Evan J. Zucker

Drug-review deadlines and safety problems

BACKGROUND The Prescription Drug User Fee Act (PDUFA) imposes deadlines for the completion of drug reviews by the Food and Drug Administration (FDA). Critics have suggested that these deadlines may result in rushed approvals and the emergence of unanticipated safety problems once a product is in clinical use. METHODS We assessed the association between the PDUFA deadlines and the timing of FDA drug approval by constructing dynamic Cox proportional-hazards models of review times for all new molecular entities approved between 1950 and 2005. To determine whether the deadlines were associated with postmarketing safety problems, we focused on drugs submitted since January 1993, when the deadlines were first imposed. We used exact logistic regression to determine whether drugs approved immediately before the deadlines were associated with a higher rate of postmarketing safety problems (e.g., withdrawals and black-box warnings) than drugs approved at other times. RESULTS Initiation of the PDUFA requirements concentrated the number of approval decisions made in the weeks immediately preceding the deadlines. As compared with drugs approved at other times, drugs approved in the 2 months before their PDUFA deadlines were more likely to be withdrawn for safety reasons (odds ratio, 5.5; 95% confidence interval [CI], 1.3 to 27.8), more likely to carry a subsequent black-box warning (odds ratio, 4.4; 95% CI, 1.2 to 20.5), and more likely to have one or more dosage forms voluntarily discontinued by the manufacturer (odds ratio, 3.3; 95% CI, 1.5 to 7.5). CONCLUSIONS PDUFA deadlines have appreciably changed the approval decisions of the FDA. Once medications are in clinical use, the discovery of safety problems is more likely for drugs approved immediately before a deadline than for those approved at other times.

Hemodynamic safety and efficacy of ferumoxytol as an intravenous contrast agents in pediatric patients and young adults

PURPOSE To evaluate the safety and feasibility of off-label use of ferumoxytol as an intravenous MRI contrast agents in pediatric patients and young adults. MATERIALS AND METHODS With HIPAA compliance and IRB approval, 86 consecutive patients who had undergone 3 T or 1.5 T MRI with ferumoxytol were retrospectively identified. The blood pressure and heart rate of patients before and after ferumoxytol injection were compared. The overall image quality was evaluated independently by two radiologists with a four-point scale. Interobserver agreement was calculated using weighted kappa statistics. RESULTS The mean±standard deviation (SD) pre and post-contrast systolic blood pressures (SBP) were 101±18 and 95±20, respectively. There was a statistically significant difference between pre-SBP and post-SBP (P=0.003). The pre-contrast diastolic blood pressure (DBP) and the post-contrast diastolic blood pressure (DBP) were 60±14 and 51±17, respectively. There was a statistically significant difference between pre-DBP and post-DBP (P<0.001). The number of patients with SBP and DBP increase, SBP increase and DBP decrease, SBP decrease and DBP increase, SBP and DBP decrease, SBP increase and DBP unchanged were 14 (16%), 9 (10%), 6 (7%), 56 (65%), 1 (1%), respectively. There was moderate agreement on all individual assessments of image quality (kappa=0.45). Eighty-two of 86 (95.4%) studies were scored 3 or above (at least diagnostic quality) by both readers, with 90% confidence interval of 92-99%. CONCLUSION Ferumoxytol is effective as an MR contrast agent. In our sample, there was on average a small but clinically insignificant drop in SBP and DBP post-contrast injection. Large, randomized, controlled trials are needed to establish optimal dosing, imaging procedures, and safety monitoring.

Pulmonary MDCT Angiography: Value of Multiplanar Reformatted Images in Detecting Pulmonary Embolism in Children

OBJECTIVE The purpose of this study was to determine whether the use of multiplanar reformatted (MPR) MDCT images in the diagnosis of pulmonary embolism (PE) in children by faculty pediatric radiologists and radiology residents affects reader performance parameters and adds diagnostic value compared with the use of axial MDCT images alone. MATERIALS AND METHODS This retrospective study was conducted with the images of 60 children (28 boys, 32 girls; mean age, 14.7 ± 3.5 years; range, 3.2-18 years) who consecutively underwent pulmonary CT angiography (CTA) for clinically suspected PE. Two faculty pediatric radiologists and two radiology residents independently reviewed images from each study initially using only axial MDCT images and later using MPR MDCT images in any x-, y-, or z-axis. Diagnostic accuracy, confidence level (1-5 ordinal scale), and interpretation time for MPR MDCT images were compared with those for axial MDCT images by use of the McNemar test and paired Student t test. The kappa coefficient was calculated to assess interobserver agreement. Diagnostic accuracy was compared between faculty pediatric radiologists and radiology residents by logistic regression analysis, and confidence level, interpretation time, and added diagnostic value were evaluated by analysis of variance. RESULTS Nine of 60 pulmonary CTA studies (15%) were found to show PE. Diagnostic accuracy in detection of PE ranged from 91.7% to 100% (mean, 96.7%) with no significant differences between axial and MPR MDCT images (McNemar test for matched binary pairs, p > 0.50 for each reviewer). Logistic regression showed no significant difference between faculty pediatric radiologists and radiology residents in diagnostic accuracy in detection of PE on axial MDCT images (p = 0.48) or MPR MDCT images (p = 0.24). Confidence level and interobserver agreement were significantly higher and average interpretation time was longer in the evaluation of PE with MPR MDCT images than with axial MDCT images for all reviewers (p < 0.001). Compared with faculty pediatric radiologists, radiology residents had significantly greater increases in confidence level, interobserver agreement, interpretation time, and added diagnostic value using MPR MDCT images than they did using axial MDCT images to diagnose PE (p < 0.001). CONCLUSION Use of MPR MDCT images for pulmonary CTA in the diagnosis of PE in children significantly increases confidence, interobserver agreement, and interpretation time among faculty pediatric radiologists and radiology residents. Because use of MPR MDCT images results in significantly greater improvements in reading parameters for residents than for faculty members, the routine use of this technique by trainees should be encouraged.

Imaging of venous compression syndromes

Venous compression syndromes are a unique group of disorders characterized by anatomical extrinsic venous compression, typically in young and otherwise healthy individuals. While uncommon, they may cause serious complications including pain, swelling, deep venous thrombosis (DVT), pulmonary embolism, and post-thrombotic syndrome. The major disease entities are May-Thurner syndrome (MTS), variant iliac vein compression syndrome (IVCS), venous thoracic outlet syndrome (VTOS)/Paget-Schroetter syndrome, nutcracker syndrome (NCS), and popliteal venous compression (PVC). In this article, we review the key clinical features, multimodality imaging findings, and treatment options of these disorders. Emphasis is placed on the growing role of noninvasive imaging options such as magnetic resonance venography (MRV) in facilitating early and accurate diagnosis and tailored intervention.

Image Quality of Thoracic 64-MDCT Angiography: Imaging of Infants and Young Children With or Without General Anesthesia

OBJECTIVE The purpose of this study was to compare the image quality of thoracic CT angiography (CTA) studies performed with two techniques--with general anesthesia and without general anesthesia--for infants and for children younger than 5 years. MATERIALS AND METHODS All consecutively registered infants and young children (age, ≤ 5 years) who underwent contrast-enhanced thoracic CTA from November 2005 to October 2010 were categorized into two groups: general anesthesia and awake (i.e., no general anesthesia). Two radiologists independently evaluated image quality by quantifying the degree of motion artifact at three anatomic levels (upper, middle, and lower lung zones). Motion artifacts were graded on an ordinal scale (0, no motion; 1, mild; 2, moderate; 3, severe), and the Pearson chi-square test was used to assess whether the degree of motion artifact differed between the general anesthesia and awake groups in the upper, middle, and lower lung zones. Logistic regression analysis was performed to determine whether image quality based on the presence or absence of motion artifact in any lobe was related to general anesthesia versus the awake state; age and sex were covariates. Interobserver agreement between two reviewers was evaluated with kappa statistics. RESULTS There were a total of 135 patients (mean age 1.0 year), 95 in the awake group (70%) and 40 in the general anesthesia group (30%). No significant difference was found between the two groups in percentage of studies with motion artifact detected in each lung zone and the total motion artifact score. Results of multivariable logistic regression analysis indicated that image quality was not influenced by age (p = 0.52) or sex (p = 0.20). There was excellent interobserver kappa agreement between reviewers for detecting motion artifact in the upper, middle, and lower lung zones (all κ > 0.90, p < 0.001). CONCLUSION There is no significant difference in image quality of thoracic CTA with 64-MDCT assessed by degree of motion artifact with and without general anesthesia. The results of this study support use of thoracic CTA without general anesthesia in the care of young pediatric patients who meet screening criteria for awake imaging studies.

Added Value of Radiologist Consultation for Pediatric Ultrasound: Implementation and Survey Assessment

OBJECTIVE The purpose of this study was to determine whether radiologist-parent (guardian) consultation sessions for pediatric ultrasound with immediate disclosure of examination results if desired increases visit satisfaction, decreases anxiety, and increases understanding of the radiologists role. SUBJECTS AND METHODS Parents chaperoning any outpatient pediatric ultrasound were eligible and completed surveys before and after ultrasound examinations. Before the second survey, parents met with a pediatric radiologist on a randomized basis but could opt out and request or decline the consultation. Differences in anxiety and understanding of the radiologists role before and after the examination were compared, and overall visit satisfaction measures were tabulated. RESULTS Seventy-seven subjects participated, 71 (92%) of whom spoke to a radiologist, mostly on request. In the consultation group, the mean score (1, lowest; 4, highest) for overall experience was 3.8 ± 0.4 (SD), consultation benefit was 3.7 ± 0.6, and radiologist interaction was 3.7 ± 0.6. Demographics were not predictive of satisfaction with statistical significance in a multivariate model. Forty-six of 68 (68%) respondents correctly described the radiologists role before consultation. The number increased to 60 (88%) after consultation, and the difference was statistically significant (p < 0.001). There was also a statistically significant decrease in mean anxiety score from 2.0 ± 1.0 to 1.5 ± 0.8 after consultation (p < 0.001). Sixty-four of 70 (91%) respondents indicated that they would prefer to speak with a radiologist during every visit. CONCLUSION Radiologist consultation is well received among parents and associated with decreased anxiety and increased understanding of the radiologists role. The results of this study support the value of routine radiologist-parent interaction for pediatric ultrasound.

Cyanotic Congenital Heart Disease: Essential Primer for the Practicing Radiologist

The cyanotic congenital heart diseases are a rare and heterogeneous group of disorders, often requiring urgent neonatal management. Although echocardiography is the mainstay for imaging, continued technological advances have expanded the role for computed tomography and magnetic resonance imaging, helping to limit invasive cardiac catheterization. In this article, the authors review the broad spectrum of cyanotic congenital heart disease, focusing on the utility of advanced noninvasive imaging modalities while highlighting key clinical features and management considerations.

Perinatal Thoracic Mass Lesions: Pre- and Postnatal Imaging.

Chest masses present a common problem in the perinatal period. Advances in prenatal ultrasound, supplemented by fetal magnetic resonance imaging, now allow early detection and detailed characterization of many thoracic lesions in utero. As such, in asymptomatic infants, assessment with postnatal computed tomography or magnetic resonance imaging can often be delayed for several months until the time at which surgery is being contemplated. Bronchopulmonary malformations comprise most of the thoracic masses encountered in clinical practice. However, a variety of other pathologies can mimic their appearances or produce similar effects such as hypoplasia of a lung or both lungs. Understanding of the key differentiating clinical and imaging features can assist in optimizing prognostication and timely management.

Radiologist Compliance With California CT Dose Reporting Requirements: A Single-Center Review of Pediatric Chest CT

OBJECTIVE Effective July 1, 2012, CT dose reporting became mandatory in California. We sought to assess radiologist compliance with this legislation and to determine areas for improvement. MATERIALS AND METHODS We retrospectively reviewed reports from all chest CT examinations performed at our institution from July 1, 2012, through June 30, 2013, for errors in documentation of volume CT dose index (CTDIvol), dose-length product (DLP), and phantom size. Reports were considered as legally compliant if both CTDIvol and DLP were documented accurately and as institutionally compliant if phantom size was also documented accurately. Additionally, we tracked reports that did not document dose in our standard format (phantom size, CTDIvol for each series, and total DLP). RESULTS Radiologists omitted CTDIvol, DLP, or both in nine of 664 examinations (1.4%) and inaccurately reported one or both of them in 56 of the remaining 655 examinations (8.5%). Radiologists omitted phantom size in 11 of 664 examinations (1.7%) and inaccurately documented it in 20 of the remaining 653 examinations (3.1%). Of 664 examinations, 599 (90.2%) met legal reporting requirements, and 583 (87.8%) met institutional requirements. In reporting dose, radiologists variably used less decimal precision than available, summed CTDIvol, included only series-level DLP, and specified dose information from the scout topogram or a nonchest series for combination examinations. CONCLUSION Our institutional processes, which primarily rely on correct human performance, do not ensure accurate dose reporting and are prone to variation in dose reporting format. In view of this finding, we are exploring higher-reliability processes, including better-defined standards and automated dose reporting systems, to improve compliance.

Free-breathing pediatric chest MRI: Performance of self-navigated golden-angle ordered conical ultrashort echo time acquisition

To assess the feasibility and performance of conical k‐space trajectory free‐breathing ultrashort echo time (UTE) chest magnetic resonance imaging (MRI) versus four‐dimensional (4D) flow and effects of 50% data subsampling and soft‐gated motion correction.