James R. Duncan

Metabolism of receptor targeted 111In-DTPA-glycoproteins: Identification of 111In-DTPA-ϵ-lysine as the primary metabolic and excretory product

The hepatic and renal retention of indium-111 (111In) from 111In-labeled polypeptides has been the subject of many investigations. Because the lysosome is a common intracellular destination for the degradation of polypeptides, we studied the lysosomal metabolism of 111In-DTPA-labeled glycoproteins targeted to cell surface receptors in vitro and in vivo. We found that 111In-DTPA-glycoproteins were degraded to 111In-DTPA-epsilon-lysine, which was slowly released from cells and recovered intact in urine and feces. These results suggest a mechanism for 111In retention at target and non-target sites.

Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis

Background The post‐thrombotic syndrome frequently develops in patients with proximal deep‐vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter‐directed thrombolysis (hereafter “pharmacomechanical thrombolysis”) rapidly removes thrombus and is hypothesized to reduce the risk of the post‐thrombotic syndrome. Methods We randomly assigned 692 patients with acute proximal deep‐vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter‐mediated or device‐mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post‐thrombotic syndrome between 6 and 24 months of follow‐up. Results Between 6 and 24 months, there was no significant between‐group difference in the percentage of patients with the post‐thrombotic syndrome (47% in the pharmacomechanical‐thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24‐month follow‐up period (12% in the pharmacomechanical‐thrombolysis group and 8% in the control group, P=0.09). Moderate‐to‐severe post‐thrombotic syndrome occurred in 18% of patients in the pharmacomechanical‐thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post‐thrombotic syndrome were lower in the pharmacomechanical‐thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow‐up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups. Conclusions Among patients with acute proximal deep‐vein thrombosis, the addition of pharmacomechanical catheter‐directed thrombolysis to anticoagulation did not result in a lower risk of the post‐thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335.)

Biodistribution and metabolism of targeted and nontargeted protein-chelate-gadolinium complexes: Evidence for gadolinium dissociation in vitro and in vivo

The intracellular metabolism of receptor-targeted 153Gd-DTPA-glycoproteins was studied in vitro and in vivo. These agents bound to cell surface receptors, underwent receptor mediated endocytosis, and were rapidly degraded to a metabolite which co-migrated with a 153Gd-DTPA-lysine standard on thin layer chromatography. The rates of dissociation of 153Gd and 111In from a glycoprotein-chelate conjugate were determined in vitro. Gadolinium readily dissociated, in a pH-sensitive manner, from glycoprotein-DTPA, and to a lesser degree glycoprotein-MX-DTPA. The biodistribution of targeted and blood pool 153Gd/111In labeled proteins also suggested that gadolinium dissociates from protein-DTPA and protein-MX-DTPA and their metabolites leading to an accumulation of gadolinium in bone. Metal-DTPA-glycoprotein agents targeted to cell surface receptors can still produce very high concentrations of radioactive or paramagnetic metals within the lysosome due to the high rate of accumulation afforded by receptor mediated endocytosis and the low release rate of metabolites such as metal-DTPA-lysine. However, the continued development of gadolinium based macromolecular agents will require improvements in bifunctional chelates.

Retained guidewires after intraoperative placement of central venous catheters

Guidewire retention is a rare complication of central venous catheter placement, and has been related to operator fatigue, inexperience, and inattention, and inadequate supervision of trainees. The true incidence of guidewire loss after intraoperative placement of central venous catheters is unknown. We report 4 cases of guidewire loss after central venous access procedures performed by anesthesia providers in the operating room. Worsening of patients’ clinical condition during catheter placement and complex procedures necessitating more than one guidewire insertion are recurring scenarios in cases involving guidewire loss. Over 6 years at our institution, intraoperative wire loss occurred at a rate of 1:3291 procedures (95% confidence interval of 1/10,000 to 8/10,000).

PROOF Trial: Protection from Pulmonary Embolism with the OptEase Filter

PURPOSE A postmarketing surveillance registry was conducted to monitor the safety and effectiveness of the OptEase vena cava filter when used as a permanent filter. MATERIALS AND METHODS This study was a nonrandomized, multicenter prospective trial with all patients receiving the OptEase vena cava filter for the prevention of pulmonary embolism (PE). A total of 11 clinical sites in the United States enrolled patients. A 1-month postimplantation follow-up examination was performed to determine potential filter migration and the presence of symptomatic thrombosis of the inferior vena cava (IVC) or lower extremities. At 6-month postimplantation follow-up, patients were again assessed for the safety and stability of the filter and any clinical evidence of symptomatic thrombosis. RESULTS One hundred fifty patients were enrolled in this study. Fifty-five patients (36.6%) were unable to complete all of the necessary follow-up at 6 months. At 1 month, filter migration and filter-related symptomatic deep vein thrombosis was observed in one patient each (0.9% and 0.8%, respectively). At 6 months, no new cases of filter migration or filter-related symptomatic thrombosis were observed. Filter tilting (> or = 15 degrees off the IVC axis) was observed in one patient at baseline (0.7%), four patients at 1-month follow-up (3.6%), and three patients (11.4%) at 6-month follow-up. Incidental findings on follow-up radiographs included filter fracture in two patients (1.8%) at 1 month and in one additional patient (4.3%) at 6 months. There were no clinical sequelae associated with the filter fracture. CONCLUSIONS The co-primary endpoints of filter migration and symptomatic thrombus formation at 1 month had an observed frequency of 0.9% and 0.8%, respectively. These co-primary endpoints were stable and unchanged at 6 months.

Percutaneous Stent-Graft Treatment of Superior Mesenteric and Internal Iliac Artery Pseudoaneurysms

Traumatic pseudoaneurysms can cause compression of adjacent structures and hemorrhage. The mortality rate for bleeding visceral artery pseudoaneurysms is particularly high, and surgical repair is all but impossible in some cases. The authors describe two cases in which traumatic pseudoaneurysms of the internal iliac and superior mesenteric arteries were successfully treated with a low-profile stent-graft (Jostent) designed for coronary use. The technical and regulatory issues pertinent to this device are discussed.

Strategies for improving safety and quality in interventional radiology.

PATIENT safety and the quality of health care are at the center of multiple initiatives such as Medicare’s Pay for Performance and American Board of Radiology’s Practice Quality Improvement program. Responding to these initiatives requires a reassessment of the role interventional radiology plays within the health care system. This article is the first in a series of four that summarize how some of the knowledge gained from other fields might be used to improve patient safety and quality in interventional radiology. Before starting, it is worthwhile to state that, although millions of patients have derived tremendous benefit from the dedicated efforts of thousands of interventional radiology teams, we can clearly do better. Improving patient safety and quality will always be a continuous process that revolves around two fundamental questions. First, how might a particular procedure fail to provide the predicted benefit? Second, how can we change our current process so as to increase the probability of success in the future? These articles are meant to introduce a series of topics. This first article serves as an overview. The second article will provide guidance on choos-

Using Information to Optimize Medical Outcomes

AN IMPORTANT HEALTH CARE–RELATED DECISION OF the Obama administration is to reduce waste and harm by modernizing health care information technology systems. This decision would be met with more enthusiasm if the design of the final system were driven by the goal of improving the efficacy and efficiency of medical processes through a strategy of collecting meaningful data. Before spending billions creating and implementing such systems, careful consideration must be given to how this information will be integrated into medical decision making. Some of the current health care information technology systems seem to have been planned using a “ready, fire, aim” approach, with little or no concern for how the data will be used. Ideally, health care information technology systems should collect and use information to improve the probability that patients will receive optimal care. Optimized decision making is the essence of evidence-based medicine. However, collecting, organizing, and storing information is only the first step in this process. The systems must also be designed to facilitate data analysis. Information by itself is useless. Deming, a pioneer in datadriven optimization programs, acknowledged that many systems are drowning in information. Most physicians will agree. Deming argued that what is needed is knowledge. Knowledge is generated from analyzing information and finding the relevant patterns within the data set. These patterns are typically obscured by random noise, but once revealed, provide an understanding or mental model of the underlying processes. These models allow observations of past events to be transformed into future predictions. Although all attempts to predict the future are imperfect, predictions are useful because a series of failed predictions signals that mental models could be inaccurate. Once recognized, such errors prompt improvement in predictive models and can optimize future performance.

The biodistribution of [153Gd]Gd-labeled magnetic resonance contrast agents in a transgenic mouse model of renal failure differs greatly from control mice

Nephrogenic systemic fibrosis occurs in renally impaired patients who have undergone contrast enhanced MR examination using intravenous gadolinium‐based contrast agents. The effect of impaired kidney function on the biodistribution of gadolinium‐based contrast agents was investigated using radiolabeled 153/Natgadolinium‐DOTA, 153/Natgadolinium‐DTPA, and 153/Natgadolinium‐DTPA‐BMA in a transgenic mouse model of renal impairment. Renally impaired animals had more activity associated with their tissues than did control mice, and this increase varied according to the radiotracer injected. For example, after 7 days, renally impaired animals that received 153/NatGd‐DOTA had 3‐fold (P < 0.037) more activity in their bone tissue, whereas renally impaired animals receiving 153/NatGd‐DTPA and 153/NatGd‐DTPA‐BMA had 8‐fold (P < 0.0001) and 24‐fold (P < 0.0001) more activity in their bone tissue, respectively. These findings demonstrate that renal impairment dramatically alters the tissue distribution of Gd3+ ions in vivo, which are likely a critical factor in the development of nephrogenic systemic fibrosis. Magn Reson Med, 2010.

Gadolinium, carbon dioxide, and iodinated contrast material for planning inferior vena cava filter placement: A prospective trial

PURPOSE To prospectively compare the diagnostic accuracy of CO(2) and gadolinium to iodinated contrast material for inferior vena cavography before inferior vena cava (IVC) filter placement. MATERIALS AND METHODS Forty patients underwent injection of iodinated contrast material, CO(2), and gadolinium. Iodinated contrast material was used as the standard. Caval diameter was determined with calibrated software. Three readers blinded to contrast agent used measured the distance from the superior image border to the inferior margin of the renal veins and from the inferior image border to the iliac bifurcation. The measurements with CO(2) and gadolinium were compared to those with iodinated contrast material to obtain the interobserver and intraobserver variability. The presence or absence of caval thrombus and variant anatomy was noted. The same readers reexamined 12 studies in a separate session to determine intraobserver variability and correlation. RESULTS Caval diameter differed by 0.4 mm or less for all three agents. Measurements with all agents were within 2 mm of each other for all patients. Gadolinium and CO(2) were not significantly different from one another in measuring caval diameter. At the initial reading, compared with iodinated contrast material, gadolinium had greater mean interobserver error in measuring the distance to the iliac bifurcation and both renal veins (range, 1.6-1.8 mm) than CO(2) (range, 0.2-1.4 mm). This finding, although statistically significant for gadolinium (P <.05), was of doubtful clinical relevance. Interobserver correlation was significantly worse for CO(2) at the levels of the iliac bifurcation (P =.02) and right renal vein (P =.008). Interobserver correlation for gadolinium was similar to that for iodinated contrast material at all levels. At repeat reading, there was significantly inferior intraobserver correlation with use of CO(2) for both renal veins (P <.05) compared to iodinated contrast material and for the left renal vein (P <.05) compared to gadolinium. Gadolinium identified three of three renal vein anomalies identified with iodinated contrast material whereas CO(2) localized one of three. CONCLUSION CO(2) and gadolinium had limitations when compared with iodinated contrast material. Gadolinium provided superior consistency in identifying relevant landmarks for filter placement. CO(2) demonstrated significantly greater mean correlative error than gadolinium at initial and repeat readings.