Background:Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.Methods:In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.Results:A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.Conclusions:These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.
Osteosarcoma is the most common primary malignant bone tumor. Patients often develop lung metastasis and have a poor prognosis despite extensive chemotherapy and surgical resections. Tissue Factor is associated with poor clinical outcome in a wide range of cancer types, and promotes angiogenesis and metastasis. The role of Tissue Factor in OS tumorigenesis is unknown. 53 osteosarcoma pre-treatment biopsies and four osteosarcoma cell lines were evaluated for Tissue Factor expression, and a possible association with clinical parameters was investigated. Tissue Factor function was inhibited in an osteosarcoma cell line (143B) by shRNA knockdown or specific antibodies, and pro-tumorigenic gene expression, proliferation, matrigel invasion and transwell migration was examined. 143B cells were implanted in mice in the presence of Tissue Factor-blocking antibodies, and tumor volume, micro-vessel density and metastases in the lung were evaluated. Tissue Factor was highly expressed in 73.6% of osteosarcoma biopsies, and expression associated significantly with disease-free survival. Tissue Factor was expressed in all four investigated cell lines. Tissue Factor was knocked down in 143B cells, which led to reduced expression of IL-8, CXCL-1, SNAIL and MMP2, but not MMP9. Tissue Factor knockdown or inhibition with antibodies reduced matrigel invasion. Tissue Factor antibodies limited 143B tumor growth in vivo, and resulted in decreased intra-tumoral micro-vessel density. Furthermore, lung metastasis from the primary tumor was significantly reduced. Thus, Tissue Factor expression in osteosarcoma reduces metastasis-free survival in patients, and increases pro-tumorigenic behavior both in vitro and in vivo.
Imatinib has a mild toxicity prole, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained signicant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benet from intensied follow-up.
BackgroundTrabectedin has shown efficacy against soft tissue sarcomas (STS) and has manageable toxicity. Trabectedin is administered through central venous access devices (VAD), such as subcutaneous ports with tunneled catheters, Hickman catheters and PICC lines. Venous access related adverse events are common, but have not yet been reported in detail.MethodsA retrospective analysis of patient files of STS patients receiving trabectedin monotherapy between 1999 and 2014 was performed in all five STS referral centers in the Netherlands. This survey focused on adverse events related to the VAD and the actions taken in response to these events.ResultsIn the 127 patients included in this analysis, 102 venous access ports (VAP), 15 Hickman catheters and 10 PICC lines were used as primary means of central venous access. The most frequently reported adverse events at the VAD site were erythema (30.7%), pain (28.3%), inflammation (11.8%) and thrombosis (11.0%). Actions taken towards these adverse events include oral antibiotics (17.3%), VAD replacement (15.0%) or a wait-and-see policy (13.4%). In total, 45 patients (35.4%) with a subcutaneous port developed a varying degree of inflammation along the trajectory of the tunneled catheter. In all but three patients, this was a sterile inflammation, which was considered a unique phenomenon for trabectedin. Microscopic leakage of trabectedin along the venous access device and catheter was considered the most plausible cause for this adverse event. Placing the catheter deeper under the skin resolved the issue almost completely.ConclusionTrabectedin infusion commonly leads to central venous access related adverse events. Sterile inflammation along the catheter trajectory is one of the most common adverse events and can be prevented by placing the catheter deeper under the skin.
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