Joel G. Fletcher

Managing Incidental Findings in Human Subjects Research: Analysis and Recommendations

No consensus yet exists on how to handle incidental findings (IFs) in human subjects research. Yet empirical studies document IFs in a wide range of research studies, where IFs are findings beyond the aims of the study that are of potential health or reproductive importance to the individual research participant. This paper reports recommendations of a two-year project group funded by NIH to study how to manage IFs in genetic and genomic research, as well as imaging research. We conclude that researchers have an obligation to address the possibility of discovering IFs in their protocol and communications with the IRB, and in their consent forms and communications with research participants. Researchers should establish a pathway for handling IFs and communicate that to the IRB and research participants. We recommend a pathway and categorize IFs into those that must be disclosed to research participants, those that may be disclosed, and those that should not be disclosed.

Development of the Crohn's disease digestive damage score, the Lemann score.

Crohns disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohns disease (IPNIC) group. This instrument, called the Crohns Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patients disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)

Frequent Detection of Pancreatic Lesions in Asymptomatic High-Risk Individuals

BACKGROUND & AIMS The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, noninvasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRIs). METHODS We screened 225 asymptomatic adult HRIs at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. RESULTS Ninety-two of 216 HRIs (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n = 5) by any of the imaging modalities. Fifty-one of the 84 HRIs with a cyst (60.7%) had multiple lesions, typically small (mean, 0.55 cm; range, 2-39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects younger than 50 years old, 34% of subjects 50-59 years old, and 53% of subjects 60-69 years old (P < .0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRIs, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRIs (82 intraductal papillary mucinous neoplasms and 3 pancreatic endocrine tumors). Three of 5 HRIs who underwent pancreatic resection had high-grade dysplasia in less than 3 cm intraductal papillary mucinous neoplasms and in multiple intraepithelial neoplasias. CONCLUSIONS Screening of asymptomatic HRIs frequently detects small pancreatic cysts, including curable, noninvasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT.

Prospective Comparison of State-of-the-Art MR Enterography and CT Enterography in Small-Bowel Crohn's Disease

OBJECTIVE The objective of our study was to prospectively obtain pilot data on the accuracy of MR enterography for detecting small-bowel Crohns disease compared with CT enterography and with a clinical reference standard based on imaging, clinical information, and ileocolonoscopy. SUBJECTS AND METHODS The study group for this blinded prospective study was composed of 33 patients with suspected active Crohns ileal inflammation who were scheduled for clinical CT enterography and ileocolonoscopy and had consented to also undergo MR enterography. The MR enterography and CT enterography examinations were each interpreted by two radiologists with disagreements resolved by consensus. The reports from ileocolonoscopy with or without mucosal biopsy were interpreted by a gastroenterologist. The reference standard for the presence of small-bowel Crohns disease was based on the final clinical diagnosis by the referring gastroenterologist after reviewing all of the available information. RESULTS All 33 patients underwent CT enterography and ileocolonoscopy, 30 of whom also underwent MR enterography. The sensitivities of MR enterography and CT enterography for detecting active small-bowel Crohns disease were similar (90.5% vs 95.2%, respectively; p = 0.32). The image quality scores for MR enterography examinations were significantly lower than those for CT enterography (p = 0.005). MR enterography and CT enterography identified eight cases (24%) with a final diagnosis of active small-bowel inflammation in which the ileal mucosa appeared normal at ileocolonoscopy. Furthermore, enterography provided the only available imaging in three additional patients who did not have ileal intubation. CONCLUSION MR enterography and CT enterography have similar sensitivities for detecting active small-bowel inflammation, but image quality across the study cohort was better with CT. Cross-sectional enterography provides complementary information to ileocolonoscopy.

Small-bowel imaging in Crohn's disease: a prospective, blinded, 4-way comparison trial

BACKGROUND With the introduction of new techniques to image the small bowel, there remains uncertainty about their role for diagnosing Crohns disease. OBJECTIVE To assess the sensitivity and specificity of capsule endoscopy (CE), CT enterography (CTE), ileocolonoscopy, and small-bowel follow-through (SBFT) in the diagnosis of small bowel Crohns disease. METHODS Prospective, blinded trial. SETTING Inflammatory bowel disease clinic at an academic medical center. PATIENTS Known or suspected Crohns disease. Exclusion criteria included known abdominal abscess and non-steroidal anti-inflammatory drug (NSAID) use. Partial small-bowel obstruction (PSBO) at CTE excluded patients from subsequent CE. INTERVENTIONS Patients underwent all 4 tests over a 4-day period. MAIN OUTCOME MEASUREMENTS Sensitivity, specificity, and accuracy of each test to detect active small-bowel Crohns disease. The criterion standard was a consensus diagnosis based upon clinical presentation and all 4 studies. RESULTS Forty-one CTE examinations were performed. Seven patients (17%) had an asymptomatic PSBO. Forty patients underwent colonoscopy, 38 had SBFT studies, and 28 had CE examinations. Small-bowel Crohns disease was active in 51%, absent in 42%, inactive in 5%, and suspicious in 2% of patients. The sensitivity of CE for detecting active small-bowel Crohns disease was 83%, not significantly higher than CTE (83%), ileocolonoscopy (74%), or SBFT (65%). However, the specificity of CE (53%) was significantly lower than the other tests (P < .05). One patient developed a transient PSBO due to CE, but no patients had retained capsules. LIMITATION Use of a consensus clinical diagnosis as the criterion standard-but this is how Crohns disease is diagnosed in practice. CONCLUSIONS The sensitivity of CE for active small-bowel Crohns disease was not significantly different from CTE, ileocolonoscopy, or SBFT. However, lower specificity and the need for preceding small-bowel radiography (due to the high frequency of asymptomatic PSBO) may limit the utility of CE as a first-line test for Crohns disease.

Quantitative measurement and visual assessment of ileal Crohn's disease activity by computed tomography enterography: correlation with endoscopic severity and C reactive protein

Background: Few studies have correlated computed tomography (CT) enterography findings with endoscopic severity and C reactive protein (CRP) concentrations. Aim: To examine whether small bowel inflammation at CT enterography correlates with endoscopic severity and CRP in patients with Crohn’s disease (CD). Methods: CT enterography datasets from 143 CD patients undergoing ileoscopy were examined for three different CT parameters: CT bowel enhancement, as defined by the ratio of terminal ileal versus control ileal loop attenuation; vascular enlargement of the vasa recta (“the comb sign”); and mesenteric fat density. Correlations between CT scan parameters, endoscopy, and histology severity scores, and CRP were assessed using Spearman’s rank correlation and logistic regression. Results: Endoscopic score was significantly correlated with CT bowel enhancement, comb sign, and fat density (Spearman correlation coefficients 0.33–0.39; p<0.001). Correlations with histological inflammation were strongest for bowel enhancement (r = 0.34–0.38; p<0.001). CRP was elevated in patients with increased fat density versus those with increased bowel enhancement only (median 0.96 v 0.23, p = 0.002). CRP did not differ significantly between patients without evidence of active Crohn’s and those with bowel enhancement and endoscopic inflammation not involving the perienteric tissues by CT (median 0.24 v 0.36; p = 0.38). Conclusion: Quantitative measures of bowel enhancement at CT enterography correlate with endoscopic and histological severity. CRP correlates with radiological findings of perienteric inflammation (increased fat density), but not of inflammation limited to the small bowel wall, underscoring the potential role of perienteric inflammation in CRP response in CD.

Diagnostic ionizing radiation exposure in a population-based cohort of patients with inflammatory bowel disease

OBJECTIVE:For diagnosis, assessing disease activity, complications and extraintestinal manifestations, and monitoring response to therapy, patients with inflammatory bowel disease undergo many radiological studies employing ionizing radiation. However, the extent of radiation exposure in these patients is unknown.METHODS:A population-based inception cohort of 215 patients with inflammatory bowel disease from Olmsted County, Minnesota, diagnosed between 1990 and 2001, was identified. The total effective dose of diagnostic ionizing radiation was estimated for each patient. Linear regression was used to assess the median total effective dose since symptom onset.RESULTS:The number of patients with Crohns disease and ulcerative colitis was 103 and 112, with a mean age at diagnosis of 38.6 and 39.4 yr, respectively. Mean follow-up was 8.9 yr for Crohns disease and 9.0 yr for ulcerative colitis. Median total effective dose for Crohns disease was 26.6 millisieverts (mSv) (range, 0–279) versus 10.5 mSv (range, 0–251) for ulcerative colitis (P < 0.001). Computed tomography accounted for 51% and 40% of total effective dose, respectively. Patients with Crohns disease had 2.46 times higher total effective dose than ulcerative colitis patients (P= 0.001), adjusting for duration of disease.CONCLUSIONS:Annualizing our data, the radiation exposure in the inflammatory bowel disease population was equivalent to the average annual background radiation dose from naturally occurring sources in the U.S. (3.0 mSv). However, a subset of patients had substantially higher doses. The development of imaging management guidelines to minimize radiation dose, dose-reduction techniques in computed tomography, and faster, more robust magnetic resonance techniques are warranted.

Relationship between symptoms and disordered continence mechanisms in women with idiopathic faecal incontinence

Background and aims: Anal sphincter weakness and rectal sensory disturbances contribute to faecal incontinence (FI). Our aims were to investigate the relationship between symptoms, risk factors, and disordered anorectal and pelvic floor functions in FI. Methods: In 52 women with “idiopathic” FI and 21 age matched asymptomatic women, we assessed symptoms by standardised questionnaire, anal pressures by manometry, anal sphincter appearance by endoanal ultrasound and magnetic resonance imaging (MRI), pelvic floor motion by dynamic MRI, and rectal compliance and sensation by a barostat. Results: The prevalence of anal sphincter injury (by imaging), reduced anal resting pressure (35% of FI), and reduced squeeze pressures (73% of FI) was higher in FI compared with controls. Puborectalis atrophy (by MRI) was associated (p<0.05) with FI and with impaired anorectal motion during pelvic floor contraction. Volume and pressure thresholds for the desire to defecate were lower, indicating rectal hypersensitivity, in FI. The rectal volume at maximum tolerated pressure (that is, rectal capacity) was reduced in 25% of FI; this volume was associated with the symptom of urge FI (p<0.01) and rectal hypersensitivity (p = 0.02). A combination of predictors (age, body mass index, symptoms, obstetric history, and anal sphincter appearance) explained a substantial proportion of the interindividual variation in anal squeeze pressure (45%) and rectal capacity (35%). Conclusions: Idiopathic FI in women is a multifactorial disorder resulting from one or more of the following: a disordered pelvic barrier (anal sphincters and puborectalis), or rectal capacity or sensation.

Virtual monochromatic imaging in dual-source dual-energy CT: Radiation dose and image quality

PURPOSE To evaluate the image quality of virtual monochromatic images synthesized from dual-source dual-energy computed tomography (CT) in comparison with conventional polychromatic single-energy CT for the same radiation dose. METHODS In dual-energy CT, besides the material-specific information, one may also synthesize monochromatic images at different energies, which can be used for routine diagnosis similar to conventional polychromatic single-energy images. In this work, the authors assessed whether virtual monochromatic images generated from dual-source CT scanners had an image quality similar to that of polychromatic single-energy images for the same radiation dose. First, the authors provided a theoretical analysis of the optimal monochromatic energy for either the minimum noise level or the highest iodine contrast to noise ratio (CNR) for a given patient size and dose partitioning between the low- and high-energy scans. Second, the authors performed an experimental study on a dual-source CT scanner to evaluate the noise and iodine CNR in monochromatic images. A thoracic phantom with three sizes of attenuating rings was used to represent four adult sizes. For each phantom size, three dose partitionings between the low-energy (80 kV) and the high-energy (140 kV) scans were used in the dual-energy scan. Monochromatic images at eight energies (40 to 110 keV) were generated for each scan. Phantoms were also scanned at each of the four polychromatic single energy (80, 100, 120, and 140 kV) with the same radiation dose. RESULTS The optimal virtual monochromatic energy depends on several factors: phantom size, partitioning of the radiation dose between low- and high-energy scans, and the image quality metrics to be optimized. With the increase of phantom size, the optimal monochromatic energy increased. With the increased percentage of radiation dose on the low energy scan, the optimal monochromatic energy decreased. When maximizing the iodine CNR in monochromatic images, the optimal energy was lower than that when minimizing noise level. When the total radiation dose was equally distributed between low and high energy in dual-energy scans, for minimum noise, the optimal energies were 68, 71, 74, and 77 keV for small, medium, large, and extra-large (xlarge) phantoms, respectively; for maximum iodine CNR, the optimal energies were 66, 68, 70, 72 keV. With the optimal monochromatic energy, the noise level was similar to and the CNR was better than that in a single-energy scan at 120 kV for the same radiation dose. Compared to an 80 kV scan, however, the iodine CNR in monochromatic images was lower for the small, medium, and large phantoms. CONCLUSIONS In dual-source dual-energy CT, optimal virtual monochromatic energy depends on patient size, dose partitioning, and the image quality metric optimized. With the optimal monochromatic energy, the noise level was similar to and the iodine CNR was better than that in 120 kV images for the same radiation dose. Compared to single-energy 80 kV images, the iodine CNR in virtual monochromatic images was lower for small to large phantom sizes.

Magnetic resonance imaging of anatomic and dynamic defects of the pelvic floor in defecatory disorders.

OBJECTIVE:Endoanal ultrasound identifies anal sphincter anatomy, and evacuation proctography visualizes pelvic floor motion during simulated defecation. These complementary techniques can evaluate obstructed defecation and fecal incontinence. Our aim was to develop a single, nonionizing, minimally invasive modality to image global pelvic floor anatomy and motion.METHODS:We studied six patients with fecal incontinence and seven patients with obstructed defecation. The anal sphincters were imaged with an endoanal magnetic resonance imaging (MRI) coil and endoanal ultrasound (five patients). MR fluoroscopy acquired images every 1.4–2 s, using a modified real-time, T2-weighted, single-shot, fast-spin echo sequence, recording motion as patients squeezed pelvic floor muscles and expelled ultrasound gel; no contrast was added to other pelvic organs. Six patients also had scintigraphic defecography.RESULTS:Endoanal ultrasound and MRI were comparable for imaging defects of the internal and external sphincters. Only MRI revealed puborectalis and/or external sphincter atrophy; four of these patients had fecal incontinence. MR fluoroscopy recorded pelvic floor contraction during squeeze and recorded relaxation during simulated defecation. Corresponding comparisons for angle change and perineal descent during defecation were not significant; only MRI, but not scintigraphy, identified excessive perineal descent in two patients.CONCLUSIONS:Pelvic MRI is a promising single, comprehensive, nonradioactive modality to measure structural and functional pelvic floor disturbances in defecatory disorders. This method may provide insights into mechanisms of normal and disordered pelvic floor function in health and disease.