Computer-Aided Imaging Analysis of Probe-Based Confocal Laser Endomicroscopy With Molecular Labeling and Gene Expression Identifies Markers of Response to Biological Therapy in IBD Patients: The Endo-Omics Study.

BACKGROUND: We aimed to predict response to biologics in inflammatory bowel disease (IBD) using computerized image analysis of probe confocal laser endomicroscopy (pCLE) in vivo and assess the binding of fluorescent-labeled biologics ex vivo. Additionally, we investigated genes predictive of anti-tumor necrosis factor (TNF) response. METHODS: Twenty-nine patients (15 with Crohn's disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4ß7 therapy. Biopsies were taken for fluorescein isothiocyanate-labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort. RESULTS: In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn's disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7). CONCLUSIONS: Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF-responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders.

Cannabis is associated with clinical but not endoscopic remission in ulcerative colitis: A randomized controlled trial.

BACKGROUND: Cannabis is often used by patients with ulcerative colitis, but controlled studies are few. We aimed to assess the effect of cannabis in improving clinical and inflammatory outcomes in ulcerative colitis patients. METHODS: In a double-blind, randomized, placebo-controlled trial, patients received either cigarettes containing 0.5 g of dried cannabis flowers with80mgTetrahydrocannabinol (THC)or placebo cigarettes for 8 weeks. Parameters of disease including Lichtiger disease activity index, C reactive protein (CRP), calprotectin, Mayo endoscopic score and quality of life (QOL) were assessed before, during and after treatment. RESULTS: The study included 32 patients. Mean age was 30 years, 14 (43%) females. Lichtiger index improved in the cannabis group from 10.9 (IQR 9-14) to5 (IQR 1-7), (p<0.000), and in the placebo group from 11 (IQR 9-13) to 8 (IQR 7-10)(p = 0.15, p between groups 0.001). QOL improved in the cannabis group from 77±4 to 98±20 (p = 0.000) but not in the placebo group (78±3 at week 0 and 78±17 at week 8;p = 0.459; p between groups 0.007). Mayo endoscopic score changed in the cannabis group from 2.13±1 to 1.25±2 (p = 0.015) and in the placebo group from 2.15±1to 1.69±1 (p = 0.367, p between groups 0.17). CONCLUSION: Short term treatment with THC rich cannabis induced clinical remission and improved quality of life in patients with mild to moderately active ulcerative colitis. However, these beneficial clinical effects were not associated with significant anti-inflammatory improvement in the Mayo endoscopic score or laboratory markers for inflammation.(clinicaltrials.gov NCT01040910).

Twice-daily Budesonide 2-mg Foam Induces Complete Mucosal Healing in Patients with Distal Ulcerative Colitis.

BACKGROUND AND AIMS: Mucosal healing is an important therapeutic goal for ulcerative colitis. Once-daily administration of budesonide 2-mg foam is widely used for inducing clinical remission. No study has assessed the usefulness of twice-daily budesonide 2mg foam on mucosal healing in ulcerative colitis patients. We explored the efficacy for mucosal healing of once- or twice-daily budesonide foam in distal ulcerative colitis patients. METHODS: This study was a multicentre, randomised, double-blind, placebo-controlled trial. In all, 165 patients with active, mild to moderate distal ulcerative colitis were randomised to three groups: once- or twice-daily budesonide 2mg/25ml foam, or placebo foam, for 6 weeks. Complete mucosal healing [endoscopic subscore = 0] and the safety profile were assessed at Week 6. Prespecified and post hoc analyses were used. RESULTS: The percentages of complete mucosal healing in the twice-daily budesonide foam group were 46.4% compared with 23.6% in the once-daily group [p = 0.0097], or 5.6% in the placebo group [p < 0.0001]. The percentages of clinical remission and the percentages of endoscopic subscore ≤ 1 in the twice-daily budesonide foam group were 48.2% and 76.8%, compared with 50.9% and 69.1% in the once-daily group [no difference], or 20.4% and 46.3% in the placebo group [p = 0.0029 and p = 0.0007], respectively. In the subgroup of patients with previous use of a 5-aminosalicylic acid suppository or enema, there was a greater percentage of complete mucosal healing in the twice-daily budesonide foam group [32.0%] compared with that in the once-daily [8.7%, p = 0.0774] or placebo groups [4.8%, p = 0.0763], though there was no significant difference. No serious adverse event occurred. CONCLUSIONS: A significantly greater percentage of patients receiving twice-daily administration of budesonide foam compared with once-daily administration/placebo achieved complete mucosal healing. This is the first study to evaluate the endoscopic efficacy of twice-daily administration of 6-week budesonide foam treatment for ulcerative colitis.

ACR Appropriateness Criteria on colorectal cancer screening.

Colorectal cancer remains one of the most common causes of cancer death in this country. This malignancy is ideally suited for screening because the detection and removal of the precursor adenomatous polyp can prevent most colorectal cancers from ever forming. The choice of a test for screening involves consideration of various individual parameters, including patient age and the presence of risk factors for the development of colorectal cancer. Computed tomographic colonography (CTC) has emerged as the leading imaging technique for colorectal cancer screening in average-risk individuals on the basis of the evidence presented in this paper. The double-contrast barium enema is an alternative imaging test that is appropriate particularly when CTC is not available. In 2008, the American Cancer Society guideline for colorectal cancer screening was revised jointly with the US Multi-Society Task Force on Colorectal Cancer and the ACR to include CTC every 5 years as an option for average-risk individuals. Computed tomographic colonography is also the preferred test for colon evaluation after an incomplete colonoscopy. Imaging tests including CTC and the double-contrast barium enema are usually not indicated for colorectal cancer screening in high-risk patients with polyposis syndromes or inflammatory bowel disease. This paper presents the new colorectal cancer imaging test ratings and is the result of evidence-based consensus by the ACR Appropriateness Criteria Expert Panel on Gastrointestinal Imaging.

[Analysis of risk factors for low bone mineral density in patients with inflammatory bowel disease].

BACKGROUND/AIMS: Several clinical risk factors for low bone mineral density (BMD) in the patients with inflammatory bowel disease (IBD) have been suggested. However, its prevalence and pathophysiology in Korean population have not been fully studied. The aim of this study was to investigate the prevalence and risk factors for low BMD in Korean IBD patient. METHODS: BMD of the lumbar spine and femur was evaluated using dual-energy X-ray absorptiometry in 30 patients with IBD. Biochemical parameters of bone metabolism, such as serum calcium, phosphorus, osteocalcin, and deoxypyridinoline were measured. The associations between low BMD and clinical parameters such as disease duration, disease activity, drug history, body mass index (BMI), and others were evaluated retrospectively using medical records. RESULTS: Low BMD at the lumbar spine or femur was observed in 63.3% of the patients, and there was no significant difference between the patients with Crohns disease and ulcerative colitis. Clinical and biochemical parameters were irrelevant to BMD. In the patients without glucocorticoid treatment prior to BMD measurement, already 50.0% of patients had low BMD. CONCLUSIONS: Low BMD is a common feature in Korean IBD patients, even those who do not use glucocorticoid. The multiple factors may be involved in the pathogenesis of low BMD. Therefore, BMD should be examined in all IBD patients, irrespective of glucocorticoid treatment.

Diagnostic performance of CT colonography in a population with high prevalence of large bowel disease.

BACKGROUND: Although CT colonography (CTC) is a well-known diagnostic modality, it is not yet established as an official screening method mainly due to discrepancies in diagnostic accuracy values reported in the literature. We examined the diagnostic accuracy of CTC in a population with suspicion of large bowel disease. MATERIAL/METHODS: CTC was performed in 77 patients with 2- and 16-slice CT units after the standard preparation. The results were compared with optical colonoscopy (39%) and/or barium enema (35%) and pathomorphological examinations (44%) and statistically evaluated. RESULTS: CTC visualized large bowel pathology in 75% of patients. Its diagnostic accuracy vs. optical colonoscopy was significant (C=0.8719, p<0.0001) and higher than that of barium enema (C=0.7774, p<0.0001). CTC was the most accurate in the diagnosis of colorectal carcinoma (C=0.7071). There was statistically significant accuracy between CTC and optical colonoscopy in the evaluation of polyps diameter (C=0.7657), localization (C=0.8913), and morphology (C=0.7568). CTC was the most accurate in depicting large polyps (<10 mm): its sensitivity was 100% and specificity 98%. The diagnostic accuracy of CTC was also statistically significant compared with pathomorphology (C=0.7812, p<0.0001). In 78% of the examined patients, extra-colonic findings were visualized with CTC, 13% of which were clinically important and 22% of which had been occult before. CONCLUSIONS: The diagnostic accuracy of CTC in patients from a population with a high prevalence of large bowel disease was statistically significant. It also enabled the visualization of pathological findings in extra-colonic locations.

[X-ray colonometry in the diagnosis of colonic dyskinesias and inflammatory diseases].

Clinical and X-ray studies were made in 316 patients, which revealed intestinal dyskinesia, chronic colitis, and nonspecific ulcerative colitis in 105, 133, and 78 patients, respectively. Irrigoscopy (administration of a contrast enema, examination of the mucosal contour, and double contrasting) was performed in all the patients, by analyzing X-ray planimetric indices. X-ray colonoplanimetry makes it possible to objectify the interpretation of the X-ray pattern in chronic inflammatory diseases of the large bowel and colonic dyskinesia.

[Radiological diagnosis of ulcerative colitis].

In cases with ulcerative colitis, barium enema is valuable in objectively determining the stage (active, inactive) and defining the extent and aggressiveness of the disease that often varies during the course. The preparation, findings, and differential diagnosis of the technique are reviewed.

[Imaging diagnosis of inflammatory bowel disease]. / Bildgebende Diagnostik chronisch entzündlicher Darmerkrankungen.

The term "chronic inflammatory bowel disease" represents a spectrum of diseases out of which ulcerous colitis and Crohn's disease are the far most common. Large bowel enemas have lost their relevance compared to colonoscopy over the past years and small bowel enteroclysis has also been widely replaced by CT- and especially MR-enteroclysis meanwhile. The diagnostic value of computed tomography and MR-tomography in chronic inflammatory bowel disease is based on the excellent visualization and documentation of extent and severity of bowel wall inflammation, estimation of inflammatory activity of the disease and of detection of potential extraintestinal complications and/or additional diagnoses by these two methods. Nevertheless, conventional radiological techniques as well as sonography may still be valuable under certain conditions. Furthermore, nowadays imaging of chronic inflammatory bowel diseases includes also White Blood Cell scintigraphy as well as Positrone Emission Tomography which provide informations about extent and especially activity of the disease. The presented article provides an overview of the possibilities and limitations of the available imaging modalities in inflammatory bowel diseases and helps the reader to decide under what conditions which one of the available examinations should be regarded as the most appropriate and promising one.

[Barium examinations of the small intestine and the colon in inflammatory bowel disease]. / Konventionelle Dünn- und Dickdarmdiagnostik bei entzündlichen Darmerkrankungen.

PURPOSE: This article gives an overview of the possibilities of conventional radiography in the diagnosis of inflammatory bowel disease of the small intestine and colon. MATERIAL AND METHODS: For more than 25 years we examine the small bowel employing enteroclysis with barium and methylcellulose and the colon with the usual double-contrast method. In the last 152 months 1560 small bowel enemas were performed. In the last 40 months 410 examinations of the colon were performed. RESULTS: There is a thirty percent decrease in enteroclysis examinations within the past 5 years,however, the rate of examinations with positive results increased from 46 to 57%. The proportion of the inflammatory small intestinal diseases (not only Crohn's disease) remained constant with 18%.Concerning the examinations of the colon for inflammatory disease we confirmed the diagnosis in seven cases. The radiation exposure for the enteroclysis in inflammatory diseases was 7 mSv, for colon examinations 14 mSv. CONCLUSION: Barium examinations, especially of the stomach and colon are decreasing in frequency. Therefore the art of performance and interpretation might get lost.Enteroclysis, however, is still the method of reference for the other imaging methods. The advantages compared to the other imaging methods are the excellent presentation of the details of the mucosal surface and the observation of functional disorders.

[Computed tomography in the diagnosis of inflammatory bowel disease -- methodology of MSCT and clinical results]. / Die Computertomographie in der Diagnostik entzündlicher Darmerkrankungen: Methodik der MSCT und klinische Ergebnisse.

PURPOSE: This paper discusses the diagnostic yield of multislice computed tomography (MSCT) in inflammatory bowel disease. METHODS: Contrast media are administered intraluminally (colon, small intestine) and intravenously (triple contrast CT). Filling of small bowel is achieved by means of jejunal tube ("Sellink CT") or via the oral route. Pharmacological relaxation of the intestine decreases motion artifact. Intraluminal contrast media consist of either hyperdense, "positive" or hypodense, "negative" liquids. RESULTS: Thin-slice MSCT of the entire abdomen allows high-quality post processing (MPR, thin-slice MIP). Due to superior distension, Sellink CT improves estimation of stenosis or changes in thickness and contrast of bowel wall. Positive contrast is superior in the detection and preoperative localization of abscess, fistula or conglomerate tumour, because it accurately differentiates between intra- and extraluminal structures.However, negative contrast facilitates quantitative evaluation of bowel wall thickening or enhancement and demonstrates gastrointestinal bleeding. CONCLUSION: MSCT of the small intestine is superior to conventional enteroclysis, especially in the diagnosis of mesenterial or other extraintestinal disease. As a side effect, the colon is assessed in the same examination. Radiation dose is less in MSCT (7.8-13.3 mSv) than in conventional fluoroscopy (13.99+/-7.57 mSv). MSCT can be performed as an alternative or adjunct to colonoscopy, if endoscopic access is restricted. It is already the imaging modality of choice in acute diverticulitis.

[Hydrocolonic sonography in the diagnostics of ulcerative colitis]. / Zastosowanie hydrosonografii w diagnostyce wrzodziejacego zapalenia jelita grubego.

The present study was to assess the diagnostic value of hydrocolonic sonography in patients with ulcerative colitis (UC). 32 patients with clinical diagnosis of UC or with the symptoms of the disease were examined with hydrocolonic sonography, and subsequently with double-contrast enema radiography. 18 healthy subjects were examined as controls. Special attention was paid to the bowel wall thickness and stratification, the bowel lumen, haustration and peristaltic activity. Mean colonic wall thickness in UC patients was 2.45 +/- 0.5 mm and it was significantly higher than in the controls (p < 0.001). In UC patients the wall was hypoechoic with usually stratification preserved. Hydrocolonic sonography had sensitivity of 90.6% in the determination of the extent of lesions. Hydrocolonic sonography seems to be a valuable modification of the classic sonography, which enables noninvasive monitoring of the large intestine.

Doppler sonography of the inferior and superior mesenteric arteries in ulcerative colitis.

PURPOSE: The purpose of this study was to evaluate the Doppler sonographic blood-flow parameters and spectral patterns in the inferior mesenteric artery (IMA) and superior mesenteric artery (SMA) in patients with active and inactive (remission-phase) ulcerative colitis (UC). METHODS: The IMAs and SMAs of 25 patients with active-phase UC (group 1), 19 patients with remission-phase UC (group 2), and 22 healthy, asymptomatic subjects (control group) were evaluated by duplex Doppler sonography. The 25 patients in group 1 were categorized into 2 subgroups on the basis of the extent of disease as determined by double-contrast barium enema x-ray study and colonoscopy. The first subgroup (group 1a) consisted of 11 patients with active involvement of the left colon from the rectum to the splenic flexure. The second subgroup (group 1b) consisted of 14 patients with active involvement of the entire colon. The peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (Vmean), resistance index (RI), and pulsatility index (PI) were determined from the Doppler spectral analysis. The inner diameter and cross-sectional area of the IMA and SMA were measured, and the blood-flow volume was calculated. The results were compared between the patient groups and control subjects. RESULTS: In the IMA, the mean blood-flow volume, mean PSV, mean EDV, and Vmean were significantly higher, the mean PI was significantly lower, and the mean diameter and the mean cross-sectional area were significantly larger in group 1 than in group 2 or in the control group (p < 0.001). The mean PSV and the Vmean of the IMA were significantly higher in group 1a than in group 1b (p < 0.05). The mean blood-flow parameters in the SMA were not significantly different between groups 1 and 2 or between either group 1 or group 2 and the control subjects. The mean EDV in the SMA was significantly higher and the mean PI and the mean RI were significantly lower in group 1b than in group 1a (p < 0.01). CONCLUSIONS: Duplex Doppler sonography of the IMA and SMA can be used to evaluate inflammatory disease of the large bowel, to assess disease extent, and to document response to therapy.

Functional results and visceral perception after ileo neo-rectal anastomosis in patients: a pilot study.

INTRODUCTION: To reduce pouch related complications after restorative proctocolectomy, an alternative procedure was developed, the ileo neo-rectal anastomosis (INRA). This technique consists of rectal mucosa replacement by ileal mucosa and straight ileorectal anastomosis. Our study provides a detailed description of the functional results after INRA. PATIENTS AND METHODS: Eleven patients underwent an INRA procedure with a temporary ileostomy. Anorectal function tests were performed two months prior to and six and 12 months after closure of the ileostomy and comprised: anal manometry, ultrasound examination, rectal balloon distension, and transmucosal electrical nerve stimulation (TENS). Function was subsequently related to the histopathology of rectal biopsy samples. RESULTS: Median stool frequency decreased from 15/24 hours (10-25) to 6/24 hours (4-11) at one year. All patients reported full continence. Anal sensibility, and resting and squeeze pressures did not change after INRA. Rectal compliance decreased (2.1 (0.7-2.8) v 1.5 (0.4-2.2) and 1.4 (0.8-3.7) ml/mm Hg (p=0.03)) but the maximum tolerated volume increased (70 (50-118) v 96 (39-176) (NS) and 122 (56-185) ml (p=0.03)). Decreasing rectal sensitivity was found: the maximum tolerated pressure increased (14 (8-24) v 22 (8-34) (NS) and 26 (14-40) (p=0.02)) and the rectal threshold for TENS displayed a similar tendency. All patients displayed a low grade chronic inflammatory infiltrate in neorectal biopsy samples before closure of the ileostomy, with no change during follow up. CONCLUSIONS: The technique of INRA provides a safe alternative for restorative surgery. Stool frequency after INRA improves with time and seems to be related to decreasing sensitivity and not to histopathological changes in the neorectum. Furthermore, after the INRA procedure, all patients reported full continence.

[MRI in chronic inflammatory bowel disease]. / MRT chronisch entzündlicher Darmerkrankungen.

Chronic inflammatory bowel disease is diagnosed and monitored by the combination of colonoscopy and small bowel enteroklysis. Magnetic resonance imaging has become the gold standard for the imaging of perirectal and pelvic fistulas. With the advent of ultrafast MRI small and large bowel imaging has become highly attractive and is being advocated more and more in the diagnostic work up of inflammatory bowel disease. Imaging protocols include fast T1-weighted gradient echo and T2-weighted TSE sequences and oral or rectal bowel distension. Furthermore, dedicated imaging protocols are based on breath-hold imaging under pharmacological bowel paralysis and gastrointestinal MR contrast agents (Hydro-MRI). High diagnostic accuracy can be achieved in Crohn's disease with special reference to the pattern of disease, depth of inflammation, mesenteric reaction, sinus tract depiction and formation of abscess. In ulcerative colitis, the mucosa-related inflammation causes significantly less bowel wall thickening compared to Crohn's disease. Therefore with MRI, the extent of inflammatory changes is always underestimated compared to colonoscopy. According to our experience in more than 200 patients as well as the results in other centers, Hydro-MRI possesses the potential to replace enteroklysis in the diagnosis of chronic inflammatory bowel disease and most of the follow-up colonoscopies in Crohn's disease. Further technical improvements in 3D imaging will allow interactive postprocessing of the MR data.

[Radiographic diagnosis of ulcerative colitis and Crohn disease]. / Rendgenska dijagnostika ulceroznog kolitisa i Crohnove bolesti.

Radiological diagnosis of the inflammatory bowel disease (IBD), ulcerative colitis and Crohns disease, is establishing by plain abdominal philm, barium enema study and enteroclisis. Inspite of difficult radiologic differential diagnosis during advanced stage of the IBD (regarding similar radiological signs), in the early stage of the IBD radiological diagnosis can be reached using regular algorithm of the investigation and knowing and recognising early signs. We described differential basic radiological signs of both IBD.

Ultrasonography in the evaluation of extension, activity, and follow-up of ulcerative colitis.

BACKGROUND: The purpose of the study was to establish the clinical significance of bowel-wall thickening, measured by ultrasound, in ulcerative colitis (UC) and to evaluate the usefulness of ultrasonography (US) to define the extension, the severity, and the response to medical treatment of this pathologic condition. METHODS: Thirty consecutive patients with active UC were studied on two different occasions 2 months apart and after treatment with steroids. On both occasions the clinical, endoscopic, and biochemical activity of the disease and the ultrasonographic examination of the intestinal walls were evaluated. The maximum bowel wall thickness (BWT) was considered an index of ultrasonographic activity, and the presence of thickened bowel walls and the US appearance of loss of haustra coli were considered in the evaluation of the extension of disease. The extension of colitis was evaluated by means of a double-contrast barium enema in every patient at the beginning of the study. RESULTS: US correctly defined the extension of UC in 74% of the patients as defined by double-contrast barium enema. The degree of BWT was significantly correlated to the clinical, biochemical, and endoscopic activity of UC before and after the treatment. Moreover, BWT decreased significantly (7.3 +/- 1.9 mm versus 5.1 +/- 1.2 mm; P < 0.001) in patients who experienced clinical improvement after treatment, and it did not change (7.0 +/- 1.5 mm versus 7.0 +/- 1.4 mm; P=NS) in patients showing no significant clinical improvement. The degree of pretreatment BWT did not differ between UC patient responders and non-responders. CONCLUSIONS: US evaluation of BWT may be useful in evaluating the extension of UC. The degree of BWT, as evaluated by US, correlates with the clinical, biochemical, and endoscopic activity of UC, both before and after treatment. This suggests that US may be useful to evaluate the response of UC patients to medical therapy.