[Show abstract][Hide abstract] ABSTRACT: The ErbB family consists of four proteins including (EGFR)/ErbB1, ErbB2, ErbB3, and ErbB4, and plays a crucial role in the promotion of multiple tumorigenic processes. In addition to the traditional pathways of EGFR signaling, EGFR translocates to the nucleus and acts as a transcription factor in the proliferation of cancer cells. Heregulin is known as both an ErbB3 and an ErbB4 ligand. This study aimed to investigate the expression of heregulin and its relevant EGFR family members as well as their phosphorylated forms in human colorectal cancer (CRC) tissues and to determine the relationship between their expression and clinicopathological factors including patient prognosis.
We analyzed the effects of exogenous heregulin on ErbB2, ErbB3 and ErbB4 phosphorylation in Caco-2, DLD-1, and HCT 116 colon cancer cell lines by western blot analysis. We examined 155 surgical resections from colorectomy patients. Cellular localization of ErbB1-4, their phosphorylated forms and heregulin protein was analyzed in CRC surgical resections by immunohistochemical analysis. Immunohistochemical results were compared with clinicopathological factors and patient prognosis.
Phosphorylated ErbB2 (pErbB2) and phosphorylated ErbB3 (pErbB3) were detected in both nuclear and cytosolic fractions of Caco-2 and DLD-1 cells stimulated by exogenous heregulin. Whereas, phosphorylated ErbB4 (pErbB4) was detected only in cytosolic fractions of HCT 116 cells stimulated by exogenous heregulin. Phosphorylated EGFR (pEGFR) immunoreactivity was observed in the cytoplasm and nuclei of cancer cells, whereas the pattern of EGFR staining was membranous and cytoplasmic. Subcellular localization of pErbB2, cytoplasmic, membranous, or nuclear, varied among cases. pErbB3 immunoreactivity was exclusively observed in the nuclei of cancer cells. pErbB4 immunoreactivity was observed in the cell membrane of cancer cells. Statistically, heregulin immunoreactivity correlated with pErbB2 and pErbB4 expression. In multivariate analysis for disease free survival, lymph node status, pErbB3 and pErbB4 expression retained independent prognostic significance. In multivariate analysis for overall survival, lymph node status, pEGFR and pErbB4 retained independent prognostic significance.
ErbB2 and ErbB3 phosphorylated by heregulin localized in the nucleus of CRC cells. Phosphorylated ErbB1-4 and heregulin contribute to poorer patient prognosis in CRC. This heregulin-ErbB family member autocrine loop may be a candidate for targeted treatment of CRC.
BMC Cancer 11/2014; 14(1):863. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Double-balloon endoscopy has enabled direct, detailed examination of the entire small bowel with interventional capabilities. Although its usefulness is recognized, efficacy and safety have not been extensively evaluated by prospective multicenter studies. To evaluate the efficacy and safety of double-balloon endoscopy performed by expert and non-expert endoscopists, a prospective, multicenter study was conducted in five university hospitals and a general hospital in Japan.MethodsA total of 120 patients, who underwent 179 procedures were enrolled to the study. Experts performed 129 procedures and non-experts performed 50 procedures. The primary end point was the rate of achievement of the procedural objectives, namely, identification of a new lesion, detailed examination to establish a therapeutic strategy, or exclusion of significant lesions by total enteroscopy. The secondary end points were the rate of successful examination of the entire small bowel, and evaluation of safety.ResultsThe overall rate of achievement of the procedural objectives was 82.5% (99/120). The overall success rate for examination of the entire small bowel was 70.8% (34/48). The incidence of adverse events was 1.1% (a mucosal injury and an episode of pyrexia in two of 179 examinations). No severe adverse events were encountered. There were no significant differences in any of the outcome measures comparing expert and non-expert operators.Conclusions
Double-balloon endoscopy is effective and safe for patients with suspected small bowel diseases, and can be safely performed even by a non-expert under the supervision of an expert, following a simple training program.
[Show abstract][Hide abstract] ABSTRACT: A 72-year-old male with liver dysfunction and an increase in serum total protein/albumin (TP/Alb) ratio was referred to our hospital. There was a marked increase in serum immunoglobulin (Ig) G4 level (IgG/IgG4: 3,485/2,860 mg/dl). Diagnostic imaging did not reveal any enlargement of the pancreas or narrowing of the pancreatic duct. However, bilateral submaxillary gland swelling, sclerosing cholangitis, and retroperitoneal fibrosis were noted, suggesting multifocal fibrosclerosis. Histological examination of the submaxillary gland showed the infiltration of IgG4-positive plasma cells, although there was no narrowing of the pancreatic duct, leading to a diagnosis of IgG4-related disease with various extrapancreatic lesions. Systemic investigation before the introduction of steroid therapy revealed rectal cancer. After low-position anterior resection, steroid therapy was introduced, reducing the lesions. Recent studies have reported autoimmune pancreatitis/IgG4-related disease with malignant tumors. However, the association and pathogenesis remain to be clarified. Malignant tumors are detected before or after the treatment of autoimmune pancreatitis/IgG4-related disease; pretreatment diagnosis and post-treatment follow-up should be carefully performed, bearing in mind the concomitant development of malignant tumors.
Clinical Journal of Gastroenterology 12/2011; 4(6).
[Show abstract][Hide abstract] ABSTRACT: We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II(1) GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and/or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course.
Cancer Science 05/2011; 102(8):1532-6. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A study reported that rebamipide was effective at reducing short-term nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. The purpose of this study was to re-evaluate the effect of the co-administration of rebamipide on small intestinal injuries induced by short-term NSAID treatment.
Eighty healthy male volunteers were randomly assigned to two study groups: a control group (N = 40), which received NSAID (diclofenac sodium, 75 mg/day) and omeprazole (20 mg/day) treatment along with a placebo; and a rebamipide group, which received NSAID, omeprazole and rebamipide (300 mg/day). Small intestinal injuries (mucosal breaks plus denuded areas) were evaluated by capsule endoscopy before and after 14 days of treatment.
A total of 38 control subjects and 34 rebamipide subjects completed the treatment and were evaluated by capsule endoscopy. NSAID therapy increased the mean number of mucosal injuries per subject from a basal level of 0.1 ± 0.3 to 16 ± 71 and 4.2 ± 7.8 in the control and rebamipide groups, respectively, but the difference was not significant. The difference in the percentage of subjects with at least one mucosal injury post-treatment was also not significant (control 63%; rebamipide 47%). Limiting our analysis to subjects with mucosal injuries, rebamipide co-treatment had the tendency to reduce the mean number of mucosal injuries per subject from 25 in the control group to 8.9 in the rebamipide group (multiple comparisons test; p = 0.088, Mann-Whitney U test; p = 0.038).
Rebamipide co-therapy had the potential to reduce the intensity of small intestinal injury induced by 2-week administration of diclofenac.
Journal of Gastroenterology 10/2010; 46(1):57-64. · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are no specific symptoms of patients with carcinoma of the small intestine. Therefore, it is difficult to diagnose in the early stage by imaging modalities such as radiological enteroclysis, computed tomography, and classical endoscopy. However, double balloon endoscopy makes it possible to diagnose the carcinoma of the entire small bowel by taking tissue samples for pathological assessment. The characteristic of endoscopic findings is irregular ulcerated tumor with malignant stricture. It is still difficult to find carcinoma of small intestine in patients without symptoms and most cases are advanced when diagnosis is achieved. We should try to diagnose in early stage by combining images modalities, capsule endoscopy and double balloon endoscopy safely and efficiently, resulting in improving the patients' prognosis.
Gan to kagaku ryoho. Cancer & chemotherapy 08/2010; 37(8):1446-9.
[Show abstract][Hide abstract] ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce small intestinal mucosal injuries. The concentrations of NSAIDs, bile acids and intestinal flora may differ in the proximal and distal parts of the small intestine. This study aimed to analyse types and distributions of NSAID-induced small intestinal injuries.
In total 55 healthy male volunteers were examined using baseline capsule endoscopy (CE). Subjects then undertook a 14-day regimen of NSAID medication (diclofenac sodium, 75 mg day(-1)) with proton-pump inhibitors (omeprazole 20 mg day(-1)) as gastroprotection. After 14 days, subjects underwent post-treatment CE and were assessed for three types of small intestinal injuries: denuded areas, erosions and ulcers. The proximal and distal parts of the small intestine were arbitrarily classified according to CE transit time from the duodenal bulb.
Baseline CE revealed six mucosal lesions in 6 of 55 subjects (11%), consisting of three denuded areas and three erosions. Post-treatment CE identified 636 lesions in 32 of 53 subjects (60%); including 115 denuded areas in 16 subjects, 498 erosions in 22 subjects and 23 ulcers in 8 subjects. The distribution of small intestinal injuries differed according to type; denuded areas (90%: 103/115) were predominantly located in the proximal part, erosions throughout the small intestine and all ulcers in the distal part. The location of ulcers and denuded areas differed statistically (P < 0.0001).
The impact of short-term NSAID medication on the small intestine differed according to intestinal site, with most denuded areas identified in the proximal part and all ulcers in the distal part.
European Journal of Clinical Investigation 04/2010; 40(6):504-10. · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Capsule endoscopy and balloon endoscopy, advanced modalities that now allow for full investigation of the entire small intestine, have revealed that non-steroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the small intestine. Traditional NSAIDs can induce small intestinal injuries in over 50% of patients. Several studies have shown that the preventive effect of proton pump inhibitors does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with traditional NSAIDs use. Recently, several randomized controlled trials used capsule endoscopy to evaluate the preventive effect of certain drugs on NSAID-induced small intestinal injuries. These studies show that misoprostol and rebamipide have a preventive effect for NSAID-induced small intestinal mucosal injuries. However, these studies included only a small series of healthy volunteers and tested short-term NSAID treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs.
[Show abstract][Hide abstract] ABSTRACT: Pyogenic granuloma is a lobular capillary hemangioma that occurs mostly on the skin, and occasionally on the mucosal surface of the oral cavity, but very rarely in the gastrointestinal tract. We report the case of a 63-year-old woman who suffered from palpitations, and iron deficiency anemia for 5 years. Esophagogastroduodenoscopy and colonoscopy could not reveal significant bleeding focus. She had not received medical treatment except for oral iron. Capsule endoscopy revealed a bleeding focus in the small intestine. Afterwards, we carried out double balloon endoscopy to treat the lesion. We found a subpedunculated polyp in the small intestine at 100 cm away from ileocecal valve by double balloon endoscopy and resected it endoscopically. The histological features of the polyp were consistent with pyogenic granuloma. Anemia had improved gradually without giving oral iron after polypectomy.
[Show abstract][Hide abstract] ABSTRACT: Heregulin (HRG/NRG) ligation to erbB3/4 promotes their respective heterodimerization with erbB2, and consequent erbB2 tyrosine phosphorylation. Although HRG has been shown to be expressed in a variety of cancer tissues, its expression and role in colon cancer have yet to be clarified. We therefore examined the link between the expression of these erbB receptors, and the relationship between HRG and vascular endothelial growth factor (VEGF) expression in colon cancer.
We analyzed the effects of HRG on VEGF secretion in 6 colorectal cancer cell lines by enzyme-linked immunosorbent assay, and HRG-induced p85 subunit of phosphatidylinositol 3-kinase (p85 PI-3K), Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) activation in Caco-2 colon cancer cell lines by Western blot. We also examined HRG and VEGF mRNA expression in 16 colon cancer biopsy samples by real-time PCR. The localization of HRG and VEGF protein expression in colon cancer tissue was detected by immunohistochemistry.
Exogenous HRG stimulated VEGF secretion in all cell lines examined, and VEGF mRNA expression in Caco-2 cells. HRG also activated p85 PI-3K, Akt, ERK1/2, and p38 MAPK. VEGF secretion was inhibited by both specific p38 MAPK inhibitor and proteasome inhibitor that inhibit nuclear factor kappa B (NF-kappaB) activation. In colon cancer biopsy samples, HRG mRNA expression correlated with VEGF mRNA expression. HRG immunoreactivity was observed both in cancer cells and in mesenchymal cells in colon cancer tissues.
These data suggest that HRG might affect colon cancer growth by regulating VEGF secretion via the erbB3 signaling pathway through autocrine and paracrine mechanisms.
[Show abstract][Hide abstract] ABSTRACT: The early diagnosis of small-bowel tumors (SBT) was a difficult task until the advent of capsule endoscopy (CE) and double-balloon endoscopy (DBE) allowed access to the disease site. However, although CE and DBE have greatly simplified the task, DBE studies have yet to provide sufficient data on the diagnosis and outcome of patients with SBTs.
To determine the efficacy of DBE examination in the detection and diagnosis of SBT.
A retrospective analysis of cross-sectional case series.
Seven major medical centers in Japan.
The first 1035 consecutive DBE cases at these major Japanese centers since the introduction of DBE.
The percentage of subjects with SBT and a diagnosis of SBT, their indications for DBE, and diagnostic and therapeutic DBE procedures carried out for SBT.
SBTs were identified in 144 of 1035 subjects (13.9%) who underwent DBE between September 2000 and December 2005. For subjects with SBT, the most common indication for DBE was the suspected presence of a SBT (61/144 [42.4%]). For subjects without SBT, the most common indication was obscure GI bleeding (OGIB) (419/891 [47.0%]). Malignant lymphoma and GI stromal tumor (GIST) were the most frequent (31/144 [21.5%]) and the second-most frequent SBTs (27/144 [18.8%]), respectively, in this database. We also performed 85 biopsies and 45 therapeutic procedures for the evaluation and treatment of SBTs in 144 patients. Although complications were encountered in 5.3% of cases (14/266 sessions), none of these were life threatening in the present study.
DBE proved a valuable tool for the detection and diagnosis of SBTs, especially when tumors were suspected. Biopsies and therapeutic procedures were also possible in most of these patients, which directed our management of the disease.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to investigate the expression of three prostaglandin E synthase (PGES) isomers in colorectal cancer (CRC) tissue and to evaluate their relationship to clinicopathological factors and patient prognosis. Microsomal PGES (mPGES)-1, mPGES-2, cytosolic PGES (cPGES) and cyclooxygenase (COX)-2 protein expression were analyzed by real-time polymerase chain reaction and Western blot. The localization of each PGES and COX-2 protein was examined by immunohistochemistry in 155 surgical resections and correlated to clinicopathological factors and patient prognosis. mPGES-1 mRNA and protein levels were significantly higher in CRC than in paired normal tissues. mPGES-1 immunoreactivity localized in cancer cells in 43% of cases. mPGES-2 immunoreactivity was significantly more pronounced in cancer cells than in adjacent normal epithelium in 36% of cases. cPGES immunoreactivity was homogeneous in cancer cells and thus determined constitutive. mPGES-1 and mPGES-2 correlated with significantly worse prognosis in stage I-III patients. These results indicate that mPGES-1 and mPGES-2 may each play a role in CRC progression.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2009; 454(6):667-76. · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is no known preventive agent against nonsteroidal anti-inflammatory drug (NSAID) induced small-intestinal injury.
To evaluate by capsule endoscopy whether coadministration of prostaglandin (PG) can prevent small-intestinal damage induced by short-term NSAID treatment.
Single-blind, randomized, controlled trial.
All procedures were performed at Nippon Medical School.
Thirty-four healthy male volunteers.
All subjects were randomly assigned to 2 groups: an NSAID-control group, who underwent NSAID (diclofenac sodium, 25 mg 3 times daily) and omeprazole (20 mg once daily) treatment, and an NSAID-PG group, who received PG (misoprostol, 200 microg 3 times daily) in addition to the same NSAID-omeprazole treatment. Eligible subjects, 15 per group, underwent capsule endoscopy before and 14 days after treatment.
The number of mucosal breaks at capsule endoscopy.
NSAID treatment significantly increased the mean (SD) number of mucosal breaks per subject, from a basal level of 0.1 +/- 0.3 up to 2.9 +/- 6.3 lesions in the NSAID-control group (P = .012). In contrast, there was no significant change in the mean number of mucosal breaks before and after PG cotreatment (P = 0.42). Thus, the mean number of posttreatment mucosal breaks per subject was significantly higher in the NSAID-control group than in the NSAID-PG group (P = .028). There was a significant increase in the percentage of subjects in the NSAID-control group, with at least 1 mucosal break after treatment (from 6.7% to 53.3%), whereas there was no change in the incidence of mucosal breaks in the NSAID-PG group, which remained at 13.3%. (P = .002).
Single-center, open-label study.
PG cotherapy reduced the incidence of small-intestinal lesions induced by a 2-week administration of diclofenac sodium.
[Show abstract][Hide abstract] ABSTRACT: Studies suggest that synbiotic therapy could prove more effective in the treatment of ulcerative colitis (UC) than therapies limited to probiotics or prebiotics. This study compared the effect of each of these therapies in the treatment of UC.
One hundred twenty outpatients with UC were randomly sorted into three groups of 40 patients each for probiotic, prebiotic, or synbiotic therapy. The probiotic group ingested one daily capsule consisting of Bifidobacterium longum 2 x 10(9) colony-forming units and the prebiotic group ingested daily 8.0-g doses of psyllium. The synbiotic group underwent both treatments. All patients completed Inflammatory Bowel Disease Questionnaires (IBDQs) at the onset of the trial, at the 2-wk midpoint, and at the 4-wk end of the trial. Blood variables were also evaluated in a subset of 32 patients randomly selected from all groups and values were compared with IBDQ scores.
Thirty-one patients in the probiotic group, 31 in the prebiotic group, and 32 in the synbiotic group qualified for analyses. The remaining 26 patients had incomplete questionnaires. Total IBDQ scores improved within groups by the end of the trial (probiotics 162 to 169, NS; prebiotics 174 to 182, NS; synbiotics 168 to 176, P = 0.03). Individual scores improved as follows: probiotics, emotional function (P = 0.03); prebiotics, bowel function (P = 0.04); and synbiotics, systemic and social functions (P = 0.008 and P = 0.02). C-reactive protein decreased significantly only with synbiotic therapy (from 0.59 to 0.14 mg/dL, P = 0.04). There were no adverse events.
Patients with UC on synbiotic therapy experienced greater quality-of-life changes than patients on probiotic or prebiotic treatment. These data suggest that synbiotic therapy may have a synergistic effect in the treatment of UC.