Transrectal Absorber Guide Raster-Scanning Optoacoustic Mesoscopy for Label-Free In Vivo Assessment of Colitis.

Optoacoustic imaging (OAI) enables microscale imaging of endogenous chromophores such as hemoglobin at significantly higher penetration depths compared to other optical imaging technologies. Raster-scanning optoacoustic mesoscopy (RSOM) has recently been shown to identify superficial microvascular changes associated with human skin pathologies. In animal models, the imaging depth afforded by RSOM can enable entirely new capabilities for noninvasive imaging of vascular structures in the gastrointestinal tract, but exact localization of intra-abdominal organs is still elusive. Herein the development and application of a novel transrectal absorber guide for RSOM (TAG-RSOM) is presented to enable accurate transabdominal localization and assessment of colonic vascular networks in vivo. The potential of TAG-RSOM is demonstrated through application during mild and severe acute colitis in mice. TAG-RSOM enables visualization of transmural vascular networks, with changes in colon wall thickness, blood volume, and OAI signal intensities corresponding to colitis-associated inflammatory changes. These findings suggest TAG-RSOM can provide a novel monitoring tool in preclinical IBD models, refining animal procedures and underlines the capabilities of such technologies to address inflammatory bowel diseases in humans.

Assessment of Murine Colon Inflammation Using Intraluminal Fluorescence Lifetime Imaging.

Inflammatory bowel disease (IBD) is typically diagnosed by exclusion years after its onset. Current diagnostic methods are indirect, destructive, or target overt disease. Screening strategies that can detect low-grade inflammation in the colon would improve patient prognosis and alleviate associated healthcare costs. Here, we test the feasibility of fluorescence lifetime imaging (FLIm) to detect inflammation from thick tissue in a non-destructive and label-free approach based on tissue autofluorescence. A pulse sampling FLIm instrument with 355 nm excitation was coupled to a rotating side-viewing endoscopic probe for high speed (10 mm/s) intraluminal imaging of the entire mucosal surface (50-80 mm) of freshly excised mice colons. Current results demonstrate that tissue autofluorescence lifetime was sensitive to the colon anatomy and the colonocyte layer. Moreover, mice under DSS-induced colitis and 5-ASA treatments showed changes in lifetime values that were qualitatively related to inflammatory markers consistent with alterations in epithelial bioenergetics (switch between ß-oxidation and aerobic glycolysis) and physical structure (colon length). This study demonstrates the ability of intraluminal FLIm to image mucosal lifetime changes in response to inflammatory treatments and supports the development of FLIm as an in vivo imaging technique for monitoring the onset, progression, and treatment of inflammatory diseases.

Magnetic resonance colonography assessment of acute trinitrobenzene sulfonic acid colitis in pre-pubertal rats.

Pre-pubertal murine models of acute colitis are lacking. Magnetic resonance colonography (MRC) is a promising minimally invasive tool to assess colitis. We aimed to: 1/ Adapt a model of acute experimental colitis to pre-pubertal rats and determine whether MRC characteristics correlate with histological inflammation. 2/ Test this model by administering a diet supplemented in transforming growth factor ß2 to reverse inflammation. Twenty-four rats were randomized at weaning to one of 3 groups: Trinitrobenzene Sulfonic Acid (TNBS) group (n = 8) fed a standard diet, that received an intra-rectal 60 mg/kg dose of TNBS-ethanol; Control group (n = 8) fed standard diet, that received a dose of intra-rectal PBS; TNBS+MODULEN group (n = 8) that received a dose of TNBS and were exclusively fed MODULEN-IBD® after induction of colitis. One week after induction of colitis, rats were assessed by MRC, colon histopathology and inflammation markers (Interleukin 1ß, Tumor necrosis factor α, Nitric Oxide Synthase 2 and Cyclooxygenase 2). TNBS induced typical features of acute colitis on histopathology and MRC (increased colon wall thickness, increased colon intensity on T2-weighted images, target sign, ulcers). Treatment with MODULEN-IBD® did not reduce signs of colitis on MRC. Inflammatory marker expression did not differ among study groups.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Target-Specific Fluorescence-Mediated Tomography for Non-Invasive and Dynamic Assessment of Early Neutrophil Infiltration in Murine Experimental Colitis.

The role of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) is still only incompletely understood. Here, we evaluated target-specific fluorescence-mediated tomography (FMT) for visualization of neutrophil infiltration in murine experimental DSS-induced colitis. Colitis was assessed using clinical, endoscopic, and histopathological parameters. Intestinal neutrophil infiltration was determined at day 0, 4, and 10 by targeted FMT after injection of a neutrophil-specific fluorescence-labelled monoclonal antibody (Gr-1). Complementary, immunofluorescence tissue sections with Gr-1 and ELISA-based assessment of tissue myeloperoxidase (MPO) served as the gold standard for the quantification of neutrophil infiltration. Colitic animals showed decreasing body weight, presence of fecal occult blood, and endoscopic signs of inflammation. FMT revealed a significantly increased level of fluorescence only four days after colitis induction as compared to pre-experimental conditions (pmol tracer 73.2 ± 18.1 versus 738.6 ± 80.7; p < 0.05), while neither body weight nor endoscopic assessment showed significant changes at this early time. Confirmatory, post-mortem immunofluorescence studies and measurements of tissue MPO confirmed the presence of increased neutrophil infiltration in colitic mice compared to controls. Concluding, Gr-1 targeted FMT can detect early colonic infiltration of neutrophils in experimental colitis even before clinical symptoms or endoscopic alterations occur. Therefore, FMT might be an important tool for repetitive and non-invasive monitoring of inflammatory cell infiltrate in intestinal inflammation.

In vivo MRS for the assessment of mouse colon using a dedicated endorectal coil: initial findings.

Inflammatory bowel disease is a common group of inflammation conditions that can affect the colon and the rectum. These pathologies require a careful follow-up of patients to prevent the development of colorectal cancer. Currently, conventional endoscopy is used to depict alterations of the intestinal walls, and biopsies are performed on suspicious lesions for further analysis (histology). MRS enables the in vivo analysis of biochemical content of tissues (i.e. without removing any samples). Combined with dedicated endorectal coils (ERCs), MRS provides new ways of characterizing alterations of tissues. An MRS in vivo protocol was specifically set up on healthy mice and on mice chemically treated to induce colitis. Acquisitions were performed on a 4.7 T system using a linear volume birdcage coil for the transmission of the B1 magnetic field, and a dedicated ERC was used for signal reception. Colon-wall complex, lumen and visceral fat were assessed on healthy and treated mice with voxel sizes ranging from 0.125 µL to 2 µL while keeping acquisition times below 3 min. The acquired spectra show various biochemical contents such as α- and ß-methylene but also glycerol backbone and diacyl. Choline was detected in tumoral regions. Visceral fat regions display a high lipid content with no water, whereas colon-wall complex exhibits both high lipid and high water contents. To the best of our knowledge, this is the first time that in vivo MRS using an ERC has been performed in the assessment of colon walls and surrounding structures. It provides keys for the in vivo characterization of small local suspicious lesions and offers complementary solutions to biopsies.

Endoluminal ultrasound biomicroscopy as a reliable tool for in vivo assessment of colonic inflammation in rats.

PURPOSE: Endoscopic ultrasound (EUS) imaging of the colon is an important diagnostic tool for early neoplasia, although usually restricted to the rectum in inflammatory bowel disease (IBD). This study aimed to evaluate the ability of an endoluminal ultrasound biomicroscopic (eUBM) system to detect and characterize lesions simulating Crohn's disease in the colon of rats in vivo. METHODS: Colitis was induced with trinitrobenzene sulfonic acid instillated in the distal colon. Eighteen Wistar rats were submitted to eUBM in three time points: week 1 group (18 animals examined on day 3 after colitis induction), week 2 group (12 animals on days 3 and 10), and week 3 group (7 animals on days 3, 10, and 17). This design yielded distinct inflammation intensities. Three untreated rats were used for acquisition of control images. Scores were used for comparison with histology. RESULTS: Scores for eUBM and histology in the different moments of examination achieved a Spearman's rank correlation coefficient of 0.87 (p < 0.001). Findings of wall thickening presented positive predictive value (PPV) and sensitivity of 94 and of 100 %, respectively. Superficial and deep ulcers presented a PPV of 89 and 80 %, respectively, and negative predictive values of 100 and 85 %, respectively. CONCLUSION: Accurate detection and analysis of the lesions was achieved. The model is essential for the clinical development of the technique and a reproducible method for the evaluation of experimental colitis. eUBM might be applicable in different segments of the gut, developing into a novel adjunct method for IBD evaluation.

Inflammatory bowel disease activity assessment with biologic markers and 99mTc-WBC scintigraphy: are there different trends in ileitis versus colitis?

UNLABELLED: To evaluate whether scintigraphy with (99m)Tc-labeled white blood cells (WBC) can assess the intensity of bowel inflammation, a large dataset of laboratory values and clinical activity indices was correlated with (99m)Tc-WBC scintigraphy in children with Crohn's disease (CD), ulcerative colitis (UC), and miscellaneous colitis (MC). Also evaluated was whether stratification of children with CD as ileitis versus colitis results in different correlation coefficients for laboratory values versus (99m)Tc-WBC scintigraphy. METHODS: Over a 6-y period, 313 (99m)Tc-WBC studies were performed. A dataset of 2,714 laboratory values is available for analysis. RESULTS: There is a positive correlation between the erythrocyte sedimentation rate (ESR) and large bowel uptake of (99m)Tc-WBC (P < 0.05) and a negative trend with small bowel uptake of (99m)Tc-WBC in children with CD. Similarly, there is a correlation between WBC counts and scintigraphy in most segments of the large bowel and a negative correlation with the small bowel (R = -0.32, P = 0.01) in children with CD. There is a correlation between platelets and (99m)Tc-WBC in children with CD or UC. There is no correlation between the ESR and (99m)Tc-WBC in children with UC or MC. Many clinical activity indices correlate (P < 0.001) with (99m)Tc-WBC in children with CD, but none correlates in children with UC. Numerous laboratory values correlate with each other. There is a negative correlation between protein, albumin, hemoglobin, and hematocrit versus (99m)Tc-WBC scintigraphy in children with CD. In children with UC, there is a negative correlation between hemoglobin and hematocrit versus (99m)Tc-WBC. CONCLUSION: (99m)Tc-WBC scintigraphy, ESR, and WBC counts are good indicators of the inflammatory activity in CD if the inflammation is limited to the large bowel. There is a trend toward an inverse relationship when the inflammation is limited to the small bowel; thus, scintigraphy and the aforementioned markers may be of limited value. This report also demonstrates that (99m)Tc-WBC scintigraphy correlates with clinical activity indices in CD and with numerous biologic markers. In children with UC, scintigraphy with (99m)Tc-WBC and most laboratory markers are of limited value in assessing disease activity.

123Iodine-labelled anti-VCAM-1 antibody scintigraphy in the assessment of experimental colitis.

OBJECTIVES: To evaluate the usefulness of 123I-labelled anti-vascular cell adhesion molecule-1 (VCAM-1) monoclonal antibody (MAb) scintigraphy in the assessment of colonic inflammatory damage. DESIGN: Colitis was induced by intracolonic administration of 30 mg trinitrobenzenesulphonic acid in 0.5 ml of 50% (v/v) ethanol. Rats injected with vehicle served as controls. Animals were studied at day 7 after induction of colitis. METHODS: Scintigraphy was performed in control and trinitrobenzenesulphonic acid-induced colitic rats 2, 4 and 24 h after intravenous administration of 123I-anti-VCAM-1 MAb. Scintigraphic uptake was quantified in selected areas on scintigraphs. Animals were killed, tissue 123I radioactivity accumulation was measured, and accumulation of anti-VCAM-1 MAb in each organ was calculated. 99mTc-hexamethyl propylene amine oxime-labelled leucocyte scintigraphy was performed in additional groups of animals for comparison. RESULTS: Colonic tracer uptake was visible in scans of colitic, but not control animals. Quantification of scintigraphic uptake in the colon was significantly higher in colitic rats than in control animals (P< 0.0001). The specificity of the increase was demonstrated by lack of 123I-labelled non-binding MAb uptake in the colon, and by displacement of 123I-anti-VCAM-1 MAb colonic uptake by pre-treatment with unlabelled MAb. Accumulation of anti-VCAM-1 MAb in the colon of colitic rats was eightfold higher than in control animals. Strong correlations were found between quantification of scintigraphic uptake, anti-VCAM-1 MAb accumulation, histological damage and myeloperoxidase activity in the colon. CONCLUSION: 123I-labelled anti-VCAM-1 MAb scintigraphy allows an accurate evaluation of colonic inflammatory damage in trinitrobenzenesulphonic acid-induced colitis, suggesting a potential role for this imaging technique in the assessment of human IBD.

Misdiagnosis of primary epiploic appendagitis.

BACKGROUND: The authors determined the radiological misdiagnosis rate of primary epiploic appendagitis (PEA) and its impact on patient management and hospital resource use. METHODS: A total of 660 computed tomography scans performed for clinically suspected diverticulitis (348 cases) or appendicitis (312 cases) were reviewed for cases meeting strict radiological criteria for PEA. Retrospective interpretations were compared with radiological reports. Medical records and hospital cost data were reviewed to estimate impact on patient management and resource use. RESULTS: Eleven scans (2%) met criteria for PEA. Seven scans were initially misdiagnosed as diverticulitis (6 patients) or appendicitis (1 patient). All misdiagnosed patients were hospitalized (mean 4.3 days); 6 received antibiotic therapy. Average cost per patient was $4,117. Four scans were initially correctly diagnosed as PEA. One patient was hospitalized (1 day); none received antibiotic therapy. Average cost per patient was $1,205. CONCLUSIONS: Radiological misdiagnosis of PEA leads to unnecessary hospitalization, medical treatment, and overuse of hospital resources.

Sonographic assessment of the normal and abnormal bowel wall in nondiverticular ileitis and colitis.

BACKGROUND: To assess the value of high resolution sonography (HRS) in identifying normal and inflammatory bowel wall in nondiverticular ileitis and colitis by using a segment-by-segment analysis. METHODS: Thirty-five HRS were performed in patients with nondiverticular inflammatory bowel disease, without knowledge of clinical, endoscopic, and radiologic data. HRS evaluated separately five intestinal segments (terminal ileum, cecum/ascending colon, transverse, descending colon, and sigmoid colon) and was considered positive for inflammation when wall thickness during compression exceeded 3 mm. We compared HRS findings with results of endoscopy or enteroclysis performed within 8 days of HRS; endoscopic and radiologic results were classified into two subgroups: mild inflammatory lesions and frank inflammatory lesions. RESULTS: Segment-by-segment analysis resulted in an accuracy of 81%, a sensitivity of 70%, and a specificity of 93%. Sensitivity was significantly lower for mild lesions (52%) than for frank lesions (87%, p < .001). Of the 32 patients having an inflammatory bowel condition, 29 (91%) had at least one segment correctly identified as inflammatory by HRS. CONCLUSION: Even if relatively insensitive for minor lesions, HRS is a promising, minimally invasive method for assessing normal and inflammatory bowel wall in nondiverticular ileitis and colitis.

[Contribution of digestive system ultrasonography in the assessment of abdominal pain in children]. / Apport de l'échographie digestive dans les mises au point de douleurs abdominales chez l'enfant.

The quality of modern ultrasonography allows to study not only solid abdominal organs but also digestive walls and abdominal lymphnodes, leading to accurate diagnosis in many cases, and decreasing the use of more aggressive radiological procedures (upper GI baryum studies, baryum enema, intravenous pyelography, etc.). In dealing with abdominal pain in children, the plain XRay film of the abdomen and abdominal echography are performed immediately after history taking and physical examination, and are equally important in the work up of these cases.

Salmonella colitis: assessment with double-contrast barium enema examination in seven patients.

To completely rule out the possibility of ulcerative colitis, Crohn disease, and other diseases, the authors analyzed the radiographic findings at double-contrast barium enema examination performed in seven patients with colitis caused by Salmonella organisms. In all patients, bacteriologic confirmation of nontyphoid Salmonella infection and radiographs of the upper gastrointestinal tract were obtained. Total colonoscopy was performed in five patients and sigmoidoscopy in one patient. In all patients, the radiographic findings were retrospectively analyzed. The descending colon and sigmoid colon were affected in six patients, whereas the rectum was affected in none. The findings included fine mucosal granularity (seven patients), loss of haustration (six patients), many fine ulcerations (five patients), and multiple ulcers (two patients). The radiographic features simulated those of ulcerative colitis, except for absence of rectal abnormality. It is concluded that double-contrast barium enema examination is useful for detection of fine mucosal changes.

Scintigraphic assessment of bowel involvement and disease activity in Crohn's disease using technetium 99m-hexamethyl propylene amine oxine as leukocyte label.

Using a novel labeling technique with technetium 99m-hexamethyl propylene amine oxine, we studied 29 patients with known or suspected Crohn's disease. Technetium 99m-hexamethyl propylene amine oxine leukocyte scanning (99mTc scan) was prospectively compared with the results of independently performed radiologic, endoscopic, and histologic examinations, and with findings at surgery, to assess the clinical usefulness of this technique to localize inflammatory lesions. In addition, uptake of technetium 99m-hexamethyl propylene amine oxine in the bowel was graded by comparing it with the uptake in liver and bone marrow and correlating this with established parameters of disease activity. The viability of homologous labeled leukocytes was greater than 95%. Less than 5% of lymphocytes were found in the final preparation. It was found that 45% +/- 12% of the label was bound to granulocytes, and 98% of the unbound label was washed off before reinjection. The results of 99mTc scan revealed a good correlation with those of barium enema (r = 0.880, p less than 0.001), of endoscopy/surgery (r = 0.983, p less than 0.001), and of all combined reference methods (r = 0.981, p less than 0.001). Activity as determined by 99mTc scan was weakly correlated with the results of Crohn's disease activity index (r = 0.559, p less than 0.01), van Hees index (r = 0.606, p less than 0.01), and erythrocyte sedimentation rate (r = 0.456, p less than 0.05) in 24 patients with proven Crohn's disease. The correlation was improved when the 99mTc scan was compared with a combination of these activity parameters and C-reactive protein (r = 0.781, p less than 0.001). Extraintestinal manifestations (joints) and complications (cholecystitis) were also identified correctly by the 99mTc scan. The study demonstrates that leukocyte scanning with technetium 99m-hexamethyl propylene amine oxine as a label can reliably assess the location and, to a lesser degree, activity of Crohn's disease. This technique is more convenient and provides images far superior to those produced by indium 111-labeled leukocyte scanning.

[Radiological assessment of Crohn disease]. / Bilancio radiologico della malattia di Crohn.

Fifty-eight consecutive cases of patients affected by Crohn's disease, with ileum (23/58), colon (10/58) and ileo-colic (25/58) involvement were studied. A good overall sensitivity was reached by the radiological procedures employed (barium meal, barium enema, enteroclysis). Enteroclysis is proposed as a second-step method for the study of ileum involvement, because it provides a quite precise assessment of disease stage and extent. Some criteria for a rational use of current radiological procedures in the follow-up of both surgically and medically treated patients are proposed. Moreover it is suggested that better coordination of anatomo-radiological and clinical aspects could improve the therapeutic approach and prognostic judgement in such cases.

Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease. A comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion.

Indium 111-leukocyte scanning has recently been introduced as a new method for imaging inflammatory bowel disease. The technique has recently been made more specific for acute inflammation by labeling a pure granulocyte fraction rather than the conventional mixed leukocyte preparation. We now report a prospective study comparing 111In-granulocyte scanning with endoscopy, histology, and fecal 111In-granulocyte excretion for the assessment of disease extent and severity in colonic inflammatory bowel disease. In 52 patients with Crohn's disease or ulcerative colitis, disease extent and severity were assessed macroscopically, histologically, or by scanning using a numerical grading system. Excellent correlations were found between both endoscopy and histology and 111In scans [r = 0.90 (endoscopy) and r = 0.90 (histology) for extent; r = 0.86 and r = 0.91 for disease activity]. Severity graded by scanning also showed a close correlation with fecal 111In-granulocyte excretion (r = 0.90). Indium 111-granulocyte scans are a rapid, accurate, noninvasive means of assessing both disease extent and severity of colonic involvement in inflammatory bowel disease.

The left lateral view in the plain-film assessment of abdominal distension.

Since the left lateral position facilitates the entry of air into the rectosigmoid, it has been employed in the plain-film evaluation of patients with abdominal distension. The value of this view is illustrated by examples of patients with (a) colonic ileus due to imipramine hydrochloride (Tofranil) or chlorpromazine, (b) partial mechanical obstruction due to diverticulitis, (c) involvement of the rectum by Hirschsprung's disease, and (d) sequential evaluation of a patient with clindamycin colitis. This simple maneuver is recommended for (a) evaluation of patients with plain-film evidence of low colonic obstruction, (b) problems of differential diagnosis between bowel obstruction and ileus, and (c) evaluation of patients with conditions affecting the rectosigmoid.

Assessment of severity in colitis: a preliminary study.

Clinical features, alone and in combinations of up to five, noted early in patients during 181 admissions to one hospital for treatment of acute colitis over five years, have been correlated with the success or failure of drug treatment as judged by death during medical treatment or the need for urgent surgical treatment. Many of the 56 clinical features studied were of no value in predicting the outcome of the attack. The four features of greatest predictive value were the maximum daily body temperature, the maximum daily pulse rate, the bowel frequency and plasma albumin. The simplest and most discriminating prediction at the end of the first 24 hours in hospital was obtained by combining observations on maximum body temperature and the number of stools passed. Serial observations of temperature or pulse rate over the first four days in hospital gave more prognostic information than observations confined to the first day. The predictive value of certain other features, such as x-ray appearances, is described. A simple classification of severity in acute colitis is proposed from these results as a basis for prospective testing in other hospitals.