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Robert C Brasch

Publications and source records attributed to Robert C Brasch.

16 recordsLinked to original sources
PubMed2004

Tumor microvascular changes in antiangiogenic treatment: assessment by magnetic resonance contrast media of different molecular weights.

PURPOSE: To test magnetic resonance (MR) contrast media of different molecular weights (MWs) for their potential to characterize noninvasively microvascular changes in an experimental tumor treatment model. MATERIALS AND METHODS: MD-MBA-435, a poorly differentiated human breast cancer cell line, was implanted into 31 female homozygous athymic rats. Animals were assigned randomly to a control (saline) or drug treatment (monoclonal antibody vascular endothelial growth factor (Mab-VEGF) antibody) group. In both groups, dynamic MR imaging (MRI) was performed in each animal using up to three different contrast media on sequential days at baseline and follow-up examination. The MWs of the contrast media used ranged from 557 Da to 92 kDa. Using a bidirectional kinetic model, tumor microvessel characteristics, including the fractional plasma volume (fPV) and transendothelial permeability (K(PS)), were estimated for each contrast medium. These microvascular characteristics were compared between drug and control groups and between contrast media of different MWs. RESULTS: Tumors grew significantly slower (P < 0.0005) in the drug treatment group than in the control group. Mean K(PS) and fPV values decreased significantly (P < 0.05) in the Mab-VEGF antibody-treated group compared to baseline values using intermediate or macromolecular contrast media (MMCM), but did not change significantly using small molecular contrast media (SMCM). In the control groups, mean K(PS) and mean fPV values did not reach statistical significance for any of the contrast media used. CONCLUSION: Therapeutic effects of a Mab-VEGF antibody on tumor microvessel characteristics can be monitored by dynamic MRI. Intermediate-size agents, such as Gadomer-17, offer a substantial dynamic range and are less limited by imaging precision and therefore should be considered a practical alternative to monitor antiangiogenesis treatment effects in a clinical setting.

Angiogenesis Inhibitors↗
PubMed2004

MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer.

PURPOSE: To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy. MATERIALS AND METHODS: Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (KPS) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI. RESULTS: Tumors grew more slowly, although not significantly (P=0.07), in the drug-treated group. The KPS determined for B22956/1 decreased significantly in the drug-treated group compared to baseline (P <0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA). CONCLUSION: With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting.

Angiogenesis Inhibitors↗
PubMed2004

Magnetic resonance imaging detects early changes in microvascular permeability in xenograft tumors after treatment with the matrix metalloprotease inhibitor Prinomastat.

Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular characteristics of human breast cancers implanted in athymic rats. Twice-daily intraperitoneal administration of Prinomastat over 1.5 days induced significant declines in MRI-assayed microvascular permeabilities (p<0.05); but this leak suppression effect had extinguished by the 10(th) day of MMP treatment using the same dose and time schedule. Results demonstrate that Prinomastat produces a rapid but transient decrease in tumor vascular permeability. Contrast-enhanced MRI using macromolecular contrast medium may prove useful as a biomarker for the dynamic MMP biological effect in cancers.

Animals↗
PubMed2003

Quantification of breast tumor microvascular permeability with feruglose-enhanced MR imaging: initial phase II multicenter trial.

PURPOSE: To investigate use of the macromolecular contrast agent feruglose for differentiating and grading of human benign and malignant breast tumors on the basis of their microvascular characteristics. MATERIALS AND METHODS: Sixty-three women with 63 primary breast lesions were examined with dynamic T1-weighted gradient-echo magnetic resonance (MR) imaging after intravenous injection of feruglose. A two-compartment unidirectional kinetic model applied to the dynamic data yielded estimates of the endothelial transfer coefficient, KPS, and the fractional plasma volume of the tumors. These MR imaging-derived parameters were correlated with the histologic tumor grade and quantified according to the Scarff-Bloom-Richardson (SBR) score by means of Pearson product moment correlation analyses. Differences between malignant and nonmalignant breast lesions with respect to KPS for feruglose were evaluated by means of the chi2 test and by calculating the sensitivity, specificity, and positive and negative predictive values. RESULTS: Histologic analysis revealed 26 benign and 37 malignant tumors. A moderate yet statistically significant correlation between KPS and SBR score was found (R = 0.496, P <.001). No significant correlation was observed between fractional plasma volume and SBR score (R = 0.085, P =.507). The KPS values were zero for 19 (73%) of the 26 benign tumors and were greater than zero for 27 (73%) of the 37 carcinomas. This distribution was significantly different (chi2 = 13.035, P =.001). With the criterion KPS > 0 in carcinomas, sensitivity was 0.73, specificity was 0.73, and the positive predictive value was 0.79. CONCLUSION: Quantitative measures of tumor microvascular permeability can be used for breast tumor characterization. The probability of breast tumor microvascular hyperpermeability to be associated with malignancy is 79%.

Adult↗
PubMed2003

MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model.

The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (approximately 30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (K(PS)) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P<0.05) in size and in microvascular permeability (K(PS)) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P<0.05) in rats treated with PTK787/ZK 222584 and K(PS) values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P<0.05) in the control than in the drug-treated group. MRI measurements of tumor microvascular response, particularly transendothelial permeability (K(PS)), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy.

Angiogenesis Inhibitors↗
PubMed2002

Macromolecular contrast agents for MR mammography: current status.

Macromolecular contrast media (MMCM) encompass a new class of diagnostic drugs that can be applied with dynamic MRI to extract both physiologic and morphologic information in breast lesions. Kinetic analysis of dynamic MMCM-enhanced MR data in breast tumor patients provides useful estimates of tumor blood volume and microvascular permeability, typically increased in cancer. These tumor characteristics can be applied to differentiate benign from malignant lesions, to define the angiogenesis status of cancers, and to monitor tumor response to therapy. The most immediate challenge to the development of MMCM-enhanced mammography is the identification of those candidate compounds that demonstrate the requisite long intravascular distribution and have the high tolerance necessary for clinical use. Potential mammographic applications and limitations of various MMCM, defined by either experimental animal testing or clinical testing in patients, are reviewed in this article.

Albumins↗
PubMed2002

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme.

PURPOSE: To evaluate the effects of a neutralizing anti-vascular endothelial growth factor (anti-VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model. MATERIALS AND METHODS: A dynamic contrast-enhanced magnetic resonance imaging (MRI) technique, permitting noninvasive in vivo and in situ assessment of potential therapeutic effects, was used to measure tumor microvascular characteristics and volumes. U-87, a cell line derived from a human glioblastoma multiforme, was implanted orthotopically into brains of athymic homozygous nude rats. RESULTS: Treatment with the monoclonal antibody A4.6.1, specific for VEGF, significantly inhibited tumor microvascular permeability (6.1 +/- 3.6 mL min(-1)100 cc(-1)), compared to the control, saline-treated tumors (28.6 +/- 8.6 mL min(-1)100 cc(-1)), and significantly suppressed tumor growth (P <.05). CONCLUSION: Findings demonstrate that tumor vascular permeability and tumor growth can be inhibited by neutralization of endogenous VEGF and suggest that angiogenesis with the maintenance of endothelial hyperpermeability requires the presence of VEGF within the tissue microenvironment. Changes in tumor vessel permeability and tumor volumes as measured by contrast-enhanced MRI provide an assay that could prove useful for clinical monitoring of anti-angiogenic therapies in brain tumors.

Animals↗
PubMed2001

Are chest radiographs routinely necessary following thoracostomy tube removal?

OBJECTIVE: Chest radiographs (CXRs) are routinely obtained at many institutions in all pediatric patients following thoracostomy tube removal to search for pneumothorax (PTX). To aid in evaluating the necessity of this practice, this study investigates whether clinical signs and symptoms may be a sensitive predictor of PTX in such patients. MATERIALS AND METHODS: Reports from CXRs obtained following chest tube removal in all pediatric patients (374 patients) who underwent cardiac surgery with chest tube placement over 1 year were reviewed. For cases with reported PTX, the PTX was quantified and chart review was performed to assess whether signs and symptoms of PTX preceded the CXR result. RESULTS: Fifty-one of 374 children (13.6%) had a radiographically defined PTX within 6 h after thoracostomy tube removal. The PTX was large (>40%) in 2 children, moderate (20-40%) in 5 children, and small (<20%) in 44 children. Symptoms (dyspnea, tachypnea, respiratory distress) or signs (increased oxygen requirement, worsening arterial blood gas and/or hypotension) of respiratory distress were present at the time of the initial CXR in six of seven patients, who later underwent a major clinical intervention, and in one patient who did not. Major clinical interventions were performed in all patients with a large PTX, four of five patients with a moderate PTX, and one patient with a small PTX that later enlarged. CONCLUSIONS: Clinical signs and symptoms identified nearly all patients with significant pneumothoraces. Future prospective investigations may examine reserving chest radiography following chest tube removal for select groups, such as symptomatic patients or those with tenuous cardiovascular status.

Adolescent↗
PubMedDate not supplied

Decrease in tumor apparent permeability-surface area product to a MRI macromolecular contrast medium following angiogenesis inhibition with correlations to cytotoxic drug accumulation.

BACKGROUND: New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (K(PS)) in tumors to a macromolecular contrast medium (MMCM), to follow changes in K(PS) induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin. METHODS: Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)(30)) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate K(PS). These estimates of K(PS) were correlated with cytotoxic drug accumulations in the tumors. RESULTS: Anti-VEGF treatment reduced K(PS) to MMCM in tumor tissue from 0.013 mL h(-1) cm(-3) (n = 9) at baseline to 0.003 mL h(-1) cm(-3) (n = 9) 24 h later (p <.05). The K(PS) values correlated significantly (r(2) =.78; p <.0001) with the tumor cisplatin accumulation. No correlation (r(2) =.001; p =.89) was found between K(PS) and tumor accumulation of the substantially smaller 5-FU molecule. CONCLUSIONS: MMCM-enhanced MRI can be used to detect and estimate changes in K(PS) to this contrast agent following a single dose of anti-VEGF antibody. The decline in K(PS) induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration.

Angiogenesis Inhibitors↗