No abstract

Osteopontin is a secreted phosphoprotein that has been implicated as an important mediator of tumor metastasis and has been investigated for use as a biomarker for advanced disease and as a potential therapeutic target in the regulation of cancer metastasis. The OPN DNA sequence is highly conserved and the protein contains several important functional domains including alpha(v)beta integrin and CD44 binding sites. High levels of OPN expression correlate with tumor invasion, progression or metastasis in multiple cancer. Studies demonstrate that osteopontin mediates the molecular mechanisms which determine metastatic spread, such as prevention of apoptosis, extracellular matrix proteolysis and remodeling, cell migration, evasion of host-immune cells and neovascularization. Transcriptional regulation of OPN is complex and involves multiple pathways, including AP-1, Myc, v-Src, Runx/CBF, TGF-B/BMPs/Smad/Hox, and Wnt/ss-catenin/APC/GSK-3ss/Tcf-4. The current state of knowledge of OPN biology suggests that it is an attractive target for therapeutic modulation of metastatic disease.

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

The Delta(4) diode array phantom (Scandidos, Uppsala, Sweden) was evaluated for verification of segmental intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) on an Elekta linear accelerator (Crawley UK). The device was tested for angular sensitivity by irradiating it from 36 different gantry angles, and the responses of the device to various step-and-shoot segment doses and dose rates were evaluated using an ionization chamber as a comparison. The phantom was then compared with ionization chamber and film results for two prostate and pelvic nodes IMRT plans, two head and neck IMRT plans and two lung VMAT plans. These plans were calculated using Pinnacle(3) (Philips Radiation Oncology Systems, Madison, WI). The uniformity of angular response was better than 0.5% over the range of gantry angles. The uniformity of response of the Delta(4) to different segment monitor units and dose rates was better than 0.5%. The assessment of the IMRT and VMAT plans showed that the Delta(4) measured a dose within 2.5% of the ionization chamber, and compared to film recorded a slightly larger region (range -2% to +7%) agreeing with the planned dose to within 3% and 3 mm. The Delta(4) is a complex device and requires careful benchmarking, but following the successful completion of these measurements, the Delta(4) has been introduced into clinical use.