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Evidence for the tumour‐supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer‐associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF‐related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha‐smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN‐high tumours had a significantly worse 5‐year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell‐rich, DCNLowPDPNLow); a PDPN‐dominant group (DCNMidPDPNHigh); and a DCN‐dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN‐dominant group (hazard ratio = 0.50, 95% CI = 0.26–0.96, p = 0.037) as a potential favourable factor compared with the DCN‐dominant group. Of note, DCN‐dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma‐targeting therapies may be candidate treatments for patients with CRC. [ABSTRACT FROM AUTHOR]

Background: Constipation causes substantial morbidity worldwide. Methods: This survey assessed constipation-related factors in Japan using the Japanese version of the Irritable Bowel Syndrome Quality of Life (IBS-QOL-J) instrument. We also examined the relationship among laxative type, Bristol Stool Form Scale (BSFS) scores, and treatment cost. Finally, we examined differences in satisfaction scores according to laxative type, treatment type, treatment cost, and BSFS score. Results: IBS-QOL-J was higher among those taking salt and/or irritation laxatives. Those paying >JPY 5000 (USD 50.00) had the lowest IBS-QOL-J. IBS-QOL-J was significantly lower among those with a BSFS score of 1 or 2 (severe constipation). Conclusions: This study's findings suggest that a variety of factors, including treatment type and cost, are associated with defecation satisfaction. Those who had hard stools, used multiple laxatives, or spent more on treatment were less satisfied. Future strategies should target therapies that do not require multiple laxatives with lower treatment costs. Adequate defecation with a small number of appropriate laxatives at minimal cost appears to improve defecation satisfaction. It is desirable to identify appropriate laxatives and improve dietary habits and exercise routines. It is also necessary to stop blindly increasing laxative usage and properly diagnose constipation disorders such as anatomical abnormalities other than functional constipation. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis (p = 0.0020) or incomplete resection status (p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage (p = 0.032) or peritoneal metastasis (p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients. [ABSTRACT FROM AUTHOR]

The present study analyzed the expression of five independent immunohistochemical markers, CD4, CD8, CD66b, CD68, and CD163, on immune cells within the colorectal cancer (CRC) tumor microenvironment (TME). Using hierarchical clustering, patients were successfully classified according to significant associations with clinicopathological features and/or survival. Patients with mismatch repair‐proficient (pMMR) CRC were categorized into four groups with survival differences (p = 0.0084): CD4Low, CD4High, MΦHigh, and CD8Low. MΦHigh tumors showed significantly higher expression of CD47 (p < 0.0001), a phagocytosis checkpoint molecule. These tumors contained significantly greater numbers of PD‐1+ (p < 0.0001), TIM‐3+ (p < 0.0001), and SIRPA+ (p < 0.0001) immune cells. Notably, 10% of the patients with pMMR CRC expressed PD‐L1 (CD274) on tumor cells with significantly worse survival (p = 0.00064). The Cox proportional hazards model identified MΦ High (hazard ratio [HR] = 2.02, 95%, p = 0.032), CD8Low (HR = 2.45, p = 0.011), and tumor PD‐L1 expression (HR = 2.74, p = 0.0061) as potential risk factors. PD‐L1–PD‐1 and/or CD47–SIRPA axes targeting immune checkpoint therapies might be considered for patients with pMMR CRC according to their tumor cells and tumor immune microenvironment characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. The present study revealed that patients with stromal periostin (POSTN)-positive colorectal cancer (CRC) with peritoneal and distant organ metastasis had a significantly worse 5-year survival rate. Furthermore, significant associations between stromal POSTN and complete loss of p53 were identified. POSTN was also associated with decorin and fibroblast-activation protein expression, indicating gene expression status and/or phenotypes similar to CAF-A. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK, AKT, or STAT3 activation. Co-culture assays demonstrated communication between CRC cells and fibroblasts, enhancing STAT3 and phospho-STAT3 expression in fibroblasts. On the basis of our experiments, we speculated that stromal POSTN accelerated metastasis via enhanced stromal remodeling capacity and activated migration of both tumor and stromal cells. POSTN-modulating therapies may be candidate treatments for patients with CRC. Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. To uncover clinicopathological importance of periostin (POSTN) expression in colorectal cancer (CRC), the present study immunohistochemically examined its expression status. Furthermore, to reveal its mechanisms involved, molecular experiments were performed. In CRC tissues, 44% of the cases (119/269) exhibited POSTN expression in the CAFs. In contrast, CRC cells expressed POSTN at almost undetectable levels. Survival analyses identified that patients with POSTN-positive CRC had a significantly worse 5-year survival rate (63.2% vs. 81.2%; p = 0.011). Univariate analyses revealed that POSTN positivity was associated with peritoneal (p = 0.0031) and distant organ metastasis (p < 0.001). Furthermore, immunohistochemical analyses identified a significant association between POSTN and p53 complete loss status in CRC cells. Decorin and fibroblast activation protein expression in CAFs was also associated with POSTN. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK and AKT or STAT3 activation, and co-culture assays demonstrated the communication between CRC cells and fibroblasts, which enhanced STAT3 activation in fibroblasts. On the basis of our results, we speculated that stromal POSTN accelerated metastasis via stromal remodeling capacity and activated the migration of both tumor and stromal cells. [ABSTRACT FROM AUTHOR]

Mizushima T, Sasaki M, Ando T, Wada T, Tanaka M, Okamoto Y, Ebi M, Hirata Y, Murakami K, Mizoshita T, Shimura T, Kubota E, Ogasawara N, Tanida S, Kataoka H, Kamiya T, Alexander JS, Joh T. Blockage of angiotensin II type 1 receptor regulates TNF-[alpha]-induced MAdCAM-1 expression via inhibition of NF-[kappa]B translocation to the nucleus and ameliorates colitis. Am J Physiol Gastrointest Liver Physiol 298: G255-G266, 2010. First published November 25, 2009; doi: 10.1152/ajpgi.00264.2009.-- Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (1BD). Recently, treatment of IBD with an antibody to [alpha]4137-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immunemediated colitis using AT1R-deficient (AT1R-/-) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-[alpha], but did not inhibit phosphorylation of p38 MAPK or of I[kappa]B that modulate MAdCAM-1 expression. However, NF-[kappa]B translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R-/- than in wild-type mice. The expression of MAdCAM-I was also significantly lower in AT1R-/- than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-[kappa]B into the nucleus. Furthermore, inhibition of ATIR ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1. mucosal addressin cell adhesion molecule-l; inflammatory bowel disease; nuclear factor-[kappa]B doi: 10.1152/ajpgi.00264.2009

p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the "stem-like" immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies with high morbidity and mortality rates. Several biological markers for the prognostication of patient outcome of CRCs are available. Recently, our group identified two favorable factors for the survival of CRC patients: PDZ-binding kinase (PBK) and phospho-histone H3 (PHH3). Both showed a significant inverse association to pT stage. The aim of this study was to uncover the mechanism through which these cellular proliferation–associated protein expressions lead to favorable clinical outcome in CRC patients. We first confirmed co-expression of PBK and PHH3 in CRC cells. Further investigation showed that aberrantly expressed PBK up-regulated the cellular proliferation of CRC cells with accumulation of PHH3. The PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells through down-regulation of PHH3 and induction of apoptosis. In vitro studies revealed that PBK suppressed the migration and invasion of CRC cells with suppression of Wnt/β-catenin signaling and CDH1 stabilization. Exogeneous PBK up-regulated the phosphorylated CDH1 at S840, S846, and S847 residues in cultured cells. Recombinant PBK directly phosphorylated HH3; however, it failed to phosphorylate CDH1 directly in vitro. The present study demonstrated the association of two markers PBK and PHH3 in CRC. We further identified one of the potential mechanisms by which higher expression of these cellular proliferation–associated proteins leads to the better survival of CRC patients, which likely involves PBK-mediated suppression of the migration and invasion of CRC cells. Our findings suggest that PBK-targeting therapeutics may be useful for the treatment of CRC patients with PBK-expressing tumors. [ABSTRACT FROM AUTHOR]

A 62-year-old man was referred to our hospital because of abdominal pain. Computed tomography revealed an approximately 7-cm-diameter tumor in the left abdomen with metastatic lymph nodes, an approximately 1-cm-diameter round tumor in contact with the subclavian artery in the apical lobe of the right lung, and mediastinal lymph node enlargement in contact with the superior vena cava. Esophagogastroduodenoscopy and colonoscopy revealed no abnormalities. Double-balloon endoscopy revealed a whole circumferential ulcer in the jejunum approximately 20 cm from the ligament of Treitz. Biopsy analysis of an ulcer specimen revealed a poorly differentiated carcinoma. Immunohistochemical staining of the specimen showed that it was positive for thyroid transcription factor 1 and cytokeratin 7 and negative for cytokeratin 20, GATA-binding protein 3, caudal-type homeobox protein 2, and paired box 8. Positron emission tomography revealed positive findings in the small-intestinal tumor, nearby mesenteric lymph nodes, lymph nodes around the abdominal aorta, lung tumor, and mediastinal lymph node in the apical lobe of the right lung. Accordingly, the patient was diagnosed as having a lung carcinoma with small-intestinal metastasis (T1b, N3, M1c; cStage IVB). Pathological examination helped distinguish the primary small-intestinal tumor from the metastatic small-intestinal tumor and detect the tumor origin. [ABSTRACT FROM AUTHOR]

Gastric plexiform fibromyxoma is extremely rare. In our case, upper gastrointestinal endoscopy of a 41-year-old woman patient revealed a 1-cm submucosal tumor (SMT) in the greater curvature of the lower body of the stomach. On contrast-enhanced computed tomography, the tumor was hypervascular in the arterial phase with continuous enhancement in the post-venous phase. On endoscopic ultrasonography, it had a low echo pattern. The preoperative diagnosis was a gastric SMT with a rich vasculature; however because the biosy specimen did not contain tumor tissue, a malignant tumor could not be excluded. The patient underwent nonexposed endoscopic wall-inversion surgery (NEWS), and the tumor was completely resected. Immunohistochemical examination revealed that the tumor was positive for D2-40 and α-smooth muscle actin, but negative for c-kit, discovered on gastrointestinal stromal tumor-1, desmin, S100, Melan-A, signal transducer and activator of transcription 6, insulinoma-associated protein 1, CXCL13, ETS transcription factor, follicular dendritic cell, anaplastic lymphoma kinase, human melanoma black, h-caldesmon, and CD1a, 10, 21, 23, 31, 34, 68, and 163. Approximately, 1–2% of the tumor cell nuclei were Ki-67-positive. Finally, we diagnosed the tumor as a plexiform fibromyxoma. In conclusion, NEWS is an effective method for the treatment of SMTs with a diameter of <3 cm. [ABSTRACT FROM AUTHOR]