Intraindividual variation of dose parameters in oncologic CT imaging.

The objective of this study is to identify essential aspects influencing radiation dose in computed tomography [CT] of the chest, abdomen and pelvis by intraindividual comparison of imaging parameters and patient related factors. All patients receiving at least two consecutive CT examinations for tumor staging or follow-up within a period of 22 months were included in this retrospective study. Different CT dose estimates (computed tomography dose index [CTDIvol], dose length product [DLP], size-specific dose estimate [SSDE]) were correlated with patient's body mass index [BMI], scan length and technical parameters (tube current, tube voltage, pitch, noise level, level of iterative reconstruction). Repeated-measures-analysis was initiated with focus on response variables (CTDIvol, DLP, SSDE) and possible factors (age, BMI, noise, scan length, peak kilovoltage [kVp], tube current, pitch, adaptive statistical iterative reconstruction [ASIR]). A univariate-linear-mixed-model with repeated-measures-analysis followed by Bonferroni adjustments was used to find associations between CT imaging parameters, BMI and dose estimates followed by a subsequent multivariate-mixed-model with repeated-measures-analysis with Bonferroni adjustments for significant parameters. A p-value <0.05 was considered statistically significant. We found all dose estimates in all imaging regions were substantially affected by tube current. The iterative reconstruction significantly influenced all dose estimates in the thoracoabdominopelvic scans as well as DLP and SSDE in chest-CT. Pitch factor affected all dose parameters in the thoracoabdominopelvic CT group. These results provide further evidence that tube current has a pivotal role and potential in radiation dose management. The use of iterative reconstruction algorithms can substantially decrease radiation dose especially in thoracoabdominopelvic and chest-CT-scans. Pitch factor should be kept at a level of ≥1.0 in order to reduce radiation dose.

A ten-year, single-center experience: Concordance between breast core needle biopsy/vacuum-assisted biopsy and postoperative histopathology in B3 and B5a cases.

PURPOSE: To determine the concordance rate between core needle biopsy/vacuum-assisted biopsy (CNB/VAB) and postoperative histopathology in B3 (lesions of uncertain malignant potential) and B5a (in situ) lesions found on mammograms or ultrasound. MATERIAL AND METHODS: 2,029 consecutive biopsies performed over 10 years for patients who underwent mammograms or ultrasounds. For CNB 14G needle and for VAB 8G/10G needles were used. In all biopsies, we identified the age, BI-RADS®, histopathological biopsy results, B-category, nuclear grade for DCIS and postoperative histopathology results in B3 and B5a cases from the biopsy. RESULTS: The B-categories from CNB/VAB were as follows: B2 42.2 percent (n = 856), B3 4.5 percent (n = 91), B5a 5.7 percent (n = 115), and B5b 47.6 percent (n = 967). In the B3-category, 72/91 patients underwent surgical excision, with a concordance rate of 83.3 percent (n = 60/72) and a discordance rate of 16.7 percent (n = 12/72) to postoperative histopathology. From the discordant cases, 67.7 percent (n = 8/12) showed DCIS and 32.3 percent (n = 4/12) showed invasive breast cancer. The BIRADS of the discordant cases was 4b in 41.7 percent (n = 5/12) and 5 in 58.3 percent (n = 7/12). The PPVs for malignancy of B3 lesions were 0.21, with no statistical significance between subgroups. In the B5a-category, 101 of 115 patients underwent surgery in our hospital, with a concordance rate of 80.2 percent (n = 81/101) and a discordance rate of 19.8 percent (n = 20/101) to postoperative histopathology. From the discordant cases, 55 percent (n = 11/20) showed invasive breast carcinoma of no special type (NST). CONCLUSION: Our concordance rate for B3 (83.3 percent) and B5a (80.2 percent) lesions in the biopsies to postoperative histopathology is matching to previously published literature. Surgical excision is our recommendation for lesions biopsied with a B3 category in the histopathology and a BIRADS category of (4b, 4c and 5). The PPVs for malignancy of B3 lesions showed no statistical significance between subgroups. Also, the nuclear grade of DCIS was not statistically significant in terms of upgrade into invasive breast cancer.

Functional gadoxetate disodium-enhanced MRI in patients with primary sclerosing cholangitis (PSC).

OBJECTIVES: To assess the value of variable flip angle-based T1 liver mapping on gadoxetate disodium-enhanced MRI in patients with primary sclerosing cholangitis (PSC) for evaluation of global and segmental liver function, and determine a possible correlation with disease severity. METHODS: Sixty-one patients (19 female, 42 male; mean age 41 years) with PSC were included in this prospective study. T1 mapping was performed using a 3D-spoiled GRE sequence (flip angles 5°, 15°, 20°, 30°) before, 16 (HP1) and 132 min (HP2) after contrast injection. T1 values were measured and compared (Wilcoxon-Test) by placing ROIs in each liver segment. The mean reduction of T1 relaxation time at HP1 and HP2 was calculated and correlated with liver function tests (LFTs), MELD, Mayo Risk and Amsterdam Scores (Spearman correlation). RESULTS: Significant changes of T1 relaxation times between non-enhanced and gadoxetate disodium-enhanced MRI at HP1 and HP2 could be observed in all liver segments (p < 0.0001). A significant correlation of T1 reduction could be observed with LFTs, MELD and Mayo Risk Score (p < 0.05). CONCLUSIONS: T1 mapping of the liver using a variable flip angle-based sequence is a feasible technique to evaluate liver function on a global level, and may be extrapolated on a segmental level in patients with PSC. KEY POINTS: • T1 mapping enables evaluation of global liver function in PSC. • T1 relaxation time reduction correlates with the MELD and MayoRisk Score. • Extrapolated, T1 mapping may allow for segmental evaluation of liver function.

Experimental Evaluation of the Heat Sink Effect in Hepatic Microwave Ablation.

PURPOSE: To demonstrate and quantify the heat sink effect in hepatic microwave ablation (MWA) in a standardized ex vivo model, and to analyze the influence of vessel distance and blood flow on lesion volume and shape. MATERIALS AND METHODS: 108 ex vivo MWA procedures were performed in freshly harvested pig livers. Antennas were inserted parallel to non-perfused and perfused (700,1400 ml/min) glass tubes (diameter 5mm) at different distances (10, 15, 20mm). Ablation zones (radius, area) were analyzed and compared (Kruskal-Wallis Test, Dunn's multiple comparison Test). Temperature changes adjacent to the tubes were measured throughout the ablation cycle. RESULTS: Maximum temperature decreased significantly with increasing flow and distance (p<0.05). Compared to non-perfused tubes, ablation zones were significantly deformed by perfused tubes within 15 mm distance to the antenna (p<0.05). At a flow rate of 700 ml/min ablation zone radius was reduced to 37.2% and 80.1% at 10 and 15 mm tube distance, respectively; ablation zone area was reduced to 50.5% and 89.7%, respectively. CONCLUSION: Significant changes of ablation zones were demonstrated in a pig liver model. Considerable heat sink effect was observed within a diameter of 15 mm around simulated vessels, dependent on flow rate. This has to be taken into account when ablating liver lesions close to vessels.

Value of oral effervescent powder administration for multidetector CT evaluation of esophageal cancer.

PURPOSE: To assess the value of oral effervescent powder (EP) for evaluation of esophageal distension, and for detection and staging of esophageal cancer with contrast-enhanced CT. MATERIALS AND METHODS: 84 patients without esophageal pathology and 52 patients with histological confirmed diagnosis of esophageal cancer were included in this prospective IRB-approved study. Half of the patients in both groups received EP prior to CT. Esophageal distension was assessed by planimetry of the inner (IA) and outer area (OA). Two blinded readers evaluated the datasets separately with regard to diagnosis of esophageal cancer (yes/no) and staging (T0-T4), if applicable. Distension results were compared (t-Test). In patients with cancer sensitivity, specificity, NPV and PPV were calculated. CT staging results were compared to histopathology (Cohen-k). RESULTS: IA and IA/OA were significantly larger after EP as compared to the group without EP (p<0.05). Sensitivity, specificity, NPV and PPV for cancer detection cancer were as follows: 78%/78%, 98%/98%, 95%/95%, 87%/87% with EP; 60%/68%, 98%/98%, 94%/94%, 80%/83% without EP. Staging with EP was good (k=0.84/0.67) and moderate without EP (k=0.58/0.59). CONCLUSIONS: Administration of EP prior to CT results in good distension of the esophagus, and improves detection and staging of esophageal cancer, as compared to control studies without EP.

Non-invasive quantification of anti-angiogenic therapy by contrast-enhanced MRI in experimental pancreatic cancer.

BACKGROUND: Currently, early changes of tumor vasculature after angiogenesis inhibition can only be evaluated by histopathology, a method not suitable in a clinical setting. PURPOSE: To quantify effects of different angiogenesis inhibitors on the microvasculature of orthotopically implanted pancreatic cancers by contrast-enhanced magnetic resonance imaging (MRI) in order to establish a non-invasive technique for monitoring antiangiogenic cancer treatment. MATERIAL AND METHODS: DSL-6A/C1 pancreatic cancers were implanted in the pancreas of 109 Lewis rats. Three weeks later, antiangiogenic treatment was initiated by administration of Bevacizumab (n = 38) or Suramin (n = 27) while the control group (n = 44) remained untreated. Dynamic MRI was performed 24 h, 1 week, and 4 weeks after treatment initiation. Fractional tumor plasma volume (fPV, %) and vascular permeability (K(PS), mL/min/100 cc) were calculated based on the MRI data by using a pharmacokinetic model. RESULTS: Twenty-four hours after the initial dose, a significant decline in K(PS) was observed in the Bevacizumab group compared to the control and Suramin group (0.002 ± 0.008; 0.057 ± 0.046 and 0.064 ± 0.062 (mean ± SD); P < 0.05). At 1 week, fPV was significantly smaller in Bevacizumab and Suramin treated tumors compared to control tumors (6.25 ± 2.74, 7.47 ± 3.44, and 15.10 ± 9.97, respectively; P < 0.05). Differences in tumor volumes were first observed after 4 weeks of treatment with significantly larger control tumors (4380.3 ± 1590.6 vs. 869.6 ± 717.2 and 1676.5 ± 2524.1 mm(3); P < 0.05). CONCLUSION: Dynamic MRI can quantify antiangiogenic effects on tumor microvasculature before changes in tumor volumes are detectable. Thus, this technique is a reasonable addition to morphological MRI and may be applied as an alternative to histopathology.

Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF).

PURPOSE: To correlate dynamic MRI assays of macromolecular endothelial permeability with microscopic area-density measurements of vascular endothelial growth factor (VEGF) in tumors. METHODS AND MATERIAL: This study compared tumor xenografts from two different human cancer cell lines, MDA-MB-231 tumors (n=5), and MDA-MB-435 (n=8), reported to express respectively higher and lower levels of VEGF. Dynamic MRI was enhanced by a prototype macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)35. Quantitative estimates of tumor microvascular permeability (K(PS); µl/min × 100 cm(3)), obtained using a two-compartment kinetic model, were correlated with immunohistochemical measurements of VEGF in each tumor. RESULTS: Mean K(PS) was 2.4 times greater in MDA-MB-231 tumors (K(PS)=58 ± 30.9 µl/min × 100 cm(3)) than in MDA-MB-435 tumors (K(PS)=24 ± 8.4 µl/min × 100 cm(3)) (p<0.05). Correspondingly, the area-density of VEGF in MDA-MB-231 tumors was 2.6 times greater (27.3 ± 2.2%, p<0.05) than in MDA-MB-435 cancers (10.5 ± 0.5%, p<0.05). Considering all tumors without regard to cell type, a significant positive correlation (r=0.67, p<0.05) was observed between MRI-estimated endothelial permeability and VEGF immunoreactivity. CONCLUSION: Correlation of MRI assays of endothelial permeability to a MMCM and VEGF immunoreactivity of tumors support the hypothesis that VEGF is a major contributor to increased macromolecular permeability in cancers. When applied clinically, the MMCM-enhanced MRI approach could help to optimize the appropriate application of VEGF-inhibiting therapy on an individual patient basis.

Correlative dynamic contrast MRI and microscopic assessments of tumor vascularity in RIP-Tag2 transgenic mice.

The purpose of this study was to define the feasibility of dynamic contrast-enhanced magnetic resonance imaging (MRI) to estimate the vascular density and leakiness of spontaneous islet cell tumors in RIP-Tag2 transgenic mice. Dynamic T(1)-weighted spoiled gradient echo (SPGR) imaging at 2.0 T was performed in 17 RIP-Tag2 mice using a prototype blood pool macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)(35). Kinetic analysis of the dynamic enhancement responses based on a two-compartment model was used to estimate fractional plasma volume (fPV) and the coefficient of endothelial permeability (K(PS)) for each tumor. The MRI estimate of fPV was correlated on a tumor-by-tumor basis with corresponding microscopic measurements of vascular density. The fPV assays by MMCM-enhanced imaging ranged from 2.4%-14.1% of tissue volume. Individual tumor fPV values correlated significantly (r = 0.79, P < 0.001) with the corresponding microscopic estimates of vascularity consisting of the combined area densities of lectin-perfused microvessels plus erythrocyte-stained blood lakes. A biotinylated derivative of the albumin-based MMCM confirmed extravasation of the contrast agent from some tumor blood vessels and accumulation in 25% of blood lakes. The K(PS) values ranged from 0 (no detectable leak) to 0.356 mL/min/100 cm(3). Dynamic MMCM-enhanced MRI is feasible in RIP-Tag2 pancreatic tumors, yielding estimates of vascular permeability and microscopically validated measurements of vascular richness.

In vivo monitoring of angiogenesis inhibitory treatment effects by dynamic contrast-enhanced computed tomography in a xenograft tumor model.

RATIONALE AND OBJECTIVES: To evaluate the potential of dynamic CT enhanced by iohexol or a novel macromolecular contrast agent, PEG12000-Gen4-triiodo, to monitor microvascular changes in tumors treated with the angiogenesis inhibitor bevacizumab. MATERIALS AND METHODS: Ten female nude rats with MDA-MB 435 xenograft tumors were treated with 1 mg intraperitoneal bevacizumab when tumors reached 1 cm diameter and, for 4 rats, treated again 7 days later. Just before and 24 hours after the first injection of anti-VEGF antibody, the tumors were imaged by dynamic CT scans enhanced with PEG12000-Gen4-triiodo (n = 3 rats) or iohexol (n = 3 rats). The other 4 rats underwent dynamic CT scans enhanced with PEG12000-Gen4-triiodo just before and 24 hours after the second injection of anti-VEGF antibody. Microvascular leakiness (K(PS)) was calculated for the tumors using a 2-compartment tissue model. RESULTS: PEG12000-Gen4-triiodo-enhanced CT scans showed progressive reductions in K(PS) from day 1 to 2 to 9 (from 2.55 to 1.27 to 0.69 microL min(-1) cm(-3), respectively, P < 0.005 for each comparison of day 1-2 and day 2-9). No significant difference was seen in the K(PS) estimates derived from iohexol-enhanced CT scans obtained before or after treatment (276 vs. 223.8 microL min(-1) cm(-3), respectively, P = 0.54). The microvascular leak (K(PS)) was significantly larger for iohexol than for PEG12000-Gen4-triiodo-enhanced CT, P < 0.05. CONCLUSION: Dynamic macromolecular contrast-enhanced CT can be used to monitor serial decreases in tumor microvessel leakiness induced by repeated doses of an angiogenesis inhibitor drug.

Vascular permeability during antiangiogenesis treatment: MR imaging assay results as biomarker for subsequent tumor growth in rats.

PURPOSE: To prospectively evaluate in rats the acute change in tumor vascular leakiness (K(PS)) assayed at magnetic resonance (MR) imaging after a single dose of the angiogenesis inhibitor bevacizumab as a predictive biomarker of tumor growth response after a prolonged treatment course. MATERIALS AND METHODS: Institutional animal care and use committee approval was obtained. Seventeen female rats with implanted human breast cancers underwent dynamic albumin-(Gd-DTPA)(30)-enhanced MR imaging followed by an initial dose of bevacizumab or saline (as a control). Treatment was continued every 3rd day, for a total of four doses at five possible dose levels: 0 mg bevacizumab (n = 4 [control rats]), 0.1 mg bevacizumab (n = 3), 0.25 mg bevacizumab (n = 2), 0.5 mg bevacizumab (n = 5), and 1.0 mg bevacizumab (n = 3). A second MR imaging examination was performed 24 hours after the initial dose to enable calculation of the acute change in MR imaging-assayed leakiness, or Delta K(PS). This acute change in K(PS) at MR imaging was correlated with tumor growth response for each cancer at the completion of the 11-day treatment course. For statistical analyses, an unpaired two-tailed t test, analysis of variance, and linear regression analyses were used. RESULTS: The MR imaging-assayed change in tumor microvascular leakiness, tested as a potential biomarker, correlated strongly with tumor growth rate (R(2) = 0.74, P < .001). K(PS) and tumor growth decreased significantly in all bevacizumab-treated cancers compared with these values in control group cancers (P < .05). CONCLUSION: The MR imaging-assayed acute change in vascular leakiness after a single dose of bevacizumab was an early, measurable predictive biomarker of tumor angiogenesis treatment response.

New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues.

PURPOSE: To compare three new macromolecular polyethylene glycol (PEG) -core dendrimeric gadolinium(Gd)-based MRI contrast agents for their applicability in quantitative assays of endothelial leakiness and tissue vascular density for the differentiation of cancer from normal soft tissues. MATERIALS AND METHODS: Thirty-two athymic rats with human breast cancer xenografts (MDA-MB-435) were imaged by dynamic MRI following enhancement with one of three new (Gd-DOTA)-conjugated PEG-core dendrimer contrast agents (effective molecular weights 161 to 323 kDa). Results were compared with a prototype macromolecular contrast agent, albumin (Gd-DTPA). Assays of permeabilities (K(PS); microL/min . 100 cm(3)) and tumor fractional plasma volumes (%) based on a two-compartment kinetic model were performed for skeletal muscle and tumors. RESULTS: The largest PEG-core contrast agent, PEG(20,000)-Gen4-(Gd-DOTA), leaked in breast tumors (K(PS) = 50 +/- 23 microL/min . 100 cm(3)), while exhibiting no measurable transendothelial leak (K(PS) = 0 microL/min . 100 cm(3)) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG(12,000)-Gen4-(Gd-DOTA) leaked in tumors and in normal muscle (K(PS) = 51 +/- 26 and K(PS) = 21 +/- 18 microL/min . 100 cm(3), respectively). The smallest agent, PEG(12,000)-Gen3-(Gd-DOTA) also showed a measurable leak in both normal and malignant microvessels. CONCLUSION: MRI assays of vascular endothelial leakiness using new PEG-core, (Gd-DOTA)-conjugated macromolecular contrast agents proved applicable for the differentiation of human breast cancer from normal soft tissue. The apparent threshold in effective molecular weight for a clear differentiation of cancer from normal muscle with no measurable leak in the muscle is between 194 and 323 kDa.

Cascade polymeric MRI contrast media derived from poly(ethylene glycol) cores: initial syntheses and characterizations.

Diagnostic contrast media for magnetic resonance imaging (MRI) are often applied to enhance the signal of blood allowing for quantitative definition of vascular functional characteristics including tissue blood volume, flow, and leakiness. Well-tolerated and safe macromolecular formulations are currently being sought that remain in the blood for a relatively long period and that leak selectively from diseased vessels, particularly cancer vessels. We synthesized a new class of macromolecular, water-soluble MRI contrast media by introducing two diverging polylysine cascade amplifiers at each end of a poly(ethylene glycol) (PEG) backbone, followed by substitution of terminal lysine amino groups with Gd-DTPA chelates. Four candidate PEG cascade conjugates are reported here, PEG3400-Gen4-(Gd-DTPA)8, PEG6000-Gen4-(Gd-DTPA)8, PEG12000-Gen4-(Gd-DTPA)8, and PEG3400-Gen5-(Gd-DTPA)13 with descriptions of their basic physical, biological, and kinetic properties, including real and effective molecular sizes, proton T1 relaxivities in water and plasma, partition coefficients, osmolalities, chelate stability, stability in plasma, stability to autoclaving, certain in vivo pharmacokinetics (blood half-life, blood clearance, volume of distribution), and whole body elimination profiles in normal rodents. These candidate PEG-core cascade MRI contrast media showed a range of effective molecular sizes similar to proteins weighing 74-132 kDa, although their actual molecular weights were much smaller, 12-20 kDa. All compounds exhibited a narrow range of size dispersity and relatively high T1 relaxivities (approximately 3 times the value for unconjugated Gd-DTPA at 2 T and 37 degrees C). Representative compounds also showed a high degree of hydrophilicity, stability in solution buffer and plasma, and lack of binding to proteins. The two candidate compounds with the largest effective molecular sizes, PEG12000-Gen4-(Gd-DTPA)8 and PEG3400-Gen5-(Gd-DTPA)13, had longer blood half-lives, 36 and 73 min, respectively (monoexponential kinetics for both), and showed strong, prolonged MRI enhancement of vessels. Results also indicate that in vivo pharmacokinetics and bodily elimination profiles can be adjusted by the selection of molecular size for the PEG core and the selection of the amplification degree of the cascade polylysine clusters. The initially evaluated compounds from this new class of contrast media show acceptable, desirable characteristics in many, but not all, respects. Further efforts are directed toward candidate macromolecules having higher thermodynamic stability, higher degree of substitution by gadolinium chelates, and more rapid bodily elimination.

MR imaging of antigen-induced arthritis with a new, folate receptor-targeted contrast agent.

The purpose of this study was to investigate if the new folate receptor-targeted Gd-chelate P866 may enhance immune-mediated arthritis. A monoarthritis was induced in the right knee of 15 Sprague-Dawley rats. MR imaging of both knees was performed at 2 T before and up to 2 h and 24 h after injection (p.i.) of P866 (n = 3 dose finding study and n = 6, 0.02 mmol Gd/kg), the non-FR targeted P866 analog P1001 (n = 3 at 24 h after P866-administration, 0.02 mmol Gd/kg) or Gd-DOTA (n = 6, 0.1 mmol Gd/kg). Pulse sequences comprised T(1)-SPGR 80 degrees /50 ms/1.7 ms (flip angle/TR/TE) and inversion recovery 10 degrees /3000 ms/1500 ms/50-3050, 10 000 ms (flip angle/TR/TE/TI) sequences. DeltaSI-data and T(1)-relaxation times of arthritic knees and contralateral normal knees were determined. Folate receptor expression was confirmed with histopathology. All three contrast agents showed an initial perfusion effect with significantly higher DeltaSI-data of arthritic knees compared with normal knees (p < 0.05). In addition, P866, but not P1001 or Gd-DOTA, showed a prolonged enhancement of the synovitis. Compared with precontrast values, the T(1)-relaxation times of inflamed synovia were significantly decreased at 2 h p.i. of P866 (p < 0.05), but not P1001 or Gd-DOTA (p > 0.05). Histopathology confirmed the presence of folate receptors in the inflamed joints, but not normal joints. Thus, results suggest a specific accumulation of the folate receptor-targeted Gd-chelate P866 in this arthritis model.

Magnetic resonance imaging enhancement of normal tissues and tumors using macromolecular Gd-based cascade polymer contrast agents: preclinical evaluations.

OBJECTIVES: We sought to compare magnetic resonance imaging (MRI) enhancement using 4 novel macromolecular polyethyleneglycol (PEG)-based cascade-polymer gadolinium contrast agents (macromolecular contrast media) in normal soft tissues and a breast cancer model. MATERIALS AND METHODS: Four candidate PEG cascade polymers with effective molecular weights of 74, 82, 106, and 132 kDa, respectively, and T1-relaxivities of 8.1, 9.1, 9.7, and 10.0, respectively (at 2 Tesla and 37 degrees C in HEPES buffer), initially were used to characterize liver and kidney MRI-enhancement patterns in normal Sprague-Dawley rats (n = 4-5 per contrast agent). Kinetic analysis of dynamic MRI enhancement was used in 8 nude rats bearing MDA-MB 435 breast cancers to estimate fractional plasma volume and apparent endothelial leakiness (K) in tumors and muscle. RESULTS: Soft-tissue enhancement patterns followed closely the blood enhancement over the course of 30-50 minutes with estimated blood half-lives between 23 and 73 minutes, which varied with effective molecular weights. The 2 smaller compounds yielded measurable leaks in normal muscle [K = 204 and 56 microL/(min.100 cm), respectively], whereas the 2 larger molecules did not leak in muscle [K = 0 microL/(min.100 cm)]; however, MRI-assayed leakiness of tumor vessels with respect to those 2 larger macromolecular contrast media was 68 +/- 27 and 16 +/- 8 microL/(min.100 cm), respectively. CONCLUSIONS: Two relatively large (effective molecular weight >82 kDa) PEG-based cascade polymer contrast agents were well-suited for MRI quantification of tissue plasma volume and for differentiating leaky cancer microvessels from nonleaky normal vessels.

Dendritic iodinated contrast agents with PEG-cores for CT imaging: synthesis and preliminary characterization.

The purpose of this study was to design, synthesize, and initially characterize a representative set of novel constructs for large-molecular radiographic/computed tomography (CT) contrast agents, intended for a primarily intravascular distribution. A new assembly of well-known and biocompatible components consists of paired, symmetrical dendritic polylysines initiated from both ends of a poly(ethylene glycol) (PEG) core, yielding an array of multiple free amino groups to which were conjugated highly soluble and stable triiodophthalamide ("triiodo") moieties. An array of six dendritic contrast agents was synthesized originally, using three different PEG cores (3, 6, 12 kDa) with t-Boc lysine-generated dendrimer "amplifiers" (from three to five generations) containing 16 to 64 amino groups for conjugation with reactive triiodo moieties. A clinically used, nonionic, small molecular CT contrast agent, iobitridol, was derivatized via a hydroxyl protection/deprotection strategy, introducing a new carboxyl group available for conjugation to the lysine amino groups of dendrimers. Final products were purified by size exclusion chromatography and characterized by NMR, UV, HPLC, and elemental analysis. Preliminary evaluations were conducted for physicochemical characterization and in vivo CT contrast enhancement in a rat model. All six iodinated PEG-core dendrimer conjugates were synthesized in good yields, with a high degree of size monodispersity, large apparent molecular weight, favored physicochemical properties. A representative compound, PEG12000-carbamate-Gen4-IOB conjugate, 27% (w%) rich in iodine, demonstrated a desirable strong and persistent intravascular enhancement with a monoexponential blood half-life of approximately 35 min assayed by dynamic CT imaging and also showed high water solubility (>550 mg/mL at 25 degrees C), large apparent molecular size (comparable to a 143-kDa protein), high hydrophilicity (butanol-water partition coefficient 0.015), and stability to autoclaving conditions. This study showed the synthetic feasibility, desired basic characteristics, and potential utility for CT contrast enhancement achieved with a new type of iodinated, large-molecular PEG-core dendritic construct. Further development of this class of macromolecular contrast agents will be required to define the optimal formulation, pharmacology, safety profile, and the full range of diagnostic applications including tumor microvascular quantitative characterization by CT imaging.

Ultrasmall superparamagnetic iron-oxide-enhanced MR imaging of normal bone marrow in rodents: original research original research.

RATIONALE AND OBJECTIVES: The objective is to compare three different ultrasmall superparamagnetic iron oxides (USPIOs) for magnetic resonance (MR) imaging of normal bone marrow in rodents. MATERIALS AND METHODS: Femoral bone marrow in 18 Sprague-Dawley rats was examined by using MR imaging before and up to 2 and 24 hours postinjection (PI) of 200 mumol of Fe/kg of SHU555C (n = 6), ferumoxtran-10 (n = 6), or ferumoxytol (n = 6), using T1-weighted (50 ms/1.7 ms/60 degrees = repetition time [TR]/echo time [TE]/flip angle) and T2*-weighted (100 ms/15 ms/38 degrees = TR/TE/flip angle) three-dimensional spoiled gradient recalled echo sequences. USPIO-induced bone marrow was evaluated qualitatively and quantified as signal-to-noise ratio (SNR) and change in signal intensity (DeltaSI) values. A mixed-effect model was fitted to the SNR and DeltaSI values, and differences among USPIOs were tested for significance by using F tests. RESULTS: At 2 hours PI, all three USPIOs showed marked positive signal enhancement on T1-weighted images and a corresponding marked signal loss on T2*-weighted images. At 24 hours PI, the T1 effect of all three USPIOs disappeared, whereas T2*-weighted images showed persistent signal loss on SHU555C and ferumoxytol-enhanced MR images, but not ferumoxtran-10-enhanced MR images. Corresponding SNR and DeltaSI values on T2*-weighted MR images at 24 hours PI were significantly different from baseline for SHU555C and ferumoxytol, but not ferumoxtran-10. CONCLUSION: All three USPIO contrast agents, ferumoxtran-10, ferumoxytol, and SHU555C, can be applied for MR imaging of bone marrow. Ferumoxtran-10 apparently reveals a different kinetic behavior in bone marrow than ferumoxytol and SHU555C.