in-vivo-imaging-tumor-angiogenesis-using-fluorescence-confocal

<em>In vivo</em> Imaging of Tumor Angiogenesis using Fluorescence Confocal Videomicroscopy

Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite ...

Université Paris Descartes Sorbonne Paris Cité, INSERM UMR-S970

Hôpital Européen Georges Pompidou, Service de Radiologie

We assessed the capacity of chest radiography and CT to determine the cause and site of bleeding in patients with either large or massive hemoptysis compared with bronchoscopy.

Can CT replace bronchoscopy in the detection of the site and cause of bleeding in patients with large or massive hemoptysis?

Case report. Pyothorax-associated lymphoma: Diagnosis at percutaneous core biopsy with CT guidance.

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.

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

Macromolecular contrast-enhanced functional CT was performed to characterize early perfusion changes in hepatocellular carcinoma (HCC). Fourteen rats with chemically induced primary liver tumors ranging pathologically from hyperplasia to HCC and 15 control rats were investigated. Two dynamic CT scans using an experimental macromolecular contrast agent were performed on a single slice 11 and 18 weeks after tumor induction followed by pathological examination. A deconvolution mathematical model was applied, yielding the hepatic perfusion index (HPI), mean transit time (MTT), liver distribution volume (LDV) and arterial, portal and total blood flows (FA, FP, FT). Analysis was performed on one slice per rat, containing overall two hyperplasia, six dysplasia and 15 HCC. On the first scans, HCC at an early pathological stage had a low FP (-30%, P=0.002) but a normal arterial-portal balance. On the scan contemporary to pathology, HCC perfusion parameters showed an inversion of the arterial-portal balance (HPI +212%, P<0.0001), with a high FA (+56%, P=0.002) and a low FP (-69%, P<0.0001). Sensitivity and specificity of detection of HCC by perfusion CT were high (87 and 80%) on late scans; but also on the earlier scans (86 and 65%), even though only one (7%) was visible to the eye. Perfusion-CT allowed early detection of HCC. This technique could contribute in the detection and characterization of liver lesions in clinical studies.

Early modifications of hepatic perfusion measured by functional CT in a rat model of hepatocellular carcinoma using a blood pool contrast agent.

The objective of this study was to evaluate computed tomography (CT) enhancement characteristics for a new iodinated macromolecular contrast medium (MMCM), PEG12000-Gen4-triiodo, for angiographic effect and for assessment of abnormal vascular permeability in cancer.

Initial computed tomography imaging experience using a new macromolecular iodinated contrast medium in experimental breast cancer.

To prospectively evaluate the ability of macromolecular contrast medium (MMCM)-enhanced dynamic magnetic resonance (MR) imaging to depict vascular changes in response to cyclooxygenase-2 (COX-2) inhibition of angiogenesis in a human breast cancer model.

MR monitoring of cyclooxygenase-2 inhibition of angiogenesis in a human breast cancer model in rats.

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.

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

To prospectively determine the diagnostic accuracy of optical absorption imaging in patients with Breast Imaging Reporting and Data System (BI-RADS) 3-5 breast lesions.

Dynamic optical breast imaging: a novel technique to detect and characterize tumor vessels.

We investigate in vivo detection of mammary tumors in a rat model using autofluorescence imaging in the red and far-red spectral regions. The objective was to explore this method for non-invasive detection of malignant tumors and correlation between autofluorescence properties of tumors and their pathologic status. Eighteen tumor-bearing rats, bearing eight benign and seventeen malignant tumors were imaged. Autofluorescence images were acquired using spectral windows centered at 700-nm, 750-nm and 800-nm under laser excitation at 632.8-nm and 670- nm. Intensity in the autofluorescence images of malignant tumors under 670-nm excitation was higher than that of the adjacent normal tissue. whereas intensity of benign tumors was lower compared to normal tissue.

In-vivo NIR autofluorescence imaging of rat mammary tumors.

To determine whether tumor perfusion parameters assessed by using dynamic contrast material-enhanced computed tomography (CT) could help predict and detect response in patients receiving antiangiogenic therapy for metastatic renal cell carcinoma.

Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT.

To develop a new automated filtering technique and to evaluate its ability to compensate for the known low contrast-to-noise ratio (CNR) in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) and computed tomographic (CT) data, without substantial loss of information.

Signal-to-noise ratio improvement in dynamic contrast-enhanced CT and MR imaging with automated principal component analysis filtering.

Objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) is low among patients with metastatic renal cell carcinoma (mRCC) treated with targeted agents, despite significantly improved progression-free survival (PFS). A modified response threshold may be more clinically meaningful than RECIST for identifying patients who may derive a PFS benefit from targeted therapy.

Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study.

Kidney cancer is composed of several bio-histological entities. The most frequent type, clear-cell carcinoma, is not homogenous regarding gene mutations or transcriptomic profiles, but the biologic classifications are not yet mature. Therefore, biologically driven strategies of treatment have not yet been developed in the clinical setting. The choice of first-line agent currently depends on the prognostic criteria published by Motzer et al. [J Clin Oncol 1999;17:2530-2540] and recently by Heng et al. [J Clin Oncol 2009;27:5794-5799], with anti-vascular endothelial growth factor (VEGF) therapies for good- or intermediate-prognosis groups and anti-mammalian target of rapamycin (mTOR) for poor-risk patients. In the past years, biological changes leading to resistance to targeted agents have been widely investigated. Discoveries resulted in the development of second-generation VEGF receptor tyrosine kinase inhibitors, characterized by an improved potency and selectivity. Besides, co-inhibition of signalling pathways mediating resistance to anti-VEGF are being developed targeting fibroblast growth factor and c-Met. Dual mTOR/phosphatidylinositol 3-kinase inhibitors have greater efficacy than rapalogs in preclinical models and are being investigated in early clinical trials. In conclusion, the changing landscape in the biology and treatment of kidney cancer offers new opportunities for clinicians to treat patients, but, due to relatively high costs, the use of targeted therapies will likely be strongly controlled by health authorities.

New insights into the management of renal cell cancer.

PURPOSE: To determine whether diffusion-weighted imaging (DWI) characteristics could predict the effectiveness of uterine arterial embolization in treatment of fibroids. METHODS: This retrospective study included 17 women (27 fibroids) who underwent uterine arterial embolization for fibroids. MR imaging (1.5 T) was performed before, 1 week and 6 months after uterine arterial embolization. The volume, T2 signal, T1 signal, enhancement after contrast media injection, DWI signal (b = 500 s/mm(2) ) and apparent diffusion coefficient (ADC) were assessed for fibroids. RESULTS: DWI signal or ADC, whether before or 1 week after the procedure, did not show a statistical relationship to success of uterine arterial embolization. On the 1-week follow-up, 22% of fibroids enhanced vs. 85% on baseline, P < 0.0001 and DW signal intensity increased. ADC values in fibroids decreased between baseline and 1-week (1.61 vs. 1.53 Ã— 10(-3) mm(2) /s, P = 0.13). On 6-months, ADC continued to decrease compared with baseline (1.27 Ã— 10(-3) mm(2) /s, P = 0.002), but with a lower signal on DWI. No changes were observed in myometrium ADC at any time point. CONCLUSION: Our study demonstrated that DWI and ADC reflected early and delayed changes in fibroids after embolization; however, we were not able to demonstrate a statistically significant relationship with outcome. Magn Reson Med, 2013. Â© 2013 Wiley Periodicals, Inc.

Laure S. Fournier

Université Paris Descartes Sorbonne Paris Cité, INSERM UMR-S970

In vivo Imaging of Tumor Angiogenesis using Fluorescence Confocal Videomicroscopy