Influence of interface condition and implant design on bone remodelling and failure risk for the resurfaced femoral head.

Resurfacing of the femur has experienced a revival, particularly in younger and more active patients. The implant is generally cemented onto the reamed trabecular bone and theoretical remodelling for this configuration, as well as uncemented variations, has been studied with relation to component positioning for the most common designs. The purpose of this study was to investigate the influence of different interface conditions, for alternative interior implant geometries, on bone strains in comparison to the native femur, and its consequent remodelling. A cylindrical interior geometry, two conical geometries and a spherical cortex-preserving design were compared with a standard implant (ASR, DePuy International, Ltd., UK), which has a 3° cone. Cemented as well as uncemented line to line and press-fit conditions were modelled for each geometry. A patient-specific finite element model of the proximal femur was used with simulated walking loads. Strain energy density was compared between the reference and resurfaced femur, and input into a remodelling algorithm to predict density changes post-operatively. The common cemented designs (cylindrical, slightly conical) had strain shielding in the superior femoral head (>35% reduction) as well as strain concentrations (strain>5%) in the neck regions near the implant rim. The cortex-preserving (spherical) and strongly conical designs showed less strain shielding. In contrast to the cemented implants, line to line implants showed a density decrease at the centre of the femoral head, while all press-fit versions showed a density increase (>100%) relative to the native femur, which suggests that uncemented press-fit implants could limit bone resorption.

Integrin alpha2 mediates selective metastasis to the liver.

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells.

The liver represents a major and frequently sole site of metastases for many types of cancer, particularly gastrointestinal cancers. We showed previously that coadministration of an engineered hepatic-targeting Listeria monocytogenes (LM) with a cancer vaccine enhanced the antitumor effect of vaccine-induced T cells selectively against hepatic metastases. Here, we show that administration of multiple doses of LM, in the absence of vaccine, generates therapeutic responses against hepatic metastases. LM treatment of mice bearing hepatic metastases induced tumor-specific CD8+ T-cell responses that were enhanced by depletion of regulatory T (Treg) cells by either anti-CD25 or cyclophosphamide treatment. Antitumor activity of LM further depended on natural killer (NK) cell activation but was inhibited by presence of a subset of NK T cells. These results show the utility of LM in the treatment of hepatic metastases even in the absence of vaccine administration and further suggest that blockade of Treg cells and NK T cells will enhance antitumor activity.

Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes.

Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.