Direct Comparison of the Thickness Of The Parietal Peritoneum Using Peritoneal Biopsy and Ultrasonography of the Abdominal Wall in Patients Treated with Peritoneal Dialysis.

Background:Long-term treatment with peritoneal dialysis (PD) results in peritoneal fibrosis. Peritoneal biopsies have been used to determine the severity of fibrosis. Ultrasonography (US) of the abdominal wall has been used to measure peritoneal thickness non-invasively. However, direct comparison of both methods in the same patient has never been done. Furthermore, the validity of US to measure peritoneal thickness has not been investigated.Methods:We performed 3 studies: 1) a human biopsy study to compare US measurement of peritoneal thickness with histological examination; 2) a human cadaver study to investigate the effect of removing the peritoneum on US results; and 3) a phantom study in which we used US to measure the thickness of membrane-like structures with a known thickness to investigate the influence of different US settings.Results:The median thickness in biopsies of the peritoneum was 113 µm (interquartile range [IQR] 72 -129 µm), while this was 370 µm (IQR 324 - 458 µm) when measured by US (p < 0.0001). The mean difference between the 2 measures was -257 µm (limits of agreement -4.6 and -511 µm). In the cadaver study, removal of the peritoneum did not have an effect on the presence or thickness of the hyperechoic line reported to represent the peritoneum. In the phantom study, results were highly dependent on frequency of the transducer, scan depth, and gain settings.Conclusions:Ultrasonography results differ markedly from histological measurement using peritoneal biopsies. However, the hyperechoic line generated by US represents the interface between 2 neighboring tissues and not a separate morphological structure. Moreover, its thickness is greatly influenced by user-defined US settings.

Inter-reader reproducibility of dynamic contrast-enhanced magnetic resonance imaging in patients with non-small cell lung cancer treated with bevacizumab and erlotinib.

UNLABELLED: Objectives When evaluating anti-tumor treatment response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) it is necessary to assure its validity and reproducibility. This has not been well addressed in lung tumors. Therefore we have evaluated the inter-reader reproducibility of response classification by DCE-MRI in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab and erlotinib enrolled in a multicenter trial. MATERIALS AND METHODS: Twenty-one patients were scanned before and 3 weeks after start of treatment with DCE-MRI in a multicenter trial. The scans were evaluated by two independent readers. The primary lung tumor was used for response assessment. Responses were assessed in terms of relative changes in tumor mean trans endothelial transfer rate (K(trans)) and its heterogeneity in terms of the spatial standard deviation. Reproducibility was expressed by the inter-reader variability, intra-class correlation coefficient (ICC) and dichotomous response classification. RESULTS: The inter-reader variability and ICC for the relative K(trans) were 5.8% and 0.930, respectively. For tumor heterogeneity the inter-reader variability and ICC were 0.017 and 0.656, respectively. For the two readers the response classification for relative K(trans) was concordant in 20 of 21 patients (k=0.90, p<0.0001) and for tumor heterogeneity in 19 of 21 patients (k=0.80, p<0.0001). CONCLUSIONS: Strong agreement was seen with regard to the inter-reader variability and reproducibility of response classification by the two readers of lung cancer DCE-MRI scans.

Dynamic contrast-enhanced MRI of muscle perfusion combined with MR angiography of collateral artery growth in a femoral artery ligation model.

To assess the use of MRI for evaluating changes in muscle blood flow and number of collateral arteries, serial dynamic contrast-enhanced MRI (DCE-MRI) was combined with high-spatial-resolution contrast-enhanced MR angiography (MRA) in a peripheral ischemia model. The combined MRI (DCE-MRI and MRA) protocol was performed serially in 15 male rabbits at 2 h (day 0(+)), 7 days, and 21 days after femoral artery ligation. In the anterior tibial and soleus muscle, changes in resting muscle blood flow determined as the endothelial transfer coefficient (K(trans)) and arterial inflow delay from DCE-MRI and changes in the number of sub-millimeter sized collateral arteries as scored with MRA were measured. Directly after ligation, K(trans) in the anterior tibial muscle was reduced to 23% of that in the control limb, then recovered to 81% on day 7, and to 85 % on day 21. K(trans) in the soleus muscle recovered from a reduction to 63% on day 0(+), to 85% on day 7, and to 90% on day 21. The number of collaterals around the ligated femoral artery increased from 1.1 on day 0(+) to 4.2 on day 7, and 6.0 on day 21 in the ligated limb only. Combined DCE-MRI and MRA allows non-invasive serial monitoring of changes in muscle blood flow and growth of sub-millimeter sized collateral arteries in a rabbit femoral artery ligation model.

Evaluation of Gd(III)DTPA-terminated poly(propylene imine) dendrimers as contrast agents for MR imaging.

Different generations of Gd(III)DTPA-terminated poly(propylene imine) dendrimers {G1 [n = 4 Gd(III) ions per molecule], G3 (n = 16) and G5 (n = 64)} and reference Gd(III)DTPA complex [G0 (n = 1)] were characterized in terms of (i) longitudinal (r1) and transverse (r2) relaxivities in mouse blood plasma, (ii) concentration detection limits in vitro and (iii) in vivo contrast-enhanced MR imaging (CE-MRI) in mice at 1.5 T. Serial and dynamic CE-MRI were performed to monitor the distribution of MRI contrast agent in the heart, arteries, renal system, liver, spleen, bladder and tumor periphery. The relaxivities increased non-linearly with molecular weight (for G0 ionic r1 = 8.1 mM(-1) s(-1) and ionic r2 = 8.6 mM(-1) s(-1) to G5 19.3 and 25.0, respectively). The minimal detectable dendrimer concentration was more than two orders of magnitude lower for G5 (8.1 x 10(-8) M) than for G0 (3.1 x 10(-5) M). Sub-millimeter-sized blood vessels were well visualized with serial CE-MRI with each contrast agent. Dynamic CE-MRI showed timely renal clearance for all contrast agents, but a stronger and a prolonged blood signal enhancement for the higher generations of the dendritic contrast agent. Moreover, G0 and G1 showed a rapid tumor wash-in and wash-out, whereas G3 and G5 displayed a more gradual and prolonged tumor wash-in. In conclusion, both G0 and dendritic contrast agents G1, G3 and G5 are well suited for non-tissue-specific MRI of sub-millimeter-sized blood vessels and evaluating tumor microcirculatory characteristics in mice. Higher generations of dendritic contrast agents display lower concentration detection limits, which suggests their future use for molecular imaging.

Magnetic resonance angiography of collateral vessel growth in a rabbit femoral artery ligation model.

Collateral vessel growth was visualized in a rabbit femoral artery ligation model by serial contrast-enhanced magnetic resonance angiography (MRA) at 1.5 T in comparison with X-ray angiography (XRA). XRA and MRA were performed directly after femoral artery ligation (day 0+) and after 7 and 21 days. XRA (in-plane resolution, 0.3x0.3 mm) was performed with arterial catheterization for fast injection of iodinated contrast agent just proximal to the aortic bifurcation. MRA (in-plane, 0.6x0.6 mm) was performed at 1.5 T with a five-element phased-array coil and slow injection of gadolinium-based MR contrast agent into an ear vein. Collateral vessel scores on two-dimensional XRA projections and on three-dimensional digitally subtracted rotational MRA maximum intensity projections were obtained by two observers and compared. Collateral vessel counts and minimal detectable vessel diameters for MRA and XRA were combined in a computational flow model to interpret differences in spatial detection limits between imaging modalities in terms of flow. Collateral vessel scores were significantly higher in the ligated limb at day 7 (P < 0.05) and more so at day 21 (P < 0.001), in comparison with day 0+ or in the non-ligated control limb on both XRA and MRA. Significantly more (smaller) vessels were visualized with XRA than with MRA, particularly on day 21 (P < 0.05). Inter-observer agreement was high for both XRA (kappa = 0.82) and MRA (kappa = 0.78). The flow model showed that collateral vessels with diameters > 0.3 mm scored by XRA as well as MRA represent nearly 100% of the total blood flow, whereas smaller (0.1-0.3 mm diameter) vessels that can only be detected with XRA contribute little to the blood flow. Serial contrast-enhanced MRA can non-invasively visualize sub-millimeter collateral vessels that represent nearly 100% of the restored blood flow, in a femoral artery ligation model.

Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer.

PURPOSE: Dynamic contrast-enhanced T1-weighted magnetic resonance imaging (DCE-MRI) allows noninvasive evaluation of tumor microvasculature characteristics. This study evaluated radiation therapy related microvascular changes in locally advanced rectal cancer by DCE-MRI and histology. METHODS AND MATERIALS: Dynamic contrast-enhanced-MRI was performed in 17 patients with primary rectal cancer. Seven patients underwent 25 fractions of 1.8 Gy radiation therapy (RT) (long RT) before DCE-MRI and 10 did not. Of these 10, 3 patients underwent five fractions of 5 Gy RT (short RT) in the week before surgery. The RT treated and nontreated groups were compared in terms of endothelial transfer coefficient (K(PS), measured by DCE-MRI), microvessel density (MVD) (scored by immunoreactivity to CD31 and CD34), and tumor cell and endothelial cell proliferation (scored by immunoreactivity to Ki67). RESULTS: Tumor K(PS) was 77% (p = 0.03) lower in the RT-treated group. Histogram analyses showed that RT reduced both magnitude and intratumor heterogeneity of K(PS) (p = 0.01). MVD was significantly lower (37%, p = 0.03) in tumors treated with long RT than in nonirradiated tumors, but this was not the case with short RT. Endothelial cell proliferation was reduced with short RT (81%, p = 0.02) just before surgery, but not with long RT (p > 0.8). Tumor cell proliferation was reduced with both long (57%, p < 0.001) and short RT (52%, p = 0.002). CONCLUSION: Dynamic contrast-enhanced-MRI-derived K(PS) values showed significant radiation therapy related reductions in microvessel blood flow in locally advanced rectal cancer. These findings may be useful in evaluating effects of radiation combination therapies (e.g., chemoradiation or RT combined with antiangiogenesis therapy), to account for effects of RT alone.

Dynamic contrast-enhanced MR imaging kinetic parameters and molecular weight of dendritic contrast agents in tumor angiogenesis in mice.

PURPOSE: To evaluate the relationship between dynamic contrast agent-enhanced magnetic resonance (MR) imaging-derived kinetic parameters and contrast agents of equal chemical composition and configuration but with different molecular weights in a tumor angiogenesis model. MATERIALS AND METHODS: This study was approved by the ethical review committee. Maintenance and care of animals was in compliance with guidelines set by the institutional animal care committee. Dynamic contrast-enhanced MR imaging was performed with dendritic contrast agents in 16 mice with tumor xenografts; mice were placed in groups of four for each molecular weight of the contrast agent. The magnitude and spatial distribution of kinetic parameters (transfer coefficient [K(PS)] and plasma fraction [f(PV)]) were compared with molecular weight of the contrast agent by determining the Spearman correlation coefficient (r) and the quantitative relationship between the endothelial K(PS) and molecular weight. RESULTS: Inverse relationships between molecular weight of contrast agent and K(PS) and f(PV) of tumor rim (r = -0.8, P < .001 and r = -0.5, P = .04, respectively) and core (r = -0.7, P = .004 and r = -0.6, P = .01, respectively) were observed. The quantitative relationship between K(PS) and molecular weight (MW) was K(PS) = 0.4/MW(0.44). A decreasing stepwise pattern in f(PV) was noted between contrast agents with low (0.7- and 3.0-kDa) molecular weight and those with high (12- and 51-kDa) molecular weight. CONCLUSION: Macromolecular permeability is best measured with high-molecular-weight contrast agents; endothelial K(PS) values measured with low-molecular-weight contrast agents incorporate tissue perfusion and permeability and demonstrate heterogeneous microcirculatory flow.

Design and synthesis of a bimodal target-specific contrast agent for angiogenesis.

[structure: see text] A bimodal target-specific contrast agent based on a cyclic peptide containing the target-specific NGR sequence, gadolinium(III) diethylenetriaminepentaacetic acid (Gd(III)DTPA), and Oregon Green 488 (OG488) suitable for both MR imaging and optical imaging of angiogenesis is developed. The synthetic strategy for this target-specific contrast agent exploits the use of highly efficient, chemoselective reactions, such as native chemical ligation, and gives a straightforward approach for double labeling of peptides in general.

Gadopentetate dimeglumine versus ultrasmall superparamagnetic iron oxide for dynamic contrast-enhanced MR imaging of tumor angiogenesis in human colon carcinoma in mice.

PURPOSE: To compare the kinetic physiologic properties of a clinical contrast agent, gadopentetate dimeglumine, with those of ultrasmall superparamagnetic iron oxide (USPIO) particles for dynamic contrast material-enhanced magnetic resonance (MR) imaging of tumor angiogenesis in human colon carcinoma in mice with a clinical MR imaging unit. MATERIALS AND METHODS: Thirty-two mice with human colon carcinoma were injected with either gadopentetate dimeglumine (n = 16) or USPIO (n = 16) for dynamic contrast-enhanced MR imaging and pre- and postcontrast T2 and T2* measurements. Dynamic contrast-enhanced MR imaging measurements were analyzed by using a two-compartment model to calculate the endothelial transfer coefficient surface area product (KPS) for the tumor microvasculature, the reflux coefficient (k), and the fractional plasma volume (fPV). KPS, k, and fPV maps were compared with histologic microvessel density (MVD) and used to observe differences between core and rim regions of tumor. RESULTS: Results in 30 mice (15 in the gadopentetate dimeglumine group and 15 in the USPIO group) could be used. KPS values measured with both agents correlated well with MVD in hot spots (gadopentetate dimeglumine: r = 0.6, P =.02; USPIO: r = 0.6, P =.01). No significant difference (P =.4) in correlation was found between the two agents. Both USPIO and gadopentetate dimeglumine demonstrated higher MVD and KPS values in tumor rim than in tumor core (P <.01). Tumor k values correlated poorly with whole-tumor MVD for both gadopentetate dimeglumine (r = 0.3, P =.4) and USPIO (r = 0.2, P =.6), while fPV values correlated well with whole-tumor MVD for USPIO (r = 0.6, P =.02) but not gadopentetate dimeglumine (r = -0.01, P =.98). T2 and T2* measurements showed small differences between areas of high and low angiogenic activity with both agents. CONCLUSION: The kinetic physiologic properties of gadopentetate dimeglumine are as good as those of USPIO for dynamic contrast-enhanced MR imaging for calculating KPS as a measurement of angiogenesis in human colon carcinoma. Further studies with patients may reveal whether gadopentetate dimeglumine might be used for this purpose in clinical practice.

The designer anti-angiogenic peptide anginex targets tumor endothelial cells and inhibits tumor growth in animal models.

The de novo designed angiogenesis inhibitor anginex was tested in vitro and in vivo for its mechanism of action and antitumor activity. The data presented here demonstrate that anginex is a powerful antiangiogenic agent with significant antitumor activity. The mechanism of action of anginex was found to be the induction of anoikis leading to apoptosis in angiogenically activated endothelial cells, resulting in an up to 90% inhibition of migration in the wound assay. Anginex inhibited angiogenesis as demonstrated in the in vitro mouse aortic ring assay. In addition, tumor-induced angiogenesis in the chick chorioallantoic membrane was markedly inhibited. Anginex showed profound antitumor activity in the syngeneic mouse B16F10 melanoma model and in a xenograft human tumor model. Microvessel density determination as well as magnetic resonance imaging showed that the antitumor activity in these tumor models resulted from the antiangiogenic activity of anginex. A complete absence of toxicity was observed in these models. The data presented here demonstrate that anginex is a promising agent for further clinical development.