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Item does not contain fulltext The incidence of endometrial carcinoma is rising and the patients with distant metastases have a poor prognosis, especially when progression of disease occurs after systemic treatment with hormonal therapy or chemotherapy. Pazopanib, a multi-targeted inhibitor of several oncogenic receptor tyrosine kinases, has been investigated in patients with chemotherapy-resistant endometrial carcinoma or patients for whom chemotherapy is contraindicated. In this report we will describe a spectacular response to pazopanib in a patient with recurrent metastatic endometrial carcinoma.

Purpose: In malignant lymphoma, angiogenesis has been associated with adverse outcome or more aggressive clinical behavior. This correlation has been established in groups of patients with a large heterogeneity regarding lymphoma subtypes and treatment regimens. The aim of this study is to investigate the significance of vascularization in patients with follicular lymphoma receiving uniform first-line treatment. Experimental Design: We assessed microvessel density (MVD) in pretreatment lymph node biopsies of 46 previously untreated patients with follicular lymphoma using anti-CD34 immunohistochemical staining and interactive quantification. In a selection of cases, vascular endothelial growth factor (VEGF)-RNA in situ hybridization was done. Patients were treated with cyclophosphamide-vincristine-prednisone induction chemotherapy combined with IFN-α2b. Thirty-six patients responded and received IFN-α as maintenance therapy. Results: MVD ranged from 10 to 70 per measurement field of 0.19 mm2 (median, 38). Median progression-free survival was 47 months in patients with MVD in the highest tertile and only 13 months in patients with lower MVD. Overall survival in patients with low vessel density was 59 months. In patients with high vessel density, median overall survival was not reached. Multivariate analysis indicated that MVD was independently associated with overall survival. There was a lack of correlation between VEGF-RNA expression and vessel density. Conclusion: This study shows that in follicular lymphoma increased vascularization is associated with improved clinical outcome. Furthermore, VEGF-A expression seems not to be involved in follicular lymphoma angiogenesis.

Detailed characterization of the tumor vasculature provides a better understanding of the complex mechanisms associated with tumor development and is especially important to evaluate responses to current therapies which target the tumor vasculature. Magnetic resonance imaging (MRI) studies of tumors have been mostly performed using gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) contrast-enhanced imaging, which relies on Gd-DTPA leakage from hyperpermeable tumor vessels and subsequent accumulation in the tumor interstitium. In certain tumor types, especially diffuse glioma in the brain, incorporated tumor vessels are not necessarily leaky, complicating effective diagnosis via Gd-DTPA contrast-enhanced MRI. Another class of contrast agents, based on superparamagnetic ultrasmall iron oxide particles (USPIO), allows for non-invasive assessment of vascular volume within the tumor. Vascular volume can be obtained by calculating the change in water proton transverse relaxation rate (R (2) or R (2)) following USPIO administration. This allows for an objective comparison between vascular volumes of different tumors and also allows to perform longitudinal studies in order to assess, for example, treatment efficacy. Moreover, since the USPIO T (2) relaxivity is up to 20 times that of Gd-DTPA, USPIO provides a highly sensitive marker for alterations in vascular volume among tissues; this characteristic might be exploited for tumor detection. Thus, USPIO imaging may be a very attractive alternative to the most commonly used Gd-DTPA imaging and will at least have added value, especially for detection and delineation of diffuse infiltrative brain tumors.

Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the 'seed and soil' hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously reported that constitutive VEGF-A expression in tumour xenografts facilitates this type of metastatic seeding by promoting shedding of multicellular tumour tissue fragments, surrounded by vessel wall elements, into the circulation. After transport through the vena cava, such fragments may be trapped in pulmonary arteries, allowing them to expand to symptomatic lesions. Here we tested whether this process has clinical relevance for clear cell renal cell carcinoma (ccRCC), a prototype tumour in the sense of high constitutive VEGF-A expression. To this end we collected and analysed outflow samples from the renal vein, directly after tumour nephrectomy, in 42 patients diagnosed with ccRCC. Tumour fragments in venous outflow were observed in 33% of ccRCC patients and correlated with the synchronous presence or metachronous development of pulmonary metastases (p0.001, Fisher's exact test). In patients with tumours that, in retrospect, were not of the VEGF-A-expressing clear cell type, tumour fragments were never observed in the renal outflow. These data suggest that, in ccRCC, a VEGF-A-induced phenotype promotes a release of tumour cell clusters into the circulation that may contribute to pulmonary metastasis.

Tumors arise initially as avascular masses in which central hypoxia induces expression of vascular endothelial growth factor-A (VEGF-A) and subsequently tumor vascularization. However, VEGF-A can also be constitutively expressed as a result of genetic events. VEGF-A is alternatively spliced to yield at least 6 different isoforms. Of these, VEGF-A(121) is freely diffusible whereas basically charged domains in the larger isoforms confer affinity for cell surface or extracellular matrix components. We previously reported that in a mouse brain metastasis model of human melanoma, VEGF-A(121) induced a qualitatively different tumor vascular phenotype than VEGF-A(165) and VEGF-A(189): in contrast to the latter ones, and VEGF-A(121) did not induce a neovascular bed but rather led to leakage and dilatation of preexistent brain vessels. Here, we correlate vascular phenotypes with spatial VEGF-A expression profiles in clinical brain tumors (low grade gliomas; n = 6, melanoma metastases; n = 4, adenocarcinoma metastases; n = 4, glioblastoma multiforme; n = 3, sarcoma metastasis; n = 1, renal cell carcinoma metastasis; n = 1). We show that tumors that constitutively express VEGF-A present with different vascular beds than tumors in which VEGF-A is expressed as a response to central hypoxia. This phenotypic difference is consistent with a model where in tumors with constitutive VEGF-A expression, all isoforms exert their effects on vasculature, resulting in a classical angiogenic phenotype. In tumors where only central parts express hypoxia-induced VEGF-A, the larger angiogenic isoforms are retained by extracellular matrix, leaving only freely diffusible VEGF-A(121) to exert its dilatation effects on distant vessels.

Ferumoxtran-10 (Combidex) is an ultra-small superparamagnetic iron oxide molecular resonance imaging contrast agent under development by Advanced Magnetics Ltd and Guerbet for the principal indication of lymph node imaging.

We have previously shown that the dense vascular network in mouse brain allows for growth of human melanoma xenografts (Mel57) by co-option of preexisting vessels. Overexpression of recombinant vascular endothelial growth factor-A (VEGF-A) by such xenografts induced functional and morphologic alterations of preexisting vessels. We now describe the effects of VEGF-A expression on visualization of these brain tumors in mice by magnetic resonance imaging (MRI), using gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA) and ultra small paramagnetic iron oxide particles (USPIO) as contrast agents. Brain lesions derived from (mock-transfected) Mel57 cells were undetectable in MRI after Gd-DTPA injection. However, the majority of such lesions became visible after injection of USPIO, due to the lower vascular density in the lesions as compared to the surrounding parenchyma. In contrast, VEGF-A-expressing lesions were visualized using Gd-DTPA-enhanced MRI by a rapid circumferential enhancement, due to leaky peritumoral vasculature. USPIO-enhanced MRI of these tumors corroborated the immunohistochemic finding that peritumorally located, highly irregular and dilated vessels were present, while intratumoral vessel density was low. Our study shows that VEGF-A is a key factor in imaging of brain neoplasms. Our data also demonstrate that, at least in brain, blood-pool agent-enhanced MRI may be a valuable diagnostic tool to detect malignancies that are not visible on Gd-DTPA-enhanced MRI. Furthermore, the involvement of VEGF-A in MRI visibility suggests that care must be taken with MRI-based evaluation of antiangiogenic therapy, as anti-VEGF treatment might revert a tumor to a co-opting phenotype, resulting in loss of contrast enhancement in MRI.

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