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Experimental Studies |
1 From the Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California, San Francisco, Box 0628, 505 Parnassus Ave, San Francisco, CA 94143-0628 (K.T., S.H., T.H., T.P.L.R., D.M.S., M.F.W., R.C.B.); Dept of Radiology, Univ of Vienna, Austria (K.T., T.H.); Dept of Radiology, KH Lainz, Vienna, Austria (S.H.); Dept of Pathology, Pfizer Central Research, Groton, Conn (E.F.); and Nycomed Amersham Imaging, Wayne, Pa (K.S.T.). Received Feb 3, 2000; revision requested Mar 21; final revision received Jun 22; accepted Jun 28. Supported by NIH grant RO1 CA82923-01 and the Cancer Research Fund, State of Calif, interagency agreement #97-12013 with Dept of Health Services, Cancer Research Program. K.T. supported by a grant from the Max Kade Foundation. Address correspondence to R.C.B.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: NC100150 injection, a USPIO in clinical trials, and albumin-(Gd-DTPA)30 were compared at MR imaging on sequential days in the same 19 rats with mammary tumors. Kinetic analysis of dynamic T1-weighted three-dimensional spoiled gradient-recalled imaging data with a two-compartment bidirectional model yielded MR imaging estimates of microvascular permeability (KPS) and fractional plasma volume (fPV) for each contrast medium.
RESULTS: Strongly positive and significant correlations were observed between MR imaging–derived KPS estimates and histologic tumor grade with either the soluble albumin-(Gd-DTPA)30 (r = 0.88; P < .001) or larger particulate USPIO (r = 0.82; P < .001). A significant correlation (P < .05) was observed with each contrast medium between KPS and the histologic microvascular density (MVD), an angiogenesis indicator. Despite the considerable difference in molecule and particle sizes, no significant difference was observed in the MR imaging–derived mean permeability values generated with the two contrast media.
CONCLUSION: USPIO, a macromolecular particulate MR imaging contrast agent, can be applied successfully to characterize tumor microvessels in animals. USPIO-derived KPS correlated strongly with histopathologic tumor grade, MVD, and KPS values derived by using albumin-(Gd-DTPA)30 in the same tumors.
Index terms: Animals • Breast neoplasms, 00.30 • Contrast media • Iron • Magnetic resonance (MR), three-dimensional, 00.121411, 00.121412, 00.121419
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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At the time this research was undertaken, evaluations of macromolecular contrast media to define tumor microvessels had not focused on the large particulate agents such as iron oxide particles. Ultrasmall superparamagnetic iron oxide (USPIO) particles, which are already used in human clinical trials, have been examined as angiographic agents and for enhancing the reticuloendothelial system (2,9–11). Thus, the purpose of this study was to examine the diagnostic potential of MR imaging with USPIO particles such as NC100150 injection for characterizing microvascular permeability in benign or malignant breast tumors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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A spectrum of breast tumors, from benign (fibroadenoma) to highly malignant (anaplastic adenocarcinoma), was induced in 19 rats (Sprague-Dawley, Indianapolis, Ind) weighing 250–370 g, with intraperitoneal injection of N-ethyl-N-nitrosurea (ENU) (ENU Isopack; Sigma Chemicals, St Louis, Mo) (12,13). ENU, a potent carcinogen, was injected at doses of 45 (n = 7), 90 (n = 7), or 180 mg (n = 5); tumors appeared in the mammary area as early as 65 days later. Animals were visually checked for tumor growth every 2nd day. Tumors were imaged when they reached 1–2 cm in diameter.
Before MR imaging, anesthesia was induced with intraperitoneal injection of 50 mg per kilogram of body weight of sodium pentobarbital (Abbott Laboratories, North Chicago, Ill); analgesia was achieved by injecting 0.03 mg/kg of buprenorphine hydrochloride (Buprenex; Reckitt & Cloman, Richmond, Va), an opiate. A 23-gauge butterfly catheter (Abbott Laboratories, North Chicago, Ill) was inserted into the tail vein for contrast media injection.
Immediately after the MR imaging examination, 0.32 mg/kg of naloxone (Narcan; Abbott Laboratories) was injected intraperitoneally to reverse the opioid effects. In addition, 2 mL of normal saline was injected subcutaneously to avoid dehydration effects that might have occurred after anesthesia.
MR Imaging
MR imaging was performed in the animals by using a 2-T superconducting system (Omega CSI-II; Bruker Instruments, Fremont, Calif) that was equipped with self-shielded gradient coils (Acustar S-150; Bruker Instruments) (±20 G/cm, 15-cm inner diameter). The rats were placed in a supine position within a birdcage radio-frequency coil (inner diameter, 4.5 cm; length, 7.6 cm). A phantom filled with diluted 0.01-mmol/L gadopentetate dimeglumine was positioned in the field of view to normalize data from day to day and thus correct for potential spectrometer variation.
Dynamic contrast-enhanced MR imaging was performed with a transverse T1-weighted three-dimensional spoiled gradient-recalled sequence with the following parameters: 100.0/1.4 (repetition time msec/echo time msec), one signal acquired, 128 x 128 x 16 matrix, 60 x 60 x 48-mm field of view, 3-mm section thickness, and 1-minute 42-second acquisition time. Precontrast T1-weighted images were obtained with varying flip angles (10°, 30°, 60°, and 90°) to calculate baseline R1 values for blood and tumor with curve fitting (14). Dynamic postcontrast images (25 per rat) were acquired serially at 1.8-minute intervals for 45 minutes by using the parameters described, except that the repetition time was fixed at 50 msec; and the flip angle, at 90°.
MR Imaging Contrast Media
Two macromolecular contrast agents, albumin-(Gd-DTPA)30, and NC100150 injection (Clariscan; Nycomed Imaging, Oslo, Norway), were used on sequential days. Albumin-(Gd-DTPA)30 is a 92-kDa prototype of a water-soluble macromolecular contrast medium with a 6-nm diameter, synthesized in our laboratory by following the method of Ogan et al (15). Albumin-(Gd-DTPA)30 has a distribution volume of 0.05 L/kg (which closely approximates the blood volume) and a plasma half-life of 3 hours in rats; this produces nearly constant enhancement of normal tissues for 30 minutes or longer after injection (15–17). Albumin-(Gd-DTPA)30 was injected on imaging day 1 at a dose of 0.03 mmol of gadolinium per kilogram.
NC100150 injection consists of USPIO particles composed of single crystals (4–7-nm diameter) and stabilized with a carbohydrate polyethylene glycol coat. The iron oxide particles were suspended in an isotonic glucose solution. The final diameter of the USPIO particles was approximately 20 nm. The R1 of the iron-containing agent is 20 mmol/L/sec, and the R2 is 35 mmol/L/sec at 37°C and 0.5 T. The mean plasma half-life in rats is about 3.3 hours, and the particles are taken up by the mononuclear phagocyte system and distributed mainly to the liver and spleen. NC100150 injection was administered at a dose of 1 mg of iron per kilogram 24–30 hours after the first MR imaging examination.
MR Imaging Data and Kinetic Analysis
Images were transferred to, processed, and qualitatively examined and analyzed at a workstation (Sun Spark 10; Sun Microsystems, Mountain View, Calif) by using an MR-VISION software package (MR-Vision, Stanford, Calif). In each rat and at each time point, a single operator defined three to six regions of interest, each with a minimum of 30 pixels. Regions of interest were drawn on the phantom and inferior vena cava and on these sections that involved portions of the tumor periphery. The tumor periphery was defined as the peripheral zone of strong contrast enhancement, which was usually 1–2 mm thick. After the signal intensities in three regions of interest from each tumor were averaged at each time point, the dynamic signal responses were corrected for potential temporal spectrometer variation by dividing by the signal intensity of the phantom. Kinetic analysis of tumor enhancement responses was limited to the tumor periphery, which is typically the most vascularized and least necrotic region of the tumor (18,19). In addition, results of previous studies have shown that the tumor periphery is the most representative region for oncologic activity (20) and the most responsive to angiogenesis inhibition (21), radiation therapy, and chemotherapy (5,22).
Postcontrast R1 values were calculated on the basis of signal intensity and knowledge of precontrast values (14). Differences between the precontrast and postcontrast R1 values at any time were assumed to be proportional to the concentration of the contrast medium in either the blood or tissue of interest (23,24). Furthermore, we assumed that the fully relaxed signal intensity would not vary substantially on pre- and postcontrast spoiled gradient-recalled images. The 
R1 data from blood and tumor were used for kinetic analysis to estimate the coefficient of KPS (in milliliters per minute per 100 cm3 of tissue) and the fractional plasma volume (fPV) (in milliliters per cubic centimeter of tissue) by using a two-compartment bidirectional model for tumor tissue, as previously described in detail (3,24). In this model, a monoexponential function fitted to the R1 data from blood was used as a forcing function for the plasma response in the tumor after correction for hematocrit and scaling for fPV. (The term "forcing function" is commonly used among physiologically based pharmacokineticists when referring to some mathematic function that describes the input to a mathematic model that was developed to explain the kinetic pattern of a drug—in this case, a contrast agent.) The KPS values determined by using the model were multiplied by 100, thereby scaling our permeability measure for 100 cm3 of tissue. All data fitting was performed with the commercially available SAAM II computer program (SAAM Institute, Seattle, Wash), which uses standard variance-weighted nonlinear regression. The uncertainty of the estimates of the model parameters was determined from the covariance matrix at the least-squares fit.
Histologic Analysis
After completing the second MR imaging examination, all animals were killed immediately with an intravenous overdose of 0.3 mL of sodium pentobarbital and bilateral thoracotomy. Tumors were excised, immediately fixed in 10% buffered formalin (Poly Scientific Research and Development, Bay Shore, NY) for 18–24 hours, processed routinely into paraffin, sectioned in the plane of the MR images at 4 µm, and stained with hematoxylin and eosin for diagnosis and grading. Additional sections were immunostained for von Willebrand factor and factor VIII by using an avidin-biotin peroxidase technique (Sigma rabbit antihuman polyclonal, F-3520; Vector ABC Kit, PK-6100; Sigma Chemicals).
Tumors were scored in accordance with the Scarff-Bloom-Richardson (SBR) method (25–27). This scoring system has been used extensively for invasive breast adenocarcinomas by evaluating the (a) ductoglandular formation, (b) nuclear pleomorphism, and (c) mitotic activity. Each of these three morphologic features is scored by assigning one to three points; an overall score is then obtained at summation of the individual characteristic scores. SBR scores range from three to nine points; the higher the score, the more malignant and poorly differentiated the tumor. For microvascular density (MVD) determination, all discrete positively immunostained endothelial (brown-staining) clusters with lumina were counted in 20 400x fields (Vanox AH-2 microscope; Olympus, Tokyo, Japan) sampled from two sections of each tumor. When possible, fields were chosen in the areas of highest MVD. Stromal microvessels were included in the counts, but capsular and preexistent small-to-medium host vessels were excluded. MVD is reported as the number of vessels per high power field. MVD counting and SBR scoring were performed by the same pathologist (E.F.), who did not have knowledge of MR imaging findings.
Statistical Analyses
Mean KPS and fPV values for a given contrast agent were compared between fibroadenomas and carcinomas by performing unpaired Student t tests. These mean values in the same tumors were compared between albumin-(Gd-DTPA)30 and USPIO by performing paired t tests. Nonparametric Spearman correlation analyses were performed by comparing the estimated MR imaging-derived parameters (KPS, fPV) with the histologic tumor grade (SBR score) and MVD. Pearson correlation analyses were performed to compare the albumin-(Gd-DTPA)30–derived KPS and fPV values with the USPIO-derived KPS and fPV values in the same tumors. A P value less than .05 was considered to indicate a significant difference. In addition, sensitivity, specificity, and positive and negative predictive values were calculated to differentiate between benign and malignant tumors with both contrast media.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Albumin-(Gd-DTPA)30– and USPIO-enhanced dynamic images were acquired successfully in all 19 animals (Figure). With both contrast media, the enhancement pattern tended to be homogeneous in the smaller tumors and more heterogeneous in the larger tumors. In tumors with heterogeneous enhancement, the periphery tended to enhance more than the center; this likely was due to the higher interstitial pressure of the tumor core (28). In general, tumor enhancement with USPIO was less pronounced than that with the albumin-based contrast medium; this difference was considered a function of respective dosage. Enhancement with either contrast medium yielded data that were suitable for kinetic analysis.
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Mean KPS values were significantly higher in the carcinomas, as compared with those in the fibroadenomas, for both albumin-(Gd-DTPA)30 (0.017 ± 0.016 vs 0, respectively, P = .05) and USPIO (0.019 ± 0.024 vs 0, respectively, P = .09). On the basis of these findings (Table 2), the overall sensitivity and specificity of KPS for differentiating between benign and malignant tumors with both contrast media were 64% (nine of 14) and 100% (six of six), respectively. The positive predictive values were 100%, whereas the negative predictive values were 50% for both macromolecular contrast agents.
With regard to fPV, no significant differences were found between carcinomas and fibroadenomas by using albumin-(Gd-DTPA)30 (0.040 ± 0.020 vs 0.026 ± 0.015, respectively, P = .20) or USPIO (0.032 ± 0.018 vs 0.030 ± 0.034, respectively, P = .89). Furthermore, no significant differences were found for mean KPS values between albumin-(Gd-DTPA)30 and USPIO for either fibroadenomas (0 vs 0, respectively) or carcinomas (0.017 ± 0.016 vs 0.019 ± 0.024, respectively, P = .78). The same absence of significant differences was found for mean fPV values between albumin-(Gd-DTPA)30 and USPIO for fibroadenomas (0.026 ± 0.015 vs 0.030 ± 0.034, respectively, P = .68) and carcinomas (0.040 ± 0.020 vs 0.032 ± 0.018, respectively, P = .27).
Results of the Spearman correlation analyses are shown in Table 3. Individual KPS values obtained by using albumin-(Gd-DTPA)30 and USPIO correlated strongly with SBR score (r = 0.88 and 0.82, respectively). Weaker but significant correlations were found also for KPS values between albumin-(Gd-DTPA)30 or USPIO and MVD (r = 0.67 and 0.76, respectively). Estimates of fPV did not correlate significantly with SBR score or MVD for either contrast agent.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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These results have diagnostic relevance for patients because USPIO, in contrast with albumin-(Gd-DTPA)30, is being developed for human use. If we assume successful completion of clinical trials with documented safety, USPIO could be used, in a manner similar to that used in this animal study, to noninvasively and quantitatively characterize individual human tumors in vivo.
To our knowledge, USPIO particles have not been previously tested for their potential to characterize microvessels; at the time this study was performed and repeated, USPIO particles had been studied in animal models and human trials for their potential in enhancing tissues of the reticuloendothelial system (9,29–31), which includes the liver, spleen, bone marrow, and lymph nodes, and in large-vessel angiography (1,2,32,33). In clinical trials now being conducted in Europe and North America, USPIO particles (11) from various manufacturers have generally been highly tolerable in human subjects. NC100150 is a relatively large insoluble USPIO particle with a mean diameter of less than 20 nm. The smaller size of USPIO (as compared with that of SPIO) leads to a prolonged plasma half-life, because the particles are not quickly phagocytized by the reticuloendothelial system; this makes their use favorable for MR angiography (1,2). NC100150 injection, similar to our prototype macromolecular contrast medium, albumin-(Gd-DTPA)30, does not leak through the normal endothelium of benign tumors but diffuses gradually through malignant vascular endothelia into the interstitial spaces. However, low-grade malignant tumors might exhibit intact or slightly impaired vessel wall integrity and yield only low or normal permeability values to macromolecular solutes.
Albumin-(Gd-DTPA)30, a 92-kDa water-soluble macromolecule, has been used extensively in animal studies (20–22,24, 36–40) as a prototype MR imaging probe to define microvessel characteristics. Although it has shown substantial diagnostic value as a prototype macromolecule in many experimental disease models, to our knowledge, albumin-(Gd-DTPA)30 was never intended for development as a clinical pharmaceutical agent. The gadolinium in this prototype macromolecule is only partly eliminated by 2 weeks after administration (34), and the protein backbone of the compound offers the possibility of immunologic reactivity (35). Although, to our knowledge, albumin-(Gd-DTPA)30 has not been proposed for human use, investigators in studies conducted with it have highlighted the diagnostic benefits of macromolecules for microvessel characterization in multiple tumor types (breast, prostatic, and ovarian cancer; sarcoma) (3,36), arthritis (37), myocardial and cerebral ischemic states (38), wound healing (39), and toxin exposure (5,40). Despite the differences in size and molecular weight, the strong correlation of KPS values between USPIO and albumin-(Gd-DTPA)30 in the current study of endogenous breast tumors (r = 0.81) suggest that similar results might be found in other tumors and diseases characterized by abnormally increased microvascular permeability.
The strong correlation observed between KPS values with the use of albumin-(Gd-DTPA)30 and SBR scores in our ENU-induced breast tumor model is consistent with the results of a study by Daldrup et al (3), who reported a strong correlation between MR imaging estimates of tumor permeability and histologic tumor grade (r = 0.87).
Also in general agreement with the findings of the Daldrup et al (3) study, weak correlations (r = 0.33 with albumin-[Gd-DTPA]30; r = 0.37 with USPIO) were observed between MR imaging estimates of fPV and tumor grade (SBR score) in the current study. Contrary to intuition, fPV, a numeric expression of vascularity, is a weaker indicator of tumor grade (SBR score) and tumor angiogenic status (MVD) than is vascular leakiness (KPS). It should be emphasized that this experimental mammary tumor model yields a high rate of malignancy (14 of 19 tumors in the current study), which differs strongly from the proportion of malignancy in masses detected with screening mammography in human subjects, which is roughly 1 in 5. Our model was not chosen to reflect a clinical distribution of benign and malignant breast masses and therefore is not well suited as a method to estimate clinical sensitivity and specificity. Because this ENU model does not produce a typical clinical distribution of tumors, the temptation to compare the relatively low sensitivity of these data for detecting malignancy (64% [nine of 14]) with the published sensitivity of gadolinium-enhanced breast tumor imaging (>90%) should be avoided (41). In this same breast tumor model, Daldrup et al (3), who used gadopentetate dimeglumine, could not significantly differentiate benign from malignant tumors; all tumors, benign and malignant, showed high transendothelial permeability ("leakiness") to gadopentetate dimeglumine and yielded a high sensitivity (100% [34 of 34]) but no specificity (0% [zero of 10])(3).
Despite the differences between our two histologic measurements—tumor grade, as reflected in the SBR score, and MVD, a surrogate of angiogenesis—our MR imaging measures of microvascular permeability (KPS) correlated strongly with both.
The SBR method of grading tumors is based exclusively on morphologic characteristics of the tumor cells themselves; one to three points are assigned for each of the following characteristics: mitotic rate, nuclear pleomorphism, and glandular and tubular differentiation. The SBR score does not consider any features of microvessels and is independent of angiogenesis. In contrast, MVD, the relative frequency of immunostained microvessel endothelial clusters within the tumor parenchyma, is a parameter of vascular status only, and tumor cell morphology is ignored. Although it is potentially flawed by problems with sampling and interobserver differences, MVD assays are, to our knowledge, currently the best available indicators of angiogenesis.
It is tempting to speculate about why microvascular permeability, a functional property of the endothelium, should strongly correlate with either SBR score or MVD, both morphologic features. The microvessels of cancers, which are extensively studied with invasive techniques, have unique structural and functional properties. Microvessels in malignant tumors have an irregular endothelial lining, discontinuity of basement membranes, and fewer pericytes and smooth muscle cells (42). In addition, cancer vessels contain more open interendothelial junctions, which lead to increased microvascular permeability (42). Cancers show a high density of microvessels, vessels that are hyperpermeable to macromolecular solutes (6,18,43–45). This increased density and the macromolecular hyperpermeability are the results, in large part, of an acceleration in angiogenesis.
Angiogenesis is the process by which new microvessels arise from preexistent blood vessels and is of fundamental importance in physiologic processes (wound healing, embryogenesis) and abnormal conditions such as proliferative retinopathy and tumor growth (46). It is interesting that tumor blood vessel endothelium proliferates up to 20,000 times faster than any normal adult tissue endothelium, except for placental endothelium (47).
The exact nature of the "angiogenic switch," which tumors must "turn on" to enter an accelerated growth phase, is not completely understood. Yet it is now postulated that an imbalance probably related to genetic transformations, in which the natural promoters of angiogenesis overpower the natural inhibitors, must arise. Vascular endothelial growth factor (VEGF), a particularly well-studied promoter, is a 45-kDa peptide also known as vascular permeability factor (VPF) (48,49). It is interesting that these two effects of this potent signaling molecule were identified independently: Only later was it recognized that VPF and VEGF are the same molecule (50,51). These effects—increased microvascular permeability and mitogenicity for vascular endothelial cells—are interrelated in the overall angiogenesis process and may explain our observed correlation between MR imaging–estimated macromolecular permeability and angiogenesis. The VEGF-VPF connection also predicts the near-significant observed correlation between MR imaging-estimated tumor plasma volume and histologic microvessel density.
Mechanistically, it has been postulated that the VEGF-VPF–induced increase in microvascular permeability is a crucial step in tumor angiogenesis; the increased plasma protein leakage leads to formation of an extracellular gel, which provides a favorable substrate for endothelial cell growth (49). VEGF-VPF is elaborated at high levels by a large number of, if not all, solid tumors (52,53).
Explaining the observed correlation between MR imaging microvessel characteristics and tumor cell morphology, as reflected by SBR score, is more difficult. With intuition, the status of tumor cell differentiation and that of intratumor blood vessels, derived from the nontumorous host vascular system, might not be expected to correlate; Weidner and colleagues (8) have stated that MVD, a surrogate of angiogenesis, is an independent indicator of prognosis. However, our data showed a strong positive correlation between SBR and MVD scores (r = 0.72, P < .005). Perhaps the genetic transformations that lead to the dedifferentiation of tumor cells are related to additional genetic changes that direct the acceleration of angiogenesis. Our data suggest that tumor cell morphology and the status of tumor microvessels are, indeed, interrelated.
Conclusions from our data are limited in several ways: Results from a subcutaneous rodent breast cancer model may not apply directly to human neoplasms. Although the spectrum of breast tumor abnormalities induced by ENU is generally parallel to the spectrum of human breast tumors (13), not all human tumor types may be represented in this model.
Also, the single dose of USPIO tested, 1 mg of iron per kilogram, may not be optimal, and other doses should be investigated. This low dose was specifically chosen to minimize the effects of iron on tissue T2*, which increases exponentially with doses and tends to counteract the sought-after T1-shortening effects that predominate at low doses. The disadvantages of our low dose include low signal-to-noise and less than dramatic tumoral enhancement. Testing of a higher dose, for example, 2 or 3 mg of iron per kilogram, may yield higher tumor enhancement and useful quantitative measures of microvascular characteristics. The larger SPIO particles are currently approved for use in humans at a dose of 10–15 µmol of iron per kilogram (54); to our knowledge, tolerance levels of USPIO in humans have not yet been established.
Pathologic examination results were the reference standard for comparisons with the MR imaging-estimated characteristics, KPS and fPV. SBR score for tumor grade and MVD for angiogenesis were assayed by an experienced veterinary pathologist. However, the scoring of tumor cell morphology is somewhat subjective, and all pathologic assays in these often-heterogeneous lesions are subject to potential sampling errors. The pathologist noted that grading of tumors, in particular those near the border between benign and low-grade malignancy, was difficult. It is possible that, in those few cases in which there was disagreement between pathologic assay result and permeability measurement, the pathologic reference standard may have been incorrect. Yet we know of no better standard for validating our MR imaging tumor characterizations.
Additional investigations might be performed by using other doses; other species, including humans; additional tumor types; and even other disease states for which altered microvascular characteristics are suspected. With regard to tumor characterization, we plan to evaluate dynamic USPIO enhancement responses as a means to monitor tumor treatment responses. By using albumin-(Gd-DTPA)30, our group has previously demonstrated the usefulness of dynamic MR imaging in detecting significant declines in microvascular permeability within 24 hours of tumor treatment by using an angiogenesis inhibitor (21). Similar sensitivity to acute tumor response may be detectable with USPIO.
The data in this study support the hypothesis that dynamic MR imaging with a particulate USPIO contrast medium allows noninvasive differentiation of breast tumors of varying histopathologic grade and angiogenic activity. Quantitative estimates of microvascular permeability, expressed as KPS, appeared to be better indicators of tumor status than estimates of vascularity, expressed as fPV.
Practical application: Results of this study indicate that USPIO, an MR imaging contrast agent that is being evaluated in clinical trials for reticuloendothelial system enhancement, may find additional clinical efficacy in the characterization of tissue microvessels. Quantitative microvascular characterization with dynamic macromolecular MR imaging could prove to be clinically useful for tissue differentiation, tumor grading, prognostication of life, and treatment monitoring.
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FOOTNOTES |
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R1 = change in R1,
SBR = Scarff-Bloom-Richardson,
USPIO = ultrasmall superparamagnetic iron oxide,
VEGF = vascular endothelial growth factor,
VPF = vascular permeability factor Author contributions: Guarantors of integrity of entire study, K.T., R.C.B.; study concepts, R.C.B., D.M.S., T.P.L.R.; study design, T.P.L.R., R.C.B.; definition of intellectual content, R.C.B., M.F.W.; literature research, S.H.; experimental studies, E.F., T.H., K.S.T.; data acquisition, K.S.T., T.H.; data analysis, T.P.L.R., K.T.; statistical analysis, D.M.S., T.P.L.R.; manuscript preparation, K.T., S.H.; manuscript editing, K.T., K.S.T.; manuscript review, K.T., R.C.B.
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B M Seddon and P Workman The role of functional and molecular imaging in cancer drug discovery and development Br. J. Radiol., December 1, 2003; 76(suppl_2): S128 - S138. [Abstract] [Full Text] [PDF]
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Q. G. de Lussanet, W. H. Backes, A. W. Griffioen, J. M. A. van Engelshoven, and R. G. H. Beets-Tan Gadopentetate Dimeglumine versus Ultrasmall Superparamagnetic Iron Oxide for Dynamic Contrast-enhanced MR Imaging of Tumor Angiogenesis in Human Colon Carcinoma in Mice Radiology, November 1, 2003; 229(2): 429 - 438. [Abstract] [Full Text] [PDF]
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 V. Kostourou, S. P. Robinson, G. St. J. Whitley, and J. R. Griffiths Effects of Overexpression of Dimethylarginine Dimethylaminohydrolase on Tumor Angiogenesis Assessed by Susceptibility Magnetic Resonance Imaging Cancer Res., August 15, 2003; 63(16): 4960 - 4966. [Abstract] [Full Text] [PDF]
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G. A. Krombach, M. F. Wendland, C. B. Higgins, and M. Saeed MR Imaging of Spatial Extent of Microvascular Injury in Reperfused Ischemically Injured Rat Myocardium: Value of Blood Pool Ultrasmall Superparamagnetic Particles of Iron Oxide Radiology, November 1, 2002; 225(2): 479 - 486. [Abstract] [Full Text] [PDF]
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S. C. A. Michel, T. M. Keller, J. M. Frohlich, D. Fink, R. Caduff, B. Seifert, B. Marincek, and R. A. Kubik-Huch Preoperative Breast Cancer Staging: MR Imaging of the Axilla with Ultrasmall Superparamagnetic Iron Oxide Enhancement Radiology, November 1, 2002; 225(2): 527 - 536. [Abstract] [Full Text] [PDF]
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D. M. McDonald and P. Baluk Significance of Blood Vessel Leakiness in Cancer Cancer Res., September 15, 2002; 62(18): 5381 - 5385. [Abstract] [Full Text] [PDF]
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 E. Fosslien Molecular Pathology of Cyclooxygenase-2 in Cancer-induced Angiogenesis Ann. Clin. Lab. Sci., October 1, 2001; 31(4): 325 - 348. [Abstract] [Full Text] [PDF]
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