non-UC Patients Research Articles

1139 MICRORNAS DETECTION AS URINE MARKERS IN PATIENTS WITH UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 20101139 MICRORNAS DETECTION AS URINE MARKERS IN PATIENTS WITH UROTHELIAL CARCINOMA Hideki Enokida, Takeshi Chiyomaru, Kazumori Kawakami, Kazuya Kawahara, Masahiko Inahara, Satoko Kojima, Kenryu Nishiyama, Naohiko Seki, and Masayuki Nakagawa Hideki EnokidaHideki Enokida Kagoshima, Japan More articles by this author , Takeshi ChiyomaruTakeshi Chiyomaru Kagoshima, Japan More articles by this author , Kazumori KawakamiKazumori Kawakami Kagoshima, Japan More articles by this author , Kazuya KawaharaKazuya Kawahara Kagoshima, Japan More articles by this author , Masahiko InaharaMasahiko Inahara Chiba, Japan More articles by this author , Satoko KojimaSatoko Kojima Chiba, Japan More articles by this author , Kenryu NishiyamaKenryu Nishiyama Kagoshima, Japan More articles by this author , Naohiko SekiNaohiko Seki Chiba, Japan More articles by this author , and Masayuki NakagawaMasayuki Nakagawa Kagoshima, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.638AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Currently, tumor marker for urothelial carcinoma (UC) depends on urine cytology because of its high sensitivity (around 95%) despite of its low sensitivity (around 30%). Bladder tumor antigen (BTA) and nuclear matrix protein (NMP)-22 are are not widely used because of their low specificity for distinguishing UC from non-malignant diseases. MicroRNAs are small noncoding RNAs of about 22 nucleotides in length, that function as negative regulators of gene expression through antisense complimentarily to specific messenger RNAs. Recent studies suggest that aberrant microRNA expression contribute to the development of various human malignancies. Our previous miRNA screening of UC demonstrated that miR-96 and miR-183 were the top 2 up-regulated miRNAs among 667 miRNAs examined. We hypothesize that these microRNAs are detectable in urine and useful biomarkers for distinguishing UC- from non-UC patients. METHODS Total RNA of urine was extracted from 54 UCs, 15 urinary tract infections (UTIs) and 27 healthy controls (HCs). A real-time PCR based experiment was used to evaluate expression levels of the miRNAs. The expression level of each miRNA was calculated by a following formula: expression level = 2(40-Ct). RESULTS The expression levels of miR-96 and miR-183 in urine from UCs were significantly higher than that from UTIs or HCs (each p < 0.0001). ROC curve analysis revealed that miR-96 and miR-183 have good sensitivity (70.4 and 74.1%, respectively) and specificity (90.5 and 71.4%, respectively) to distinguish UC from non-UC patient. We found significant difference in miR-96 expressions between invasive (> pTa) and non-invasive (pTa) UCs (p = 0.0271), but a trend in miR-183 (p = 0.0508). There were significant differences in miR-96 or miR-183 expressions between the samples from pre- and post operation (p < 0.05). To our surprise, miR-96 was positively detected in 11 of 20 UC patients who had a negative diagnosis by urine cytology. When we combined microRNA analysis with urine cytology in our cohort, the sensitivity and the specificity reached to 78% and 90.5%, respectively for UC detection. CONCLUSIONS Our data suggest that detection of miR-96 and miR-183 may serve as potential biomarkers for UC. Diagnostic accuracy for urothelial carcinoma can be improved by a combination of urine cytology and the microRNAs detection. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e441 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hideki Enokida Kagoshima, Japan More articles by this author Takeshi Chiyomaru Kagoshima, Japan More articles by this author Kazumori Kawakami Kagoshima, Japan More articles by this author Kazuya Kawahara Kagoshima, Japan More articles by this author Masahiko Inahara Chiba, Japan More articles by this author Satoko Kojima Chiba, Japan More articles by this author Kenryu Nishiyama Kagoshima, Japan More articles by this author Naohiko Seki Chiba, Japan More articles by this author Masayuki Nakagawa Kagoshima, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Presence of a marked nonneuronal cholinergic system in human colon: Study of normal colon and colon in ulcerative colitis

The body has not only a neuronal but also a nonneuronal cholinergic system. Both systems are likely to be very important, particularly in inflammatory conditions. The patterns and importance of the nonneuronal cholinergic system in patients with ulcerative colitis (UC) are largely unknown. The colons of UC and non-UC patients were examined for expression patterns of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and the muscarinic receptor of the M(2) subtype. ChAT and VAChT immunoreactions and mRNA reactions for ChAT were detected in epithelial and endocrine cells, in cells in the lamina propria, and in blood vessel walls. Furthermore, a marked M(2) immunoreaction was noted for epithelium, blood vessel walls, and smooth musculature. ChAT and VAChT immunoreactions were significantly higher in endocrine and epithelial cells, respectively, in non-UC mucosa than in UC mucosa. On the other hand, there was a tendency toward higher M(2) levels in epithelium of UC patients. There is a pronounced nonneuronal cholinergic system in the colon, which has previously been ignored when discussing cholinergic influences in UC. Furthermore, it is evident that certain changes in the nonneuronal cholinergic system occur in response to inflammation/derangement in UC. Cholinergic effects in the colon can be considered to be related not only to nerve-related effects but also to effects of acetylcholine from nonneuronal local cells. Thus, the recently discussed phenomenon of a "cholinergic antiinflammatory pathway" in the intestine may have a pronounced nonneuronal component.

Decrease in Binding for the Neuropeptide VIP in Response to Marked Inflammation of the Mucosa in Ulcerative Colitis

The neuropeptide vasoactive intestinal peptide (VIP) is involved in the neuroimmunomodulation of the intestine. In the present study, specimens from the sigmoid colon of ulcerative colitis (UC) and non-UC patients were examined for immunohistochemistry and in vitro receptor autoradiography. Marked occurrence of VIP binding was observed in the mucosa. However, there were very low levels of binding in areas showing pronounced inflammation/derangement. The study shows that marked derangement of the mucosa leads to a distinct decrease in VIP binding. Thus, it is possible that a decrease in trophic and anti-inflammatory VIP effects occurs in areas exhibiting a very marked inflammation.

HEALTH OUTCOMES AMONG PATIENTS WITH ULCERATIVE COLITIS

Purpose: To assess the occurrence of health outcomes among patients with ulcerative colitis (UC) by age and sex, rates of medical encounters were compared between UC patients and a comparable population without any inflammatory bowel disease. Methods: The data source was medical claims of a health plan, which has over 7 million members within 25 states (Ingenix Lab/Rx Database™). Among members with at least two continuous years in the health plan, UC patients were identified by a medical claim with a diagnosis code of ICD-9-CM 556 in at least two ambulatory visits or one hospitalization. The control cohort, matched 4:1 on sex and year of birth, had no diagnoses of inflammatory bowel disease (ICD-9-CM 555.0 – 558.9). Three outcome measures were rates of ambulatory visits, hospitalizations, and hospitalizations for a surgical operation on the digestive system. Results: During 3.5 years of observation there were 12,061 UC patients, corresponding to a prevalence of 236 per 100,000 persons within the plan. The demographic profile of the UC population was 53% males and 47% females; 24% less than 35 years of age, 64% ages 35–64, and 12% age 65 and over. Among the UC population, an individual averaged 15 ambulatory visits per year. Of every 1,000 UC patients during a one year period, there were 202 hospitalizations, of which 57 included a gastrointestinal surgery. Among the non-UC population, an individual averaged 7 ambulatory visits per year. Of every 1,000 non-UC patients during a one year period, there were 63 hospitalizations, of which 7 included a gastrointestinal surgery. The rate ratios of medical outcomes between UC and non-UC patients were the most pronounced among younger males (< 35 years old) as shown in the table below.Table 1: Rate ratios for occurence of selected medical events between population with ulcerative colitis and population without IBD, by age and sex.Conclusions: The substantial increase in hospitalizations and subsequent surgeries of younger men with UC is a new finding. It presents a unique challenge to raising both disease awareness and treatment adoption in these patients and warrants further study.

Annexin 1 is secreted in situ during ulcerative colitis in humans.

Although annexin l exerts extracellular anti-inflammatory properties, little is known about its release in inflammatory diseases. Here, we characterized annexin 1 secretion in ulcerative colitis (UC) patients. Annexin 1 was detected by immunoblotting, in tissue homogenates and supernatants of colonic biopsies incubated in culture media, and in luminal colonic perfusates of UC patients. Annexin 1 was released by inflamed colonic biopsies from patients having severe UC but not by biopsies from healthy colon of the same patient or by biopsies from non-UC patients or from patients with slight or moderate UC. Annexin 1 was detected in luminal colonic perfusates of patients having moderate or slight UC but not in perfusates from control patients. The level of annexin 1 expression and secretion was unrelated to long-term glucocorticoid treatment, but annexin 1 secretion in perfusates was induced, in some patients, by short-term glucocorticoid exposure. These results show that annexin 1 is secreted endogenously in the colon of patients with UC. This secretion, which occurs both in vitro and in vivo, depends on the severity of inflammation. Given the anti-inflammatory effects of annexin 1, this protein may serve to down-regulate the inflammatory response in the course of inflammatory bowel disease.

Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis

Background & Aims: A previously published study by our group suggested that adenoma-like dysplasia-associated lesions or masses (DALMs) in ulcerative colitis (UC) may be treated adequately by polypectomy and continued endoscopic surveillance. The length of follow-up evaluation in these patients averaged only 42 months. The purpose of this study was to evaluate the long-term outcome of our previously defined group of UC patients, all with adenoma-like DALMs, who were treated by polypectomy. Methods: The clinical, endoscopic, and pathologic outcome of 34 UC patients, 24 with an adenoma-like DALM, and 10 with a coincidental sporadic adenoma, 28 of whom were treated by polypectomy and continued endoscopic surveillance, and 6 by colonic resection, were compared with the outcome of 49 non-UC patients who were treated similarly for a sporadic adenoma. The mean length of follow-up evaluation averaged 82.1 months and 71.8 months for the 2 UC subgroups, respectively, and 60.4 months for the non-UC controls. Results: Overall, 20 of 34 UC patients (58.8%) developed at least one further adenoma-like DALM on follow-up evaluation. One patient had flat low-grade dysplasia present in the colon, which was resected within 6 months of the initial polypectomy, and another patient, with primary sclerosing cholangitis, developed adenocarcinoma 7.5 years after her initial polypectomy. There was no significant difference in the prevalence of polyp formation on follow-up evaluation between UC patients with an adenoma-like DALM (62.5%) and UC patients with a sporadic adenoma (50%), or between either of these 2 UC patient subgroups and the non-UC sporadic adenoma patient group (49%; P > 0.05). Conclusions: UC patients who develop an adenoma-like DALM may be treated adequately by polypectomy with complete excision and continued endoscopic surveillance.

Autoimmunity in ulcerative colitis (UC): a predominant colonic mucosal B cell response against human tropomyosin isoform 5.

We set out to examine if the IgG-producing cells in the colonic mucosa in UC are committed to tropomyosin isoform 5 (hTM5), a putative autoantigen in UC. Lamina propria mononuclear cells (LPMC) were isolated from colonoscopic biopsy specimens from recto-sigmoid and proximal colon. Twenty-three patients with UC, eight with Crohn's colitis (CC), and 10 non-inflammatory bowel disease (non-IBD) controls were included. The ELISPOT assays were used to quantify lamina propria B cells producing total immunoglobulin (IgA, IgG, IgM), IgG, IgA, as well as IgG against hTM5 isoform. The median value of percentage of total IgG-producing lymphocytes was similar in UC (12%) and CC (11%), but was significantly (P < 0.0002) higher than non-IBD controls (6%). However, in UC, but not in CC and non-IBD, a large number of lamina propria B cells produced IgG against hTM5 (median values: UC 42%, CC 2.5%, non-IBD 0%). This difference in UC when compared with CC and non-IBD was highly significant (P < 0.00001). Twenty-one of 23 (91%) patients with UC had percentage of anti-hTM5 IgG-producing immunocytes more than 2 s. d. above the mean for non-UC patients. In UC but not in CC and non-IBD controls, the increased number of IgG-producing cells are largely committed to produce IgG against hTM5-related epitope(s).

Colon carcinoma in patients undergoing liver transplantation

Background: Organ recipients are at risk for certain neoplasms. Ulcerative colitis (UC) is itself a strong risk factor for the development of colon carcinoma (CCa). Transplant patients with UC might be at higher risk for CCa. We analyzed these patients to compare the incidence and pattern of CCa development in these and non-UC patients following liver transplantation (OLTX). Patients and methods: Retrospective study of 1,085 OLTX patients. Results: In 1,022 patients without UC, 1 patient (<0.1%) developed adenocarcinoma in a colonic polyp 46 months after OLTX. Sixty-three of 108 (60%) patients undergoing OLTX simultaneously had UC. Five OLTX patients (8%) with UC developed colon adenocarcinoma 22 to 66 (mean 48) months after OLTX. Two have died. Conclusions: Coexistent UC in patients requiring OLTX constitutes a potentially high risk for the development of colonic cancer, a late-appearing event. These patients require close observation and frequent colonoscopic/histologic screening of the colon.

Modulatory effects of the colonic milieu on neutrophil oxidative burst: A possible pathogenic mechanism of ulcerative colitis

An important hallmark of ulcerative colitis (UC) is mucosal neutrophil (PMN) infiltration associated with mucosal damage. This suggests that colonic chemoattractants such as bacterial products (e.g., N-formyl-methionyl-leucyl-phenylalanine (fMLP), lipopolysaccharide (LPS)) reach systemic circulation and attract PMNs to the colon. PMNs are then activated in the colonic mucosa and release their toxic oxidative metabolites. However, bacterial products are also present in the systemic circulation of healthy subjects. Thus we hypothesized that PMNs develop tolerance to colonic factors in the normal state and that this tolerance is absent in UC. We evaluated the PMN respiratory burst in response to stimulation with fMLP, LPS, or phorbol 12-myristate 13-acetate (PMA) by measuring the production of reactive oxygen species (ROS) with both luminol-enhanced chemiluminescence and a cytochrome C reduction assay. PMNs were obtained from control subjects, inactive UC patients, patients with UC who had undergone colectomies, and non-UC patients with colectomies. All three stimuli induced a significant rise in ROS. PMNs from non-UC colectomy subjects produced significantly higher ROS than PMNs from control subjects with intact colons in response to both fMLP and LPS. In contrast, PMNs from UC colectomy patients produced levels of ROS similar to those produced by PMNs from UC patients with intact colons in response to fMLP and LPS. Colectomy had no effect on PMA-induced ROS production in controls. The observed difference in fMLP-induced ROS production in control subjects with intact colons was not due to fMLP receptor down-regulation because a competition assay performed with the fMLP blocker BMLP showed a similar receptor apparent affinity in all four groups. We conclude the following: (1) the normal colonic milieu modulates the PMN respiratory burst, resulting in hyporesponsiveness of PMNs to “physiologic” but not “pharmacologic” stimulation. This effect is not due to receptor down-regulation. (2) UC colonic milieu does not appear to modulate PMN respiratory burst. This loss of PMN “tolerance” to colonic factors may have a pathogenic role in the sustained inflammation and tissue damage in UC.