EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma

The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7–9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90–110 mg/m²) and dasatinib (100–200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2–1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.     

Tumor treating fields: a novel treatment modality and its use in brain tumors

Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. This novel treatment modality has shown promise in a variety of tumor types. It has been evaluated in randomized phase 3 trials in glioblastoma (GBM) and demonstrated to prolong progression-free survival (PFS) and overall survival (OS) when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM. TTFields are continuously delivered by 4 transducer arrays consisting each of 9 insulated electrodes that are placed on the patient’s shaved scalp and connected to a portable device. Here we summarize the preclinical data and mechanism of action, the available clinical data, and further outlook of this treatment modality in brain tumors and other cancer indications.     

Capturing the stem cell paracrine effect using heparin‐presenting nanofibres to treat cardiovascular diseases

The mechanism for stem cell‐mediated improvement following acute myocardial infarction has been actively debated. We support hypotheses that the stem cell effect is primarily paracrine factor‐linked. We used a heparin‐presenting injectable nanofibre network to bind and deliver paracrine factors derived from hypoxic conditioned stem cell media to mimic this stem cell paracrine effect. Our self‐assembling peptide nanofibres presenting heparin were capable of binding paracrine factors from a medium phase. When these factor‐loaded materials were injected into the heart following coronary artery ligation in a mouse ischaemia‐reperfusion model of acute myocardial infarction, we found significant preservation of haemodynamic function. Through media manipulation, we were able to determine that crucial factors are primarily < 30 kDa and primarily heparin‐binding. Using recombinant VEGF‐ and bFGF‐loaded nanofibre networks, the effect observed with conditioned media was recapitulated. When evaluated in another disease model, a chronic rat ischaemic hind limb, our factor‐loaded materials contributed to extensive limb revascularization. These experiments demonstrate the potency of the paracrine effect associated with stem cell therapies and the potential of a biomaterial to bind and deliver these factors, pointing to a potential therapy based on synthetic materials and recombinant factors as an acellular therapy. Copyright © 2010 John Wiley & Sons, Ltd.     

Do statins,ACE inhibitors or sartans improve outcome in primary glioblastoma?

The prognosis of the association between Breast Cancer (BC) and Meningioma (M) is unknown. To evaluate the survival impact of tumor exposure sequence in patients with both tumors. Patients were divided in groups according to the tumors sequence: BC before M (group 1), synchronous BC?+?M (group 2) and BC after M (group 3). The SEER database was used. Demographics, meningioma and breast cancer variables were analyzed. The primary outcome was oncological survival. A total of 1715 patients were included (median follow-up:84 months). Group 2 had the shortest survival (median:32 months) and group 1 the longest (median:110 months). On the unadjusted analysis, group 2 had the shortest survival (HR:3.13, 95% CI 1.62–6.04) and adjusted analysis confirmed this finding (HR 3.11, 95% CI 1.58–6.19), with no statistical difference between the metachronous tumors groups. Increasing age (HR:1.13, 95% CI 1.11–1.15, p?<?0.005) and grade III meningioma (HR:4.51, 95% CI 1.90–10.69, p?<?0.005) were related with lower survival. Meningioma treatment had no influence on the survival (p?>?0.05). The association between surgery and radiotherapy in BC treatment improved the outcome (HR 0.37, 95% CI 0.23–0.93, p?<?0.05). Grade III meningioma and receptor hormonal status influenced synchronous tumors (p?<?0.05) but had no influence on metachronous tumors survival (p?>?0.05) on stratified analysis. Synchronous tumors were associated with lower survival. Increasing age had a negative influence on patient survival. Although surgery and radiotherapy for breast cancer had a positive influence in the outcome, meningioma treatment was not related with survival. Grade III meningioma and hormonal receptor status only influenced synchronous tumors patient survival.