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Supplementary Figure 1, Figure 2, Figure 3. Representative photomicrographs detailing immunohistochemical analysis of ANGPTL2 expression, Figure S2: ANGPTL2 expression in 5 colorectal cancer cell lines, Figure S3: Receiver operating characteristics curve analysis using serum ANGPTL2 for distinguishing patients with CRC with normal CEA levels from normal controls (NC).

Purpose: Angiopoietin-like protein 2 (ANGPTL2) is a mediator of chronic inflammation and inflammatory carcinogenesis. The biologic and clinical significance of ANGPTL2 remains unknown in human cancer. Therefore, we investigated the function of ANGPTL2 and evaluated its clinical significance in both primary tumors and matched sera in patients with colorectal cancer.Experimental Design: A colorectal cancer cell line was transfected with siRNA against ANGPTL2 for the assessment of its function. We examined ANGPTL2 expression in colorectal cancer tissues (n = 195) by immunohistochemistry. Finally, we screened serum ANGPTL2 levels from 32 colorectal cancers and 23 normal controls (NC), and validated these results in serum samples obtained from 195 colorectal cancers and 45 NCs by ELISA.Results: Knockdown of ANGPTL2 in vitro significantly inhibited cell proliferation, migration, and invasion, whereas it enhanced anoikis. ANGPTL2 was overexpressed in colorectal cancer tissues, and was significantly associated with advanced T stage, lymph node, and liver metastasis. Likewise, serum ANGPTL2 levels in colorectal cancers were significantly higher than NCs (P < 0.01), and allowed distinguishing of colorectal cancers from NCs with high accuracy (AUC = 0.837). The subsequent validation step confirmed that serum ANGPTL2 levels in colorectal cancers were significantly higher than in NCs (P < 0.0001), and had a high AUC value (0.885) for distinguishing colorectal cancers from NCs. High serum ANGPTL2 was significantly associated with advanced T stage, lymph node and liver metastasis, early relapse, and poor prognosis in colorectal cancers.Conclusion: Serum ANGPTL2 is a novel diagnostic and recurrence-predictive biomarker in patients with colorectal cancer. Clin Cancer Res; 20(23); 6175–86. ©2014 AACR.

Supplementary Tables S1-3. Table S1:Patient characteristics in the validation set, Table S2:Primer Sequences for KRAS and BRAF mutation analysis, Table S3:Comparison between ROC from screening step and validation step.

Supplementary material and methods. Detailed patient characteristics in the validation step, Cell culture condition, 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, yellow tetrazole (MTT) assay, Anoikis assay, Invasion assay, Wound healing assay,Immunohistochemistry, Enzyme-Linked Immunosorbent Assay (ELISA).

Sarcopenia consists of two dysregulation patterns of body composition, myopenia and myosteatosis. The aim of this study is to compare the preoperative status of various body composition indexes including our newly developed modified intramuscular adipose tissue content (mIMAC) to investigate these clinical values in esophageal cancer patients.We assessed preoperative psoas muscle mass index (PMI), IMAC, and mIMAC in 150 esophageal cancer patients.Preoperative high IMAC and low mIMAC status were significantly associated with older age. Preoperative decreased mIMAC was significantly associated with advanced T classification and the presence of distant metastasis and low preoperative mIMAC was an independent prognostic factor for poor overall survival and disease-free survival in esophageal cancer patients. Combined assessment of preoperative mIMAC with PMI could help stratify risk for oncological outcomes. Finally, preoperative PMI and mIMAC were positively correlated with various nutritional factors in esophageal cancer patients.Combined assessment between preoperative PMI and mIMAC could stratify risk for oncological outcomes, and preoperative mIMAC might be surrogate marker for aging and nutritional status in esophageal cancer patients.

Objectives Systemic inflammatory response is strongly associated with poor oncological outcome in colorectal cancer (CRC). Perioperative inflammation caused by surgical stress can lead to the development of postoperative infectious complications (PIC) as well as cancer-related inflammation. We aimed to evaluate the prognostic potential of perioperative systemic inflammation by calculating the time-dependent cumulative C-reactive protein (CRP) levels during the perioperative period. Methods We analyzed clinicopathological data from 540 patients with CRC who underwent potentially curative surgery at our institution. The time-dependent aggregated CRP level was denoted "cumulative CRP," which represents the area under the line of time (days) and the CRP levels preoperatively and on postoperative days 1, 3, and 7. Results Cumulative CRP was significantly higher in patients with CRC undergoing open surgery than in patients undergoing laparoscopic surgery. In multivariate analysis, high cumulative CRP was an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both the laparoscopic and open surgery groups. Patients with CRC and high cumulative CRP had significantly poorer DFS and OS than those with low cumulative CRP, including those patients without PIC. Conclusions Cumulative CRP is an independent predictive marker of OS and DFS in patients with CRC who undergo curative surgery.

There are still no useful predictive biomarkers for esophago-gastric junction (EGJ) cancer. We compared 15 candidate inflammation-based markers and investigated the clinical impact of the selected biomarker.One hundred three patients with EGJ cancer between 2002 and 2020 were enrolled, and associations between clinicopathological data and inflammatory biomarkers were retrospectively analyzed. Area under the curve (AUC) values of 15 candidate biomarkers were compared in receiver operating characteristic (ROC) curves regarding overall survival (OS). Clinical impacts of the selected marker were further investigated regarding long-term prognosis, postoperative complications, and preoperative chemotherapy effects.Lymphocyte/CRP ratio (LCR) demonstrated the highest AUC (0.68552) and was chosen as a candidate biomarker. The high LCR group (LCR4610) demonstrated significantly better OS (p 0.0001) and relapse-free survival (RFS) (p 0.0001) compared with the low LCR group (LCR ≤4610), and preoperative LCR was an independent prognostic factor for both OS (HR 4.97, 95% CI:2.24-11.58; p 0.0001) and RFS (HR 2.84, 95% CI:1.33-6.14, p = 0.007) in EGJ cancer patients. Another cut-off value was established for postoperative complications, and the incidence rates were significantly higher in the low LCR group (LCR ≤12000) than in the high LCR group (LCR12000) for all postoperative complications, infectious complications, and surgical site infection (p = 0.013, p = 0.016, and p = 0.030, respectively). Furthermore, patients with decreased LCR after preoperative chemotherapy demonstrated significantly worse RFS compared with patients with increased LCR (p = 0.043).LCR is a potential biomarker to predict long-term prognosis as well as occurrence of postoperative complications in patients with EGJ cancer.

Targeting protein for

Tumor-infiltrating immune cells play an essential role in cancer progression and may help supplement the Tumor, Node, Metastasis (TNM) classification for cancer prognosis. Currently, there are numerous conflicting reports discussing the significance of tumor-associated neutrophils (TANs) in colorectal cancer (CRC). In particular, the role of TANs in the invasive margin is unclear. The present study investigated the prognostic significance of CD66

Systemic inflammatory response influences cancer development and perioperative surgical stress can affect the survival of patients with colorectal cancer (CRC). We developed a system to cumulatively assess perioperative inflammatory response and compare the prognostic value of various cumulative inflammatory and nutritional markers in patients with CRC. We assessed perioperative cumulative markers using the trapezoidal area method in 307 patients who underwent surgery for CRC and analyzed the results statistically. The cumulative lymphocyte to C-reactive protein (CRP) ratio (LCR) predicted survival more accurately than other well-established markers (sensitivity: 80.0%, specificity: 69.3%; area under the curve (AUC): 0.779; P

Sarcopenia was initially described as a decrease in muscle mass associated with aging and subsequently also as a consequence of underlying disease, including advanced malignancy. Accumulating evidence shows that sarcopenia has clinically significant effects in patients with malignancy, including an increased risk of adverse events associated with medical treatment, postoperative complications, and a poor survival outcome. Colorectal cancer (CRC) is one of the most common cancers worldwide, and several lines of evidence suggest that preoperative sarcopenia negatively impacts various outcomes in patients with CRC. In this review, we summarize the current evidence in this field and the clinical relevance of sarcopenia in patients with CRC from three standpoints, namely, the adverse effects of medical treatment, postoperative infectious complications, and oncological outcomes.

Background Although the etiology of pouchitis remains unknown, inflammatory cytokines are significantly associated with the pathogenesis of pouchitis. The cytokine responses that characterize inflammatory bowel diseases (IBD) are key pathogenic components of the disease. Although cytokine profiles in the colonic mucosa have been investigated in experimental colitis models or IBD patients, cytokine profiles in the ileal mucosa at colectomy have been rarely assessed. Aim To assess the relationship between pouchitis and T helper (Th) cytokines in the ileal mucosa collected at the time of colectomy and pouch construction. Methods This retrospective study involved 68 consecutive patients from January 2004 to May 2011 who underwent ileal pouch–anal anastomosis for ulcerative colitis. Samples were obtained from the terminal ileum of resected specimens at time of total colectomy or subtotal colectomy. mRNA expression levels of Th cytokines (IFN-γ, IL-23A, IL-5, IL-13 and IL-17A) were determined. Results Forty of 68 patients (58.8%) developed pouchitis. There was no association between IL-23A expression levels and incidence of pouchitis (p = 0.301). Patients with elevated IFN-γ had a significantly higher incidence of pouchitis compared with low IFN-γ patients (p = 0.043). Univariate analysis demonstrated a total dose of prednisolone > 7000 mg administered before colectomy (p = 0.04) and high IFN-γ expression (p = 0.02) were significant risk factors for pouchitis onset. In multivariate analysis, elevated IFN-γ messenger(m)RNA levels were significantly associated with pouchitis onset (p = 0.03). Conclusion IFN-γ expression in the normal ileal mucosa at the time of colectomy may be an important factor in the pathophysiology of pouchitis.

Background: Gastric cancer (GC) is one of the most common cancers and leading cause of cancer-related deaths worldwide, primarily because of rapid disease progression to advanced stages and highly malignant potential. Methyltransferase-like 3 (METTL3) is a crucial component of the m6A methyltransferase complex, and plays pivotal roles in tumour progression. This study investigated the prognostic significance of METTL3 expression in gastric cancer (GC). Methods: We assessed expression levels of METTL3 by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissue specimens from one hundred fifty-eight GC patients. Propensity score matching (PSM) analysis was performed to clarify its prognostic potential. The METTL3 gene expression was also investigated in fresh frozen specimens from another independent cohort of fifty-seven GC patients to establish its clinical relevance. Knockdown of METTL3 by siRNA transfection was performed to evaluate its function in vitro. Results: METTL3 expression was significantly higher in cancerous tissues vs. corresponding normal mucosa (P Conclusion: METTL3 expression may be used as a clinically feasible prognostic marker and could serve as a potential therapeutic target in GC patients. Citation Format: Yoshinaga Okugawa, Yuji Toiyama, Chengzeng Yin, Ma Ruiya, Akul Goel, Takashi Ichikawa, Hiroki Imaoka, Takahito Kitajima, Tadanobu Shimura, Mikio Kawamura, Hiromi Yasuda, Hiroyuki Fujikawa, Takeshi Yokoe, Ikuyo Mochiki, Masaki Ohi, Kaname Nakatani. Clinical value and oncogenic role of METTL3 expression in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 653.

Purpose Despite recent progress in the diagnosis and treatment of colorectal cancer (CRC), the prognosis remains poor, and metastatic recurrence is the leading cause of poor prognosis. We systemically evaluated the levels of differentially-expressed serum cytokines using array-based techniques to identify a novel and reliable serum biomarker with which to predict metastasis and poor outcomes of CRC. Methods We examined cytokine profiling using preoperative serum from two different cohorts to identify differentially-expressed serum cytokines in patients with metastatic CRC. In the validation phase, serum monocyte chemotactic protein-4 (MCP-4) concentration was assessed in 194 patients by enzyme-linked immunosorbent assay, and its relationships with clinicopathological findings were investigated. Results In discovery phase, three cytokines were differentially expressed in serum from patients with metastatic CRC. In validation phase, high MCP-4 was significantly associated with older age, advanced T stage, distant metastasis, and UICC stage. Cox regression analysis showed that elevated MCP-4 was an independent prognostic factor of disease-free survival and overall survival. Furthermore, logistic regression analysis revealed that high serum MCP-4 was an independent predictor of distant metastasis. Conclusion Quantification of serum MCP-4 concentration might support the early detection/prediction of recurrence and may contribute to the prediction of clinical outcomes in CRC. J. Surg. Oncol. 2016;114:483–489. © 2016 Wiley Periodicals, Inc.

The coexistence of sarcopenia is associated with postoperative complications, including infection after abdominal surgery. We evaluated the association between sarcopenia and surgical site infection (SSI) after surgery for ulcerative colitis. The subjects of this retrospective study were 69 patients who underwent restorative proctocolectomy with perioperative abdominal computed tomography (CT). Sarcopenia was diagnosed by measuring the cross-sectional area of the right and left psoas muscles as the total psoas muscle area on CT images. We assessed whether sarcopenia was associated with SSI and clinical factors, including nutritional and inflammatory markers. The lowest quartiles defined as sarcopenia in men and women were 567.4 and 355.8 mm2/m2, respectively. According to this classification, 12 men and 6 women had sarcopenia. Patients with sarcopenia had a lower body mass index (p = 0.0004) and a higher C-reactive protein concentration (p = 0.05) than those without sarcopenia. SSIs were identified in 12 patients (17.3 %) and included six pelvic abscesses and seven wound infections. According to multivariate analysis, sarcopenia was an independent risk factor for SSI (odds ratio = 4.91, 95 % confidence interval 1.09–23.5, p = 0.03). Sarcopenia is predictive of SSI after pouch surgery for ulcerative colitis.

Apart from primary pouchitis, patients with secondary pouchitis caused by surgical complications require surgical management. The use of abdomino-anal salvage surgery to treat secondary pouchitis caused by surgical complications in pediatric patients with ulcerative colitis (UC) has not been reported in detail. A girl was diagnosed with UC at 8 years old. She underwent restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) at 9 years old. She presented at 12 years old because of chronic antibiotic-refractory pouchitis. The fistula and stricture failed to improve despite multiple local salvage surgeries and ileostomy construction. At 15 years old, she underwent redo IPAA. The patient was well at 20 years old with no signs of pouchitis. Early treatment by abdomino-anal salvage surgery might be indicated to improve quality of life in pediatric patients with secondary pouchitis caused by surgical complication unresponsive to defunctioning and local salvage surgery.

Afferent limb syndrome (ALS) is a type of small bowel obstruction (SBO) caused by obstruction of the afferent intestinal limb after ileal pouch-anal anastomosis (IPAA). The aim of this study was to reveal the clinical features and management of ALS. Of 320 patients undergoing IPAA for ulcerative colitis, we analyzed data from patients presenting with SBO. Six of 19 patients with SBO were diagnosed with ALS. All patients with ALS presented with recurrent intermittent obstructive symptoms before admission, whereas 15 % of patients without ALS presented with these symptoms (P

Pouch-vaginal or vestibular fistula is an uncommon, but devastating complication that occurs in women after ileal J pouch-anal anastomosis. The management of these fistulae is challenging, and it is associated with high recurrence and pouch loss rates. This report describes the use of the modified Martius flap procedure for three patients with ulcerative colitis who developed refractory pouch-vestibular fistulae. Three patients with ulcerative colitis, who underwent total colectomy, mucosal proctectomy, and ileal pouch-anal anastomosis, developed pouch-vestibular fistulae. The fistulae originated in the pouch-anal anastomosis site in all three cases. We performed fistulectomy and transvaginal closure with sphincteroplasty followed by the modified Martius flap procedure under diversion ileostomy. No complications occurred after ileostomy closure, and the postoperative anal function was good. The modified Martius flap procedure is among the best options for patients with ulcerative colitis who develop refractory pouch-vestibular fistula as a complication of mucosal proctectomy.

Diagnostic markers facilitate more selective screening and treatment strategies for ulcerative colitis (UC)-associated cancer (UCAC). The expression of trefoil factor-3 (TFF3), which is involved in mucosal protection and repair in the gastrointestinal tract, was analyzed and its significance for UCAC was evaluated. A total of 145 patients with UC who underwent proctocolectomies were enrolled, including 15 patients (10.8%) with UCAC. TFF3 expression in the rectal mucosa and in cancer cells was assessed using immunohistochemistry, and the expression in UCAC and sporadic colorectal cancer was compared. Analyzing the mucinous granules of goblet cells located in crypts revealed that the non-cancerous rectal mucosa of patients with UCAC had significantly lower mean TFF3 staining scores compared with patients with UC without UCAC or patients with sporadic cancer. TFF3 staining score was revealed to be an independent predictor of UCAC development. These results indicated that low TFF3 expression in the rectal mucosa was associated with the development of UCAC. Thus, TFF3 expression in the rectal mucosa may be a useful biomarker for monitoring patients with UC.

Colony‑stimulating‑factor‑1 (CSF‑1) is a hematopoietic growth factor that exerts its effects through the c‑fms/CSF‑1 receptor (CSF‑1R). The CSF‑1/CSF‑1R axis is thought to be involved in the development of several types of cancer. This study aimed to clarify the clinical and biological significance of the CSF‑1/CSF‑1R axis in gastric cancer (GC). For this purpose, we evaluated CSF‑1 and CSF‑1R expression in GC tissues from 148 patients by RT‑qPCR and immunohistochemistry. The biological roles of the CSF‑1/CSF‑1R axis were investigated by measuring the cell proliferation and migration, and anoikis resistance in a human GC cell line following treatment with recombinant human CSF‑1 and/or CSF‑1R inhibitor. The results revealed that an elevated expression of CSF‑1 or CSF‑1R significantly correlated with disease progression and with a poor overall survival (OS, P=0.037 and 0.016, respectively) and disease‑free survival (DFS, P

Aim The current trial was designed to study and compare the postoperative outcomes and systemic acute responses between patients undergoing laparoscopic-ileal pouch anal anastomosis (LAP-IPAA) and open IPAA for ulcerative colitis. Methods The clinical records of patients who underwent 89 restorative proctocolectomy procedures with IPAA were reviewed. After determining which patients underwent LAP-IPAA versus open IPAA, an equivalent number of controls matched for age and ulcerative colitis severity were selected. Results Twenty of 22 patients who underwent laparoscopic surgery met the inclusion criteria. Patients who underwent LAP-IPAA had significantly shorter times to first walking (P=0.021) and food intake (P=0.0003). The LAP-IPAA group had significantly lower interleukin-6 and interleukin-1ra levels soon after surgery (P=0.011 and P=0.0076). The LAP-IPAA group had significantly lower C-reactive protein levels on postoperative day 1 (P=0.0027). Conclusions LAP-IPAA is a less-invasive operative procedure than open IPAA with respect to the postoperative systemic inflammatory response and postoperative recovery.

CD26 is a transmembrane glycoprotein whose role in various types of malignancies, along with the potential therapeutic and diagnostic targets, has been evaluated. Preoperative chemoradiotherapy (CRT) is an effective tool for local control of rectal cancer, but the rate of disease recurrence remains high. The aim of this study was to clarify the association between CD26 expression and rectal cancer after preoperative CRT. A total of 85 patients with rectal cancer who had undergone preoperative CRT were enrolled in this study. We investigated CD26 expression in residual tumors and the surrounding stromal tissue using immunohistochemistry. Additionally, stromal CD26 gene expression was assessed by real-time quantitative polymerase chain reaction. Patients with high CD26 expression in cancer tissue more frequently had serosal invasion, vascular invasion, and a poor pathological response. High expression of CD26 in the tumor stroma was significantly correlated with histology and tumor recurrence. High CD26 expression in the stroma, but not the tumor itself, was significantly correlated with a poor prognosis. Patients expressing CD26 in the tumor stroma, based on transcriptional analysis, also had a significantly poorer prognosis than those without the expression. In multivariate analysis, lymph node metastasis and high stromal CD26 expression were identified as independent prognostic factors in patients with rectal cancer after neoadjuvant CRT. Stromal CD26 expression after preoperative CRT was significantly associated with tumor recurrence and prognosis in rectal cancer patients. Our data suggest that stromal CD26 plays an important role and is a potential therapeutic target in tumor relapse.

Rac GTPase-activating protein (RacGAP) 1 plays a key role in controlling various cellular phenomena including cytokinesis, transformation, invasive migration and metastasis. This study investigated the function and clinical significance of RacGAP1 expression in colorectal cancer (CRC). The intrinsic functions of RacGAP1 in CRC cells were analyzed using small interfering RNA (siRNA). We analyzed RacGAP1 mRNA expression in surgical specimens from 193 CRC patients (Cohort 1) by real-time PCR. Finally, we validated RacGAP1 protein expression using formalin-fixed paraffin-embedded samples from 298 CRC patients (Cohort 2) by immunohistochemistry. Reduced RacGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration and invasion. In Cohort 1, RacGAP1 expression in CRC was significantly higher than in adjacent normal mucosa and increased according to tumor node metastasis stage progression. High RacGAP1 expression in tumors was significantly associated with progression and prognosis. In Cohort 2, RacGAP1 protein was overexpressed mainly in the nuclei of CRC cells; however, its expression was scarcely observed in normal colorectal mucosa. RacGAP1 protein expression was significantly higher in CRC patients with higher T stage, vessel invasion and lymph node and distant metastasis. Increased expression of RacGAP1 protein was significantly associated with poor disease-free and overall survival. Multivariate analyses revealed that high RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence and poor prognosis in CRC. Our data provide novel evidence for the biological and clinical significance of RacGAP1 as a potential biomarker for identifying patients with lymph node metastasis and poor prognosis in CRC.

Afferent limb obstruction can be a persistent complication after restorative proctocolectomy with ileal pouch-anal anastomosis. We present a case of afferent limb obstruction complicated by a long efferent limb of the ileal pouch that we successfully treated with side-to-side anastomosis of the afferent and efferent limbs. The procedure involved using a transanal endoscopic stapling device assisted by transanal endoscopy with a thin intestinal video endoscope. This allowed reliable, safe visualization of the lesion from the tight pouch-anal anastomosis and facilitated repair with an endoscopic stapling device. Because the technique was performed without enterotomy, it reduced the risks of contamination and leakage from transabdominal small bowel anastomosis. Laparotomy view also prevented of injury to the pouch itself and entrapment of the mesentery of the afferent and efferent limbs of the pouch between the stapler anvils.

MicroRNAs (miRNAs) are small noncoding RNA strings of 19–25 nucleotides, encoded by eukaryotic genomic DNA, which function in the posttranscriptional regulation of target gene expression via base pairing with complementary sequences in messenger RNAs (mRNAs), to induce mRNA degradation and translational inhibition. Aberrant miRNA modifications occur at a very early stage in colorectal cancer (CRC) development and are widely described as essential players in its progression. As circulating cell-free miRNAs have become identified, the potential of cell-free miRNAs in the blood or other body fluids for use as biomarkers for cancer detection has become increasingly evident. In this review, we summarize the progress of miRNA analyses as noninvasive biomarkers for cancer detection, estimation of prognosis, and prediction of chemotherapeutic agent response in CRC. We also discuss the obstacles that have limited the routine use of miRNA biomarkers in the clinical setting and describe how these obstacles could be overcome.

Chronic inflammation increases the risk of developing several gastrointestinal malignancies. Chemokines that are produced by colonic epithelial cells play significant roles in the maintenance and repair of the epithelial barrier. The present study aimed to clarify whether the expression of CCL20 and its receptor, CCR6, was correlated with the development of ulcerative colitis (UC)-associated neoplasia. A total of 93 patients with UC who underwent proctocolectomies were enrolled in the present study. Immunohistochemical analysis for CCL20 and CCR6 expression in the rectal mucosa was performed and the correlation between expression and the pathogenesis of UC-associated neoplasia was investigated. A total of 16 (17.2%) patients presented with UC-associated neoplasia. The immunohistochemistry (IHC) score for CCL20 was significantly increased in the patients with a mild form of the disease (P=0.0363). The IHC score for CCL20 expression in the patients with UC-associated neoplasia was higher compared with the patients without neoplasia (P=0.0294). In contrast, there was no significant correlation between CCR6 expression and the clinicopathological variables. The logistic regression analysis revealed that a high IHC score for CCL20 expression in the rectal mucosa and a disease duration of more than eight years were significantly correlated with the development of UC-associated neoplasia (P

A 79-year-old woman with bloody diarrhea was diagnosed with ulcerative colitis. She developed intestinal perforation after high-dose steroid therapy. An emergency laparotomy revealed a perforation in the ascending colon, and a subtotal colectomy was performed with an ileostomy and a mucous fistula in the sigmoid colon. Histological findings of the resected colon showed the presence of cytomegalovirus in the endothelial cells of vessels around the ulcer floor. Twelve days after the laparotomy, she developed an ileal perforation with a bloody discharge from the ileostomy and underwent an emergency laparotomy. Multiple intestinal perforations were found in the ileum, and the perforated ileum was resected. Cytomegalovirus infection was controlled with ganciclovir postoperatively. Histological findings of the resected ileum showed the presence of cytomegalovirus in the endothelial cells of vessels around the ulcer floor. This is the first report of ileal perforation due to cytomegalovirus infection confirmed pathologically in a patient with ulcerative colitis.

Aim: Oval cells with ductular reactions (DR) in damaged liver are referred to as “intermediate hepatobiliary cells”. In a preliminary study, we had found expression of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) known as a potential marker for stem cells in the small intestine and colon in DR in liver damaged by chemotherapy for metastatic colorectal cancer (CRC). The aim of this study was to confirm LGR expression in DR in damaged liver after chemotherapy. Methods: A total of 68 liver specimens obtained after surgical resection were stained with monoclonal antibodies for cytokeratin (CK)7, neural cell adhesion molecule (NCAM; a bile ductular and liver progenitor cell marker), CD133 (a candidate stem cell marker of hepatocellular carcinoma as well as CRC) and LGR5. Additionally, these mRNA levels were investigated according to the location in damaged liver after chemotherapy using microdissected specimens. Results: We observed that LGR5 was expressed in DR with CD133, CK7 and NCAM expression. By contrast, LGR5, CD133 and NCAM were not expressed in mature bile ducts with CK7. In transcriptional analysis, LGR5 mRNA levels in fibrotic tissue including DR were higher compared with that in adjacent normal liver without significant difference. Conclusion: These findings suggest that LGR5 may be involved in maintaining DR in damaged liver.

The metastasis-associated (MTA) gene family is a critical component of the nucleosome remodeling and histone deacetylase complex, and plays an important role in metastatic processes. We systematically evaluated dysregulation of the MTA family to clarify their clinical significance in gastric cancer (GC). One hundred and forty-five patients who underwent surgery for GC were evaluated. We analyzed the expression levels of the MTA family (MTA1, 2 and 3) by qPCR in GC tissue, and the MTA1 protein expression in primary cancer and matched normal mucosa (NM) was measured using immunohistochemical analysis. The expression of all the MTA family members was significantly increased in a stage-dependent manner, and elevated expression of all of the MTA family members was correlated with metastatic factors and prognosis in GC patients. Multivariate analysis revealed that MTA1 overexpression was an independent risk factor for survival. Especially, elevated expression of MTA1 was significantly correlated with recurrence, and was an independent risk factor for lymph node metastasis. Immunohistochemical analysis demonstrated that MTA1 was predominantly expressed in the nuclei of primary GC cells but was not expressed in NM and in the cancer stroma. In conclusion, quantification of MTA expression may support the accurate diagnosis of disease staging and may help predict clinical outcomes.

Despite recent progress in the diagnosis and treatment of colorectal cancer (CRC), the prognosis remains poor, and metastatic recurrence is the leading cause of poor prognosis. We systemically evaluated the levels of differentially-expressed serum cytokines using array-based techniques to identify a novel and reliable serum biomarker with which to predict metastasis and poor outcomes of CRC.We examined cytokine profiling using preoperative serum from two different cohorts to identify differentially-expressed serum cytokines in patients with metastatic CRC. In the validation phase, serum monocyte chemotactic protein-4 (MCP-4) concentration was assessed in 194 patients by enzyme-linked immunosorbent assay, and its relationships with clinicopathological findings were investigated.In discovery phase, three cytokines were differentially expressed in serum from patients with metastatic CRC. In validation phase, high MCP-4 was significantly associated with older age, advanced T stage, distant metastasis, and UICC stage. Cox regression analysis showed that elevated MCP-4 was an independent prognostic factor of disease-free survival and overall survival. Furthermore, logistic regression analysis revealed that high serum MCP-4 was an independent predictor of distant metastasis.Quantification of serum MCP-4 concentration might support the early detection/prediction of recurrence and may contribute to the prediction of clinical outcomes in CRC. J. Surg. Oncol. 2016;114:483-489. © 2016 Wiley Periodicals, Inc.

Restorative proctocolectomy with ileal pouch-anal anastomosis is a surgical procedure for ulcerative colitis, but pouch failure or pelvic sepsis still occurs in some patients. We conducted this study to investigate the cause of pouch failure and evaluate defecatory function after pelvic sepsis. A total of 234 patients who underwent restorative proctocolectomy were enrolled. We analyzed the cause of pouch failure, as well as defecatory function and manometric outcomes, with and without the complication of pelvic sepsis. Pelvic sepsis developed in 29 (12.3%) of the 234 patients who underwent restorative proctocolectomy (pelvic sepsis group). The pelvic sepsis led to pouch failure in two of these patients (as a vaginal fistula in one and ileo-anal anastomotic leakage in one). Of the remaining majority of patients who did not suffer pelvic sepsis (control group), nine suffered pouch failure (as vaginal fistula in four, perianal abscess in two, pouch-spinal marrow fistula in one, and chronic pouchitis in two). There were no significant differences in defecatory function or manometric outcomes between the two groups. In the pelvic sepsis group, stool frequency was significantly correlated with white blood cell count (P = 0.01) and the duration until onset of pelvic sepsis (P

Smad interacting protein 1 (SIP1) is an epithelial–mesenchymal transition (EMT)-inducible gene that plays a key role in tumor progression in various cancers. This study seeks to clarify the clinical and biological significance of SIP1 expression, especially in intestinal type gastric cancer. We analyzed the mRNA levels of SIP1 and other EMT regulators by real-time reverse transcription PCR in gastric tissue samples of 134 gastric cancer patients, and in five gastric cancer cell lines. SIP1 gene knockdown by siRNA transfection was performed to evaluate SIP1 function in gastric cancer cells. Expression of the SIP1 gene was significantly higher in cancerous tissue than in adjacent normal mucosa. Although the mRNA expression of the other EMT regulators tested (Snail, Slug, and Twist) was not correlated with clinicopathological factors, increased SIP1 expression was an independent prognostic factor and an independent risk factor for peritoneal dissemination. In addition, SIP1 expression was significantly positive and correlated with vimentin expression. For intestinal type gastric cancer in particular, elevated SIP1 expression was significantly correlated with peritoneal dissemination and poor prognosis (p < 0.05). In vitro, cell proliferation, migration, invasion, and resistance to anoikis were significantly inhibited in SIP1 siRNA-transfected MKN7 cells compared to control siRNA. SIP1 appears to play an important role in progression to peritoneal carcinomatosis and may be a therapeutic target for patients with intestinal type gastric cancer.

Background: Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer. Methods: We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis. Results: The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth. Conclusion: The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression.

Purpose Serum CXCL5 levels in patients with colorectal cancer (CRC) were assessed to evaluate correlation with clinicopathologic features and prognosis. The effects of CXCL5 on CRC cells were also investigated in vitro . Methods Based on cytokine array analysis, CXCL5 was identified as a novel prognostic serum marker. Serum levels of CXCL5 were assessed in 250 CRC patients and 33 normal volunteers by enzyme-linked immunosorbent assay (ELISA), and their relation to clinicopathologic findings and survival investigated. CXCL5 levels in CRC cell lines were also measured by ELISA, and CXCL5 and CXCR2 expression was evaluated by immunohistochemistry. To investigate the biological role of the CXCL5/CXCR2 axis, recombinant human CXCL5 and CXCR2 neutralisation antibodies were used for proliferation, migration and invasion assays. Results Preoperative serum CXCL5 was significantly elevated in patients with CRC compared with healthy volunteers ( p = 0.013). High serum CXCL5 was significantly associated with female sex ( p = 0.0098) and liver metastasis ( p = 0.0040). Univariate analysis correlated elevated CXCL5 with poor overall survival ( p = 0.0002). Multivariate analysis showed that elevated CXCL5 was a significant and independent prognostic factor of survival in all CRC patients ( p = 0.038). CRC cells secreted CXCL5, and administration of recombinant human CXCL5 promoted proliferation, migration and partial invasion. These effects were generally inhibited by CXCR2 neutralisation antibody. Conclusions Preoperative serum CXCL5 could serve as a novel predictive marker for prognosis determination of CRC patients. CXCL5/CXCR2 axis might be associated with colorectal cancer progression.

In vivo real-time visualization of chemotherapy response at the cellular level provides us with direct evidence of what happens on the tumor microenvironment of metastatic organs. We imaged the response of metastatic tumor cells and host stromal cells to chemotherapeutics on liver metastatic xenografts in living mice using intravital two-photon laser scanning microscopy (TPLSM). Red fluorescent protein-expressing human colorectal cancer cells (HT29) was inoculated to the spleen of green fluorescent protein-expressing nude mice. 5-Fluorouracil or irinotecan was intraperitoneally administered after the formation of macroscopic liver metastases. Intravital TPLSM was performed at multiple time-points for time-series imaging of liver metastatic xenografts in the same mice. Under the 1st TPLSM, HT29 cells were visualized in hepatic sinusoids at the single cell level. Liver metastatic nodules consisting of viable cancer cells and surrounding stroma with tumor vessels were visualized under the 2nd TPLSM. After chemotherapy, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed under the 3rd TPLSM. There was no obvious morphological difference in tumor response between these chemotherapeutics. Time-series intravital TPLSM imaging on the metastatic tumor xenografts may be useful for screening and evaluating new chemotherapeutics with less interindividual variability.

LGR5, known as a target of Wnt signaling, has been reported as an intestinal stem cell marker. Recent reports showed that LGR5 was associated with carcinogenesis and tumor invasion in colorectal cancer. CD44 is a ubiquitously expressed cell adhesion molecule and also a potential cell surface marker on colon cancer stem cells. Both LGR5 and CD44 have been also reported to be Wnt signal targets. The aim of this study was to investigate the association of these markers with clinical outcome in rectal cancer after preoperative chemoradiotherapy (CRT). A total of 52 rectal cancer specimens were obtained from patients who underwent preoperative CRT. We performed transcriptional and immunohistochemical analyses, and retrospectively studied the association of LGR5 and CD44 expression levels with clinical outcomes. For CD44, its expression in cancer stroma was also evaluated. The levels of cancer LGR5 and CD44 gene expression were significantly and positively correlated. LGR5 gene expression level in cancer and positivity of CD44 gene expression in cancer stroma were significantly correlated with disease recurrence. Elevated cancer LGR5 gene expression and positive CD44 gene expression in cancer stroma were significantly associated with poor recurrence-free and overall survival. Multivariate analysis indicated that positivity of stromal CD44 gene expression was an independent prognostic factor for the recurrence and overall survival of patients with rectal cancer after preoperative CRT. In conclusion, LGR5 and CD44 expression may be coordinately associated with tumor relapse in locally advanced rectal cancer after preoperative CRT.

Tumor regression grading (TRG) reportedly has a prognostic value in rectal cancer patients who have undergone preoperative chemoradiotherapy (CRT). However, TRG is difficult to evaluate objectively. The aim of this study was to identify pathological features associated with clinical outcome, compared with conventional TRG, following preoperative CRT. A total of 67 patients with locally advanced rectal cancer underwent preoperative CRT and curative surgery. The association of two pathological features, solitary single glandular appearance (SSGA) and superficial viable cancer cells (SVCC), with clinicopathological variables was investigated, and the clinical significance of these features was compared to conventional TRG. Moreover, transcriptional analyses were performed on residual cancer cells associated with these pathological features. Of the 67 patients, 34.3 and 74.6 % had detectable SSGA and SVCC, respectively. Patients with tumor recurrence had a significantly higher frequency of SSGA (P

Afferent limb obstruction can be a persistent complication after restorative proctocolectomy with ileal pouch-anal anastomosis. We present a case of afferent limb obstruction complicated by a long efferent limb of the ileal pouch that we successfully treated with side-to-side anastomosis of the afferent and efferent limbs. The procedure involved using a transanal endoscopic stapling device assisted by transanal endoscopy with a thin intestinal video endoscope. This allowed reliable, safe visualization of the lesion from the tight pouch-anal anastomosis and facilitated repair with an endoscopic stapling device. Because the technique was performed without enterotomy, it reduced the risks of contamination and leakage from transabdominal small bowel anastomosis. Laparotomy view also prevented of injury to the pouch itself and entrapment of the mesentery of the afferent and efferent limbs of the pouch between the stapler anvils.