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Colonoscopy surveillance reduces the incidence of colorectal cancer through the detection and endoscopic removal of adenomas. Current guidelines recommend that patients with Lynch syndrome should have colonoscopy surveillance every 1-2 years starting at the age of 20-25. However, insufficient data are available to evaluate the quality and safety of colonoscopy surveillance for patients with Lynch syndrome nationwide in Japan.Patients with Lynch syndrome (The colonoscopy completion rate was 98.8% and a history of previous colorectal cancer surgery was significantly associated with a higher completion rate. All complications were associated with endoscopic treatment and the rate of bleeding needing hemostasis and perforation needing surgical repair were both 0.16% after colonoscopy with polypectomy. The adenoma detection rate at the first colonoscopy was 25%. Although there was no difference in the completion and complication rates based on differences in the colonoscopy experience of the endoscopist, the detection rate of adenomas and intramucosal cancers was significantly higher with more experienced endoscopists. The proportion of patients developing cancer was significantly higher with a 24 months than a ≤24 months interval.High-volume experienced endoscopists and appropriate surveillance intervals may minimize the risk of developing colorectal cancers in patients with Lynch syndrome.

Background/Aim: We previously reported three items that preoperatively predicted complicated appendicitis (body temperature, C-reactive protein, and fluid retention around the appendix). In this study, we aimed to compare other predictors to confirm the usefulness of our predictors with those of previous reports on the items as predictors of complicated appendicitis preoperatively (criteria A which consist of 8 items, criteria B which consist of 7 items). Patients and Methods: We retrospectively evaluated 417 adult patients who underwent surgery for acute appendicitis between January 2013 and December 2019 and compared our items with criteria A and criteria B according to the results of the area under the receiver operating characteristic curve (AUC), homogeneity, discriminatory ability, and Akaike information criterion (AIC). Results: The AUC for the sensitivity to diagnose complicated appendicitis according to according to our criteria, as well as criteria A, and criteria B was 0.823, 0.839, and 0.856, respectively. The discriminatory ability linear trend χ(2) of our criteria and those of criteria A and B were 128.9, 121.1, and 142.5, respectively. The homogeneity likelihood ratios χ(2) calculated using the Cox regression model, which indicate homogeneity, were 146.4, 143.6, and 172.8, respectively. The AIC of each criterion was 397.0, 345.8, and 369.0, respectively. Conclusion: Although the criteria B were the best, it was possible to predict complicated appendicitis preoperatively by all criteria. Above all, our criteria have only three items, therefore they have the advantage of making it possible to make decisions quickly with a certain degree of accuracy, regardless of the degree of experience.

Background and Aim: The nature and characteristic of human mucinous colorectal adenocarcinomas have not been well elucidated yet. We previously reported a genetically-engineered mouse model for colonic neoplasia producing mucin based on inactivation of Transforming Growth Factor β Receptor Type II (Tgfbr2) and Apc (CDX2P-G19Cre;Apc flox/+;Tgfbr2flox/flox), which is useful to investigate the mechanism of tumor formation. This mouse model developed colonic neoplasia from 12 weeks of age. Despite the same genotype, 40% of the tumors were found mucinous adenocarcinoma and 28% were high-grade adenoma. For further investigation, we herein perform transcriptomic analysis to clarify the molecular differences in these two histologically different tumors. Method: Total RNA were extracted from mucinous adenocarcinomas and high-grade adenomas in CDX2P-G19Cre;Apcflox/+;Tgfbr2 flox/flox mice from fresh frozen tumors (n=3, each). Then, RNA-seq and Gene Set Enrichment Analysis were performed. Samples were sequenced on NovaSeq 6000, and gene sets queried included the Hallmark. Results: Mucinous adenocarcinoma and high-grade dysplasia were differentially clustered in principal component analysis despite the same genotype. Gene set enrichment analysis showed 19 upregulated signaling pathways including KRAS signaling and epithelial mesenchymal transition, and 8 suppressed signaling pathways including E2F targets and MYC targets in mucinous adenocarcinoma compared to high-grade dysplasia (FDR < 0.05). Conclusions: By comparing transcriptome of mucinous adenocarcinoma with high-grade adenoma in our mouse model, 27 differential signal pathways were detected. Some of these pathways are presumably associated with the nature and the characteristics of mucinous adenocarcinoma. We are further investigating the effects of these differences in signal pathways and the correlation with human mucinous adenocarcinoma. Citation Format: Haruki Sada, Hiroaki Niitsu, Hikaru Nakahara, Masashi Miguchi, Naoya Sakamoto, Naohide Oue, Hirotaka Tashiro, Hideki Ohdan, Takao Hinoi. Transcriptomic analysis of mucinous adenocarcinoma in genetically-engineered mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 18.

Purpose FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. Methods Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). Results Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8–77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. Conclusions FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

Highlights • Appendicular endometriosis a rare entity which usually presents with symptoms of abdominal pain, melena, and constipation. • Appendicular endometriosis can present as a submucosal tumor in the cecum without any abdominal symptoms. • Single-incision laparoscopic surgery is an useful procedure for cecum tumor resection., Introduction We report the case of characteristic findings of appendicular endometriosis that presented as a submucosal tumor in the cecum without any abdominal symptoms treated with single-incision laparoscopic ileocolectomy. Presentation of case The patient was a 51-year-old woman (body mass index: 21.5) who underwent an examination to investigate the cause of a positive fecal occult blood test. Her laboratory test results were normal, without anemia or tumor marker elevation. Colonoscopy revealed a submucosal tumor in the cecum. Enhanced computed tomography (CT), fluorodeoxyglucose-positron emission tomography-CT and magnetic resonance imaging failed to produce a clear diagnosis. Given the malignant potentiality of the tumor, ileocolectomy was considered potentially necessary, but she wished for minimally invasive surgery. She ultimately underwent ileocolectomy and lymphadenectomy with single-incision laparoscopic surgery. A pathological examination revealed the lesion to be appendicular endometriosis, and 14 lymph nodes with no malignancy were resected. Conclusion Appendicular endometriosis can present as a submucosal tumor in the cecum without any abdominal symptoms. Appendicular endometriosis should be considered in the differential diagnosis of ileocecal submucosal tumor. Single-incision laparoscopic ileocolectomy was useful procedure for cecum tumor resection.

Background: Complicated appendicitis is an indication for emergency surgery. Therefore, the predictive factors for appendicitis based on the patient background needs identification. Previously, factors predicting non-complicated and complicated appendicitis were reported. However, most of those reports were deemed unsuitable as a standard for emergency use, since those comprised too many items as predictors. We previously reported three items that preoperatively predicted complicated appendicitis (body temperature, C-reactive protein, and fluid retention around the appendix). In this study, we re-evaluated different cases to confirm the usefulness of these three items can for accurately predicting complicated appendicitis preoperatively. In addition, we compared the effectiveness of these predictor items with those reported by other researchers.Methods: We retrospectively evaluated 417 adult patients who underwent surgery for acute appendicitis between January 2013 and December 2019, and compared our predictor items with those used in previous reports on the preoperative prediction of complicated appendicitis (criteria A consisting of eight predictor items and criteria B consisting of seven predictor items). Results: The area under the receiver operating characteristic curve (AUC) for the sensitivity to diagnose complicated appendicitis according to our criteria, criteria A, and criteria B were 0.823, 0.839, and 0.856, respectively. The AUC of our criteria and criteria A were similar (P = 0.356); those of criteria A and B were also similar (P = 0.352). However, the AUC of criteria B was statistically higher than that of our criteria (P < 0.05).Conclusion: Diagnostic criteria B were statistically the best predictor items for characterizing complicated and uncomplicated appendicitis. However, like criteria A and B, the AUC of our criteria exceeded 0.8, and only involved three predictor items; therefore, they can be considered useful predictors.

Background and Aim: Mucinous colorectal adenocarcinoma (CRC) is characterized by abundant extracellular mucin which occupies more than 50% of the tumor volume. Mucinous CRCs account for 10% of all CRCs and are likely to be microsatellite unstable including Lynch syndrome. Mucinous CRCs metastasize less frequently. However, once they metastasize, they exhibit resistance to cytotoxic chemotherapeutics, and are associated with poorer prognosis. Although there are some issues to be addressed in mucinous CRCs, mouse models are lacking for mucinous CRCs. Here, we report genetically-engineered mouse models (GEMMs) for mucin-producing colonic tumors with microsatellite instability (MSI), resembling human mucinous CRCs. Method: To induce genetic alterations specifically in colonic epithelial cells, we used CDX2P-G19Cre transgenic mice. In this mouse model, a 9.5-kb fragment in the CDX2 promoter lesion (CDX2P9.5) regulates Cre expression specifically in colonic epithelium (Hinoi et al. Cancer Research 2007). In addition, 19 guanine nucleotides are inserted just after the first ATG, and Cre only expresses in the epithelial cells in which the number of the guanine tract stochastically turns a multiple of three. This mechanism helps our GEMMs to avoid embryonic death due to the genetic events we introduce. We have also reported that tumors in CDX2P9.5-G19Cre;Apcflox/flox mice have an abnormality in two of four MSI markers, suggesting that the tumors are driven by MSI (Sasada et al. PLoS One 2015). TGFBR2 mutation is frequently seen in human MSI CRCs, and inactivation of both Tgfrbr2 and Apc by Villin-Cre results in small intestinal neoplasm producing mucin. Therefore, to test if Tgfbr2 conditional knockout affects the mucin-producing phenotype in the context of MSI-high in this mouse model, we generated CDX2P-G19Cre;Apcflox/+;Tgfbr2flox/flox. Results: In CDX2P-G19Cre; Apcflox/+; Tgfbr2 flox/flox mice, colonic neoplasia developed in 27 out of 40 mice. Approximately 60% of the tumors are well-differentiated adenocarcinoma producing mucin, while the remaining 40% are regular colonic adenomas. In these mucinous adenocarcinomas, tumor cells invade into the muscular layer. We also confirmed the immunoreactivity of β-catenin in cytoplasm and nuclei at the invasive front of the tumors in IHC analysis, indicating that these tumors are driven by abnormal Wnt activity. Nearby to the invasive front, there were mucin that were positive for a PAS reaction. Conclusion: Mucin-producing adenocarcinomas develop in CDX2P9.5-G19Cre;Apcflox/+; Tgfbr2flox/flox mice. This GEMM is a potential mouse model recapitulating human mucinous and microsatellite unstable colorectal adenocarcinoma. The precise mechanism in which mucinous adenocarcinoma develops needs to be elucidated by genomic and transcriptomic analyses. Citation Format: Haruki Sada, Takao Hinoi, Hiroaki Niitsu, Masashi Miguchi, Naoya Sakamoto, Naohide Oue, Hirotaka Tashiro, Hideki Ohdan. Genetically-engineered mouse model for colonic neoplasia presenting mucinous and microsatellite unstable phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6035.

Background/aim Right ventricular cardiac metastasis from colorectal cancer (CRC) is rare and clinically silent. There is no standardised treatment. To date, only twelve cases have been reported in the literature. This is a case report and literature review of right ventricular cardiac metastasis from CRC. Case report A 75-year-old woman with a history of CRC treated with sigmoidectomy followed by liver and lung metastasectomy presented with a right ventricle tumour. Biopsy showed metastatic adenocarcinoma not suitable for resection because multiple lung metastases coexisted. The metastases were controlled for a prolonged duration by chemotherapy with capecitabine plus bevacizumab. According to the review of 13 cases, the median age of metastatic CRC that involves the right ventricle is 71 years and the primary site is half the colon and rectum. Half of cases have non-cardiac metastases at cardiac metastasis diagnosis. Chemotherapy is more suitable than resection in cases with metastases other than heart because resection of the right ventricle has a high risk. Conclusion Cardiac right ventricular metastasis from CRC can be controlled by capecitabine plus bevacizumab.

Background Rectovaginal fistula (RVF) following aluminum potassium sulfate hydrate-tannic acid (ALTA) injection therapy for hemorrhoids is a rare complication. We report the first case of RVF after ALTA injection therapy successfully treated by gluteal-fold flap. Case presentation A 49-year-old female suffered from a fever and rectal ulcer after undergoing internal hemorrhoid treatment with a submucosal ALTA injection at a previous clinic. One week after ALTA therapy, she noted obvious passage of flatus and stool through the vagina, and was diagnosed with RVF by anoscope at another clinic. She was referred to our hospital 3 weeks after ALTA therapy. Sigmoid colostomy was performed for fecal diversion as a preliminary step for fistula repair. However, the fistula was scarred and the defect between the rectum and vagina did not improve at all. Ten months after ALTA therapy, we performed fistula repair by gluteal-fold flap. Seven months later, sigmoid-colostomy reversal was performed. The patient has experienced no RVF in the 3 years since sigmoid-colostomy reversal. Conclusions The gluteal-fold flap strategy is a useful option for severe RVF management.

BRAFV600E mutation accounts for up to 90% of all BRAF mutations in human colorectal cancer (CRC), and constitutively activates the MEK‐MAPK pathway. It is recognized that neutralizing mAbs for epidermal growth factor receptor alone are not effective for CRC with BRAFV600E mutation. Therefore, there is increasing interest in identification of the possible therapeutic targets in downstream of BRAF mutation in CRCs. To address this, we studied genome engineered mouse models for colonic neoplasia that has BrafV600E mutation on the basis of Apc inactivation, induced in 2 distinct Cre mouse models, CDX2P‐G22Cre and CDX2P‐CreERT2 mice. We carried out oligonucleotide microarray analysis for colonic neoplasia generated in these mouse models, and compared gene expression profiles among Kras/Braf WT, Kras‐mutated, and Braf‐mutated mouse colon tumors to seek new molecular targets corresponding to the KRAS‐BRAF‐MAPK axis. We found that the expression of the growth regulation by estrogen in breast cancer protein 1 (Greb1) was the most upregulated gene in Braf‐mutated mouse tumors compared to Kras/Braf WT counterparts. The silencing of GREB1 significantly reduced the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GREB1 promoted cell proliferation. Although GREB1 was first identified as a hormone‐responsive gene mediating estrogen‐stimulated cell proliferation in endometriosis, breast, and ovarian cancers, these results suggest that RAS‐RAF‐MAPK signaling upregulates GREB1 expression in CRC, resulting in cellular proliferation. Thus, GREB1 is a possible therapeutic target for CRCs with BrafV600E mutation., Greb1 was the most highly upregulated gene in Braf‐mutated mouse tumors compared to WT Kras/Braf. GREB1 functions as an oncogene, promoting cell proliferation in colorectal cancer.

Rectal tumors are traditionally resected by proctectomy to ensure the achievement of negative margins, an approach associated with an adverse impact on subsequent quality of life due to sequelae such as permanent stoma and urinary and sexual dysfunction. Many studies have now demonstrated that recurrence after local excision of early rectal tumors is significantly higher than would typically be expected. We have developed a new procedure, described herein, that combines local resection with endoscopic submucosal dissection for low rectal tumor. We report four consecutive cases (three submucosal tumors and one tumor with clinical deep submucosal invasion) treated at Hiroshima City Asa Citizens Hospital between January 2009 and March 2018. The mean duration of the procedure was 137 minutes. The en bloc resection and histologically complete resection rates were 100 %. Delayed bleeding and perforation rates were 0 %. Postoperative complications were fever and anal pain (one case each). All patients recovered with conservative therapy. No recurrence was found in any of the four patients during a follow-up period of 56 months. Our combined endoscopic and surgical procedure for low rectal tumors enabled definite negative vertical margins, reduced tumor volume, allowed for accurate pathological diagnosis, preserved rectal function, and aided the decision on additional therapy.

Highlights • Intestinal obstructions caused by external compression from the appendix are rare. • Low-grade appendiceal mucinous neoplasm (LAMN) with torsion is rarer still. • LAMN have the potential to lead to pseudomyxoma peritonei. • Surgical resection for LAMN is the standard treatment. • The appropriate surgical procedure, however, remains controversial., Introduction Intestinal obstructions due to appendiceal pathology are rare. Obstructions caused by low-grade appendiceal mucinous neoplasms (LAMNs) are rarer still. Presentation of case A 79-year-old woman was referred to our hospital for mechanical small intestinal obstruction. The patient had undergone prior left oophorectomy via a lower abdominal incision. Physical examination revealed abdominal distension and slight tenderness. Laboratory analysis was unremarkable. Contrast enhanced computed tomography (CT) demonstrated dilation of an obstructed small intestinal loop without evidence of strangulation. There appeared to be a low density mass measuring 3.0 × 1.5 cm with a potential twist in the mesentery near the transition point in the small intestine. The patient was diagnosed with mechanical small intestinal obstruction and was treated conservatively with nasogastric tube decompression for one week. After no clinical improvement, we elected to surgically explore her. Intraoperative findings revealed that the ileum was compressed by the appendix, which had a cystic mass on its tip. There was no evidence of intestinal ischemia. Laparotomy appendectomy alone was performed. Pathology revealed a LAMN measuring 3.0 × 1.5 cm. She remains disease-free with 18 months of postoperative follow-up. Discussion Intestinal obstruction due to external compression by an appendiceal mass is rare, and is often difficult to preoperatively diagnose with CT. Conclusions The etiology of small intestinal obstruction with a transition point in the right lower quadrant of abdomen includes an appendiceal mass on the broad differential for this common problem.

A 61-year-old man presenting with abdominal pain and fever refractory to antibiotics underwent diagnostic laparoscopy and non-mass-forming isolated omental panniculitis was identified. He presented with left-upper-quadrant abdominal pain. Laboratory data and the CT findings suggested intraabdominal bacterial disease in the splenic flexure, which we treated with antibiotics and fasting. He clinically improved once, but later relapsed with abdominal pain migration to the left-lower-quadrant. CT re-examination revealed no inflammation in the splenic flexure, but attenuation of adipose tissue in the greater omentum. We partially extracted the greater omentum during diagnostic laparoscopy and diagnosed omental panniculitis and administered steroids. He improved and was discharged three days after starting oral prednisone and is recurrence-free with a close follow-up. The characteristic CT feature of omentum panniculitis is a high-density fatty mass, but we noted only an attenuation of adipose tissue in the greater omentum. Diagnositic laparoscopy is useful for diagnosing this condition.

Highlights • Few cases of splenic hamartomas associated with thrombocytopenia have been reported. • Imaging findings in splenic hamartomas are non-specific, variable, and making definitive preoperative diagnosis difficult. • Surgery is necessary for diagnosis when malignancy cannot be ruled out. • Surgery may also improve symptoms of hypersplenism, including thrombocytopenia., Introduction Hamartomas are rare, benign tumors of the spleen. Few cases of splenic hamartomas associated with thrombocytopenia have been reported. Presentation of case An asymptomatic 64-year-old man with myelodysplastic syndrome was found to have a splenic tumor. Laboratory tests were significant for thrombocytopenia, with a platelet count of 7.8 × 104/μL. Ultrasonography showed splenomegaly (10.8 × 6.6 cm), and a hypoechoic splenic mass (8.0 × 7.0 cm). Color doppler ultrasound revealed blood flow within the mass, and the mass density was homogeneous on abdominal computed tomography (CT). Contrast-enhanced CT showed heterogeneous enhancement of the splenic mass during the arterial phase. Positron emission tomography (PET)-CT showed no significant fludeoxyglucose (FDG) accumulation within the mass. The differential diagnosis included splenic hamartoma, splenic hemangioma, splenomegaly associated with extramedullary hematopoiesis, and malignant tumor, including solitary splenic metastasis. A laparoscopic splenectomy was performed due to the possibility of malignancy, the presence of thrombocytopenia, and the risk of splenic rupture. The resected specimen showed a localized, well-demarcated, 8.0 × 7.0 cm splenic mass. Histological examination revealed abnormal red pulp proliferation and the absence of normal splenic structures. The patient’s post-operative course was uneventful. His platelet count improved on post-operative day 1 and he was discharged on post-operative day 9. He remained in good health with a normal platelet count one month after surgery. Discussion Making definitive preoperative diagnosis is difficult in splenic hamartomas. Surgery is necessary for diagnosis when malignancy cannot be ruled out. Conclusions Surgery may also improve symptoms of hypersplenism, including thrombocytopenia.

Although synbiotics may be effective in maintaining remission of inflammatory bowel disease, their anticarcinogenic effects are still debated. To address this issue, we evaluated the effects of synbiotics, probiotics, and prebiotics on tumorigenesis using a CDX2P-Cre; Apc+/flox mouse model harboring a colon-specific Apc knock out, which develops adenoma and adenocarcinoma of the colon. Dextran sodium sulfate (DSS)-administration promoted colonic tumor development in CDX2P-Cre; Apc+/flox mice, and these tumors were associated with loss of Apc heterozygosity, as confirmed by observation of well-differentiated adenocarcinomas with β-catenin accumulation in tumor cell cytoplasm. Synbiotics-treatment suppressed dextran sodium sulfate-induced colitis in CDX2P-Cre; Apc+/flox mice, thereby reducing mortality, and inhibited tumorigenesis accelerated by DSS-administration. Conversely, neither probiotics nor prebiotics had any effect on inflammation and tumorigenesis. Lactobacillus casei and Bifidobacterium breve were detected in the fecal microbiota of probiotics-treated mice. Synbiotics-treatment suppressed DSS-induced expression of IL-6, STAT-3, COX-2, and TNF-α gene transcripts in normal colonic epithelium, indicating the possibility of suppressing tumor development. Importantly, these genes may be potential therapeutic targets in inflammation-associated colon cancer.

Epithelial ovarian cancer is an aggressive gynecological malignancy with a high mortality rate. Resistance against chemotherapeutic agents often develops in ovarian cancer patients, contributing to high recurrence rates. The multidrug resistance 1 (MDR1/ABCB1) gene encodes P‐glycoprotein, which affects the pharmacokinetic properties of anticancer agents. We previously reported that the Caudal‐related homeobox transcription factor CDX2 transcriptionally regulates MDR1 expression in colorectal cancer. CDX2 is a factor that influences cancer cell differentiation, malignancy, and cancer progression. We hypothesized that profiling of CDX2 and MDR1 expression could be an effective strategy for predicting anticancer drug resistance. We studied the expression of these factors in clinical samples from ovarian cancer patients. We found that endogenous MDR1 expression was positively associated with CDX2 expression in ovarian mucinous adenocarcinoma. Using ovarian mucinous adenocarcinoma cell lines, we also observed decreased MDR1 expression following inhibition of CDX2 by RNA interference. In addition, CDX2 overexpression in MN‐1 cells, which display low endogenous CDX2, resulted in upregulation of MDR1 expression. CDX2 induced MDR1‐dependent resistance to vincristine and paclitaxel, which was reversed by treatment with the MDR1‐specific inhibitor verapamil. Our findings show that CDX2 promotes upregulation of MDR1 expression, leading to drug resistance in ovarian mucinous adenocarcinoma. Therefore, our study demonstrates the potential of novel chemotherapy regimens based on CDX2 status and MDR1 expression in ovarian mucinous adenocarcinoma.

Highlights • Single-incision laparoscopic surgery has been performed for resection of benign and malignant gastrointestinal tumors in recent years; however, its safety and feasibility is still controversial, and there have been no reports of its use in resecting mesenteric cysts. • This report deals with the first case of a mesenteric chylous cyst successfully treated by single-incision laparoscopic surgery., Introduction Chylous mesenteric cysts are rare intra-abdominal lesions located in the mesentery of the gastrointestinal tract and may extend from the base of the mesentery into the retroperitoneum. The treatment is the complete removal of the cyst Presentation of case A 49-year-old female presented with abdominal pain. Abdominal computed tomography showed a 5.0-cm-diameter intraabdominal, homogenous cystic lesion located on the mesentery of the small intestine. Single-incision laparoscopic surgery was performed for complete resection. Discussion Only a handful of cases of laparoscopic surgery for a mesenteric cyst have been reported, and no reports have been published regarding single-incision laparoscopic surgery for a mesenteric cyst. Conclusion We report the first known case of a chylous mesenteric cyst that was successfully treated by single-incision laparoscopic surgery.

Highlights • Non-perforating acute appendicitis with septic DIC is extremely rare. • Nowadays, interval appendectomy has become popular. • However, judging the limit of conservative treatment for acute appendicitis is a critically important matter. • Appendectomy should be performed for non-perforating acute appendicitis with septic DIC., Introduction Perforating appendicitis and abscess-forming appendicitis may cause septic disseminated intravascular coagulation (DIC). However, non-perforating acute appendicitis with septic DIC is extremely rare. Presentation of case A 67-year-old man was referred to our hospital one day after starting oral antibiotic treatment for acute appendicitis. Physical examination revealed only slight spontaneous abdominal pain without tenderness and peritoneal irritation. Contrast-enhanced computed tomography demonstrated an enlarged appendix (10 mm in diameter) without fecalith, ascites, intraperitoneal free air, and abscess. There was no evidence of perforating appendicitis. Laboratory analysis revealed septic DIC. The patient was diagnosed with non-perforating acute appendicitis with septic DIC. The patient was distressed regarding whether he should be treated conservatively with an antibiotics-first strategy or undergo an appendectomy. Ultimately, a laparoscopic appendectomy was performed. Histopathological examination showed non-perforating gangrenous appendicitis. He required DIC therapy for 2 days postoperatively. He was discharged on postoperative day 9, and remained in good health 1 month after surgery. Discussion There is no absolute index of conversion to surgery with an antibiotics-first strategy of appendicitis treatment. Judging the limit of conservative treatment and determining the best moment to perform surgery is a critically important matter for patients with acute appendicitis. Conclusions The incidence of conservative treatment preceding an antibiotics-first strategy for acute appendicitis is increasing. However, it is thought that appendectomy should be performed when acute appendicitis is complicated with septic DIC, even if it is a non-perforating appendicitis in which improvement with conservative treatment is anticipated.

Highlights • Appendiceal neurofibromas (AN) in Neurofibromatosis type (NF) 1 are rare. • AN in NF1 with Low-grade appendiceal mucinous neoplasms (LAMNs) are extremely rare. • AN and LAMNs have potential for malignant transformation. • Surgical resection is the standard treatment for patients with AN and LAMNs. • However, appropriate surgical procedure remains controversial., Introduction Neurofibromas are a characteristic of the autosomal dominant disorder Neurofibromatosis type 1 (NF1), also known as von Recklinghausen’s disease. Appendiceal neurofibromas are extremely rare, and low-grade appendiceal mucinous neoplasms (LAMNs) have not previously been reported in NF1. Presentation of case A 62-year-old man with NF1 was scheduled for elective surgical treatment of an asymptomatic, enlarged and diffusely thickened appendix that remained after curative antimicrobial treatment of acute appendicitis. Laboratory analysis revealed all normal. Colonoscopy showed thickened appendiceal mucosa projecting into the cecum. A sample of the mucosa was found to be pathologically benign. The patient was preoperatively diagnosed with treated acute appendicitis with chronic appendiceal inflammation versus appendiceal neoplasms. Laparoscopic cecectomy was performed. Multiple neurofibromas were observed in the muscle layer, submucosa, and mucosa of the appendix on histopathological examination. Immunohistochemical examination showed positive staining for S-100. Pathologically, the patient was diagnosed with appendiceal neurofibroma consistent with NF1 with LAMNs. His postoperative course was unremarkable. He was discharged on post-operative day 3 and remained in good health 7 month after surgery. Conclusions Appendiceal neurofibromas are often preoperatively diagnosed as appendicitis. Appendiceal neurofibromas should be considered in patients with NF1 who are suspected of having appendicitis.

Few studies have investigated the risk factors in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) who die within 3 months of undergoing surgical intervention and systemic chemotherapy. This study aimed to identify the risk factors associated with the post-treatment 3-month mortality rate. Retrospectively collected data from Hiroshima University were analyzed for patients presenting with synchronous PC from CRC between 1992 and 2012. The clinical, histological and survival data were evaluated and correlated with the overall survival rate at 3 months after surgical intervention. In patients who underwent surgical intervention with systemic chemotherapy for synchronous PC from CRC (N = 65), a Kaplan–Meier analysis and the log-rank test revealed that systemic chemotherapy (P = 0.023) and the modified Glasgow Prognostic Score (mGPS) (P = 0.00001) were associated with the 3-month mortality rate. Multivariate analyses using these two factors revealed that the mGPS (0/1, 2) (odds ratio 8.087; 95 % CI 1.512–43.25; P = 0.015) was an independent risk factor for the 3-month mortality rate. The mGPS is an important independent predictor of the 3-month mortality rate in patients who undergo surgical intervention with systemic chemotherapy for synchronous PC from CRC. The mGPS could aid surgeons in choosing the appropriate treatment strategy and best care for patients.

A sporadic colon cancer mouse model with conditional mutations in adenomatous polyposis coli (Apc) is biologically relevant for human colorectal cancer (CRC). This study aimed to determine the utility and limitations of colonoscopy for evaluating colon tumors in this mouse model. We compared the estimates of location, size, and miss rate of tumors detected during colonoscopy with those determined by necropsy. Sixty-six CPC-Apc mice originating from Apc F/wt mice harbor a Cdx2-Cre transgene in which colorectal tumorigenesis was driven by Apc allelic loss. The sensitivity and specificity of colonoscopy for detecting tumors in a mouse CRC model were investigated. A strong positive correlation was found between tumor location as measured by colonoscopy and the location determined by necropsy (p

Purpose Surgical site infection (SSI) is a frequent complication of elective surgery for colorectal cancer. The classical clinical markers of infection—elevations in white blood cell count, C-reactive protein (CRP) level, and body temperature—do not precisely predict SSI after elective colorectal resection. The objective of this study was to evaluate the efficacy of procalcitonin (PCT) as a tool for diagnosis of SSI in elective surgery for colorectal cancer.

Mutations in TGFBR2, a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models, Tgfbr2 inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by TGFBR2 inactivation following disruption of the Wnt-β-catenin pathway. We previously described CDX2P-G19Cre;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice, with simultaneous loss of Apc and Tgfbr2. These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis. Our results showed that the expression of the murine homolog of GSDMC was significantly upregulated by 9.25-fold in tumors of CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice compared with those of CDX2P-G19Cre;Apcflox/flox mice. We then investigated the role of GSDMC in regulating CRC tumorigenesis. The silencing of GSDMC led to a significant reduction in the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GSDMC enhanced cell proliferation. These results suggested that GSDMC functioned as an oncogene, promoting cell proliferation in colorectal carcinogenesis. In conclusion, combined inactivation of both Apc and Tgfbr2 in the colon epithelium of a CRC mouse model promoted development of adenocarcinoma in the proximal colon. Moreover, GSDMC was upregulated by TGFBR2 mutation in CRC and promoted tumor cell proliferation in CRC carcinogenesis, suggesting that GSDMC may be a promising therapeutic target.

In the present study, we observed that the adenocarcinoma component in the mucosa was continuous with neuroendocrine carcinoma (NEC) in the deeper layers; this suggests the normal course of NEC carcinogenesis at the histological level. A 72-year-old man was admitted to our hospital with a chief complaint of tarry stools. Endoscopic examination of the upper gastrointestinal tract revealed a 2-cm tumor, with a deep central depression, surrounded by a smooth elevated area, in the middle of the stomach body. A biopsy showed that the tumor was a moderately differentiated gastric adenocarcinoma. The patient underwent total gastrectomy and standard lymph node dissection. The resected tumor was a 3.5 × 2.5 cm type 2 lesion. It comprised two elements at the histological level: (i) a moderately differentiated adenocarcinoma in the superficial portion of the mucous membrane layer, and (ii) NEC-like cells with dark, round nuclei and scant cytoplasm, presenting a solid and trabecular pattern, in the submucosal and muscularis propria layers. Immunohistochemical findings showed that the NEC-like cells were diffusely positive for chromogranin A, synaptophysin, neural cell adhesion molecule, and neuron-specific enolase, but were negative for carcinoembryonic antigen. The Ki-67 labeling index was 95%. The final pathological diagnosis was gastric NEC with an adenocarcinoma component and a high cellular proliferative potential.

症例は57歳の女性で，約3年前より脾嚢胞性病変を指摘されていた．2度の上腹部疝痛発作を主訴に来院した．発作時腹膜刺激症状および血清CA19-9の異常高値，CTでは脾嚢胞を認めたが嚢胞壁の形態変化なく腹水はなかった．保存的加療にて一時軽快したが，症状が再燃したため腹腔鏡下脾臓摘出術を行った．組織学的には脾類上皮嚢胞と診断され，嚢胞壁の一部に出血，壊死巣を認めた．嚢胞内のCA19-9は高値で，免疫組織学的には類上皮に一致してCA19-9がびまん性に陽性であった．術後経過は良好で，術後1か月で血清CA19-9値は正常化した．嚢胞壁一部の出血，壊死により腹部疝痛発作，血清CA19-9値の上昇を来したと考えられた．血清CA19-9が高値を示した脾嚢胞の本邦報告例は28例で，これらに自験例を加えて検討した．

近年，肝細胞癌症例の高齢化に伴い，高齢者手術症例は増加傾向にある．それに伴い，術前から様々な併存症を有する症例も増加傾向にある．これら併存症を有する症例をより安全に手術することを目的に当科での肝細胞癌初回手術症例を対象に全身状態，肝局所因子の両面から術後合併症発生の予測を行った． 2002年7月から2008年12月に当科にて経験した肝細胞癌初回手術例131例のうち，何らかの処置を必要とする術後合併症を認めた51例を合併症群，合併症の無い80例を非合併症群として検討を行った． 背景肝機能の単変量解析では合併症群でコリンエステラーゼ，アルブミン，ヘパプラスチンが有意に低く，総ビリルビン，AST，ZTT，ICG-R15値が有意に高かった．多変量解析ではアルブミンが有意な因子であった．腫瘍因子では両群間に差を認めなかった．治療因子では術中出血量に有意差を認め500 g以上が合併症発生の危険因子であった．幕内基準を基に手術適応を決定していること，アルブミンが有意な因子であったことからこれらを含む肝障害度を背景肝機能因子とし，出血量を含むH-POSSUMを全身状態評価・手術因子評価とし多変量解析した結果，肝障害度BまたはC，H-POSSUM合併症発生予測50%以上はともに合併症発生の危険因子であった． これらを用い症例を4群に分類すると，予測術後合併症発生率50%未満かつ肝障害度BまたはCの症例での合併症発生率は60.0%，予測術後合併症発生率50%以上かつ肝障害度Aの症例での合併症発生率は50.0%，予測術後合併症発生率50%以上かつ肝障害度BまたはCの症例での合併症発生率は80.0%であり，予測術後合併症発生率50%未満かつ肝障害度Aの症例での合併症発生率21.6%と比較して有意に合併症発生は高率であった． 標準的な検査で算定できる肝障害度とH-POSSUMの組み合わせにより，肝切除の術前状態を正確に把握し，術後合併症を予測することが可能で，肝疾患以外の合併症を有する症例でも，術前肝障害度AでH-POSSUM 50%未満の症例では安全に肝切除手術を施行することが可能である．

今回われわれは梅の種子が原因でイレウスをきたした1例を経験したので報告する．症例は82歳，女性．8年前に子宮癌で放射線療法施行歴があった．嘔吐，腹痛を主訴に当院を受診した．イレウスと診断しイレウス管減圧による保存的加療を2週間施行したが，軽快しなかったため手術を施行した．回腸全体に放射性腸炎を認め，回腸末端の狭窄部位に梅の種子が嵌頓し穿孔しており同部位を切除した．植物種子によるイレウスの本邦報告例は自験例を含めて15例のみで非常に稀である．原因となった異物としては梅の種子が11例と圧倒的に多かった．また，13例は原因となる器質的疾患が存在していた．大腸の場合は大腸癌，小腸の場合は放射性腸炎が多かった．何らかの腸管狭窄を伴う場合は，異物が梅の種のように比較的小さくてもイレウスの原因となりうることを十分考慮する必要がある．また全例術前に異物誤嚥を確認できておらず繰り返しの問診が重要であると考えられた．

74歳，女性．当院整形外科入院中に粘血便を主訴に当科紹介受診となった．直腸診にて肛門縁より約6cmの部位に弾性硬の腫瘤を触知した．腹部CTで直腸にmulti concentric ring signを呈する腫瘤を指摘され，直腸腫瘍による腸重積が疑われた．注腸造影では腫瘍は蟹の爪様の陰影欠損として描出され，先進部はRa，Rbの境界部にありRsより重積している直腸粘膜が描出された．整復を試みたが不可能であった．以上より，腸重積症を合併した直腸癌と診断し手術を施行した．術中所見ではRsからRbにかけて腸重積が確認された．用手的整復を試みたが，重積腸管が損傷する危険性があったため整復を断念しハルトマン手術を行った．組織学的診断は高分化腺癌，SE，N1 StageIIIaであった．成人の直腸S状部癌を先進部とする成人腸重積症は非常に稀である．成人の腸重積症例は，症状・所見に乏しい慢性の経過を取ることが多く，診断時には整復困難な状態に陥っておることが予想される．そのため，無理な保存的整復には固執せずに手術を施行するべきであると考えられた．

KRAS mutations occur in 30–40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apcflox/flox; LSL-KrasG12D and CDX2P-G22Cre;Apcflox/flox mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription–PCR (qRT–PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT–PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin–nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin–NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.

Purpose: Oncogenic KRAS mutations are found in 40-50% of human colorectal cancers. However, specific therapeutics has not been yet available. We aimed to search new therapeutic molecular targets or biomarkers in KRAS mutated colorectal cancers. Experimental design: We generated Apcflox/flox; CDX2P9.5-G22Cre and LSL-KrasG12D; Apcflox/flox; CDX2P9.5-G22Cre mice, that had been considered as sporadic colon cancer mouse model with Kras wild and mutant, respectively. We observed the carcinogenesis at the age of 3-4 weeks by necropsy, and harvested the tumors for gene expression profiling. We compared the gene expression by Microarray (GeneChip, Affymetrix) between each 3 tumors from these mice strains. Genes with >5 fold changes between the two groups were selected as candidate genes, and subsequently narrow these down by bibliographic search for further analyses in human colorectal cancers. Result: In macroscopic findings, extensive polyps were generated in cecum and proximal colon, but not in other site of gastrointestinal tract. Tumors occurred in the both strains were considered as well differentiated adenocarcinomas in hematoxylin-eosin staining. It was confirmed that tumors generated in Apcflox/flox; CDX2P9.5-G22Cre mice had Cre-targeted Apc 580D alleles and wild-type Kras, and that tumors generated in LSL-KrasG12D; Apcflox/flox; CDX2P9.5-G22Cre mice had both Cre-targeted Apc 580D alleles and activated oncogenic KrasG12D. In the subsequent gene expression profiling, we identified 31 genes with >5 fold change in Microarray analyses. Of these, we focused on some genes that showed lower expression in Kras mutant tumor than in Kras wild type tumor. We confirmed the lower expressions of these genes in murine tumors by quantitative RT-PCR, and the lower expression in early-staged human colorectal cancers with oncogenic KRAS mutant by immunohistochemistry staining. To analyze the functions, the retroviral vectors that lead overexpression of these genes were constructed and infected to SW480 and RKO CRC cell lines. Proliferation and migration is being analyzed using these cell lines. Conclusion: We identified novel genes associated with oncogenic KRAS mutation, using the analyses of gene expression in colon cancer mouse model. Citation Format: Hiroaki Niitsu, Takao Hinoi, Yasuo Kawaguchi, Kazuhiro Sentani, Naohide Oue, Yusuke Sotomaru, Tomohiro Adachi, Yasufumi Saito, Masashi Miguchi, Masatoshi Kochi, Manabu Shimomura, Wataru Yasui, Hideki Ohdan. Gene expression profiling for oncogenic Kras mutation in mice and human colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 823. doi:10.1158/1538-7445.AM2015-823

Background & Aims: The transforming growth factor-beta (TGF-beta) signal is a tumor-suppressor pathway that is commonly inactivated in about 90% of microsatellite instability (MSI) colorectal cancer (CRC). However, there was little evidence what gene is regulated by TGF-beta signal in the multistep progression sequence of CRC. The first aim of the present study was to generate a mouse model that is null for Tgfbr2 and Apc in the colon epithelium and forms tumors in the colon. The second aim was to analyze the tumors that arose in the mice model for the purpose to identify the gene regulated by TGF-beta signal. Method & Result: Previously we have described the generation of the ‘CDX2P-G19Cre;Apcflox/flox mice’ (called Apc KO mice) which is randomly null for Apc in the colonic epithelium. By mating Tgfbr2flox/flox mice with Apcflox/flox and CDX2P9.5-G19Cre mice, we have finally generated a mouse model ‘CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice’ (called Apc+Tgfbr2 KO mice) which is null for Apc and Tgfbr2. In these model, the tumors with well differentiated adenocarcinoma arose mainly in proximal colon and most of mice died at 4 weeks age due to tumor bleeding. Therefore the mice were harvested at 3 weeks age to evaluate the development of colon tumors. Total RNAs of only cancerous tissue areas were extracted from frozen samples by the laser capture microdissection method. We compared gene expression profiles of these mice's tumors (n = 3, respectively) with Mouse Exon 1.0 ST Array (Affymetrix). Gene X expression of Apc+Tgfbr2 KO mice tumors was most highly upregurated by 9.25-fold compared with Apc KO mice (p = 0.045). The array data was validated by quantitative PCR. For human CRC samples, mutations of repetitive mononucleotide tracts in the coding regions of TGFBR2 were identified by direct sequencing. By immunohistochemical analysis, the expression of X was classified according to the percentage of stained cancer cells. The expression was considered to be ‘positive’ if ≥30% of cancer cells were stained. An analysis demonstrated that 11 (100%) of 11 mutated TGFBR2 cases were positive for X, whereas 10 (66.7%) of 15 wild type TGFBR2 cases were positive (P = 0.033), indicating that high expression of X was correlated with TGFBR2 mutation in human CRCs samples. Additionally, the cell proliferation assay revealed that silencing of X led to a significant reduction in CRC cell proliferation. Conversely, forced expression of X enhanced CRC cell proliferation in vitro. Conclusion: We have generated an in vivo model system that Apc and Tgfbr2 were inactivated only in the colonic epithelium and tumors with well differentiated adenocarcinoma arose mainly in proximal colon. The analysis of this model revealed that Gene X is regulated by a TGF-beta signal and likely promotes cell proliferation in CRC. Citation Format: Masashi Miguchi, Takao Hinoi, Manabu Shimomura, Tomohiro Adachi, Yasufumi Saito, Hiroaki Niitsu, Masatoshi Kochi, Yusuke Sotomaru, Hideaki Ijichi, Tsuneo Ikenoue, Kunitoshi Shigeyasu, Kohji Tanakaya, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Hideki Ohdan. The generation of colorectal cancer mouse model based on microsatellite instability and the identification of transforming growth factor-beta signal target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2301. doi:10.1158/1538-7445.AM2015-2301

Introduction: Previous study showed that Synbiotics might have beneficial effect in human and animal colitis like ulcerative colitis. However, it is not well known that the influence of Synbiotics for tumorigenesis in colon cancer. The aim of present study was to investigate the influence of Synbiotics in colon cancer mouse model and colitis associated cancer mouse model. Methods: Mouse stains carrying colon epithelium-preferential Apc mutation (CPC;Apc mice), that show sporadic colorectal adenomas and carcinomas are used in this study. We also used CPC;Apc mice consumed 1%Dextran Sulfate Sodium (DSS) as colitis associated colon cancer model, developing apploximately fourfold more adenomas and adenocarcinomas than CPC;Apc not consumed. At first, 9 of CPC;Apc mice were administerated symbiotics (Probiotics (Lactobacillus) 0.1g + Prebiotics (Oligosaccharide) 10mg/0.3ml/body) between 7 and 20 age in weeks and 10 was not administerated. Secondaly, using 9 of CPC;Apc consumed 1%DSS was administrated Symbiotics, 8 of not administrated, 7 of only Probiotics, and 7 of only Prebiotics. Body weight was measured weekly. Fecal microbial analysis was performed. At sacrifice in 21 age in weeks, the small and large bowel were histologically assessed. Results: Synbiotics administration group has no differences of tumorigenesis comparing to control group (tumor incidence rate(88.9%(8/9) vs. 62.5% (5 / 8); control vs. Synbiotics; p = 0.21)average tumor number(3.2 vs. 2.1; p = 0.38), average tumor greatest diameter 5.8 vs. 5.1 mm; p = 0.51). Using CPC;Apc consumed 1%DSS, Symbiotics administration group showed inhibiting morbidity (50% (8 / 16) vs. 80% (8 / 10); control vs. Synbiotics; p = 0.04) and weight loss, and less tumor incidence than control (18.8 vs. 9.6; control vs. Synbiotics; p = 0.01). On the other hands, administration of probiotics or prebiotics alone had no significant differences of tumorigeneis. Conclusion: This data suggest that Synbiotics administration may have influence of inhibiting tumorigenesis in the colitis associated colon cancer. Citation Format: Yasufumi Saito, Takao Hinoi, Tomohiro Adachi, Manabu Shimomura, Masashi Miguchi, Hiroaki Niitsu, Masatoshi Kochi, Hideki Ohdan, Kazuhiro Sentani, Naohide Oue, Wataru Yasui. Impact of synbiotics administration on tumorigenesis of colon cancer mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2303. doi:10.1158/1538-7445.AM2015-2303

Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) have shown potential as chemopreventive agents against cancer formation, especially colorectal cancers. However, the mechanisms by which these drugs act are not fully understood. In this study, CPC;Apc mice, a human colorectal cancer mouse model treated with sulindac, were evaluated according to tumor initiation and prognosis and gene expression profile of the tumors were analyzed. Methods CPC;Apc mice, originating from ApcFlox/wt mice harbor a Cdx2-Cre transgene in which colorectal tumorigenesis was driven by Apc allelic loss and represent a genetic model of human colorectal cancer (CRC) were treated with control (n=20) or sulindac (160ppm, n=22) for 12 weeks and their colorectal tumors were evaluated. Gene expression analysis was performed to identify genes differentially expressed in tumor cells from sulindac-treated mice. The gene expression was validated through quantitative real-time polymerase chain reaction in vivo. Results Body weight of mice with control or sulindac was no significantly difference ( P = 0.801). However, we observed that sulindac significantly suppressed the tumor progression relative to untreated controls (the colon tumors size per mouse: median of 4.2mm, range 2.3-5.9 versus 5.0mm, range 3.1-8.7, respectively ; P = 0.007 ), but not the initiation (the colon tumor numbers per mouse: median of 1.5, range 0-5 versus 1.0 tumors, range 0-8 respectively ; P = 0.979) in CPC;Apc mice. We identified some upregulated (n = 6, >1.4 fold ) and downregulated (n = 5, >1.4 fold) target genes by microarray assay. We validated expression of these candidate genes in human colorectal cancer. Conclusion We have identified for the first time that sulindac affected tumor progression by delayed and suppressing it, but had no effect on the initiation of tumor in CRC mice model. Citation Format: Tomohiro Adachi, Takao Hinoi, Yuu Sasaki, Manabu Shimomura, Yasufumi Saito, Masashi Miguchi, Hiroaki Niitsu, Yuusuke Sotomaru, Naohide Oue, Wataru Yasui, Hideki Ohdan. Sulindac delayed and suppressed the tumor progression, was not effective on inhibition of tumor initiation in a human colorectal cancer mouse model (CPC;Apc mouse). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 250. doi:10.1158/1538-7445.AM2014-250

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue tumors that arise from a peripheral nerve or exhibit nerve sheath differentiation. Most of these tumors arise on the trunk, extremities, or head and neck regions; they are very rarely located in the abdominal cavity. The patient was a 71-year-old man who was referred to our hospital for a mass and pain in the right lower abdomen. Abdominal computed tomography revealed a large (9 × 9 cm), well-circumscribed, lobulated, heterogeneously enhanced mass in the pelvis. Exploratory laparotomy revealed a large mass in the greater omentum, and the tumor was completely excised. Histopathological analysis revealed that the tumor was composed of spindle cells with high mitotic activity. On staining the tumor, positive results were obtained for S-100 but negative results were obtained for c-kit, cluster of differentiation (CD)34, α-smooth muscle actin, and desmin. These findings strongly supported a diagnosis of MPNST primarily arising from the greater omentum. To the best of our knowledge, this is the first reported case of an MPNST arising from the greater omentum. In this report, we have described the case of a patient with an MPNST arising from the greater omentum and have discussed the clinical characteristics and management of MPNSTs.

The standard operation for colitic cancer in ulcerative colitis (UC) is restorative proctocolectomy; however, sporadic colorectal cancer (CRC) can coincidentally arise in patients with UC and the optimal procedure remains controversial. Therefore, it is crucial to preoperatively determine whether the CRC in UC is a sporadic or colitic cancer. We report a case of avoiding proctocolectomy for sporadic CRC in a patient with UC based on preoperative diagnosis involving p53 immunostaining. A 73-year-old man with CRC in UC had undergone sigmoid colectomy with lymphadenectomy because of the submucosal deep invasion pathologically after endoscopic mucosal resection. The cancer was diagnosed sporadic cancer preoperatively not only based on the endoscopic, clinical, and histological patterns but also that the colon epithelium was unlikely to develop dysplasia as the circumference and unaffected UC mucosa did not detect p53 protein overexpression. Recent reports have shown that the immunohistochemical detection of p53 protein overexpression can be useful for a differential diagnosis and as a predictor of dysplasia and colitic cancer. The analysis of p53 mutation status based on immunostaining of p53 protein expression in the unaffected UC mucosa can be useful for the decision regarding a surgical procedure for CRC in patients with UC.

Lynch syndrome (LS) is a disorder caused by mismatch repair gene mutations, which have been recognized to be associated with an increased frequency of colorectal and extracolorectal tumors. However, it remains controversial as to whether total or segmental colectomy should be performed to treat colorectal cancer in patients with LS. A 58-year-old male underwent total colectomy with ileostomy for advanced transverse colon cancer. He was also found to have LS based on his characteristic family history and the findings of a preoperative examination, including a microsatellite instability analysis of past multiple metachronous cancers. The postoperative histological findings showed mucinous adenocarcinoma without lymph node metastasis, and the loss of the MSH2 protein expression was confirmed on an immunohistochemical examination. The present case provided important information on the clinical management of multiple developing metachronous colorectal cancers in patients with LS.

Background In stage IV colorectal cancer (CRC) with unresectable metastases, whether or not resection of the primary tumor should be indicated remains controversial. We aim to determine the impact of primary tumor resection on the survival of stage IV CRC patients with unresectable metastases. Methods We retrospectively investigated 103 CRC patients with stage IV colorectal cancer with metastases, treated at Hiroshima University Hospital between 2007 and 2013. Of these, those who had resectable primary tumor but unresectable metastases and received any chemotherapy were included in the study. We analyzed the overall survival (OS) and short-term outcomes between the patients who received up-front systemic chemotherapy (USC group) and those who received primary tumor resection followed by chemotherapy (PTR group). Results Of the 57 included patients, 15 underwent USC and 42 PTR. The median survival times were 13.4 and 23.9 months in the USC and PTR groups, respectively (P = 0.093), but multivariate analysis for the overall survival showed no significant difference between the two groups (hazard ratio, 1.30; 95% confidence interval (CI), 0.60 to 2.73, P = 0.495). In the USC group, the disease control rate of primary tumor was observed in 12 patients (80.0%), but emergency laparotomy was required for 1 patient. Morbidity in the PTR group was observed in 18 cases (42.9%). Conclusions The overall survival did not differ significantly between the USC and PTR groups. USC may help avoid unnecessary resection and consequently the high morbidity rate associated with primary tumor resection for stage IV CRC with unresectable metastases.