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.

Influence of diffusion weighted imaging and contrast enhanced T1 sequences on the diagnostic accuracy of magnetic resonance enterography for Crohn's disease.

OBJECTIVES: To evaluate the additional diagnostic benefit of diffusion weighted imaging (DWI) and contrast enhanced (CE) images during MR enterography (MRE) of Crohn's disease. METHODS: Datasets from 73 patients (mean age 32; 40 male) (28 new-diagnosis, 45 relapsed) were read independently by two radiologists selected from a pool of 13. Radiologists interpreted datasets using three sequential sequence blocks: (1) T2 weighted and steady state free precession gradient echo (SSFP) images alone (T2^); (2) T2 weighted and SSFP images with DWI (T2 + DWI^) and; (3) T2 weighted images, SSFP, DWI and post-contrast enhanced (CE) T1 images (T2 + DWI + CE^), documenting presence, location, and activity of small bowel disease. For each sequence block, sensitivity and specificity (readers combined) was calculated against an outcome-based construct reference standard. RESULTS: 59/73 patients had small bowel disease. Per-patient sensitivity for disease detection was essentially identical (80 % [95 % CI 72, 86], 81 % [73,87], and 79 % [71,86] for T2^, T2 + DWI^and T2 + DWI + CE^respectively). Specificity was identical (82 % [64 to 92]). Per patient sensitivity for disease extent was 56 % (47,65), 56 % (47,65) and 52 % (43 to 61) respectively, and specificity was 82 % (64 to 92) for all blocks. Sensitivity for active disease was 97 % (90,99), 97 % (90,99) and 98 % (92,99), and specificity was also comparable between all sequence combination reads. Results were consistent across segments and newly diagnosed/relapse patients. CONCLUSION: There is no additional diagnostic benefit of adding either DWI or CE to T2 FSE and SSFP sequences for evaluating small bowel Crohn's disease, suggesting MRE protocols can be simplified safely.

Interobserver variation in the interpretation of magnetic resonance enterography in Crohn's disease.

OBJECTIVES: To evaluate interobserver variability for diagnosis of disease presence and extent of small bowel and colonic Crohn's disease using MR enterography (MRE). METHODS: Data from the first 73 consecutive patients (mean age 32, 33F, 28 new diagnosis, 45 suspected relapse) recruited to a multicentre, prospective diagnostic accuracy trial evaluating MRE for small bowel Crohn's disease were each read independently by three (from a pool of 20) radiologists. Radiologists documented presence and segmental location of small bowel Crohn's disease and recorded morphological mural/extramural parameters for involved segments. Per patient percentage agreement for disease presence and extent were calculated against an outcome-based construct reference standard (averaged between pairs of readers). Prevalence-adjusted bias-adjusted κ (PABAK) was calculated. RESULTS: Agreement for small bowel disease presence for new diagnosis/relapsed patients was 68%(κ = 0.36)/ 78% (κ = 0.56) and 43%(κ = 0.14)/ 53% for disease extent (κ = 0.07), respectively. For disease presence, all three radiologists agreed correctly with the reference standard in 41/59 (69%) of patients with small bowel involvement, and in 8/14 (57%) cases of without small bowel disease. Agreement was highest for multisegment disease, greater than 5 cm in length, with mural thickness>6 mm, and increased mural T2 signal. Agreement for colonic disease presence was 61% (κ = 0.21 fair agreement) for new diagnosis/ 60% (κ = 0.20, slight agreement) for relapsed patients. CONCLUSION: There is a reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed Crohn's disease, and patients with suspected relapse, respectively. Agreement is lower for disease extent. ADVANCES IN KNOWLEDGE: There is reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed (68%) Crohn's disease, and patients with suspected relapse (78%). Agreement is lower for disease extent (43% new diagnosis and 53% suspected relapse).

Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer.

PURPOSE: PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. PATIENTS AND METHODS: Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. RESULTS: At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (K(i)) at day 2 predicted for nonprogression of disease. CONCLUSION: The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK >/= 1,000 mg total daily dose is the biologically active dose.