北山 丈二

Lysophosphatidic acid (LysoPA) has been proposed to be involved in the pathogenesis of various cancers. Moreover, glycero-lysophospholipids (glycero-LysoPLs) other than LysoPA are now emerging as novel lipid mediators. Therefore, we aimed to elucidate the possible involvement of glycero-LysoPLs in the pathogenesis of gastric cancer by measuring glycero-LysoPLs, autotaxin (ATX), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) in ascites obtained from patients with gastric cancer and those with cirrhosis (as a control). We observed that after adjustments according to the albumin levels, the lysophosphatidylserine (LysoPS) and lysophosphatidylglycerol (LysoPG) levels were significantly higher, while the LysoPA and ATX levels were lower, in the ascites from patients with gastric cancer. We also found that multiple regression analyses revealed that ATX was selected as a significant explanatory factor for all the detectable LysoPA species only in the cirrhosis group and that a significant positive correlation was observed between LysoPS and PS-PLA1 only in the gastric cancer group. In conclusion, the LysoPA levels might be determined largely by LysoPC and LysoPI (possible precursors) and the PS-PLA1-mediated pathway might be involved in the production of LysoPS in gastric cancer. Glycero-LysoPLs other than LysoPA might also be involved in the pathogenesis of cancer directly or through being converted into LysoPA.

Gastric cancer is a common malignancy and remains potentially lethal. The prognosis of patients with stage IV gastric cancer is thought to be poor, but new molecular targeted therapy may benefit patients with advanced gastric cancer. Currently, conversion surgery after chemotherapy with a trastuzumab-containing regimen is reported to be effective in these patients. We present 3 patients with human epidermal growth factor receptor 2 (HER2)–positive advanced gastric cancer who underwent conversion surgery after receiving a trastuzumab-containing chemotherapy regimen. Interestingly, the primary lesion acquired resistance to the trastuzumab-containing regimen, although the metastatic lesions maintained a complete response. The reason why the primary lesions became resistant to trastuzumab remains unclear. More studies are needed to clarify the mechanism of resistance. Conversion surgery, made possible by the use of molecular-targeted therapy, may improve the prognosis of patients with stage IV gastric cancer, particularly if metastatic lesions show a complete response to therapy.

Although the incidence of port-site metastasis after laparoscopic surgery for colorectal cancer has markedly decreased since laparoscopic colectomy was first reported in 1991, it still has not reached zero. In colorectal cancer, the safety of laparoscopic surgery, including the low incidence of port-site metastasis, has been proven in large, randomized trials. In gastric cancer, reports of port-site metastasis are extremely rare, but we should await the results of ongoing trials. This brief review summarizes the current knowledge regarding port-site metastasis after laparoscopic surgery for colorectal and gastric cancer.

BACKGROUND: Despite recent progress in systemic chemotherapy, the prognosis of gastric cancer patients with peritoneal metastasis (P1) or positive peritoneal cytology findings (CY1) is still poor. We developed a regimen combining intraperitoneal (IP) paclitaxel (PTX) with S-1 and PTX, which can produce notable efficacy with regard to peritoneal lesions. Surgery after response to combination chemotherapy is a promising option for P1 or CY1 gastric cancer. A retrospective study was performed to evaluate the safety and efficacy. METHODS: This study enrolled 100 primary P1 or CY1 gastric cancer patients treated with IP PTX plus S-1 and PTX at the University of Tokyo Hospital between 2005 and 2011. Radical gastrectomy was performed when peritoneal cytology findings became negative, and the disappearance or obvious shrinkage of peritoneal metastasis was confirmed by laparoscopy. The same chemotherapy regimen was restarted after surgery and repeated with appropriate dose reduction. RESULTS: Gastrectomy was performed in 64 (P1 56, P0CY1 8) of 100 (P1 90, P0CY1 10) patients. R0 resection was achieved in 44 patients (69%). The median survival time was 30.5 months [95% confidence interval (CI) 23.6-37.7 months] from the initiation of intraperitoneal chemotherapy and 34.6 months (95% CI 26.8-39.4 months) from the diagnosis of gastric cancer. Postoperative complications included anastomotic leakage and pancreatic fistula, each in two patients, which were cured conservatively. There were no treatment-related deaths. The median survival time of the 36 patients who did not undergo surgery was 14.3 months (95% CI 10.0-17.8 months). CONCLUSIONS: Surgery after response to intraperitoneal and systemic chemotherapy is safe and may prolong the survival of P1 and CY1 gastric cancer patients.

INTRODUCTION: Carbohydrate antigen (CA) 19-9 is a widely used tumor marker in colorectal cancer (CRC). However, its prognostic impact in patients with stage IV CRC who have undergone curative resection is not clear. We evaluated the prognostic power of preoperative serum CA 19-9 in these patients. PATIENTS AND METHODS: We performed a retrospective review of 173 patients with stage IV CRC who had undergone curative resection at our institution. Patients were categorized into normal and high CA 19-9 groups, and relapse-free survival and overall survival were compared using Kaplan-Meier curves. Multivariate analyses were performed using a Cox proportional hazard model. RESULTS: The preoperative serum CA 19-9 level was elevated in 80 patients (46%). The 3-year relapse-free survival of the high CA 19-9 group was significantly worse than that of the normal CA 19-9 group (18% vs. 28%, respectively; P = .026). The 3-year overall survival of the high CA 19-9 group was significantly lower than that of the normal CA 19-9 group (75% vs. 82%; P = .047). Multivariate analyses indicated that elevated preoperative serum CA 19-9 level was an independent prognostic factor for poor relapse-free survival and overall survival, with a hazard ratio of 1.46 (95% confidence interval, 1.03-2.06; P = .035) and 1.90 (95% confidence interval, 1.10-3.29; P = .023), respectively. CONCLUSION: The preoperative serum CA 19-9 level is a good predictive marker of tumor recurrence and prognosis in patients with stage IV CRC who have undergone curative resection.

Peritoneal metastasis of gastric cancer remains a refractory disease, and the standard treatment strategy is still unclear. Intraperitoneally administered paclitaxel(PTX)remains in the intraperitoneal(IP)cavity for a long time and directly infiltrates peritoneal metastatic nodules, thereby producing antitumor effects. We designed an IP chemotherapy regimen of S-1 combined with weekly intravenous(IV)and IP PTXadministration. In our phase I study, the recommended dose of IP PTXwas determined to be 20mg/m2. In our phase II study for patients with P1(macroscopic peritoneal metastasis-positive)or CY1 (cytology-positive)gastric cancer, the 1-year overall survival(OS)rate was 78%and the median survival time(MST)was 23.6 months. In another phase II study of patients with P1 gastric cancer, the 1-year OS rate was 77%and the MST was 17.1 months. A phase III PHOENIX-GC trial comparing IP chemotherapy to S-1 plus cisplatin has recently been completed. Phase II studies of the IP administration of docetaxel have also shown favorable results. Recently, the results of several clinical studies investigating the effects of S-1 combined with weekly IV and IP PTXadministration for peritoneal metastasis of pancreatic cancer have been published.

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.

UNLABELLED: Objectives The aim of this study was to evaluate the safety and efficacy of intravenous and intraperitoneal paclitaxel (PTX) combined with S-1 for treatment of gemcitabine-refractory pancreatic cancer with malignant ascites. Methods After the feasibility of this regimen was first confirmed in an interim analysis in 10 patients, a total of 35 patients were enrolled between April 2011 and December 2014. PTX was administered intravenously (50 mg/m(2)) and intraperitoneally (20 mg/m(2)) on days 1 and 8, and 80 mg/m(2) S-1 was administered on days 1-14 every 3 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), the objective tumor response, efficacy against malignant ascites, and safety. Result In all 35 patients, the median OS and PFS were 4.8 (95 % confidence interval [CI], 2.1-5.3) months and 2.8 (95 % CI, 0.9-4.1) months, respectively. The 26 patients who were evaluable for efficacy achieved a response rate of 8 % and a disease control rate of 69 %. Malignant ascites had disappeared or decreased in 18 (69 %) patients, including complete resolution in 4 (15 %), and a negative change in cytological status was achieved in 8 (31 %) patients. The major grade 3/4 adverse events included neutropenia (34 %), anemia (31 %), nausea (9 %), and catheter-related infections (6 %). Conclusion Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 showed acceptable toxicity and favorable efficacy in pancreatic cancer patients with malignant ascites. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005306).

Aberrant activation of Wnt/β-catenin signaling is a major driving force in colon cancer. Wnt/β-catenin signaling induces the expression of the transcription factor c-Myc, leading to cell proliferation and tumorigenesis. c-Myc regulates multiple biological processes through its ability to directly modulate gene expression. Here, we identify a direct target of c-Myc, termed MYU, and show that MYU is upregulated in most colon cancers and required for the tumorigenicity of colon cancer cells. Furthermore, we demonstrate that MYU associates with the RNA binding protein hnRNP-K to stabilize CDK6 expression and thereby promotes the G1-S transition of the cell cycle. These results suggest that the MYU/hnRNP-K/CDK6 pathway functions downstream of Wnt/c-Myc signaling and plays a critical role in the proliferation and tumorigenicity of colon cancer cells.

BACKGROUND: We present a case of asynchronously occurring adenocarcinomas 29 and 36 years after ureterosigmoidostomy for bladder cancer, respectively, at both anastomosis sites. CASE PRESENTATION: A colonoscopy that was performed on a 69-year-old man because of bloody stool and an elevated carcinoembryonic antigen (CEA) level revealed a polypoid lesion at the right ureterosigmoid anastomosis site 29 years after the patient's ureterosigmoidostomy. Endoscopic resection was performed, and the lesion was diagnosed as adenocarcinoma. Seven years later (36 years after ureterosigmoidostomy), an elevated lesion was detected at the left ureterosigmoid anastomosis site by colonoscopy performed after detection of high CEA levels. Biopsy revealed an adenocarcinoma that was immunohistologically positive for CDX2; sigmoidectomy and ureterectomy were subsequently performed. The pathological diagnosis of the second tumor was adenocarcinoma arising in the ureterosigmoid anastomosis site and invading the left ureter. CONCLUSIONS: Diligent long-term follow-up of patients who underwent ureterosigmoidostomy is essential.

BACKGROUND: CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined. METHODS: CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed. RESULTS: CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133- patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001). CONCLUSIONS: Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133- patients had a significantly higher rate of extrahepatic recurrence.

Colon cancers in male and female patients are suggested to be oncologically different. The aim of this study is to elucidate the prognostic impact of lymph node dissection (LND) in male and female colon cancer patients. A total of 5941 stage I-III colon cancer patients who were curatively operated on during the period from 1997 to 2007 were retrospectively studied. Cancer-specific survival (CSS) was individually compared between for male and female patients treated with D3, D2, and D1 LND. Background differences of the patients were matched using propensity scores. D3, D2, and D1 LND were performed in 3756 (63 %), 1707 (29 %), and 478 (8 %), respectively, and more extensive LND was indicated for younger patients and more advanced disease. D2 LND was significantly associated with decreased cancer-specific mortality compared to D1 LND in male patients (HR 0.54, 95 % CI 0.32-0.89, p = 0.04), but not in female patients. D3 LND did not correlate to an improved prognosis compared to D2 LND both in male and female patients. D2 LND was associated with an improved CSS in male, but not female colon cancer patients, compared to D1 LND. This suggested that colon cancer in male and female patients might be oncologically different, and that the prognostic impact of the extent of surgical intervention for colon cancer might therefore be different between sexes.

Background: Diabetes mellitus (DM) is suggested to be associated with colorectal cancer (CRC) however, the direct relationship between DM and CRC has not been proven. Objective: The aim of this study is to clarify oncological behavior of CRC with DM. Methods: This study is a retrospective cohort study. We investigated 1216 patients with curatively resected CRC. Clinicopathological factors and prognosis were compared between the patients with and without DM. Results: DM was observed in 34% of the patients. The patients with DM were significantly older, were predominantly males, had larger tumors, and died more frequently of causes other than CRC than those without DM. While overall survival (OS) was significantly inferior in the patients with DM than in those without (83% vs. 88%, p=0.01), there was no difference in cancer-specific survival (CSS) between the two groups (91% vs. 91%, p=0.6). The examination of survival at each cancer stage showed that CSS of the patients with DM tended to be superior in stage II cancer (97% vs. 93%, p=0.07) and was worse in stage IV cancer (54% vs. 70%, p=0.05). Conclusions: OS was worse in the CRC patients with DM who more often died of causes other than CRC, and thus, DM did not affect CSS as a whole. However, with the progression of CRC, DM appeared to worsen CSS. It is unclear whether this is attributed to differences in malignancy or in treatment this should be further examined.

Long-standing ulcerative colitis patients are known to be at high risk for the development of colorectal cancer. Therefore, surveillance colonoscopy has been recommended for these patients. Because colitis-associated colorectal cancer may be difficult to identify even by colonoscopy, a random biopsy method has been recommended. However, the procedure of carrying out a random biopsy is tedious and its effectiveness has also not yet been demonstrated. Instead, targeted biopsy with chromoendoscopy has gained popularity in European and Asian countries. Chromoendoscopy is generally considered to be an effective tool for ulcerative colitis surveillance and is recommended in the guidelines of the British Society of Gastroenterology and the European Crohn's and Colitis Organisation. Although image-enhanced endoscopy, such as narrow-band imaging and autofluorescence imaging, has been investigated as a potential ulcerative colitis surveillance tool, it is not routinely applied for ulcerative colitis surveillance in its present form. The appropriate intervals of surveillance colonoscopy have yet to be determined. Although the Japanese and American guidelines recommend annual or biannual colonoscopy, the British Society of Gastroenterology and the European Crohn's and Colitis Organisation stratified their guidelines according to the risks of colorectal cancer. A randomized controlled trial comparing random and targeted biopsy methods has been conducted in Japan and although the final analysis is still ongoing, the results of this study should address this issue. In the present review, we focus on the current detection methods and characterization of dysplasia/cancer and discuss the appropriate intervals of colonoscopy according to the stratified risks.

Background: Clinical studies of intraperitoneal chemotherapy with paclitaxel in patients of gastric cancer with peritoneal carcinomatosis is well tolerated and effective, and rare cases of metastasis and recurrence have experienced during the treatment. Disseminated carcinomatosis of the bone marrow is highly rare in gastric cancer and associated with a poor prognosis. Case presentation: A 59-year-old woman of gastric cancer with peritoneal carcinomatosis received five courses of chemotherapy with intraperitoneal administration of paclitaxel, and laparoscopy showed disappearance of the peritoneal carcinomatosis. She subsequently underwent total gastrectomy, and the histopathological findings showed a complete response to the chemotherapy. Postoperatively, chemotherapy with intraperitoneal administration of paclitaxel was continued for 30 months, without apparent recurrence. However, the gastric cancer recurred as disseminated carcinomatosis of the bone marrow with disseminated intravascular coagulation, and we hence changed the chemotherapy regimen to weekly irinotecan. Remission was achieved, and she did not experience any major symptoms; however, she died 6 months after the diagnosis of disseminated carcinomatosis of the bone marrow. Conclusions: Since intraperitoneal paclitaxel administration can strongly suppress peritoneal carcinomatosis of gastric cancer, careful attention should be paid not only to peritoneal recurrence but also for rare site metastases, such as bone marrow metastases.

AimThe rate of extension of proctitis in Western countries has been reported, but no data regarding long-term follow-up have been described for the Japanese population. Additionally, patients with long-standing or extensive ulcerative colitis have an increased risk for developing colorectal cancer. This study evaluated both the rate of extension of the disease and the development of neoplasia among patients with an initial diagnosis of ulcerative proctitis. MethodWe retrospectively investigated the medical charts of patients with proctitis from 1979 to 2014. The primary focus of this research was the extension of the inflammatory area. The secondary focus included risk factors for disease extension and the development of neoplasia. ResultsSixty-six patients satisfied the inclusion criteria. Proximal extension of the disease occurred in 34 patients: 19 patients had left-sided colitis and 15 had pancolitis. According to a multivariate analysis, disease extension was significantly higher in patients with disease onset before 25years of age (P-value=0.043). The cumulative rates of disease extension at 10 and 20years were 33.8% and 52.2%, respectively. Three patients were diagnosed with dysplasia during follow-up, all of whom experienced disease extension before the development of dysplasia. ConclusionThe rate of extension of ulcerative colitis in the Japanese population was comparable to that in Western countries. A younger age of disease onset was associated with disease extension. Extension of proctitis may be associated with an increased risk of colorectal cancer.

Background. Recent advances in endoscopic therapy, including conventional endoscopic resection and endoscopic submucosal dissection (ESD), have led to a large number of patients with early colorectal cancer (CRC) being cured; however, when resected specimens obtained by these procedures manifest risk factors for lymph node metastasis, additional treatments need to be considered. The aim of our study was to evaluate the outcomes of salvage surgery in CRC patients treated initially by advanced therapeutic endoscopy. Methods. We investigated 145 patients who underwent salvage surgery in our department after endoscopic therapy for CRC between April 2006 and March 2015. Demographic and pathological data, endoscopic procedures, reasons for surgery, and operative outcomes, including perioperative details and recurrence-free and disease-specific survival after surgery, were analyzed. These data were further compared with those of 59 patients with submucosal invasive CRC treated by conventional endoscopic resection/ESD alone and 133 patients treated by surgery alone. Results. Overall lymph node metastases were observed in 14 % of patients who underwent salvage surgery after therapeutic endoscopy and 16% of those who received abdominal surgery alone. In analyses of surgical cases, patients with lymph node metastases more frequently included cases with lymphatic infiltration (63 %) and ESD-treated cases (45 %) than those without metastases (21 %, P &lt; .0001 and 22%, P = .02; respectively). A logistic regression analysis identified lymphatic infiltration as an independent predictive factor for lymph node metastases (odds ratio: 8.77, 95 % confidence interval: 2.90-33.31, P &lt; .0001). Long-term outcomes were favorable in both lymphatic infiltration negative and positive cases. Moreover, survivals were comparable among the different treatment groups. Conclusion. Because of the high rate of nodal involvement, adequate lymphadenectomy need to be performed in salvage surgery after upfront endoscopic therapy.

Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or nalonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.

Background: Mucinous cystadenocarcinoma is the second most common etiology of appendiceal mucocele. We report a relatively rare case of a giant appendiceal mucocele caused by mucinous cystadenocarcinoma, which occupied the entire abdomen of an adult woman. Case presentation: A 63-year-old woman presented with a chief complaint of abdominal distention. Imaging studies showed a giant cystic mass occupying her entire abdomen. Laparotomy confirmed a giant appendiceal mucocele, and the patient underwent ileocecal resection. A mucinous deposit was not found in her abdominal cavity, and the ovaries were grossly normal bilaterally. The pathological diagnosis was mucinous adenocarcinoma with a low-grade mucinous neoplasm that invaded the subserosa. Regional lymph node metastasis was not found. She has had recurrence-free survival for 5 years. Conclusions: The present case is the largest appendiceal cystadenocarcinoma ever reported. The optimal treatment of an appendiceal neoplasm requires further research based on consensus terminology of an appendiceal mucocele.

Background: The incidence of neoplasia after surgery has not been sufficiently evaluated in patients with ulcerative colitis (UC), particularly in the Japanese population, and it is not clear whether surveillance endoscopy is effective in detecting dysplasia/cancer in the remnant rectum or pouch. The aims of this study were to assess and compare postoperative development of dysplasia/cancer in patients with UC who underwent ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA) and to evaluate the effectiveness of postoperative surveillance endoscopy. Methods: One hundred twenty patients who received postoperative surveillance endoscopy were retrospectively reviewed for development of dysplasia/cancer in the remnant rectal mucosa or pouch. Results: Three hundred seventy-nine endoscopy sessions were conducted for 30 patients after IRA, while 548 pouch endoscopy sessions were conducted for 90 patients after IPAA. In the IRA group, 5 patients developed dysplasia/cancer during postoperative surveillance and in all cases, neoplasia was detected at an early stage. In the IRA group, no patient developed neoplasia within 10 years of diagnosis; the cumulative incidence of neoplasia after disease onset was 7.2, 12.0, and 23.9 % at 15, 20, and 25 years, respectively. In one case after stapled IPAA, dysplasia was found at the ileal pouch; a subsequent 9 endoscopy sessions in 8 years did not detect any dysplasia. Neoplasia was found more frequently during postoperative surveillance in the IRA group than in the IPAA group (p =.0028). The cumulative incidence of neoplasia after IRA was 3.8, 8.7, and 21.7 % at 10, 15, and 20 years, respectively, and that after IPAA was 1.6 % at 20 years. Conclusions: The cumulative incidence of neoplasia after IPAA was minimal. Those who underwent IRA had a greater risk of developing neoplasia than those who underwent IPAA, although postoperative surveillance endoscopy was able to detect dysplasia/cancer at an early stage. IRA can be the surgical procedure of choice only in selected cases in which it would be of benefit to the patient, with more careful surveillance.

Patients with hereditary hemorrhagic telangiectasia (HHT) are reportedly at a lower overall risk of malignancies, and small bowel adenocarcinoma (SBA) arising in a HHT patient is extremely rare. In this study, the case of a 37-year-old female with HHT who developed a poorly differentiated jejunal adenocarcinoma five years after ileocecal resection for multiple colonic adenomas is presented. The patient underwent curative resection of the cancer invading the ileum and the mesentery of the transverse colon, but had to overcome critical complications perioperatively, stemming from HHT-associated peripheral capillary dilatation and arteriovenous malformation, including nosebleeds and possible infusion-induced air embolism through pulmonary shunts. The patient subsequently received adjuvant chemotherapy including capecitabine and oxaliplatin for 6 months, and currently remains alive without any evidence of recurrence 12 months after the second surgery. This patient with SBA was an instructive case demonstrating the necessity of careful attention during major surgery in HHT.

Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its alpha-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.

Background: Peritoneal dissemination of gastric cancer is still a dismal disease and has extremely poor prognosis even with systemic intensive chemotherapy. However, intraperitoneal chemotherapy using paclitaxel has recently shown good results. In order to perform optimal intraperitoneal chemotherapy, laparoscopic examination is necessary to assess the condition of peritoneal disseminated lesions. This is the first report of a case of a patient with gastric cancer with massive peritoneal metastasis treated with intraperitoneal administration of paclitaxel and repeated laparoscopic examinations who survived more than 5 years. Case presentation: Here we report a case of a 60-year-old Japanese woman with peritoneal carcinomatosis of gastric cancer who underwent intraperitoneal chemotherapy receiving repeated laparoscopic examinations. The patient was referred to our institution for the treatment of peritoneal carcinomatosis of gastric cancer. The staging laparoscopy showed peritoneal metastasis in the whole peritoneal space with a peritoneal cancer index score of 23. An intraperitoneal access port was subcutaneously implanted. Paclitaxel was intraperitoneally and intravenously administered with oral administration of S-1. The second-look laparoscopy, which was performed after nine courses of intraperitoneal chemotherapy, revealed the disappearance of peritoneal carcinomatosis. A total gastrectomy with D2 lymphadenectomy was performed and intraperitoneal chemotherapy was continued after the surgery. The third laparoscopic examination, which was performed after 67 courses of intraperitoneal chemotherapy showed bilateral ovarian metastasis without recurrence of peritoneal carcinomatosis. Since multiple bone metastases developed after the third-look laparoscopy, bilateral adnexectomy was not performed and the chemotherapy was changed to the regimen including CPT-11. Our patient survived more than 5 years since the intraperitoneal chemotherapy started. Conclusions: Sequential intraperitoneal chemotherapy could strongly suppress the development of peritoneal metastasis for several years. Repeated laparoscopic examinations are considered to be essential to evaluate the efficacy of intraperitoneal chemotherapy on peritoneal carcinomatosis of gastric cancer.

Introduction Spontaneous esophageal perforation, or Boerhaave's syndrome, is a life-threating condition which usually requires emergent surgery. An upside down stomach is defined as a gastric volvulus in a huge supradiaphragmatic sac. In general, this condition can result in ischemia and perforation of the stomach. This is the first report of a patient with Boerhaave's syndrome and an upside down stomach. Case presentation A 79-year-old woman presented with sudden epigastric pain following hematemesis. Evaluation of the patient showed both an esophageal perforation and an upside down stomach. Surgical drainage and irrigation of the mediastinum and pleural cavities were undertaken emergently. Due to the concurrent gastric volvulus, a gastrostomy was placed to fix and decompress the stomach. The patient had an uneventful hospital course and was discharged. Discussion and conclusion Boerhaave's syndrome is a rare but severe complication caused by excessive vomiting, due to a sudden elevation in intraluminal esophageal pressure resulting in esophageal perforation. Acute gastric volvulus can result in ischemia and perforation of the stomach, but has not previously been reported with esophageal perforation. The most likely mechanism associating an upside down stomach with Boerhaave's syndrome is acute gastric outlet obstruction resulting in vomiting, and subsequent esophageal perforation. Perforation of the esophagus as well as perforation of the stomach must be considered in patients with an upside down stomach although both upside down stomach and Boerhaave's syndrome are rare clinical entities.

Introduction Cytomegalovirus (CMV) infection of the gastrointestinal tract is an uncommon illness, but can be observed in immunocompromised patients. Systemic lupus erythematosus (SLE) patients are generally at high risk of CMV infection. Here we report a subacute progressive case of colitis in SLE accompanied by cytomegalovirus infection. Presentation of case The patient, a 79-year-old woman, was hospitalized complaining of fever, polyarthritis, and skin ulcer that had lasted seven days. She additionally manifested vomiting, high fever, and right abdominal pain within two weeks thereafter, and was diagnosed with perforation of the intestine. Emergency operation was carried out for panperitonitis due to perforation of one of the multiple colon ulcers. Multidisciplinary postoperative treatment could not save her life. Pathological examination suggested that cytomegalovirus infection as well as cholesterin embolization contributed to the rapid progression of colitis. Discussion There have been only a limited number of case reports of CMV enteritis in SLE. Moreover, only two SLE patients on multiple medications have been reported to experience gastrointestinal perforation. Viral infections, including CMV, can induce clinical manifestations resembling SLE and for this reason we suspect that there are potentially many more patients misdiagnosed and/or unreported. Conclusion Our case underscores the importance of exploring the possibility of CMV infection as a differential diagnosis in SLE patients with obvious gastrointestinal symptoms who were treated by immunosuppressive drugs.

INTRODUCTION: Neuroendocrine tumors of the colon and rectum are relatively rare compared to sporadic colorectal carcinoma. There are few reports of neuroendocrine tumors of the colon and rectum in patients with ulcerative colitis. PRESENTATION OF CASE: A patient with sigmoid colon carcinoma with focal neuroendocrine features is presented. A 32-year-old man, who had been followed for ulcerative colitis for 14 years, was found to have carcinoma of the sigmoid colon on routine annual colonoscopy, and he underwent laparoscopic total colectomy. Pathologic examination showed sigmoid colon adenocarcinoma with focal neuroendocrine features. DISCUSSION: Most colorectal carcinomas associated with inflammatory bowel disease are histologically similar to the sporadic type, and tumors with neuroendocrine features are very unusual. CONCLUSION: Very rare case of sigmoid colon carcinoma with neuroendocrine features arising in a patient with UC was described.

The human peritoneal cavity contains a small number of free cells of mesenchymal cell lineage. Intraperitoneal mesenchymal cells (PMC) play supportive roles in metastasis formation on the peritoneum. In this study, we found that PMC, when co-cultuerd with human gastric cancer cells, MKN45, enhanced the proliferation of MKN45 when cultured at low, but not high, cellular density. Also, PMC suppressed apoptotic cell death of MKN45 only under low density culture conditions. Time-lapse videoanalysis clearly demonstrated that PMC randomly migrated more vigorously than did MKN45, and strongly enhanced the migration behavior of co-cultured MKN45. In fact, the majority of MKN45 migrated together in direct physical contact with PMC, and the sum of migration lengths from original position of co-cultured MKN45 for 48 hours was approximately 10 times longer than that of MKN45 cultured alone. Our data suggest that enhanced migration can increase the chance of direct contact or positional proximity among sparcely distributed MKN45, which may bring survival advantages to tumor cells. This may be one of the important mechanisms of peritoneal metastasis, since only a small number of tumor cells are considered to be disseminated in the early step of metastasis formation on the peritoneum.

Background: Recent studies have proposed that the use of the lymphocyte-to-monocyte ratio (LMR) is a good prognostic indicator for patients with nonmetastatic colorectal cancer (CRC). In the present study, we aimed to evaluate the prognostic impact of the LMR in stage IV CRC patients who have undergone curative resection. Methods: We performed a retrospective review of 117 stage IV CRC patients who underwent curative resection at our institute between 1997 and 2012. Patients were divided into a lowLMR group and a high-LMR group according to their LMR. The cutoff value of the LMR was determined based on receiver operating characteristics curve analysis. The relationships between the LMR and disease-free survival (DFS) and cancer-specific survival (CSS) rates were assessed. Results: The cutoff value for LMR was 3.00. DFS was not significantly different between the high-and low-LMR groups (P = 0.277). By contrast, CSS was significantly better in the high-LMR group than in the low-LMR group (P = 0.001). Multivariate analysis indicated that the LMR was an independent prognostic factor for CSS in patients with stage IV CRC who had undergone curative resection (hazard ratio: 2.75; 95% confidence interval: 1.40-5.44; P = 0.004), but not for DFS. Conclusions: The preoperative LMR is a simple and useful prognostic indicator in patients with stage IV CRC who have undergone curative resection. (C) 2015 Elsevier Inc. All rights reserved.

Background. This study aimed to clarify differences in prognostic factors, metastatic features, and recurrence rates between histologic types in patients with stage 4 colorectal cancer (CRC) who had undergone curative resection. Methods. The data from 1131 patients with stage 4 colorectal cancer from the databases of referral institutions were analyzed. The patients were divided into two groups according to histologic types as follows: patients with poorly differentiated adenocarcinoma, mucinous adenocarcinoma, or signet-ring cell carcinoma (Por/Muc/Sig) and patients with well-differentiated or moderately differentiated adenocarcinoma (Wel/Mod). Differences in clinicopathologic features, relapse-free survival (RFS) rates, and cancer-specific survival (CSS) rates between the groups were evaluated. Results. Although RFS did not differ between the Por/Muc/Sig and Wel/Mod groups, CSS was significantly shorter in the Por/Muc/Sig group's than in the Wel/Mod group, and survival after recurrence was significantly worse in the Por/Muc/Sig group than in theWel/Mod group. The incidence of peritoneal or local recurrence was significantly higher for the Por/Muc/Sig patients, whereas the resection recurrence rate was 16.4 %. Multivariate analysis suggested that histologic type was an independent prognostic factor for survival after recurrence. Conclusions. The patients with Por/Muc/Sig CRC synchronous metastasis had significantly shorter survival times than the patients with other CRC histologies, even if the metastases were curatively resected.

AIM: To assist in the selection of suitable nomograms for obtaining desired predictions in daily clinical practice. METHODS: We conducted electronic searches for journal articles on colorectal cancer (CRC)-associated nomograms using the search terms colon/rectal/colorectal/nomogram. Of 174 articles initially found, we retrieved 28 studies in which a nomogram for CRC was developed. RESULTS: We discuss the currently available CRC-associated nomograms, including those that predict the oncological prognosis, the short-term outcome of treatments, such as surgery or neoadjuvant chemoradiotherapy, and the future development of CRC. Developing nomograms always presents a dilemma. On the one hand, the desire to cover as wide a patient range as possible tends to produce nomograms that are too complex and yet have C-indexes that are not sufficiently high. Conversely, confining the target patients might impair the clinical applicability of constructed nomograms. CONCLUSION: The information provided in this review should be of use in selecting a nomogram suitable for obtaining desired predictions in daily clinical practice.

The effect of chemotherapy on peritoneal carcinomatosis (PC) of gastric cancer remains unclear. Recently, the intraperitoneal (IP) administration of taxanes [e.g., paclitaxel (PTX) and docetaxel (DOC)] during the perioperative period has shown promising results. Herein, we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results. IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h. The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects, making it ideal for IP chemotherapy. There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy (SPIC). In SPIC, patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery (CRS) until disease progression. Usually, a taxane dissolved in 500-1000 mL of saline at ordinary temperature is administered through an IP access port on an outpatient basis. According to phase. studies, the recommended doses (RD) are as follows: IP DOC, 45-60 mg/m(2); IP PTX [without intravenous (IV) PTX], 80 mg/m(2); and IP PTX (with IV PTX), 20 mg/m(2). Phase. studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%. A phase. study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011. The prognosis of patients who underwent CRS was better than that of those who did not; however, this was partly due to selection bias. Although several phase. studies have shown promising results, a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.

The platelet to lymphocyte ratio (PLR) is a potential prognostic marker in a number of different cancers. The aim of this study was to evaluate the prognostic impact of the PLR in patients with stage II colorectal cancer (CRC) who have undergone curative resection but not adjuvant chemotherapy. A retrospective review was performed on 234 patients with stage II CRC who underwent curative resection, but not adjuvant chemotherapy, in our institute. The patients were divided into low and high PLR groups, and patient survival as well as several clinicopathological factors were compared between the groups. Disease-free survival (DFS) and cancer-specific survival (CSS) were analyzed by using the Kaplan-Meier method, and multivariate analysis was performed by using the Cox proportional hazard model. The cutoff value of the PLR determined by using a receiver-operating characteristic curve analysis was 25.4. DFS and CSS were significantly better in patients with a low PLR compared to patients with a high PLR (P = 0.002 and P = 0.011, respectively). On multivariate analysis, we identified the PLR as an independent prognostic factor for DFS and CSS, with a hazard ratio of 2.65 (95 % confidence interval [CI], 1.26-5.45; P = 0.011) and 3.61 (95 % CI, 1.08-12.64; P = 0.038, respectively). The PLR is a good prognostic indicator in patients with stage II CRC who have undergone curative surgery but not adjuvant chemotherapy.

Aim: The postoperative administration of oxaliplatin reduces the frequency of relapse in selected patients with colorectal cancer following surgical resection. However, factors associated with recurrence despite adjuvant therapy are largely unknown. Patients and Methods: We investigated 68 patients who were pathologically diagnosed with stage II or III colorectal cancer and received oxaliplatin-including chemotherapy, FOLFOX (5-fluorouracil, folinic acid and oxaliplatin) or CapeOX (capecitabine and oxaliplatin), after curative surgery. Results: Nineteen patients developed recurrence during the median follow-up period of 17.8 months. Multivariate analyses using the Cox proportional-hazards model revealed that primary tumor size &gt;= 45 mm was a significant predictor of recurrence (hazard ratio = 3.16, 95% confidence interval = 1.06-11.54, p = 0.039). A primary tumor of 45 mm or more in size was associated with poor recurrence-free survival. Conclusion: Our results suggest that large colorectal carcinoma needs to be recognized as a high-risk factor for recurrence even after surgery and subsequent treatment with oxaliplatin.

The transcription factor GATA6 is a critical regulator of cell proliferation and development in the gastrointestinal tract. We have recently reported that GATA6 induces the expression of the intestinal stem cell marker LGR(5) and enhances the clonogenicity and tumorigenicity of colon cancer cells, but not the growth of these cells cultured under adherent conditions. Here we show that REG(4), a member of the regenerating islet-derived (REG) family, is also a target of GATA6. We further demonstrate that REG(4) is downregulated by overexpression of miR-(3)6(3), which suppresses GATA6 expression. Moreover, we show that GATA6-mediated activation of REG(4) enhances the growth of colon cancer cells under adherent conditions and is required for their tumorigenicity. Taken together, our findings demonstrate that GATA6 simultaneously induces the expression of genes essential for the growth of colon cancer cells under adherent conditions (REG(4)) and genes required for their clonogenicity (LGR(5)), and that the miR-(3)6(3)-GATA6-REG(4)/LGR(5) signaling cascade promotes the tumorigenicity of colon cancer cells.

Despite the development of new therapies, including anti-TNF alpha antibodies and immunosuppressants, a substantial proportion of patients with ulcerative colitis (UC) still require surgery. Restorative proctocolectomy with ileal-pouch anal anastomosis is the standard surgical treatment of choice for UC. With the advent of laparoscopic techniques for colorectal surgery, ileal-pouch anal anastomosis has also been performed laparoscopically. This paper reviews the history and current trends in laparoscopic surgery for UC. The accumulation of experience and improvement of laparoscopic devices have shifted the paradigm of UC surgery towards laparoscopic surgery over the past decade. Although laparoscopic surgery requires a longer operation, it provides significantly better short and long-term outcomes. The short-term benefits of laparoscopic surgery over open surgery include shorter hospital stays and fasting times, as well as better cosmesis. The long-term benefits of laparoscopy include better fecundity in young females. Some surgeons favor laparoscopic surgery even for severe acute colitis. More efforts are being made to develop newer laparoscopic methods, such as reduced port surgery, including single incision laparoscopic surgery and robotic surgery.

Robotic technology, which has recently been introduced to the field of surgery, is expected to be useful, particularly in treating rectal cancer where precise manipulation is necessary in the confined pelvic cavity. Robotic surgery overcomes the technical drawbacks inherent to laparoscopic surgery for rectal cancer through the use of multi-articulated flexible tools, three-dimensional stable camera platforms, tremor filtering and motion scaling functions, and greater ergonomic and intuitive device manipulation. Assessments of the feasibility and safety of robotic surgery for rectal cancer have reported similar operation times, blood loss during surgery, rates of postoperative morbidity, and circumferential resection margin involvement when compared with laparoscopic surgery. Furthermore, rates of conversion to open surgery are reportedly lower with increased urinary and male sexual functions in the early postoperative period compared with laparoscopic surgery, demonstrating the technical advantages of robotic surgery for rectal cancer. However, long-term outcomes and the cost-effectiveness of robotic surgery for rectal cancer have not been fully evaluated yet; therefore, large-scale clinical studies are required to evaluate the efficacy of this new technology.

Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis. (C) 2015 Elsevier B.V. All rights reserved.

Anal canal adenoma is an extremely rare disease that has the potential to transform into a malignant tumor. We herein presented a rare case of metachronous multiple adenomas of the anal canal. A 48-year-old woman underwent total colonoscopy following a positive fecal blood test. A 9-mm villous polyp arising from the posterior wall of the anal canal was removed by snare polypectomy. Histologically, the tumor was tubulovillous adenoma with high-grade dysplasia and the cut end was negative for tumor cells. Six years later, an elevated lesion, macroscopically five millimeters in size, was detected in the left wall of the anal canal in a follow-up colonoscopy. Local excision of the tumor was performed, and the lesion was pathologically confirmed to be tubular adenoma with high-grade dysplasia limited to the mucosa. The patient is currently alive without any evidence of recurrence for six months after surgery. Although she had a past history of cervical cancer, the multiple tumors arising in the anal canal were unlikely to be related to human papilloma virus infection. Our case report underscores the importance of careful observations throughout colonoscopy to detect precancerous lesions, particularly in anatomically narrow segments.

Background: Massive malignant ascites originating from peritoneal metastasis of gastric cancer is difficult to control and resistant to chemotherapy. Cell-free and Concentrated Ascites Reinfusion Therapy (CART) is one of the types of apheresis therapy, by which filtered and concentrated ascites containing albumin and globulin is reinfused intravenously to patients. We retrospectively studied the feasibility of intraperitoneal (IP) chemotherapy combined with CART in gastric cancer patients with massive malignant ascites. Methods: Paclitaxel (PTX) was administered via an FP access port implanted in the subcutaneous space. If patient had massive ascites at the start of treatment, paracentesis was performed through a percutaneous IP catheter and then CART was performed. PTX was administered through the catheter until the ascites diminished. Results: A total of 127 CART procedures in 30 patients were analyzed. The average volume of processed ascites was 3.1 L, which was concentrated to 0.33 L containing 85.5 g protein on average. Significant increases in urine volume, serum total protein and albumin level were found after the CART. Increase in body temperature (0.3 degrees C), decrease in platelet count (3.8 x 10(4)/mu l), and changes in blood pressure (2 mm Hg) were found after the CART procedure, but no clinically significant adverse event was experienced. The median survival time and 1-year survival of 30 patients who received IP chemotherapy combined with the CART procedure was 10.2 months and 43.3% respectively. Conclusions: IP chemotherapy combined with CART might be a promising strategy for patients with massive malignant ascites originating from peritoneal metastasis of gastric cancer. (C) 2015 Elsevier Ltd. All rights reserved.

The frequency of intraperitoneal free tumor cells (IPTC) is considered to reflect the severity of peritoneal metastasis (PM). We quantified the relative number of IPTC against leukocytes in peritoneal fluid and evaluated its clinical relevance in gastric cancer (GC) patients, particularly those with PM. Cells recovered from ascites or peritoneal lavage fluid were immunostained with monoclonal antibodies (mAb) to CD45 and CD326 (EpCAM). Using flow cytometry (FACS), CD326(+) and CD45(+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated in a total of 506 samples obtained from 300 patients with GC and 33 patients with liver cirrhosis (LC). Median (M) of the TLR of the initial samples obtained from 199 patients with PM(+) GC was 1.32 % (0-1,868.44 %), which was significantly higher than that in patients with PM(-) GC (M = 0 %, 0-0.35 %; n = 101) or LC (M = 0 %, 0-0.031 %; n = 33). In 104 PM(+) patients who received combination chemotherapy including intraperitoneal paclitaxel, the TLR was repeatedly measured in peritoneal fluid obtained from the port. In these patients, the TLR showed a strong correlation with clinical features as well as cytological findings and carcinoembryonic antigen messenger RNA status. Finally, the median survival time of the 11 patients with initial TLR &gt; 10 % was significantly shorter than that of the 52 patients with TLR &lt; 10 % (271 vs. 627 days; p = 0.0002). The TLR excellently reflected tumor burden in the peritoneal cavity, and could be a reliable biomarker to determine the outcome, as well as the effectiveness, of chemotherapy in patients with PM(+) GC.