Elmar M. Merkle

Phase I Trial of Pazopanib in Patients with Advanced Cancer

Purpose: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. Experimental Design: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. Results: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of ≥800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C24) ≥15 μg/mL (34 μmol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of ≥6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of ≥800 mg once daily or 300 mg twice daily. Conclusion: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.

Gadoxetate Disodium–Enhanced MRI of the Liver: Part 2, Protocol Optimization and Lesion Appearance in the Cirrhotic Liver

OBJECTIVE The purpose of this article is to review the pharmacokinetic and pharmacodynamic properties of gadoxetate disodium (Gd-EOB-DTPA), to describe a workflow-optimized pulse sequence protocol, and to illustrate the imaging appearance of focal lesions in the noncirrhotic liver. CONCLUSION Gd-EOB-DTPA allows a comprehensive evaluation of the liver with the acquisition of both dynamic and hepatocyte phase images. This provides potential additional information, especially for the detection and characterization of small liver lesions. However, protocol optimization is necessary for improved image quality and workflow.

Review of Internal Hernias: Radiographic and Clinical Findings

OBJECTIVE Internal hernias, including paraduodenal (traditionally the most common), pericecal, foramen of Winslow, and intersigmoid hernias, account for approximately 0.5-5.8% of all cases of intestinal obstruction and are associated with a high mortality rate, exceeding 50% in some series. To complicate matters, the incidence of internal hernias is increasing because of a number of relatively new surgical procedures now being performed, including liver transplantation and gastric bypass surgery. A significant increase in hernias is occurring in patients undergoing transmesenteric, transmesocolic, and retroanastomotic surgical procedures. It is important for radiologists to be familiar with and to understand the various types of internal hernias and their imaging features so that prompt and accurate diagnosis of these conditions can be made. CONCLUSION This article illustrates the imaging findings of internal hernias, with emphasis placed on the CT findings, especially in transmesenteric, transmesocolic, and retroanastomotic types of internal hernias.

Endovascular treatment of visceral artery aneurysms.

Purpose: To review a 10-year experience with endovascular embolization of visceral artery aneurysms. Methods: Twenty-five patients (13 men; mean age 52.1 years, range 31–80) presented with VAAs of varying locations and etiologies: 10 splenic, 3 gastroduodenal, 2 pancreaticoduodenal, 3 hepatic, 3 superior mesenteric, 2 celiac, 1 left gastric, and 1 jejunoileal. Ten patients were asymptomatic; 7 aneurysms were ruptured. Transcatheter coil embolization was the treatment of choice in all patients. Results: Coil placement was initially (<7 days) successful in 23 (92%) patients. One superior mesenteric artery aneurysm remained perfused, and recurrent bleeding occurred 2 days after intervention in 1 case, but repeated embolization excluded the aneurysm. One patient with necrotizing pancreatitis died from sepsis 10 days after endovascular treatment and surgery (4% 30-day mortality). Long-term follow-up revealed excellent results after an average 48.7 months (range 14–75) with only 1 recurrence after 12 months. Conclusions: Embolotherapy is the treatment of choice in visceral artery aneurysms, regardless of etiology, location, or clinical presentation.

Abdominal MRI at 3.0 T: The Basics Revisited

OBJECTIVE The purpose of our article is to describe the underlying physics concepts of abdominal MRI at 3.0 T and their impact on signal-to-noise ratio, susceptibility artifacts, chemical shift artifacts, and dielectric effects. CONCLUSION Abdominal MR sequence protocols optimized for 1.5-T scanners should not be transferred to 3.0 T without substantial modification. In addition, specific patient groups--for example, large patients with ascites--are not well suited to undergo an abdominal MRI study at 3.0 T.

Renal Stone Assessment with Dual-Energy Multidetector CT and Advanced Postprocessing Techniques: Improved Characterization of Renal Stone Composition—Pilot Study

PURPOSE To prospectively evaluate the capability of noninvasive, simultaneous dual-energy (DE) multidetector computed tomography (CT) to improve characterization of human renal calculi in an anthropomorphic DE renal phantom by introducing advanced postprocessing techniques, with ex vivo renal stone spectroscopy as the reference standard. MATERIALS AND METHODS Fifty renal calculi were assessed: Thirty stones were of pure crystalline composition (uric acid, cystine, struvite, calcium oxalate, calcium phosphate, brushite), and 20 were of polycrystalline composition. DE CT was performed with a 64-detector CT unit. A postprocessing algorithm (DECT(Slope)) was proposed as a pixel-by-pixel approach to generate Digital Imaging and Communications in Medicine dataset gray-scale-encoding ratios of relative differences in attenuation values of low- and high-energy DE CT. Graphic analysis, in which clusters of equal composition were identified, was performed by sorting attenuation values of color composition-encoded calculi in an ascending sequence. Multivariate general linear model analysis was used to determine level of significance to differentiate composition on native and postprocessed DE CT images. RESULTS Graphic analysis of native DE CT images was used to identify clusters for uric acid (453-629 HU for low-energy CT, 443-615 HU for high-energy CT), cystine (725-832 HU for low-energy CT, 513-747 HU for high-energy CT), and struvite (1337-1530 HU for low-energy CT, 1007-1100 HU for high-energy CT) stones; high-energy clusters showed attenuation value overlap. Polycrystalline calcium oxalate and calcium phosphate calculi were found throughout the entire spectrum, and dense brushite had attenuation values of more than 1500 HU for low-energy CT and more than 1100 HU for high-energy CT. The DE CT algorithm was used to generate specific identifiers for uric acid (77-80 U(Slope), one outlier), cystine (70-71 U(Slope)), struvite (56-60 U(Slope)), calcium oxalate and calcium phosphate (17-59 U(Slope)), and brushite (4-15 U(Slope)) stones. Statistical analysis showed that all compositions were identified unambiguously with the DECT(Slope) algorithm. CONCLUSION DE multidetector CT with advanced postprocessing techniques improves characterization of renal stone composition beyond that achieved with single-energy multidetector CT acquisitions with basic attenuation assessment.

Short- and Midterm Reproducibility of Apparent Diffusion Coefficient Measurements at 3.0-T Diffusion-weighted Imaging of the Abdomen

PURPOSE To test the hypothesis that there is no significant variability in apparent diffusion coefficients (ADCs) at assessment of the short- and midterm reproducibility of ADC measurements in a healthy population. MATERIALS AND METHODS Twenty healthy male volunteers were enrolled in this prospective institutional review board-approved study after they provided written informed consent. A 3.0-T magnetic resonance (MR) system was used to perform five axial diffusion-weighted (DW) abdominal acquisitions (session 1). A mean of 147 days +/- 20 (standard deviation) later, 16 of the 20 volunteers were imaged again with use of the same protocol and MR system (session 2). The mean ADCs for three regions of interest (ROIs) in five anatomic locations (right hepatic lobe, spleen, and head, body, and tail of pancreas) were calculated. The coefficient of variation (CV, equal to standard deviation divided by mean) was calculated for each subject, session, and anatomic location. The ADC and CV data were then analyzed by using repeated-measures analysis of variance. RESULTS There were significant differences (P < .001) in mean ADCs among the five anatomic locations. There were no significant differences in ADCs among the various repeated sequence acquisitions or the three ROIs. There were no significant differences in ADCs between imaging sessions 1 and 2. ADCs were fairly stable over the midterm within a given individual. Finally, there were no significant differences in resulting CVs between the imaging sessions or anatomic locations. The mean CV for ADC measurement reproducibility was 14% (95% confidence interval: 13%, 15%). CONCLUSION The mean CV for short- and midterm ADC reproducibility was 14% at abdominal DW imaging. Treatment effects of less than approximately 27% (change in ADC divided by pretreatment ADC) will not be clinically detectable with confidence with one acquisition in a single individual.

Field strength and diffusion encoding technique affect the apparent diffusion coefficient measurements in diffusion-weighted imaging of the abdomen.

Objectives:The purpose of this study is to determine what effects a variety of diffusion encoding techniques at 1.5 T and 3 T have on measured abdominal apparent diffusion coefficient (ADC) values obtained in a healthy population. Materials and Methods:Sixteen healthy male volunteers were enrolled in this prospective Institutional Review Board-approved study following written informed consent. Imaging was performed on a 1.5 T and a 3 T magnetic resonance system (Siemens, Erlangen) with several abdominal axial diffusion weighted imaging (DWI) acquisitions: an orthogonal diffusion encoding with b-values of 0/400 seconds/mm2, and a series of four 3-scan trace weighted acquisitions with b-values of 0/50, 0/400, 0/800, 0/50/400/800 seconds/mm2, respectively. The mean ADC values were calculated for 3 regions of interest (ROI) in 5 locations (right hepatic lobe, spleen, pancreatic head, body, and tail). The ADC data were analyzed using a repeated-measures analysis of variance. Results:There was a significant difference between measured ADC values at 1.5 T and 3 T for liver (P < 0.001), but not for pancreas (P = 0.427) or spleen (P = 0.167). There was no significant difference (P > 0.999) in the measured ADC values between the orthogonal encodings and the 3-scan trace weighted encoding with the same b-value. There were significant differences (P < 0.001) between all 4 weighting schemes for the 3-scan trace with the measured ADC decreasing with increasing b-value. Conclusion:Measured abdominal ADC values depend on the exact selection of b-value used for encoding for liver, pancreas, and spleen. In addition, the measured ADC values depend on the field strength of the scanner for liver.

Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer

Objective Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50–60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2−/− mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. Methods Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2−/− mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. Results Unlike controls, Mdr2−/− mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. Conclusions Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

MRI of histologically confirmed mammary carcinoma : Clinical relevance of diagnostic procedures for detection of multifocal or contralateral secondary carcinoma

PURPOSE MR mammography (MRM) is a sensitive diagnostic method for the detection of mammary carcinomas. The present study evaluates whether MRM can yield additional relevant data in cases of histologically confirmed mammary carcinoma. METHOD Thirty-four patients with histologically confirmed mammary carcinoma were examined at MRM using a T1-weighted GE sequence and a T2-weighted SE sequence. Morphologic criteria and the dynamic contrast medium behavior of the tumors were evaluated. RESULTS MRM showed a 100% sensitivity and diagnostic accuracy in the detection of mammary carcinomas. Additionally, three unexpected contralateral carcinomas were discovered. In 26 patients, there was a multifocal or multicentric tumor process. In 24 patients, peritumoral edema was visualized, which corresponded histologically in 21 patients with lymphangiosis and in 3 with an inflammatory peritumoral reaction. CONCLUSION Because of its high sensitivity in the diagnosis of multifocal disease and of contralateral carcinomas, MRM would seem to represent a useful addition to preoperative diagnostic procedures. The potential benefit to the patient and its cost efficiency, however, remain to be clarified.