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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.

We herein report the first case of rectal stenosis that developed after internal hemorrhoid treatment with aluminum potassium sulfate and tannic acid (ALTA) therapy that was successfully treated by laparoscopic surgery. A 72-year-old man suffered from a fever and rectal stenosis after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA at a previous clinic. Three months after ALTA therapy, he developed frequent mucous and bloody stools. Lower intestinal tract endoscopy revealed circumferential severe rectal stenosis. He was therefore referred to our hospital. The patient suffered from frequent stool build-up and difficulty defecating. We performed balloon-dilatation intervention. The stenosis was not improved at all. Five months after ALTA therapy, we performed laparoscopic low anterior resection with diverting ileostomy. Three months after the operation, ileostomy takedown was performed. The patient has experienced no rectal stenosis in the 2 years since his radical operation.

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/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.

Introduction The number of elderly patients with colorectal cancer has gradually increased. Laparoscopic colorectal surgery is widely used to approach colorectal cancer. The aim of this study was to evaluate long-term outcomes in octogenarians who underwent laparoscopic colorectal surgery for colorectal cancer. Methods This study included 158 patients aged 80 or over who underwent surgery for colorectal cancer between 2010 and 2015. We compared long-term outcomes of a laparoscopic colorectal surgery group with those of an open colorectal surgery group by propensity score matching equalizing factors that could affect prognosis such as prognostic nutritional index and Charlson comorbidity index score. Results Forty-eight pairs were selected after propensity score matching. The cancer-specific 5-year survival rate was 97.1% in the laparoscopic colorectal surgery group and 87.6% in the open colorectal surgery group (P = .17). The overall 5-year survival rate was 77.3% in the laparoscopic colorectal surgery group and 73.9% in the open colorectal surgery group (P = .32). The 5-year recurrence-free survival rate was 95.1% in the laparoscopic colorectal surgery group and 85.4% in the open colorectal surgery group (P = .14). Conclusion Laparoscopic colorectal surgery for octogenarians with colorectal cancer achieves similar oncological outcomes to open colorectal surgery and should be considered as a treatment option.

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.

Schwannomas are tumors originating from the Schwann cells of the peripheral nerve sheath. Only 1%-3% of schwannomas reportedly occur in the pelvis. In a 67-year-old man, a pelvic mass that was 52 mm in diameter was incidentally diagnosed during a preoperative CT evaluation for prostate cancer. Preoperative 3-D reconstruction CT showed that the feeding artery to the tumor originated from the internal iliac artery and the drainage vein from the internal iliac vein. Each vessel could be isolated, clipped, and cut with minimal bleeding. The tumor was easily dissected from adjacent structures and was completely resected via laparoscopic surgery. Histopathology and immunohistochemistry of the excised specimen revealed a benign schwannoma. Using 3-D reconstruction to recognize a tumor's positional relation with the supplying vessels is important for avoiding complications during laparoscopic resection in the narrow pelvis. Laparoscopic resection is safe, feasible, and effective for retroperitoneal schwannoma.

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.

Aim To reveal systemic chemotherapy outcomes and the suitable first-line regimens for elderly (≥75 years) metastatic colorectal cancer (mCRC) patients. Methods We retrospectively compared systemic chemotherapy outcomes between elderly (≥75 years) and adult (≤74 years) patients with mCRC who were treated between January 2007 and December 2012 at Hiroshima University Hospital and analyzed the outcomes of elderly patients after treatment with single-agent oral 5-fluorouracil chemotherapy (oral FC) or intravenous combination chemotherapy (IV CC) as the first-line regimen. Results A total of 140 patients with mCRC were enrolled. The median age of adult patients was 60 years, compared to 77 years for elderly patients. There were no significant differences between the two groups in terms of patient characteristics and the stage of cancer progression. Overall survival (OS) (median, 20.7 vs 26.5 months; P = 0.65) and first-line progression-free survival (PFS) (median, 11.0 vs 9.8 months; P = 0.36) did not differ significantly between elderly patients and adult patients. Among elderly patients, first-line PFS (median, 10.3 months vs. 11.8 months; P = 0.85) and the incidence of grade 3 adverse events (22.2% vs. 44.4%; P = 0.31) were similar in the oral FC and IV CC groups. Conclusion The results of this study suggest that elderly patients with mCRC who can receive chemotherapy derive an equivalent survival benefit to adult patients. First-line oral FC may be better suited for elderly patients with mCRC.

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.

134 Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin 200mg/m2, fluorouracil 3200 mg/m2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.

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.

We conducted this study to establish whether drinking alcohol alters the risk of early-onset colorectal cancer (CRC) in Japanese patients with Lynch syndrome (LS). The subjects were 66 LS patients with pathogenic mutation of mismatch repair genes (MLH1, MSH2, and MSH6) from the nationwide Japanese retrospective multicenter study. Cox proportional hazards modeling was used to investigate the factors correlating with early-onset CRC diagnosis, using clinical data such as gender, tobacco use, alcohol consumption, body mass index, gene mutation (MLH1, MSH2 vs MSH6), and family cancer history. Alcohol was significantly correlated with an increased risk of early-onset CRC [HR 2.44, 95% CI 1.13-5.16 (p = 0.02)], but tobacco use was not [HR 0.8, 95%CI 0.38-1.62 (p = 0.53)]. These findings suggest that alcohol consumption is correlated with an earlier onset of CRC in Japanese patients with LS.

KRAS gene mutations are found in 40–50 % of colorectal cancer cases, but their functional contribution is not fully understood. To address this issue, we generated genetically engineered mice with colon tumors expressing an oncogenic Kras G12D allele in the context of the Adenomatous polyposis coli (Apc) deficiency to compare them to tumors harboring Apc deficiency alone. CDX2P9.5-G22Cre (referred to as G22Cre) mice showing inducible Cre recombinase transgene expression in the proximal colon controlled under the CDX2 gene promoter were intercrossed with Apc flox/flox mice and LSL-Kras G12D mice carrying loxP-flanked Apc and Lox–Stop–Lox oncogenic Kras G12D alleles, respectively, to generate G22Cre;Apc flox/flox ;Kras G12D and G22Cre;Apc flox/flox ;KrasWT mice. Gene expression profiles of the tumors were analyzed using high-density oligonucleotide arrays. Morphologically, minimal difference in proximal colon tumor was observed between the two mouse models. Consistent with previous findings in vitro, Glut1 transcript and protein expression was up-regulated in the tumors of G22Cre;Apc flox/flox ;Kras G12D mice. Immunohistochemical staining analysis revealed that GLUT1 protein expression correlated with KRAS mutations in human colorectal cancer. Microarray analysis identified 11 candidate genes upregulated more than fivefold and quantitative PCR analysis confirmed that Aqp8, Ttr, Qpct, and Slc26a3 genes were upregulated 3.7- to 30.2-fold in tumors with mutant Kras. These results demonstrated the validity of the G22Cre;Apc flox/flox ;Kras G12D mice as a new mouse model with oncogenic Kras activation. We believe that this model can facilitate efforts to define novel factors that contribute to the pathogenesis of human colorectal cancer with KRAS mutations.

The number of elderly patients with colorectal cancer (CRC) treated with surgery has gradually increased. The aim of this study was to evaluate the short-term outcomes in patients ≥80 years of age who underwent laparoscopic or open surgery for CRC using a propensity score-matched analysis to make uniform the patient background characteristics affecting the postoperative morbidity and mortality. We compared the short-term outcomes of open vs. laparoscopic surgery in patients with CRC ≥80 years of age between 2010 and 2015. Fifty-two patients undergoing laparoscopic colectomy for CRC were matched to 52 patients undergoing open colectomy with respect to gender, age, body mass index, performance status, prognostic nutritional index, Charlson Comorbidity Index score, tumor-node-metastasis stage, and tumor location. The operative time, blood loss, length of hospital stay, and postoperative complications were investigated. Blood loss was less during laparoscopic surgery than during open surgery (40 vs. 140 ml, p

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.

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.