Rationale and objectivesDenosumab is a monoclonal antibody used neo-adjuvantly in giant cell tumor of bone (GCTB) to facilitate surgery, or long term for axial tumors where surgery comes with high... Show moreRationale and objectivesDenosumab is a monoclonal antibody used neo-adjuvantly in giant cell tumor of bone (GCTB) to facilitate surgery, or long term for axial tumors where surgery comes with high morbidity. Time intervals for treatment effects to occur are unclear and monitoring tools are limited, complicating optimal drug dose titration. We assessed changes in time intensity curve (TIC) - derived perfusion features on DCE-MRI in GCTB during denosumab treatment and evaluated the duration of treatment effects on tumor perfusion.Materials and methodsPatients with GCTB who underwent dynamic contrast enhanced (DCE) MRI before (t = 0) and after 3 (t = 3), 6 (t = 6) or 12 (t = 12) months of denosumab treatment were retrospectively included in a single center. Regions of interest were placed on tumor compartments with visually most intense enhancement and TICs were created. Time-to-enhancement (TTE), wash-in rate (WIR), maximal relative enhancement (MRE), and area-under-the-curve (AUC) were calculated. Differences in perfusion features were calculated with the Wilcoxon signed-rank test.ResultsIn all 24 patients decreased perfusion on DCE-MRI after start of denosumab treatment was seen. TTE increased between t = 0 and t = 3 (p < 0.001). WIR, MRE and AUC decreased between t = 0 and t = 3 (p < 0.001, p = 0.01 and p = 0.02, respectively). No significant differences in features were found between t = 3 and t = 6 or t = 6 and t = 12. No significant perfusion differences in primary versus recurrent, or axial versus appendicular tumors, were found.ConclusionMRI perfusion significantly changed in GCTB within 3 months of denosumab treatment compared to baseline. No further significant change occurred between 3 and 6, and 6 and 12 months of treatment. These findings suggest that evaluation of treatment response and subsequent consideration of maintenance with lower doses of denosumab, may already be indicated after 3 months. In cases where long term denosumab is the preferred therapy, monitoring change in tumor characteristics on DCE-MRI may aid optimal drug dose titration, minimizing side effects. Show less
After successful renal transplantation a gradual decline of renal function can be detected about 40 % of the transplant recipients. The histological substrate for this condition is chronic... Show moreAfter successful renal transplantation a gradual decline of renal function can be detected about 40 % of the transplant recipients. The histological substrate for this condition is chronic allograft nephropathy (CAN). Nephrotoxicity of immunosuppressive drugs and rejection mechanisms, due to insufficient immunosuppression, are known to play a central role in this process. In this thesis we focus on the improvement of drug monitoring of calcineurin-inhibitors, to prevent structural damage imposed by rejection mechanisms or drug-related nephrotoxicity. With the use of a population based, pharmacokinetic computer program, we developed a simple model to estimate the systemic exposure of cyclosporine and tacrolimus and we prospectively tested the model in a cohort of patients, to detect pharmacokinetic changes over time and to define optimal monitoring intervals. The model was used to guide drug dosing for 126 renal transplant recipients, included in a trial to compare the early development of CAN in patients randomized to either Cyclosporine- or Tacrolimus-based immunosuppresion. As primary read-out for this trial we obtained surveillance biopsies at 6 and 12 months, in which interstitial fibrosis was evaluated by quantitative digital analysis of Sirius red staining. Finally, we investigated the clinical relevance of the presence of subclinical rejection in these biopsies. Show less
