Characterization of Indeterminate Breast Lesions Based on Pressure Estimates by Noninvasive 3D Contrast-Enhanced Ultrasound.

OBJECTIVE: To assess the ability of the pressure gradient between breast lesions and adjacent normal tissue estimated by 3D subharmonic-aided pressure estimation (SHAPE) to characterize indeterminate breast lesions. METHODS: This prospective study enrolled patients scheduled for ultrasound-guided needle biopsies of a breast lesion. Before the biopsy, 3D SHAPE data were collected from the breast lesion during the infusion of an ultrasound contrast agent (Definity) as well as after clearance of the agent. Direct, invasive pressure measurements in the lesion and adjacent normal tissue were then obtained using an intracompartmental pressure monitoring system (C2DX) before tissue sampling as part of the biopsy procedure. The mean SHAPE gradient and invasive measurement gradient between the lesion and adjacent normal tissue were compared to the biopsy results. The SHAPE gradients were also compared to the invasive pressure gradients. RESULTS: There were 8 malignant and 13 benign lesions studied. The SHAPE gradients and invasive pressure gradients were significantly different between the benign and malignant lesions (2.86 ± 3.24 vs. -0.03 ± 1.72 a.u.; p = 0.03 and 9.9 ± 8.5 vs. 20.9 ± 8.0 mmHg; p = 0.008, respectively). The area under the curves, specificities, and sensitivities for detecting malignancy by SHAPE gradients and invasive pressure gradients were 0.79 and 0.88, 77% and 92%, and 88% and 50%, respectively. A weak negative correlation was found between the SHAPE and invasive pressure gradients (r = -0.2). CONCLUSION: The pressure gradient between a breast lesion and adjacent normal tissue estimated by 3D SHAPE shows potential for characterizing indeterminate breast lesions.

DR5 activation of caspase-8 induces DC maturation and immune enhancement in vivo.

Non-homeostatic tissue apoptosis in vivo has been shown to induce inflammatory responses and facilitate the cross-presentation of proteins within apoptotic bodies. We hypothesize that in the presence of foreign antigens, the apoptotic-inflammatory process improves immune priming; further, molecules that trigger apoptosis may be adapted for use as immune adjuvants. One very attractive molecule in this context is the tumor necrosis factor receptor (TNFR) family molecule DR5/TRAIL-receptor 2. We show a significant improvement in CD8(+) T-cell mediated vaccine immunity with the use of death receptor-5 (DR5) as an immune adjuvant, a property that is correlated with the activation of caspases-8 (casp8) and dependent on its ability to induce apoptosis in vivo.

Co-immunization with plasmid IL-12 generates a strong T-cell memory response in mice.

Plasmid encoded exogenous IL-12 delivered as a DNA vaccine adjuvant has been shown to improve vaccine-induced immunity. In particular, pIL-12 greatly improves antigen (Ag)-specific cytotoxic tlymphocyte (CTL) activity in immunized mice. The longevity of this response has not previously been studied in detail. We have studied the effect of co-immunization with pIL-12 on HIV gp160 and Influenza A Hemeagglutinnin-specific memory immune responses. Mice co-immunized with pIL-12 and plasmid encoded antigens maintained a greater memory response than those immunized with the plasmid antigen alone which could be measured at least 6 months after vaccination. Further, this translated to an improved outcome after challenge of long term rested mice that were previously immunized. The strength of the immune response as well as the number of Ag-specific T-cells is proportional to the number of Ag-specific cells primed by the vaccination regimen.

Engineering cross-presentation in vivo.

Apoptotic bodies deliver antigens (Ags) to the cross-presentation pathways of dendritic cells (DCs), where their presentation has been associated with both the maintenance of tolerance as well as the induction of protective immunity. The manner in which apoptotic bodies are generated, their abundance in relation to local DCs, and the milieu in which they are generated appear to be the major factors determining whether apoptotic bodies will induce CD8(+) T cell activation or anergy. These observations have been extended to the field of vaccination, where the engineered apoptosis of Ag-bearing/loaded cells in vivo has been used to prime strong CD8(+) T cell immunity. This review will examine Ag capture and cross-presentation by DCs, with particular emphasis on the manipulation of apoptotic bodies in vivo for the purpose of vaccination.