BACKGROUND: The objective of the current study was to determine the accuracy of magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) for detecting lymph node metastases in patients with uterine cervical carcinoma compared with thin‐section histopathologic results from systemic lymphadenectomy.METHODS: Twenty‐two patients with International Federation of Obstetrics and Gynecology (FIGO) Stage IB–IVA cervical carcinoma who underwent both MRI and PET/CT before lymphadenectomy were included in this study. Lymphadenectomy involved removing all visible lymph nodes in the surgical fields. To enable region‐specific comparisons, paraaortic and pelvic lymph nodes were divided into seven regions: the paraaortic area, both common iliac areas, both external iliac areas, and both internal iliac/obturator areas. Histopathologic evaluation of lymph nodes was the diagnostic standard. Chi‐square analysis was used to compare the accuracy of MRI and PET/CT for the detection of metastatic lymph nodes. A P value ≤ 0.05 was considered statistically significant.RESULTS: With MRI, the sensitivity, specificity, and accuracy rates for detecting metastatic lymph nodes in each lymph node group were 30.3% (10 of 33 lymph node groups), 92.6% (112 of 121 lymph node groups), and 72.7% (122 of 154 lymph node groups), respectively; with PET/CT, those rates were 57.6% (19 of 33 lymph node groups), 92.6% (112 of 121 lymph node groups), and 85.1% (131 of 154 lymph node groups), respectively. Statistical analysis showed that PET/CT was more sensitive than MRI (P = 0.026) but that there were no statistical differences noted with regard to specificity (P = 1.000) or accuracy (P = 0.180). Power analysis demonstrated that a sample size of 685 lymph node groups (98 patients) would be necessary to demonstrate that PET/CT was more accurate than MRI (α = 0.05; β = 0.80).CONCLUSIONS: PET/CT was more sensitive than MRI for detecting lymph node metastases in patients with uterine cervical carcinoma. Cancer 2006. © 2006 American Cancer Society.

Purpose: This study aimed to develop an Arg-Gly-Asp (RGD) peptide-labeled chitosan nanoparticle (RGD-CH-NP) as a novel tumor targeted delivery system for short interfering RNA (siRNA). Experimental Design: RGD peptide conjugated with chitosan by thiolation reaction was confirmed by proton-NMR (H-NMR). Binding of RGD-CH-NP with ανβ3 integrin was examined by flow cytometry and fluorescence microscopy. Antitumor efficacy was examined in orthotopic mouse models of ovarian carcinoma. Results: We show that RGD-CH-NP loaded with siRNA significantly increased selective intratumoral delivery in orthotopic animal models of ovarian cancer. In addition, we show targeted silencing of multiple growth-promoting genes (POSTN, FAK, and PLXDC1) along with therapeutic efficacy in the SKOV3ip1, HeyA8, and A2780 models using siRNA incorporated into RGD-CH-NP (siRNA/RGD-CH-NP). Furthermore, we show in vivo tumor vascular targeting using RGD-CH-NP by delivering PLXDC1-targeted siRNA into the ανβ3 integrin–positive tumor endothelial cells in the A2780 tumor-bearing mice. This approach resulted in significant inhibition of tumor growth compared with controls. Conclusions: This study shows that RGD-CH-NP is a novel and highly selective delivery system for siRNA with the potential for broad applications in human disease. Clin Cancer Res; 16(15); 3910–22. ©2010 AACR.

RNA interference holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of small interfering RNA (siRNA). To maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing its receptor: scavenger receptor type B1 (SR-B1). In this study, we exploited this cellular characteristic to achieve efficient siRNA delivery and established a novel formulation of siRNA by incorporating it into reconstituted HDL (rHDL) nanoparticles. Here, we demonstrate that rHDL nanoparticles facilitate highly efficient systemic delivery of siRNA in vivo, mediated by the SR-B1. Moreover, in therapeutic proof-of-concept studies, these nanoparticles were effective in silencing the expression of two proteins that are key to cancer growth and metastasis (signal transducer and activator of transcription 3 and focal adhesion kinase) in orthotopic mouse models of ovarian and colorectal cancer. These data indicate that an rHDL nanoparticle is a novel and highly efficient siRNA carrier, and therefore, this novel technology could serve as the foundation for new cancer therapeutic approaches.

Metastasis is a complex, multistep process that begins with the epithelial–mesenchymal transition (EMT). Circulating tumor cells (CTC) are believed to have undergone EMT and thus lack or express low levels of epithelial markers commonly used for enrichment and/or detection of such cells. However, most current CTC detection methods target only EpCAM and/or cytokeratin (CK) to enrich epithelial CTCs, resulting in failure to recognize other, perhaps more important, CTC phenotypes that lack expression of these markers. Here, we describe a population of complex aneuploid CTCs that do not express CK or CD45 antigen in patients with breast, ovarian, or colorectal cancer. These cells were not observed in healthy subjects. We show that the primary epithelial tumors were characterized by similar complex aneuploidy, indicating conversion to an EMT phenotype in the captured cells. Collectively, our study provides a new method for highly efficient capture of previously unrecognized populations of CTCs. Significance: Current assays for CTC capture likely miss populations of cells that have undergone EMT. Capture and study of CTCs that have undergone EMT would allow a better understanding of the mechanisms driving metastasis. Cancer Discovery; 1(7); 580–86. ©2011 AACR. This article is highlighted in the In This Issue feature, p. 539

Background. Little is known about the prevalence of human papillomavirus (HPV) infection in young adults in Asia.Methods. We invited female and male

Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment. Cancer Res; 71(18); 6030–9. ©2011 AACR.