Influence of oral contrast type and volume on patient experience and quality of luminal distension at MR Enterography in Crohn's disease:an observational study of patients recruited to the METRIC trial

OBJECTIVES: To compare the distention quality and patient experience of oral mannitol and polyethylene glycol (PEG) for MRE. METHODS: This study is a retrospective, observational study of a subset of patients enrolled in a multicentre, prospective trial evaluating the diagnostic accuracy of MRE for small bowel Crohn’s. Overall and segmental MRE small bowel distention, from 105 patients (64 F, mean age 37) was scored from 0 = poor to 4 = excellent by two experienced observers (68 [65%] mannitol and 37 [35%] PEG). Additionally, 130 patients (77 F, mean age 34) completed a questionnaire rating tolerability of various symptoms immediately and 2 days after MRE (85 [65%] receiving mannitol 45 [35%] receiving PEG). Distension was compared between agents and between those ingesting ≤ 1 L or > 1 L of mannitol using the test of proportions. Tolerability grades were collapsed into “very tolerable,” “moderately tolerable,” and “not tolerable.” RESULTS: Per patient distension quality was similar between agents (“excellent” or “good” in 54% [37/68] versus 46% [17/37]) with mannitol and PEG respectively. Jejunal distension was significantly better with mannitol compared to PEG (40% [27/68] versus 14% [5/37] rated as excellent or good respectively). There was no significant difference according to the volume of mannitol ingested. Symptom tolerability was comparable between agents, although fullness following MRE was graded as “very tolerable” in 27% (12/45) of patients ingesting PEG, verses 44% (37/84) ingesting mannitol, difference 17% (95% CI 0.6 to 34%). CONCLUSION: Mannitol-based solutions and PEG generally achieve comparable distension quality and side effect profiles, although jejunal distension is better quality with mannitol. Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol. KEY POINTS: • Mannitol-based and PEG-based oral preparation agents generally achieve comparable distension quality for MRE with the exception of the jejunum which is better distended with mannitol. • Mannitol-based and PEG-based oral preparation agents used for MRE have similar side effect profiles. • Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00330-022-08614-9

Diagnostic performance of sonographic activity scores for adult terminal ileal Crohn’s disease compared to magnetic resonance and histological reference standards:experience from the METRIC trial

Objectives: The simple ultrasound activity score for Crohn’s disease (SUS-CD) and bowel ultrasound score (BUSS) are promising intestinal ultrasound (IUS) indices of CD, but studied mainly in small settings with few sonographers. We compared SUS-CD and BUSS against histological and magnetic resonance enterography (MRE) reference standards in a post hoc analysis of a prospective multicentre, multireader trial. Methods: Participants recruited to the METRIC trial (ISRCTN03982913) were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA). Results: We included 284 patients (median 31.5 years, IQR 23–46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring. Against histology, sensitivity and specificity for active disease were 79% (95% CI 69–86%) and 50% (31–69%) for SUS-CD, and 66% (56–75%) and 68% (47–84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74–86%) and 75% (66–83%) for SUS-CD, and 68% (61–74%) and 85% (76–91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than that of BUSS against HAI and sMARIA (p &lt; 0.001), but its specificity was significantly lower than of BUSS against the MRE reference standard (p = 0.003). Conclusions: Particularly when compared to MRE activity scoring, SUS-CD and BUSS are promising tools in a real-world clinical setting.Clinical relevance statement: When tested using data from a multicentre, multireader diagnostic accuracy trial, the simple ultrasound activity score for Crohn’s disease (SUS-CD) and bowel ultrasound score (BUSS) were clinically viable intestinal ultrasound indices that were reasonably sensitive and specific for terminal ileal Crohn’s disease, especially when compared to a magnetic resonance reference standard.</p

Diagnostic performance of sonographic activity scores for adult terminal ileal Crohn's disease compared to magnetic resonance and histological reference standards: experience from the METRIC trial

OBJECTIVES: The simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) are promising intestinal ultrasound (IUS) indices of CD, but studied mainly in small settings with few sonographers. We compared SUS-CD and BUSS against histological and magnetic resonance enterography (MRE) reference standards in a post hoc analysis of a prospective multicentre, multireader trial. METHODS: Participants recruited to the METRIC trial (ISRCTN03982913) were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA). RESULTS: We included 284 patients (median 31.5 years, IQR 23-46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring. Against histology, sensitivity and specificity for active disease were 79% (95% CI 69-86%) and 50% (31-69%) for SUS-CD, and 66% (56-75%) and 68% (47-84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74-86%) and 75% (66-83%) for SUS-CD, and 68% (61-74%) and 85% (76-91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than that of BUSS against HAI and sMARIA (p < 0.001), but its specificity was significantly lower than of BUSS against the MRE reference standard (p = 0.003). CONCLUSIONS: Particularly when compared to MRE activity scoring, SUS-CD and BUSS are promising tools in a real-world clinical setting. CLINICAL RELEVANCE STATEMENT: When tested using data from a multicentre, multireader diagnostic accuracy trial, the simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) were clinically viable intestinal ultrasound indices that were reasonably sensitive and specific for terminal ileal Crohn's disease, especially when compared to a magnetic resonance reference standard. KEY POINTS: The simple ultrasound activity score for Crohn's disease and bowel ultrasound score are promising intestinal ultrasound indices of Crohn's disease but to date studied mainly in small settings with few sonographers. Compared to histology and the magnetic resonance reference standard in a multicentre, multireader setting, the sensitivity of simple ultrasound activity score for Crohn's disease is significantly greater than that of bowel ultrasound score. The specificity of simple ultrasound activity score for Crohn's disease was significantly lower than that of bowel ultrasound score compared to the magnetic resonance enterography reference standard. The specificity of both indices was numerically higher when the magnetic resonance enterography reference standard was adopted

Magnetic resonance enterography, small bowel ultrasound and colonoscopy to diagnose and stage Crohn’s disease; patient acceptability, and perceived burden

Objectives: To compare patient acceptability and burden of magnetic resonance enterography (MRE) and ultrasound (US) to each other, and to other enteric investigations, particularly colonoscopy. Methods: 159 patients (mean age 38, 94 female) with newly diagnosed or relapsing Crohn’s disease, prospectively recruited to a multicentre diagnostic accuracy study comparing MRE and US, completed an experience questionnaire on the burden and acceptability of small bowel investigations between December 2013 and September 2016. Acceptability, recovery time, scan burden and willingness to repeat the test were analysed using the Wilcoxon signed rank and McNemar tests; and group differences in scan burden with Mann-Whitney U and Kruskal-Wallis tests. Results: Overall, 128 (88%) patients rated MRE as very or fairly acceptable, lower than US (144, 99%; p<0.001), but greater than colonoscopy (60, 60%; p<0.001). MRE recovery time was longer than US (p<0.001), but shorter than colonoscopy (p<0.001). Patients were less willing to undergo MRE again than US (127 vs 133, 91% vs. 99%; p=0.012), but more willing than for colonoscopy (68, 75%; p=0.017). MRE generated greater burden than US (p<0.001), although burden scores were low. Younger age and emotional distress were associated with greater MRE and US burden. Higher MRE discomfort was associated with patient preference for US (p=0.053). Patients rated test accuracy as more important than scan discomfort. Conclusions.: MRE and US are well tolerated. Although MRE generates greater burden, longer recovery, and is less preferred than US, it is more acceptable than colonoscopy. Patients however place greater emphasis on diagnostic accuracy than burden

Radiology of the Post Surgical Abdomen

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Next Generation intraoperative Lymph node staging for Stratified colon cancer surgery (GLiSten): a multicentre, multinational feasibility study of fluorescence in predicting lymph node-positive disease

Background: 5-aminolevulinic acid (5-ALA) is used for fluorescence diagnosis (FD) in neurological, gynaecological and urological malignancies. The Medical Research Council/Efficacy and Mechanism Evaluation (EME) programme/National Institute for Health Research’s Next Generation intraoperative Lymph node staging for Stratified colon cancer surgery (GLiSten) study investigated its use to predict lymph node (LN)-positive disease in colon cancer as an aid to stratified surgery. Objectives: The primary objective was to optimise the dose of oral 5-ALA for intraoperative FD of metastatic LNs in colon cancer. Secondary objectives included standardisation of pre-operative computerised tomography (CT) LN reporting, intraoperative fluorescence detection, surgical resection with D3 lymphadenectomy and histopathological examination of resected specimens. Design: This was a feasibility study to determine optimal strategies for 5-ALA positive LN detection. Patients with locally advanced disease identified using the Fluoropyrimidine, Oxaliplatin and Targeted-Receptor pre-Operative Therapy for patients with high-risk, operable colon cancer (FOxTROT) criteria were recruited from two sites between October 2013 and June 2015. Cohort 1 received 20 mg/kg and cohort 2 received 30 mg/kg of oral 5-ALA, 1–6 hours preoperatively. Laparoscopic assessment of fluorescence was performed using the Storz D-Light system (KARL STORZ GmbH & Co. KG; Tuttlingen, Germany), with marking of fluorescent LNs, followed by oncological resection. The specimen was subjected to histological analysis with step sectioning of marked fluorescent LNs. Progression to an evaluation phase using the optimal dosing schedule was dependent on positively identifying at least 2 out of 10 patients with metastatic LN disease in either cohort. Results: A total of 44 patients were recruited with a male to female ratio of 26 : 18 and a mean age of 71 years (range 52–88 years). Cohort 1 consisted of 18 patients, of whom six had fluorescent primary cancers and three of these had fluorescent LNs. One out of 10 patients with metastatic LN disease had a fluorescent involved LN. Cohort 2 consisted of 26 patients, of whom eight had fluorescent primary cancers and four of these had fluorescent LNs. None of the fluorescent LNs contained disease in this cohort. No serious adverse events (SAEs) occurred but two mild, self-limiting, photosensitivity reactions were observed in cohort 2. The sensitivity and specificity for 5-ALA detection of LN-positive disease were: cohort 1 11.1%, 75%; and cohort 2 0%, 75%. Limitations: This was a feasibility study exploring the use of 5-ALA for LN disease in a select cohort of patients with advanced colorectal cancer. The study population was small and generalisation to other cancers is not possible. The study was limited by the ability to determine LN-positive patients on the basis of pre-operative CT staging, which is often inaccurate, resulting in our cohorts containing several patients without LN disease. Conclusions: 5-ALA fluorescent diagnosis has poor sensitivity for discriminating LN-positive colon cancer. Its use as an aid to stratified colon cancer surgery is not supported. No SAEs were observed, suggesting that photosensitisers may be useful for intraoperative FD. Future work: 5-ALA has poor sensitivity for detecting LN metastases and cannot be recommended for intraoperative staging. Other, more sensitive fluorescent probes are required if this strategy is to be used. Study registration: Current Controlled Trials ISRCTN79949827 and EudraCT number 2012–002623–15. Funding details: This project was funded by the EME programme, a Medical Research Council and National Institute for Health Research partnership

A novel fluorescent c-met targeted imaging agent for intra-operative colonic tumour mapping: Translation from the laboratory into a clinical trial

Background The c-Met protein is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivo murine model. Methods HT-29 SiRNA transfection confirmed specificity of EMI-137 for c-Met. A HT-29 CRC xenograft model was developed in BALB/c mice, EMI-137 was injected and biodistribution analysed through in vivo fluorescent imaging. Nine patients, received a single intravenous EMI-137 bolus (0.13 mg/kg), 1–3 h before laparoscopic-assisted colon cancer surgery (NCT03360461). Tumour and LN fluorescence was assessed intraoperatively and correlated with c-Met expression in eight samples by immunohistochemistry. Findings c-Met expression HT-29 cells was silenced and imaged with EMI-137. Strong EMI-137 uptake in tumour xenografts was observed up to 6 h post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all participants, 4/9 showed increased tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15/15) exhibited high c-Met protein expression. Interpretation EMI-137, binds specifically to the human c-Met protein, is safe, and with further refinement, shows potential for application in fluorescence-guided surgery