ABSTRACT
The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Female , Fusion Proteins, bcr-abl/genetics , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Pyrimidines/adverse effectsABSTRACT
BACKGROUND: Administration of certain chemotherapy drugs at the maximum tolerated dose, vascular-disrupting agents (VDAs) and irradiation can induce mobilisation and tumour homing of proangiogenic bone marrow-derived cells (BMDCs). Increases in cytokines and chemokines contribute to such mobilisation that eventually promotes tumour (re)growth. NGR-TNF is a vascular-targeting agent in advanced clinical development, coupling the CNGRCG angiogenic vessel-homing peptide with tumour necrosis factor-alpha (TNF). We investigated whether NGR-TNF mobilises host BMDCs and growth factors. METHODS: Blood was obtained from Lewis lung carcinoma and 4T1 tumour-bearing mice at different time points following NGR-TNF, VDA or anti-VEGFR2/flk-1 antibody treatment. Levels of circulating growth factors were assessed by ELISAs. BMDCs were characterised by FACS. Circulating endothelial progenitor cells were defined as CD45(-)/CD13(+)/flk-1(+)/CD117(+)/7AAD(-), Tie2-expressing monocytes as CD45(+)/CD11b(+)/Tie2(+) and myeloid-derived suppressor cells as CD45(+)/CD11b(+)/Gr1(+) cells. RESULTS: NGR-TNF decreases tumour blood vessel density-inducing apoptosis of tumour and tumour endothelial cells. Unlike VDAs, or high-dose NGR-TNF, lower doses of NGR-TNF, comparable to those used in clinical trials, neither mobilise nor recruit to the tumour site proangiogenic BMDCs or induce host growth factors. CONCLUSION: Low-dose NGR-TNF exerts antitumour activity without inducing proangiogenic host responses, conceivably important for preventing/overcoming resistance and designing combination therapeutic strategies.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Bone Marrow Cells/drug effects , Chemotaxis/drug effects , Cytokines/pharmacology , Molecular Targeted Therapy , Tumor Necrosis Factor-alpha/administration & dosage , Animals , Apoptosis/drug effects , Blood Vessels/drug effects , Bone Marrow Cells/pathology , Bone Marrow Cells/physiology , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology , Cell Line, Tumor , Cytokines/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neovascularization, Pathologic/pathologyABSTRACT
A 1-year study on the animal-level prevalence and concentration of Escherichia coli O157 in adult sheep at slaughter was performed, to collect qualitative and quantitative information on the diffusion of the pathogen in adult sheep from Italy. A total 533 samples were collected, with a similar distribution in the four seasons. For prevalence estimates, a simple random sampling technique was used. An immuno-magnetic separation technique was used for sample screening, with enumeration of the pathogen in positive samples, along with molecular and serological identification of isolates. An overall prevalence of 7.1% (38/ 533, 95% CI 4.9-9.3%) was observed for fully virulent E. coli O157. A wide interval of VTEC O157 per gram was observed (< 100 to 6 x 10(5) CFU g(-1)), with 28.9% (11/38) of positive samples > or = 1 x 10(3) CFU g(-1), set as the threshold for those animals defined 'active shedders' for the purpose of the study. Eight per cent (3/38) of animals shed > 1 x 10(4) g(-1) VTEC O157, which represents > 96% of the total VTEC O157 bacteria cultured from all animals tested. The prevalence estimate of active shedders was therefore 2.1% (95% CI 0.9-3.3%). Most (34/38, 89.5%) of the positive animals were found in summer (July-September). Prevalence and concentrations of virulent VTEC O157 obtained in this study contribute to the demonstration that adult sheep represent a relevant source of environmental contamination from virulent VTEC O157, as well as a source of VTEC O157 contamination for food of ovine origin (meat and dairy products), especially during warm months.