This is quite an innovative study that should lead to a multicentre validation trial. We have developed an FDG-PET/MRI texture-based model for the prediction of lung metastases (LM) in newly diagnosed patients with soft-tissue sarcomas (STSs) using retrospective analysis. In this work, we assess the model performance using a new prospective STS cohort. We also investigate whether incorporating hypoxia and perfusion biomarkers derived from FMISO-PET and DCE-MRI scans can further enhance the predictive power of the model. A total of 66 patients with histologically confirmed STSs were used in this study and divided into two groups: a retrospective cohort of 51 patients (19 LM) used for training the model, and a prospective cohort of 15 patients (two patients with LM, one patient with bone metastases and suspicious lung nodules) for testing the model. In the training phase, a model of four texture features characterising tumour sub-region size and intensity heterogeneities was developed for LM prediction from pre-treatment FDG-PET and MRI scans (T1-weighted, T2-weighted with fat saturation) of the retrospective cohort, using imbalance-adjusted bootstrap statistical resampling and logistic regression multivariable modeling. In the testing phase, this multivariable model was applied to predict the distant metastasis status of the prospective cohort. The predictive power of the obtained model response was assessed using the area under the receiver-operating characteristic curve (AUC). In the exploratory phase of the study, we extracted two heterogeneity metrics from the prospective cohort: the area under the intensity-volume histogram of pre-treatment DCE-MRI volume transfer constant parametric maps and FMISO-PET hypoxia maps (AU-IVH-Ktrans, AU-IVH-FMISO). The impact of the addition of these two individual metrics to the texture-based model response obtained in the testing phase was first investigated using Spearman's correlation (rs), and lastly using logistic regression and leave-one-out cross-validation (LOO-CV) to account for overfitting bias. First, the texture-based model reached an AUC of 0.94, a sensitivity of 1, a specificity of 0.83 and an accuracy of 0.87 when tested in the prospective cohort. In the exploratory phase, the addition of AU-IVH-FMISO did not improve predictive power, yielding a correlation of rs = −0.42 (p = 0.12) with lung metastases, and a relative change in validation AUC of 0% in comparison with the texture-based model response alone in LOO-CV experiments. In contrast, the addition of AU-IVH-Ktrans improved predictive power, yielding a correlation of rs = −0.54 (p = 0.04) with lung metastases, and a change in validation AUC of +10%. Our results demonstrate that texture-based models extracted from pre-treatment FDG-PET and MRI anatomical scans could be successfully used to predict distant metastases in STS cancer. Our results also suggest that the addition of perfusion heterogeneity metrics may contribute to improving model prediction performance.
The effect of conditioned media from implant revision membranes on tartrate resistant acid phosphatase (TRAP) secretion following PE exposure was investigated. Human Monocytes were cultured on PE/collagen coverslips, and 50 uls of culture media, conditioned media from implant revision membranes, or conditioned media from synovium was added. Cultured media were collected, and analyzed for TRAP activity. Statistical analysis showed significantly greater release of TRAP in the media with the supplement of the conditioned media from implant revision membranes, indicating that the unknown factors in the conditioned media could accelerate monocyte-macrophage TRAP secretion. Identifying and blocking of the factors would be beneficial for long-term implant performance. The purpose of this study was to investigate the effect of conditioned media from implant revision membranes on monocyte-macrophage tartrate resistant acid phosphatase (TRAP) secretion. Conditioned media from implant revision membranes significantly enhanced monocyte-macrophage TRAP secretion following PE exposure Since TRAP has been related to bone resorption, identifying and blocking factors stimulating monocyte-macrophage TRAP section would be beneficial for preventing peri-implant bone resorption. Monocytes isolated from human blood were cultured on PE/collagen coverslips, and 50 uls of fresh culture media, conditioned media from implant revision membrane, or conditioned media from synovium was added at time zero, day two and four. Cultured media were collected at day two, four and six, and analyzed for TRAP activity. As previously reported the conditioned media from the revision membranes contained TRAP activity greater than synovial membranes. Therefore the accumulative TRAP activity after culturing macrophages with PE was corrected by subtracting TRAP activity measured in the conditioned media prior to DNA normalization. Statistical analysis showed significantly greater release of TRAP in media with addition of the conditioned media from implant revision membrane when compared with either conditioned media from synovium or fresh culture media (p<
0.01, n=3). This result indicates that certain unknown soluble factors in the conditioned media from implant revision membrane could accelerate monocyte-macrophage TRAP secretion. Since TRAP enzyme has been related to bone resorption, greater TRAP secretion could lead to peri-implant osteolysis and subsequent implant loosening. Identifying and blocking of those factors would be ultimately beneficial for implant long-term clinical performance.
The blocking effects of anti-inflammatory cytokines and osteoprotergerin (OPG) on tartrate resistant acid phosphatase (TRAP) synthesis by monocyte-macrophages (MDMs) were investigated. Human Monocytes were cultured on PE/collagen coverslips supplemented with 50 mL of conditioned media from implant revision membranes, and anti-IL-6, anti-TNF- or OPG was added. Cultured media were collected and the cells were lysed. Both the cell releasates and lysates were analyzed for TRAP activity. Statistical analysis showed significantly inhibition of TRAP with addition of anti-IL-6 or anti-TNF-, but no inhibition was seen with addition of OPG. Blocking of TRAP with anti-inflammatory cytokines could provide a potential therapeutic method of preventing TRAP-associated peri-prosthesis osteolysis. To investigate the blocking effects of anti-inflammatory cytokines and osteoprotergerin (OPG) on monocyte-macrophage tartrate resistant acid phosphatase (TRAP) syhthesis. Either anti-IL-6 or anti-TNF- significantly inhibits monocyte-macrophage TRAP synthesis in vitro. Since TRAP has been related to bone resorption, blocking monocyte-macrophage TRAP synthesis would be beneficial for preventing peri-prosthesis osteolysis. Monocyte isolations were performed using blood from healthy donors. The isolated monocytes were cultured in triplicate on PE/collagen coverslips supplemented with 50 uls of fresh culture media or conditioned media from implant revision membrane. Anti-IL-6, anti-TNF-, or OPG at a concentration of 2 μg/mL was added at time zero, day two and four. The culture media were completely replaced with no addition at twenty-four hours prior to termination at day seven. On the terminating day, conditioned media were collected and the cells were lysed. Both the cell lysates and releasates were analyzed for TRAP activity, and the cell lysates were also assayed for DNA contents. The TRAP activity measured was normalized to the DNA contents. Statistical analysis showed significantly inhibition of TRAP with addition of anti-IL-6 (p<
0.01, n=3) or anti-TNF- (p<
0.01, n=3), but no inhibition was seen with addition of OPG. TRAP is believed to be mainly secreted by monocyte-macrophages and osteoclasts and associated with bone resorption. Therefore, these results suggest that the peri-prosthesis osteolysis be unlikely via the OPG-OPGL osteoclast activation axis, but possibly through the inflammatory cytokine pathway. Blocking of TRAP with anti-inflammatory cytokines could provide a potential therapeutic method of preventing peri-prosthesis osteolysis.
