%), negative predictive value (93%), and overall accuracy (87%). Sensitivity and overall accuracy of lap-NBI was superior to that of other diagnostic modalities.We clarified the usefulness of the new diagnostic strategy using lap-NBI during laparoscopic surgery for colorectal cancer in comparison with other strategies.

Background In rectal cancer surgery, insertion of transanal tube has been shown to have efficacy to prevent anastomotic leakage. This randomized controlled study aims to clarify the incidence of anastomotic leakage with or without transanal tube in patients with rectal cancer. Methods Patients who underwent elective low anterior resection were randomly allocated to either have transanal tube insertion or not for five days after surgery. We examined the incidence of anastomotic leakage, postoperative 30-day morbidity and mortality. Results 157 patients were randomized to the transanal tube group or the no-transanal tube group. Symptomatic anastomotic leakage occurred in six patients (7.6%) of the former group and eight patients (10.3%) in the latter group, without significant difference (p = 0.559). There was also no significant difference in morbidity between groups (p = 0.633) and no mortality was detected. Conclusions Transanal tube insertion had no significant benefit towards prevention of anastomotic leakage in rectal cancer surgery.

We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.

The increasingly elderly worldwide population has affected the incidence of colorectal cancer. Establishment of reliable assessment of frailty and proposals for multi-disciplinary interventions are urgently required in oncology practices. Kihon Checklist (KCL) was published by the Japanese Ministry of Health, Labor and Welfare originally to identify individuals ≥ 65 years old at probable risk for requiring care or social support. We investigate the validity of KCL for frailty assessment to predict postoperative complication in older patients with colorectal cancer. Consecutive colorectal cancer patients aged ≥ 65 (n = 500) were prospectively examined between May 2017 and December 2018. Preoperative frailty assessment was conducted by the G8 questionnaire and KCL. The main outcome measures were correlation between frailty, other clinical variables, and postoperative complications within 30 days after elective surgery. Of the 500 patients, 278 (55.6%) and 164 (32.8%) patients were classified as ‘frail’ by G8 and KCL, respectively. Overall complications counted among 97 patients (19.4%), and they were significantly associated with KCL ≥ 8-frail (46/164, p = 0.001), as opposed to G8 ≤ 14-frail (56/278, p = 0.531). Multivariate analysis showed that KCL ≥ 8 (hazard ratio 1.88, 95% confidence interval 1.16–3.04, p = 0.011) was an independent risk factor for these complications. KCL assessment can identify frail older patients likely to suffer from postoperative complications after colorectal cancer surgery. Preoperative screening of frailty, particularly by KCL, would help older patients prevent their worse outcomes in colorectal cancer. UMIN000026689.

Preoperative ctDNA status in relation to recurrence in cases of CRC remains unclear. We examined preoperative ctDNA detection by targeting KRAS gene mutations as a predictive marker for recurrence after CRC surgery. We measured the preoperative KRAS mutated ctDNA status and analyzed the correlation with clinicopathologic features of 180 patients that underwent surgery for CRC. We studied the association between preoperative KRAS mutated ctDNA and postoperative recurrence in patients (n = 150) that underwent radical surgery. KRAS mutated ctDNA was detected in 59 patients (32.8%). Median mutant allele frequency of KRAS in ctDNA was 0.20%. KRAS status in ctDNA and lymph node metastasis and distant metastasis were not significantly different. Among patients that underwent radical resection, recurrence occurred in 21 (14.0%, median follow-up 24 months). In Kaplan–Meier analysis, preoperative detection of KRAS mutated ctDNA was associated with inferior recurrence-free interval (RFI) (p = 0.002) and recurrence-free survival (RFS) (p = 0.025). In a multivariate Cox proportional hazards model, preoperative detection of KRAS mutated ctDNA was an independent factor related to both RFI (HR = 3.08; p = 0.012) and RFS (HR = 2.18; p = 0.044). Preoperative measurement of KRAS mutated ctDNA could be useful to decide postoperative treatment.

Highlights • We report a rare case of small intestinal AVM. • Distinguishing small intestinal AVM is difficult. • Intravenous injection of ICG made the location and boundary more clear., Introduction Approximately 5 % of gastrointestinal bleeding is due to small intestinal bleeding. Bleeding from small intestinal arteriovenous malformation (AVM) is rare, with few reported cases. Finding the precise location and boundary is difficult during surgery, so we tried using intravenous injection of indocyanine green (ICG). Use of ICG in a case of intestinal AVM is reported here for the first time, with a review of the literature. Presentation of case A 48-YEAR-old male had anemia and low hemoglobin level (Hb) 4.0 g/dL. After several examinations including small intestinal endoscopy, capsule endoscopy and angiography, AVM was identified. Preoperative diagnosis was AVM caused by branching of the ileocolic artery (ICA). Meanwhile, macroscopy showed engorgement of the vein in the ileum wall and mesentery, the boundary of which was unclear. We performed intra-operative monitoring with ICG. After intravenous injection of ICG, the boundary and location became clear. The abnormal ileum was 30 cm in length and located 130 cm from the Treitz ligament, which was different from angiographic findings. Pathology showed dilated vascular hyperplasia of the submucosa, tunica and chorionic membrane. Final diagnosis was ileum AVM. The postoperative course was uneventful and gastrointestinal bleeding stopped. Conclusions ICG monitoring aided diagnosis and treatment of Ileum AVM, which was treated by laparoscopic surgery.

Background: Anastomotic leakage (AL) is arguably the most troublesome complication of anterior resection (AR). In recent years, however, indocyanine green (ICG) fluorescence imaging has been recent...

Background: Synchronous colorectal peritoneal carcinomatosis (SCPC) is not a rare entity, and the prognosis is extremely poor compared to other metastatic sites such as the liver and lung. Therefore, optimal treatment based on tumor characteristics is needed. Recently, the tumor sidedness of colorectal cancer has been reported as one of the prognostic factors and also as a key factor for the treatment strategy. The purpose of this study was to assess the clinical impact of tumor sidedness in patients with SCPC. Methods: A total of 189 cases of SCPC were identified in a retrospective database at Wakayama Medical University Hospital (WMUH) between 1998 and 2014, and were analyzed with a special focus on tumor location. Results: In multivariate analysis, a right-sided location (p = 0.02) and the presence of liver metastases (p < 0.001) were found to be the worst prognostic factors. The median survival time (MST) with right-sided and with left-sided SCPC was 10 and 16 months, respectively. The right-sided SCPC group included more aged patients (p = 0.045) and fewer patients who received postoperative chemotherapy (p = 0.034). When we focused on patients with macroscopically complete resection (n = 39), the MST and disease-free survival in the right-sided SCPC group was significantly shorter than in the left-sided SCPC group (p = 0.030 and p = 0.043, respectively). The MST of the right-sided and the left-sided SCPC patients among the completely resected patients was 24 and 73 months, respectively. Conclusion: Tumor sidedness may be a potent prognostic indicator for patients with SCPC. The survival time with right-sided SCPC is dramatically reduced compared to that with left-sided SCPC, especially among completely resected cases. We should change the treatment strategy according to the location of SCPC.

Adjuvant chemotherapy with capecitabine is frequently not completed due to adverse events, including hand-foot syndrome. A higher completion rate of capecitabine by reduction of the side effects may improve disease-free survival and quality of life of affected patients. In the present study, colorectal cancer (CRC) patients were treated with capecitabine (2,500 mg/m2/day), which was taken for five days, followed by an interval of two days (5-days-on/2-days-off schedule). One course lasted three weeks, and eight courses (24 weeks) were administered. The median number of treatment courses was significantly higher in patients in the 5-days-on/2-days-off regimen group compared with that of patients in the retrospectively included conventional regimen group (P=0.0438). The frequency of completion of the scheduled treatment by patients in the 5-days-on/2-days-off regimen group was significantly higher (P=0.0389). The present phase II study suggests that toxicities associated with the 5-days-on/2-days-off regimen are lower compared with those of the conventional regimen, and that the occurrence of adverse events was higher, but less high-grade toxicities were reported. The time to treatment failure was also favorable in the new regimen and it demonstrated good feasibility. In conclusion, the present study demonstrated good feasibility with retained quality of life and acceptable adverse effects (mostly low-grade), and the 5-days-on/2-days-off regimen should be further evaluated in future randomized controlled trials. The present study was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (no. UMIN000012813).

The population affected by colorectal cancer is growing, and there is an increasing need for prevention of functional decline following treatment. We proposed that the Kihon Checklist published by the Japanese Ministry of Health, Labor, and Welfare would be an appropriate means of frailty assessment for prediction of postoperative complications in older patients with colorectal cancer. This prospective cohort study aims to identify the factors influencing postoperative frailty.We prospectively enrolled consecutive patients with colorectal cancer and aged ≥ 65 year (N = 500) between May 2017 and December 2018. Eligible patients were assessed with the Kihon Checklist prior to surgery and 30 days after surgery. The main measures were variables related to postoperative change in view of frail status.According to the Kihon Checklist questionnaire, 164 patients were frail preoperatively and 172 patients were frail postoperatively, whereas 38 patients changed from "nonfrail" before surgery to postoperative "frail." Overall complications were counted in 97 patients (19.4%), and 5 patients died. Performance status ≥ 2, history of laparotomy, open surgery, complication, ostomy creation, and delirium were significantly associated with changing postoperative "frail" (P = .014, P = .023, P = .006, P.001, P = .023, and P = .024, respectively). In multivariate analysis, independent related factors of changing postoperative "frail" were complication (odds ratio 2.69, 95% confidence interval 1.19-6.09, P = .018) and ostomy creation (odds ratio 2.32, 95% confidence interval 1.01-5.33, P = .047).The Kihon Checklist questionnaire could identify the factors related to postoperative change of frailty status in older patients with colorectal cancer. This cohort concluded that whether postoperative complication occurred or not was closely associated with perioperative change of frailty status.

Goblet cell adenocarcinoma is extremely rare tumor in which the same cells have both exocrine and neuroendocrine properties. It is considered to be more aggressive than conventional carcinoids and more likely to cause metastasis. We report a case of goblet cell adenocarcinoma that developed late peritoneal recurrence, and we review pertinent literature. A 63-year-old male underwent appendectomy for acute appendicitis. Histopathological findings of appendectomy specimen showed mixed adenoneuroendocrine carcinoma, and positive resection margin. He also underwent laparoscopic ileocecal resection and apical lymph node dissection. After 9 years, he presented with ileus and abdominal CT examination indicated possible peritoneal dissemination. Laparoscopic observation revealed disseminated nodules throughout the entire abdominal cavity, and the patient underwent resection of the omental nodule and gastrointestinal bypass surgery. Previous appendectomy specimens showed goblet cell adenocarcinoma (GCA) according to the 5th edition of the WHO classification. Omental specimens confirmed the histopathological findings, and we diagnosed peritoneal recurrence of appendiceal goblet cell adenocarcinoma. Goblet cell adenocarcinoma may develop and cause late recurrence, and long-term follow-up may be required.

Significant efficacy of induced pluripotent stem cells (iPSCs) in generating DCs for cancer vaccine therapy was suggested in our previous studies. In clinical application of DC vaccine therapy, however, few DC vaccine systems have shown strong clinical response. To enhance immunogenicity in the DC vaccine, we transfected patient-derived iPSDCs with in vitro transcriptional RNA (ivtRNA), which was obtained from tumors of three patients with colorectal cancer.We investigated iPSDCs-ivtRNA which were induced by transfecting ivtRNA obtained from tumors of three colorectal cancer patients, and examined its antitumor effect. Moreover, we analyzed neoantigens expressed in colorectal cancer cells and examined whether iPSDCs-ivtRNA induced cytotoxic T lymphocytes (CTLs) against the predicted neoantigens.CTLs activated by iPSDCs-ivtRNA exhibited cytotoxic activity against the tumor spheroids in all three patients with colorectal cancer. Whole-exome sequencing revealed 1251 nonsynonymous mutations and 2155 neoantigens (IC50 In vitro CTLs obtained by transfecting tumor-derived RNA into iPSDCs derived from three patients with colorectal cancer showed potent tumor-specific killing effect.

Risks for postoperative small bowel obstruction have been demonstrated in several reports, most of which indicated male sex was a risk factor, but with the reason remaining unknown. We tested the hypothesis that it could be because males have more visceral fat than females. This prospective observational study aims to examine risks of early postoperative small bowel obstruction (EPSBO) after colorectal cancer surgery and the association between visceral to subcutaneous fat area ratio (V/S ratio) and EPSBO.Four hundred and seventy-four patients who underwent colectomy for colorectal cancer in our hospital were enrolled in this study. The influence of several factors including V/S ratio on the development of EPSBO was analyzed.Thirty-one of the 474 patients (6.5%) developed EPSBO. EPSBO occurred more frequently in males (p = 0.03) and cases who developed postoperative anastomotic leakage (p 0.001) or wound infection (p = 0.02). Higher V/S ratio was strongly related to male sex (p 0.001). Multivariate analysis revealed higher V/S ratio (OR 2.25; p = 0.049) and anastomotic leakage (OR 5.86; p 0.001) were independent risk factors for EPSBO.Higher V/S ratio was significantly related to EPSBO, suggesting that one of the reasons EPSBO was more likely to occur in males because they have more visceral fat than females. Preoperative identification of this risk factor could help us watch out for this potential complication.

Introduction The interaction of CD155 with its ligand, the T cell immunoreceptor with Ig and ITIM domains (TIGIT), is being studied owing to its potential to act as a target in the treatment of various solid tumors. However, the relationship between CD155 and TIGIT in colorectal cancer (CRC) prognosis is not known. We hypothesized that the TIGIT–CD155 pathway suppresses the attack of T cells on tumors, thereby affecting CRC prognosis. Methods We examined the expression of CD155 and TIGIT using immunohistochemical staining in 100 consecutive patients with CRC who underwent complete resection of ≤Stage III tumors at Wakayama Medical University Hospital between January and December 2013. We assessed the correlation between CD155 and TIGIT expressions and prognosis as well as the clinicopathological background of CD155 and TIGIT. Results Patients with high CD155 and TIGIT expressions showed worse prognosis than those with other levels of expression (p = 0.026). In multivariate analysis that also included the existing prognostic markers, high CD155 and TIGIT expressions were identified as independent poor prognostic factors. Conclusions The interaction between CD155 and TIGIT possibly plays an important role in the immunological mechanism of CRC. Therefore, it may be possible to effectively predict the postoperative prognosis of CRC by evaluating the combined expression of CD155 and TIGIT. The study findings suggest that CD155 and TIGIT can predict clinical outcomes, thereby contributing to the personalized care of CRC.

Colonic mucosa-associated lymphoid tissue (MALT) lymphoma is very rare, especially those which form a mass. Although the characteristics and treatment methods of gastric MALT lymphomas are well established, those of colonic MALT lymphomas have been insufficiently described. Here, we report a case of mass-forming cecal MALT lymphoma that was successfully treated by laparoscopy-assisted bowel resection. A 60-year-old woman with right lower abdominal pain and a palpable tumor was referred to our hospital. Colonoscopy showed a smooth elevated submucosal tumor-like lesion in the cecum. Histological and immunochemical findings were consistent with MALT lymphoma. Serum tumor marker levels were within normal range. Enhanced abdominal computed tomography showed a large tumor 55 mm in diameter in the cecum and edema of a few paracolic lymph nodes. The tumor was diagnosed as cecal MALT lymphoma classified as stage II1 by Lugano classification, and laparoscopy-assisted ileocecal resection was performed. The postoperative course was uneventful and the patient underwent eradication therapy for Helicobacter pylori. A year after the operation she has had no recurrence. In patients with mass-forming colonic MALT lymphoma without dissemination, surgical resection may be a feasible treatment.

Background This study is intended to assess whether the use of pelvic drain reduces incidence of pelvic sepsis in the era of laparoscopic low anterior resection (LAR). Patients and methods In total, 200 of consecutive patients who underwent laparoscopic LAR for rectal cancer with diverting stoma were analyzed. Results Pelvic sepsis occurred in 14 of 110 patients (12.7%) in the drain group and in 9 of 90 patients (10.0%) in the no drain group (P=0.548). Furthermore, there were no differences in the incidence of anastomotic leakage, time to diagnosis of pelvic sepsis, and type of treatments for pelvic sepsis. Conclusions Prophylactic pelvic drain use after laparoscopic LAR in patients with diverting stoma does not reduce incidence of pelvic sepsis. Routine use of pelvic drain is not recommended. This study was registered at UMIN (Registration Number: UMIN000026076).

Creation of defunctioning loop ileostomy is a standard procedure in laparoscopic lower rectal surgery. Stoma-related obstruction sometimes occurs, but its cause has not been fully analyzed. This study aims to assess stoma obstructive complications and clarify the risk factors of stoma-related obstructions. Two hundred and thirty consecutive patients who underwent laparoscopic rectal cancer surgery with defunctioning loop ileostomy between April 2007 and December 2017 were recruited, numbering 230. We statistically examined the frequency and risk factor of stoma outlet obstruction. Postoperative stoma-related complications developed in 41 patients (17.8%) overall, and there was no 30-day mortality. Stoma outlet obstructions occurred in 16 patients (7.0%) during postoperative course. Thick subcutaneous fat at the stoma-marking site (vertical distance ≥ 20 mm) and body mass index (≥ 22.2) were significantly associated with the risk of stoma outlet obstruction in univariate analysis. Thick subcutaneous fat was a significant predictive factor of stoma outlet obstruction according to multivariate analysis (odds ratio 3.80). This report investigates significant predictors of stoma outlet obstruction in laparoscopic rectal cancer surgery for the first time. In laparoscopic procedure, stoma outlet obstruction should be particularly considered in obese patients who have especially thick subcutaneous fat of the abdominal wall.

Anastomotic leakage (AL) is one of the most troublesome complications in colorectal surgery. Recently, near-infrared fluorescence (NIRF) imaging has been used intraoperatively to detect sentinel lymph nodes and visualize the blood supply at the region of interest (ROI). The aim of this study was to evaluate the role of visualization and quantification of bowel perfusion around the anastomosis using NIRF system in predicting AL. A prospective study was conducted on patients who had laparoscopic surgery for colorectal cancer at our institution. Perfusion of the anastomosis was evaluated with NIRF imaging after intravenous injection of indocyanine green (ICG). The time course of fluorescence intensity was recorded by an imaging analyzer We measured the time from ICG injection to the beginning of fluorescence (T0), maximum intensity (Imax), time to reach Imax (Tmax), time to reach Imax 50% ( $$T_{{{ \text{max} }_{1/2} }}$$ ) and slope (S) after the anastomosis. Tumor locations were as follows; cecum: 2, ascending colon: 2, transverse colon: 7, descending colon: 1, sigmoid colon: 2, rectosigmoid colon: 3 and rectum: 6 (one case with synchronous cancer). All operations were performed laparoscopically. Four patients were diagnosed with or suspected to have AL (2 patients with grade B anastomotic leakage after low anterior resection, 1 patient with minor leakage in transverse colon resection and 1 patient needing re-anastomosis intraoperatively in transverse colon resection). T0 was significantly longer in the AL group than in patients without AL (64.3 ± 27.6 and 18.2 ± 6.6 s, p = 2.2 × 10−3). Perfusion of the anastomosis could be successfully visualized and quantified using NIRF imaging with ICG. T0 might be a useful parameter for prediction of AL.

A 39-year-old female patient underwent anterior resection with locoregional lymph node dissection for rectosigmoid cancer at another hospital. The procedure involved transection of the superior rectal artery just below the origin of the left colic artery. Postoperative diagnosis was stage III B. The patient received adjuvant chemotherapy with oxaliplatin plus capecitabine for 6 months. Sixteen months after the operation, PET-CT scans revealed regional lymph node metastases around the root of the inferior mesenteric artery. The patient was referred to our hospital with a recurrence of rectosigmoid cancer. We performed laparoscopic lymph node dissection with real-time indocyanine green fluorescent images superimposed on color images to prevent intraoperative vascular insufficiency. We were able to successfully observe the sufficient blood flow in the descending colon. Postoperative pathological findings showed lymph node recurrence after initial surgery. She was discharged 7 days after the operation. In the 8 months since the second operation, the patient has not had any indication of further recurrence.

Background Alpha-fetoprotein (AFP) is produced by some tumors, such as hepatocellular carcinoma and yolk sac tumors, leading to an increase in serum AFP level. However, AFP in colorectal cancer is extremely rare. Treatment for AFP-producing cancer is often performed according to conventional methods, but oncological outcomes of both surgery and chemotherapy are poor. We report a case of a patient with AFP-producing rectal cancer which successfully responded to preoperative chemoradiotherapy. Case presentation Rectal tumor was diagnosed in a 68-year-old man referred to our hospital. Colonoscopy showed a type 2 tumor in the lower rectum, and biopsy revealed an adenocarcinoma with enteroblastic differentiation. Serum tumor marker levels were 8.8 ng/ml in carcinoembryonic antigen (CEA) and 28.3 ng/ml in AFP. Clinical diagnosis was stage IIIB (T3N1M0), and preoperative chemoradiotherapy was performed to prevent local recurrence. Effective tumor reduction was observed, and serum tumor marker levels decreased to normal range. Low anterior resection with temporary diverting ileostomy was performed, and histology revealed residual adenocarcinoma. Pathological diagnosis was stage I (T2N0M0). The tumor was found to be an AFP-producing adenocarcinoma on further immunohistopathological examination. The postoperative course was uneventful, and the patient received adjuvant chemotherapy for 3 months. Conclusions The outcomes of preoperative chemoradiotherapy against AFP-producing rectal cancer are reported here for the first time. Based on our experience with this patient, it appears preoperative chemoradiotherapy for patients with AFP-producing advanced rectal cancer is feasible.

Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model. We differentiated hiPSDCs from iPSCs of three healthy donors and transduced CEA cDNA into the hiPSDCs. The surface marker expression, cytokine secretion and migratory capacity of the hiPSDCs were equivalent to those of human monocyte-derived DCs (hMoDCs). Cytotoxic T cells activated by hiPSDCs-CEA exhibited CEA-specific cytotoxic activity against the target cells expressing CEA. Furthermore, in the CEA transgenic mouse model, cytotoxic T cells activated in mice immunized with miPSDCs-CEA displayed CEA-specific cytotoxic activity against MC38-CEA. In the subcutaneous tumour model, vaccination with miPSDCs-CEA achieved a significant growth inhibitory effect on MC38-CEA. No adverse events caused by the administration of miPSDCs were observed. Genetic modification of iPSDCs, inducing the expression of CEA, is a promising tool for clinical applications of vaccine therapy for treating gastrointestinal cancer patients.

Because anorectal melanoma, a rare cancer with a poor outcome, does not respond well to local radiation therapy or systemic chemotherapy, surgery is the primary treatment. Herein, we present a case of anorectal melanoma with lateral and inguinal lymph node metastases. A 61-year-old woman presented with rectal bleeding. Colonoscopy revealed a black tumor with ulceration in the anorectum. A CT scan revealed an anorectal tumor with left lateral lymph node swelling and right inguinal lymph node swelling. We performed a laparoscopic abdominoperineal resection with lateral lymph node dissection and right inguinal lymph node dissection. One year after the initial operation, pulmonary metastases were observed, and pulmonary resection was performed. After the pulmonary resection, brain metastases developed, and surgical resection was performed. Despite the recurrence of disease, the patient has survived for 52 months since the initial surgery and continues to receive systemic chemotherapy.

Background: The level of inferior mesenteric artery (IMA) ligation for anterior resection of rectal cancer has several considerations concerning oncological outcomes. The primary endpoint of this randomized controlled trial (RCT) was to assess bowel function between high and low ligation. This study was intended to clarify oncological outcome as the secondary endpoint. Objective: The aim of this study was to assess in a prospective RCT whether the ligation level of the IMA in rectal cancer influences oncological outcomes. Methods: Between February 2008 and December 2011, 100 patients who underwent anterior resection for rectal cancer were randomized to perform either high or low ligation of the IMA. Oncological outcomes was the secondary endpoint of this RCT, whereas assessing bowel function was the primary endpoint. This RCT was registered at clinicaltrials.gov (NCT00701012). Results: There were no differences between the groups in terms of clinical data except for tumor stage. There were more advanced-stage patients in the high ligation group (p = 0.046). There were no lymph node (LN) metastases in the root of the IMA in the high ligation group. The average number of harvested LNs for the high and low ligation groups was 16.7 and 14.9, respectively. There was no difference in disease-free survival (DFS), site of first recurrence, and overall survival (OS). When patients were in stage III, there was also no difference in DFS and OS. Conclusions: The ligation level of the IMA in rectal cancer may not influence oncological outcomes. However, further large-scale RCTs are needed to conclude this issue.

It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC-based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell-derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow-derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (+) cytotoxic T lymphocytes (CTLs) was assayed using a (51) Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100-specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor-associated antigen-specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.

The difficulty in obtaining a sufficient number of functional dendritic cells(DCs)is a well-known serious problem in DCbased immunotherapy. Therefore, we used induced pluripotent stem cell-derived DCs(iPSDCs). We have reported that mouse iPSDCs are equivalent to BMDCs, in terms of maturation and antigen presentation. In this study, the antitumor immune response of human iPSDCs expressing the carcinoembryonic antigen was examined, to determine its clinical application in gastrointestinal cancer. Human iPS cells were established from healthy human fibroblasts using a Sendai virus vector, and human iPSDCs were differentiated under a feeder-free culture. Additionally, the surface marker expression, cytokine production, and migratory capacity of human iPSDCs were equivalent to those of monocyte-derived DCs(MoDCs). After 3 cycles of stimulation of autologous PBMCs by genetically modified DCs, the 51Cr-release assay was performed. The lymphocytes stimulated by iPSDCs-CEA showed cytotoxic activity against LCL-CEA and CEA652-pulsed LCL, but showed no cytotoxicity against LCL-LacZ. In addition, they showed cytotoxic activity against CEA-positive human cancer cell lines, MKN45 and HT29, but showed no cytotoxicity against CEA-negative human cancer cell line MKN1. In conclusion, CEA-specific CTLs responses could be induced by iPSDCs-CEA. This vaccination strategy may be useful in future clinical applications of cancer vaccines.

Background: Preoperative chemoradiation therapy (pCRT) is a standard procedure for patients with advanced lower rectal cancer. It has been reported that pCRT cannot prolong the survival of patients with advanced lower rectal cancer. The aim of this study is to address the controllable and uncontrollable pathological factors of pCRT in predicting local and distant recurrences. Methods: One hundred two patients with stages 2 and 3 cancer were consecutively enrolled to the study. The first 51 patients (October 2008-August 2010) underwent curative resection without pCRT. The latter 51 patients (September 2010-May 2015) underwent curative resection after pCRT. Pathological factors of patients were evaluated to assess the association between local and distant recurrences. Results: Multivariate analyses for local and distant recurrences of patients without pCRT revealed that the independent risk factors were tumor deposit and perineural invasion respectively. pCRT was able to diminish circumferential resection margin, tumor deposit, venous invasion, and lymphatic permeation but not neural invasion and lymph node involvement. Kaplan-Meier curve of local and distant recurrence-free survival of patients with pCRT illustrated that tumor deposit is controllable, whereas perineural invasion is uncontrollable by pCRT. Conclusion: pCRT-uncontrollable perineural invasion may be a factor for distant recurrence of advanced rectal cancer patients, leading to poor survival.

今回われわれは門脈浸潤合併膵管癌に対し幽門輪温存膵頭十二指腸切除術，門脈合併切除術を施行後，術後補助化学療法を施行し，単発性胃転移を認めた症例を経験した．浸潤性膵管癌の再発は肝転移，リンパ節転移，局所再発が多く，胃転移は極めて稀である．その治療に関する報告は手術例が1例しかなく，その予後に関する報告はない．症例は55歳男性，幽門輪温存膵頭十二指腸切除術を受けた3年後に胃転移を認めた．造影CT検査で胃壁に指摘された単発性腫瘤性病変は上部消化管内視鏡検査では粘膜下腫瘍として認めた．そして18F-フッ化デオキシグルコース陽電子排出X線断層撮影検査（FDG-PET）では，同部位に優位な集積を認めた．そこで同病変に対し，胃部分切除術を施行した．さらに術後ゲムシタビンによる補助化学療法を施行した．現在初回手術後5年3カ月生存している．文献的考察を加え，この症例について報告する．

Because anorectal melanoma, a rare cancer with a poor outcome, does not respond well to local radiation therapy or systemic chemotherapy, surgery is the primary treatment. Herein, we present a case of anorectal melanoma with lateral and inguinal lymph node metastases. A 61-year-old woman presented with rectal bleeding. Colonoscopy revealed a black tumor with ulceration in the anorectum. A CT scan revealed an anorectal tumor with left lateral lymph node swelling and right inguinal lymph node swelling. We performed a laparoscopic abdominoperineal resection with lateral lymph node dissection and right inguinal lymph node dissection. One year after the initial operation, pulmonary metastases were observed, and pulmonary resection was performed. After the pulmonary resection, brain metastases developed, and surgical resection was performed. Despite the recurrence of disease, the patient has survived for 52 months since the initial surgery and continues to receive systemic chemotherapy.

To determine whether the beneficial effects of alcohol on lipid concentrations are mediated by insulin levels, we performed a cross-sectional analysis in 2103 nondiabetic men and women aged 40 to 79 years from a general Japanese population in Hisayama. The multivariate-adjusted sum of fasting and 2-hour postloading insulin levels and the insulin resistance index significantly decreased with elevating alcohol intake levels in men (P < 0.01 for the trend) but not in women. No dose-response relations between alcohol intake and glucose levels were observed. In both sexes, high-density lipoprotein cholesterol (HDLC) significantly increased with elevated alcohol intake (P < 0.01), whereas total cholesterol and low-density lipoprotein cholesterol (LDLC) were inversely correlated with alcohol intake (P < 0.01). In contrast, triglycerides (TGs) levels in men showed a J-shaped relation to alcohol dose, with moderate drinkers (10-29 g/d) having the lowest levels. Estimates using regression models indicated that for men, 10% of the alcohol-induced increase in HDLC and 2% of the alcohol-induced decrease in LDLC were insulin mediated. It was also estimated for male subjects that 36% of the reduction in TGs due to low to moderate alcohol intake was mediated by low levels of insulin and that this insulin-mediated pathway reduced the positive alcohol-TG relation by 13% in cases of moderate to heavy drinking. Our data suggest that regular alcohol consumption dose-dependently increased insulin sensitivity among male nondiabetics, but the insulin-mediated beneficial effects of alcohol on lipid concentrations were relatively small.

Insulin resistance may be a factor in the etiology of hypertension, and habitual alcohol intake may modify this relationship. We prospectively examined this hypothesis in 1,133 nonhypertensive, nondiabetic Japanese subjects, aged 40–79 years. Alcohol drinkers were more frequent among men than women at baseline (57.7 vs. 8.2%). The age-adjusted incidence of hypertension significantly increased with the elevating baseline insulin levels in women (P = .003 for trend), but not in men. The age- and sex-adjusted insulin levels and insulin resistance index decreased with elevating alcohol intake, while fasting glucose levels remained unchanged, suggesting that alcohol improves insulin sensitivity. Among nondrinkers, the age-adjusted incidence of hypertension significantly increased with elevating insulin tertiles in both sexes (P = .048 and .002 for trend in men and women, respectively), but not among drinkers. Our findings suggest a close association between insulin resistance and the incidence of hypertension in Japanese. However, alcohol modified and reduced this relationship.

Background The question remains as to whether light to moderate alcohol intake is associated with an increased risk of hypertension. Methods In 1978, a total of 1101 residents (433 men and 668 women) in a subrural community, Hisayama, in Japan, aged 40 years or more, with normal blood pressure, who were free from cardiovascular disease, were enrolled in a 10-year follow-up study. Inquiries regarding regular drinking were made in an interview based on a self-administered questionnaire. Results During the follow-up, 101 men and 166 women developed hypertension (blood pressure ≥140/90 mm Hg or use of antihypertensive drugs). The age-adjusted incidence of hypertension among current male drinkers increased significantly even with a light intake of alcohol (

Objectives: Anaemia has been reported to be present in 1 to 11% of dental patients. However, little is known about the prevalence of anaemia in relation to specific oral diseases. This study compared the prevalence of anaemia in adults with 7 types of oral disease, adjusting for age and gender. Patients and Methods: Preoperative values for haemoglobin, haematocrit, and red blood cell count were retrospectively reviewed for 5032 consecutive adult dental inpatients (2650 males, 2382 females). Results: Logistic regression analysis showed that the prevalence of anaemia in patients with oral cancer was 7 to 9 times higher than that in patients with impacted teeth (odds ratio, 7.0; 95% confidence interval, 4.4–11.1 judged from haemoglobin; odds ratio 8.0; 95% confidence interval, 4.8–13.6 from haematocrit; odds ratio 9.2; 95% confidence interval, 6.0–13.9 from red blood cell count). Similarly, anaemia was 3 to 4 times more prevalent in patients with oral inflammation (odds ratio, 3.2; 95% confidence interval, 2.1–5.1 from haemoglobin; odds ratio, 3.7; 95% confidence interval, 2.2–6.1 from haematocrit; odds ratio, 3.7; 95% confidence interval, 2.5–5.5 from red blood cell count) or trauma (odds ratio, 2.6; 95% confidence interval, 1.6–4.1 from haemoglobin; odds ratio, 2.7; 95% confidence interval, 1.5–4.6 from haematocrit; odds ratio, 3.1; 95% confidence interval, 2.0–4.8 from red blood cell count) and 2 to 3 times more prevalent in patients with benign tumours (odds ratio, 2.5; 95% confidence interval, 1.5–4.1 from haemoglobin; odds ratio, 2.6; 95% confidence interval, 1.5–4.6 from haematocrit; odds ratio, 2.8; 95% confidence interval, 1.8–4.3 from red blood cell count) or oral cysts (odds ratio, 1.7; 95% confidence interval, 1.1–2.8 from haemoglobin; odds ratio, 1.9; 95% confidence interval, 1.1–3.2 from haematocrit; odds ratio, 2.1; 95% confidence interval, 1.4–3.2 from red blood cell count) than that in patients with impaction. Differences in prevalence of anaemia between patients with oral diseases remained significant after adjusting for gender and age. Conclusion: Patients with oral cancer, oral inflammation, oral trauma, benign oral tumours, or oral cysts had a higher prevalence of anaemia than that of patients with impacted teeth, irrespective of age or gender. Anaemia is most prevalent in patients with oral cancer and least prevalent in those with impacted teeth or jaw deformities.

Moderately elevated plasma total homocyst(e)ine (tHcy) levels have been linked with cardiovascular disease. However, the findings of previous studies regarding the relationship between tHcy levels and subtypes of cerebral infarction (CI) have been conflicting. The aim of the present study was to examine this issue in a community-based case-control study performed in Hisayama Town in Japan. Fasting tHcy levels were compared among 75 CI cases, of which 43 were lacunar (LI), 24 atherothrombotic (ATI) and 8 cardioembolic infarctions (CEI), and 248 age- and sex-matched healthy controls. The mean tHcy concentrations were higher in CI than in controls (13.0 vs. 11.8 µmol/l; p = 0.018). LI and CEI also had significantly higher tHcy levels than did the corresponding controls (12.3 vs. 11.3 µmol/l for LI; p = 0.037 and 16.3 vs. 12.7 µmol/l for CEI; p = 0.036). The same tendency was also observed for ATI, but the difference was only marginally significant probably due to the small number of the cases (13.4 vs. 11.9 µmol/l; p = 0.087). After adjustment for age, sex, hypertension, serum creatinine, total protein, folate and vitamin B12 levels, the risk of LI was not significant in the second tertile of the tHcy distribution, but significantly increased in the third compared with the first tertile (adjusted odds ratio, AOR, 3.4; 95% confidence limits, CL, 1.3–8.9; p = 0.015), while the risk of ATI was significant even in the second tertile (AOR, 5.0; 95% CL, 1.0–23.7; p = 0.042) and higher in the third tertile (AOR, 7.5; 95% CL, 1.5–38.3; p = 0.015). However, the odds ratios for CEI could not be estimated, as there was no case of CEI in the first tertile. These findings suggest that elevated tHcy is an independent risk factor for all subtypes of CI, but that its impact is higher in ATI and probably in CEI than in LI.

e14538 Background: We investigated whether genetically modified human dendritic cells (DCs) derived from induced induced pluripotent stem cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce the CEA specific cytotoxic T lymphcytes (CTLs) against cancer cell lines endogenously expressing CEA in vitro model using healthy volunteers. Furthermore, we established in vivo tumor model using the CEA transgenic mice (TGM) as a preclinical experiment. Methods: Human model; we differentiated hiPSDCs from iPSCs of three healthy donors and transduced the CEA cDNA into DCs. Mouse model; we differentiated miPSDCs in CEA TGM and transduced the CEA cDNA into DCs. Results: Human model; the surface marker expression, cytokine secretion, and migratory capacity of hiPSDCs were equivalent to human monocytes derived-DCs (hMoDCs). After 3 cycles of stimulation to autologous peripheral blood mononuclear cells (PBMCs) by genetically modified hiPSDCs, the cytotoxic assay was performed using a 51Cr release assay. The CTLs induced by hiPSDCs-CEA exhibited CEA specific cytotoxic activity against the target cells expressing. Mouse model; in the CEA transgenic mice model, the CTLs generated in mice immunized with miPSDCs-CEA showed CEA specific cytotoxic activity against MC38-CEA. Moreover, in the subcutaneous tumor model, vaccination with miPSDCs-CEA achieved significantly high growth inhibitory effect for the MC38-CEA. No adverse events were observed. Conclusions: This vaccine therapy using genetically modified iPSDCs is promising for clinical application for patients with gastrointestinal cancer patients.