Does the onset of bone metastasis in sunitinib-treated renal cell carcinoma patients impact the overall survival?

PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4-26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.

Increased amounts of von Willebrand factor are bound to microparticles after infusion of desmopressin.

Effects of desmopressin (DDAVP) in platelet disorders and primary haemostasis cannot be attributed solely to the increase in FVIII/VWF (von Willebrand factor), as VWF/FVIII concentrates have no effect in these circumstances. Microparticles (MP) can support haemostasis by expression of phospholipids, tissue factor and VWF on their surface. We hypothesized that significant amounts of VWF are bound to MP after DDAVP administration and that consequently depletion of MP should influence VWF:Ag and VWF:RCo plasma levels. Platelet-poor plasma was either obtained well from healthy controls or before and after DDAVP administration from patients with von Willebrand's disease (type 1 or possible type 1) or patients with other bleeding disorders as controls. Concentrations of MP and VWF parameters were determined before and after MP depletion by different methods (magnetic bead selection, plasma microfiltration, ultracentrifugation). Platelet MP and VWF-bearing MP were significantly increased after DDAVP. MP depletion by magnetic bead selection led to a significant reduction in VWF:Ag (-18.0%) and VWF:RCo (-27.7%) plasma levels without changes in VWF multimer composition. As results were similar for DDAVP control subjects, the amount of VWF bound to circulating microparticles was significantly higher after DDAVP administration compared with healthy controls (reduction -11.7%). DDAVP leads to a release of microparticles and increases the amount of VWF bound to microparticles which might explain the clinical efficacy of DDAVP in platelet disorders.

Thrombelastographic monitoring of recombinant factor VIIa in acquired haemophilia.

Monitoring of the global haemostatic capacity is desired to optimize the treatment with bypassing agents in inhibitor patients. Thrombelastographic methods have been used in ex vivo studies and were suggested useful to evaluate the individual response to bypassing agents. This study aimed at assessing changes in thrombelastographic profiles and their association to clinical outcome in patients treated with recombinant factor VIIa (rFVIIa). Ten patients with acquired haemophilia were treated with rFVIIa for acute bleeding. Thrombelastography was performed after activation with a small amount of tissue factor in samples obtained before and after in vivo administration of rFVIIa. In patients studied before and after a first dose, correction of the thrombelastographic profile was observed but did not predict cessation of bleeding. During steady-state dosing, the median Alpha angle tended to be higher in patients with a good clinical treatment response as compared with patients with a partial or poor response. Similar trends were observed for clotting time and clot formation time. A good clinical treatment response was more frequent in patients with a fully corrected trough-level thrombelastographic profile as compared with patients with an abnormal profile. However, a poor treatment response was observed also in a surgical patient with a normal thrombelastographic profile during steady-state dosing. In conclusion, thrombelastographic monitoring was sensitive to haemostatic changes in response to treatment with rFVIIa. In the limited number of patients studied here, a better clotting profile during steady-state dosing was associated with a better clinical treatment response.

Competitive cytokeratin 19 RT-PCR for quantification of breast cancer cells in blood cell suspensions.

Detection of residual tumor cells in BM and PBPC products has been correlated with worse outcome of breast cancer patients. Still, there is a considerable demand for studies investigating the influence of the actual tumor cell number on prognosis, as quantification routinely has been cumbersome and time consuming and, thus, was evaded. We developed and evaluated a competitive RT-PCR-ELISA assay for cytokeratin 19 (CK19) with standard curve quantification that allows quantification of multiple samples within a working day; mRNA isolation, RT-PCR reaction, and automated ELISA detection were carried out using commercial kits. Results were expressed as OD420nm ratios of CK19 and an internal competitor. Values were then converted into tumor cell numbers using a standard curve of MCF-7 tumor cells. The assay had high specificity because of primers and capture probes with great heterogeneity to both published pseudogenes, which was confirmed by BLAST sequence alignment. We achieved a sensitivity of detecting 1 tumor cell per 10(6) mononuclear cells (MNC). Between-batch precision (n = 8) for quantification was consistent and reasonable, with a coefficient of variation around 25%. Therefore, this assay should be suitable and sufficient for routine quantification of tumor cell numbers in BM or PBPC samples.