Marshall E. Hicks

Steps toward mapping the human vasculature by phage display.

The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized to different organs. This large-scale screening indicates that the tissue distribution of circulating peptides is nonrandom. High-throughput analysis of the motifs revealed similarities to ligands for differentially expressed cell-surface proteins, and a candidate ligand–receptor pair was validated. These data represent a step toward the construction of a molecular map of human vasculature and may have broad implications for the development of targeted therapies.

Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: The M.D. Anderson experience

BACKGROUNDCarcinoid tumors have a predilection for metastasizing to the liver. The presence of liver metastases is associated with poor prognosis and also results in significant deterioration of patients quality of life. Several reports suggest that hepatic artery embolization or chemoembolization can be used for control of liver disease in these patients. We retrospectively reviewed our experience with the use of hepatic arterial embolization or chemoembolization in patients with liver-dominant metastatic carcinoid disease, evaluating the clinical and radiologic response rates, duration of response, and progression-free and overall survival rates of these patients. MATERIALS AND METHODSThe medical records of all patients with carcinoid tumors metastatic to the liver who underwent hepatic artery embolization or chemoembolization between January 1992 and December 2000 were reviewed. For the purposes of this study, we compared the follow-up computed tomography or magnetic resonance imaging with the baseline imaging to determine each patients objective tumor response. The interval between the dates of response and disease progression was considered the response duration. Progression-free survival duration was calculated from the date of initial treatment to the date disease progression was recorded or the date of death. Survival durations were calculated using the Kaplan-Meier method. RESULTSEighty-one patients (48 men and 33 women; age range, 38–79 years) were included in this study. The mean duration of disease from the initial discovery of liver metastases until embolization was 24.5 months. Fifty patients were treated with bland hepatic artery embolization, and 31 underwent chemoembolization. Of the 69 patients in whom radiologic response could be evaluated, partial response was observed in 46 patients (67%), minimal response (MR) in six (8.7%), stable disease in 11 (16%), and progressive disease in six (8.7%). The median duration of response in the 42 patients with partial response was 17 months (range, 4–51 months). Sixty-three percent of patients had a reduction in their tumor-related symptoms. The median progression-free survival duration was 19 months (95% confidence interval, 17–21 months); the probability of progression-free survival was 75%, 35%, and 11% at 1, 2, and 3 years, respectively. The median overall survival time was 31 months (95% confidence interval, 23–38 months); the survival probability was 93% at 1 year, 62% at 2 years, and 24% at 5 years. CONCLUSIONSHepatic arterial occlusive therapy using hepatic artery embolization or chemoembolization results in symptomatic and radiologic response in most patients with carcinoid metastases in the liver. The progression-free survival of 19 months achieved with embolization in our study is encouraging, given that most patients had extensive liver involvement and had shown disease progression while receiving systemic treatment.

Transhepatic Ipsilateral Right Portal Vein Embolization Extended to Segment IV: Improving Hypertrophy and Resection Outcomes with Spherical Particles and Coils

PURPOSE To analyze outcomes after right portal vein embolization extended to segment IV (right PVE + IV) before extended right hepatectomy, including liver hypertrophy, resection rates, and complications after embolization and resection, and to assess differences in outcomes with two different particulate embolic agents. MATERIALS AND METHODS Between 1998 and 2004, transhepatic ipsilateral right PVE + IV with particles and coils was performed in 44 patients with malignant hepatobiliary disease, including metastases (n = 24), biliary cancer (n = 14), and hepatocellular carcinoma (n = 6). Right PVE + IV was considered if the future liver remnant (FLR; segments II/III with or without I) was less than 25% of the total estimated liver volume (TELV). Tris-acryl microspheres (100-700 microm; n = 21) or polyvinyl alcohol (PVA) particles (355-1,000 microm; n = 23) were administered in a stepwise fashion. Smaller particles were used to occlude distal branches, followed by larger particles to occlude proximal branches until near-complete stasis. Coils were then placed in secondary portal branches. Computed tomographic volumetry was performed before and 3-4 weeks after right PVE + IV to assess FLR hypertrophy. Liver volumes and postembolization and postoperative outcomes were measured. RESULTS After right PVE + IV with PVA particles, FLR volume increased 45.5% +/- 40.9% and FLR/TELV ratio increased 6.9% +/- 5.6%. After right PVE + IV with tris-acryl microspheres, FLR volume increased 69.0% +/- 30.7% and FLR/TELV ratio increased 9.7% +/- 3.3%. Differences in FLR volume (P = .0011), FLR/TELV ratio (P = .027), and resection rates (P = .02) were statistically significant. Seventy-one percent of patients underwent extended right hepatectomy (86% after receiving tris-acryl microspheres, 57% after receiving PVA). Thirteen patients (29%) did not undergo resection (extrahepatic spread [n = 9], inadequate hypertrophy [n = 3], other reasons [n = 1]). No patient developed postembolization syndrome or progressive liver insufficiency after embolization or resection. One death after resection occurred as a result of sepsis and hemorrhage. Median hospital stays were 1 day after right PVE + IV and 7 days after resection. CONCLUSION Transhepatic ipsilateral right PVE + IV with use of particles and coils is a safe, effective method for inducing contralateral hypertrophy before extended right hepatectomy. Embolization with small spherical particles provides improved hypertrophy and resection rates compared with larger, nonspherical particles.

Yttrium 90 Resin Microspheres for the Treatment of Unresectable Colorectal Hepatic Metastases after Failure of Multiple Chemotherapy Regimens: Preliminary Results

PURPOSE Responses to liver-directed therapy with yttrium 90 microspheres (SIR-Spheres) and adjuvant intraarterial chemotherapy have occurred in patients with unresectable colorectal hepatic metastases who had received less than one chemotherapy regimen. Now, SIR-Spheres are being used to treat patients with advanced disease who have received multiple chemotherapy regimens. A retrospective analysis was performed to determine the technical feasibility of SIR-Sphere treatment in this population. MATERIALS AND METHODS The medical records of 12 patients with hepatic metastatic disease and intrahepatic progression after multiple chemotherapy regimens for unresectable colorectal hepatic metastases who were treated with one or two infusions of SIR-Spheres were retrospectively analyzed for demographics, tumor characteristics, treatment details, response, and survival. RESULTS Twelve patients underwent 17 outpatient infusions of SIR-Spheres. Percent hepatic tumor volume was less than 25% in four patients, 25%-50% in three, and more than 50% in five. Treatment in 11 patients with bilobar disease was accomplished via single infusions in six cases and sequential unilobar infusions in five patients. A single infusion was used to treat unilobar disease in the remaining patient. Median prescribed dose was 39.6 mCi (mean, 37.2 mCi; range, 17-67.5 mCi); the prescribed dose exceeded the delivered dose in six infusions (35%) as a result of embolic arterial occlusion. Radiologic response was stable in five of nine patients. Carcinoembryonic antigen levels decreased in four of seven patients. Four patients received chemotherapy concomitantly or after completion of treatment. Gastric ulceration in one patient was managed nonoperatively. Median survival times from diagnosis and treatment were 24.6 and 4.5 months, respectively. CONCLUSIONS Treatment with SIR-Spheres induces responses in patients with advanced unresectable colorectal hepatic metastases after multiple chemotherapy regimens. Inability to deliver the prescribed dose is related to the embolic effect of SIR-Spheres.

A Review of Radiologically Guided Percutaneous Nephrostomies in 303 Patients

PURPOSE To determine the morbidity and mortality associated with radiologically guided percutaneous nephrostomy (PCN) and to identify possible contributory risk factors. MATERIALS AND METHODS The authors retrospectively reviewed 454 consecutive PCNs in 303 patients performed during a 4-year period. PCNs performed specifically for nephrolithotomy were excluded. Self-retention loop catheters (8-12 F) were placed with use of a modified Seldinger technique in all patients. Preprocedural antibiotics were administered routinely. Demographic variables, technical factors related to tube placement, and risk factors were examined with respect to tube malfunction and 30-day morbidity and mortality. RESULTS Technical success was 99%. The overall complication rate was 6.5%, including hemorrhage requiring transfusion after 13 PCNs (2.8%). A baseline platelet count of less than 100,000/mm3 was a significant risk factor for hemorrhage requiring blood transfusion. The 30-day mortality rate was 3.1%; however, none of these deaths were procedure related. CONCLUSION Radiologically guided PCN with self-retention catheters is associated with a high technical success rate and low morbidity.

Comparison of the AngioJet Rheolytic Catheter to Surgical Thrombectomy for the Treatment of Thrombosed Hemodialysis Grafts

PURPOSE To compare the clinical effectiveness of the AngioJet F105 rheolytic catheter to that of surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. MATERIALS AND METHODS This was a multicenter, prospective, randomized trial comparing technical success, primary patency, and complication rates. A total of 153 patients were enrolled: 82 patients in the AngioJet group and 71 patients in the surgical thrombectomy group. Patient follow-up was performed 24-48 hours, 1 month, and 6 months after the procedures. RESULTS Technical success, as defined by the patients ability to undergo hemodialysis treatment, was 73.2% for the AngioJet group and 78.8% for the surgical thrombectomy group (P = .41). The primary patency rates of the AngioJet group were 32%, 21%, and 15% at 1, 2, and 3 months, respectively. The primary patency rates for the surgical group were 41%, 32%, and 26% at 1, 2, and 3 months, respectively. This difference approached statistical significance (P = .053). The groups had similar complication rates-14.6% in the AngioJet group and 14.1% in the surgery group-although the surgery group had more major complications (11.3%). In the AngioJet group, there was a transient increase in plasma-free hemoglobin, which normalized within 24-48 hours. CONCLUSIONS The AngioJet F105 catheter provides similar clinical results when compared to surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. The difference in patency rates between these two techniques approached statistical significance. In addition, results of both thrombectomy methods were inferior to those suggested by the Dialysis Outcomes Quality Initiative guidelines.

Use of Research Biopsies in Clinical Trials: Are Risks and Benefits Adequately Discussed?

PURPOSE Although the incorporation of research biopsies into clinical trials is increasing, limited information is available about how study protocols and informed consents integrate and describe their use. METHODS All therapeutic clinical trials in which image-guided research biopsies were performed from January 1, 2005, to October 1, 2010, were identified from an interventional radiology database. Data from study protocols and informed consents were extracted and analyzed. Procedural complications were recorded. RESULTS A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. The analysis of the research biopsy tumor tissue was a study end point in 95% of trials. The primary indication for a research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51%, and not mentioned in 23% of trials. For studies with mandatory biopsies, biopsy was an eligibility criterion in 71% of trials, and a statistical justification for the research biopsy sample size was present in 50% of trials. A total of 745 research biopsies were performed on 576 patients. Overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complication rates for intrathoracic and abdominal/pelvic solid organ biopsies were 17.1% (36 of 211 biopsies) and 1.6% (three of 189 biopsies), respectively. Site-stratified research biopsy-related risks were discussed in five consents. CONCLUSION A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.

Percutaneous radiofrequency ablation of renal tumors: technique, complications, and outcomes.

PURPOSE To report the safety, technical success, and effectiveness of percutaneous radiofrequency (RF) ablation for renal tumors. MATERIALS AND METHODS The authors retrospectively reviewed the medical records and imaging studies of 29 consecutive patients (18 men, 11 women; mean age, 65 ± 2.62 years) with 30 renal tumors (mean diameter, 3.5 ± 0.24 cm) who underwent percutaneous RF ablation at their institution from September 2001 to March 2004. All procedures were performed with computed tomography guidance with general anesthesia, and all patients were admitted to the hospital for overnight observation. Technical success, complications, and their management were recorded. Technique effectiveness was assessed by imaging and clinical follow up. RESULTS Overall, 88 overlapping ablations were performed (mean, 2.6 ± 0.16 ablations per tumor per session) in 34 sessions. There were four major complications (12%). Three patients had gross hematuria and urinary obstruction, all were successfully treated. One patient had persistent anterior abdominal wall weakness. There were also two minor complications (6%) without significant clinical sequelae. One patient had gross hematuria which resolved spontaneously, another patient had transient paresthesia of the anterior abdominal wall. There were no significant changes in renal function after RF ablation. The intent of RF ablation was eradication of the primary tumor in 27 patients and treatment of gross hematuria in the other two. Technical success was achieved in all cases. Follow-up images were available for 26 patients. The primary tumor was completely ablated in 23 of 24 patients (96%) in whom eradication of the primary tumor was attempted (follow up period: mean, 10 months, median 7 months). The two patients treated for hematuria remained asymptomatic for 6 and 27 months each. CONCLUSION Percutaneous RF ablation for renal tumors is safe and well tolerated. High technical success rates are expected. Early reports of the techniques effectiveness are promising.

Rheolytic thrombectomy with use of the AngioJet-F105 catheter : Preclinical evaluation of safety

PURPOSE A preclinical evaluation of the safety of the AngioJet-F105 rheolytic thrombectomy catheter. MATERIALS AND METHODS The AngioJet-F105 catheter uses multiple retrograde high-speed fluid jets impinging on a primary aspiration lumen to create a hydrodynamic recirculation vortex that traps and fragments adjacent thrombus, with simultaneous evacuation of the resulting debris through the aspiration lumen. The effect of the AngioJet on treated vessels was evaluated in 10 canines. Vascular integrity on histopathologic examination and endothelial coverage on scanning electron microscopic study were examined in 15 vessel segments treated with the AngioJet-F105 catheter, compared with four vessel segments subjected to the Fogarty balloon maneuver, and 10 untreated vessel segments. The size distribution of particulate debris, upstream and downstream, after thrombectomy was determined in a flow-circuit model simulating the superficial femoral artery. Aliquots from the downstream effluent were then injected into the renal arteries of two healthy canines. RESULTS The device caused only minimal focal endothelial denudation and no significant deep injury. No significant difference in endothelial coverage occurred in AngioJet-treated vessel segments compared to untreated control vessels (mean +/- standard deviation: 88.0% +/- 7.9% vs 89.7% +/- 11.6%, P = .77). Vessels treated with the Fogarty balloon pullback maneuver had significantly less residual endothelial coverage (58.0% +/- 8.0%, P < .03). Particulate microemboli in the effluent of the flow model accounted for 12% of the initial thrombus volume (0% > 100 microm, 99.83% < or = 10 microm). Histopathologic evaluation of the four renal beds injected with the resulting debris demonstrated no signs of necrosis. A moderate transient increase in plasma-free hemoglobin occurred, with a mild corresponding decrease in hematocrit. CONCLUSIONS The AngioJet-F105 catheter resulted in only mild and focal injury to the treated vessels. The vast majority of resulting particulate debris consist of microscopic particles, without significant ischemic effect.

A phase I surrogate endpoint study of SU6668 in patients with solid tumors

Purpose. To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies. Experimental design. Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m2/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668. Results. Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cloral) measured on day 1 was 6.3 ± 2.7 L/hr/m2, yielding a mean AUC of 16.6 ± 4.3 mg/L·hr. By day 22, the Cloral was 40% more than that observed on day 1. Conclusion. It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.