The purpose of this study was to determine the reproducibility of dynamic contrast-enhanced (DCE)-MRI and compare quantitative kinetic parameters with semi-quantitative methods, and whole region-of-interest (ROI) with pixel analysis. Twenty-one patients with a range of tumour types underwent paired MRI examinations within a week, of which 16 pairs were evaluable. A proton density-weighted image was obtained prior to a dynamic series of 30 T 1 -weighted spoiled gradient echo images every 11.9 s with an intravenous bolus of gadopentetate dimeglumine given after the third baseline data point. Identical ROIs around the whole tumour and in skeletal muscle were drawn by the same observer on each pair of examinations and used for the reproducibility analysis. Semiquantitative parameters, gradient, enhancement and AUC (area under the curve) were derived from tissue enhancement curves. Quantitative parameters (K trans , k ep , v e ) were obtained by the application of the Tofts' model. Analysis was performed on data averaged across the whole ROI and on the median value from individual pixels within the ROI. No parameter showed a significant change between examinations. For all parameters except K trans , the variability was not dependent on the parameter value, so the absolute values for the size of changes needed for significance should be used for future reference rather than percentages. The size of change needed for significance in a group of 16 in tumours for K trans , k ep and v e was À14 to 16%, AE0.20 ml/ml/min (15%) and AE1.9 ml/ml (6%), respectively (pixel analysis), and À16 to 19%, AE0.23 ml/ml/min (16%) and AE1.9 ml/ml (6%) (whole ROI analysis). For a single tumour, changes greater than À45 to 83%, AE 0.78 ml/ml/min (60%) and AE 7.6 ml/ml (24%), respectively, would be significant (pixel analysis). For gradient, enhancement and AUC the size of change needed for significance in tumours was AE0.24 (17%), AE0.05 (6%) and AE0.06 (8%), respectively for a group of 16 (pixel analysis), and AE0.96 (68%), AE0.20 (25%) and AE0.22 (32%) for individuals. In muscle, the size of change needed for significance in a group of 16 for K trans , k ep and v e was À30 to 44%, AE0.81 ml/ml/min (61%) and AE1.7 ml/ml (13%). For gradient, enhancement and AUC it was AE0.09 (20%), AE0.02 (8%) and AE0.03 (12%). v e , enhancement and AUC are highly reproducible DCE-MRI parameters. K trans , k ep and gradient have greater variability, with larger changes in individuals required to be statistically significant, but are nevertheless sufficiently reproducible to detect changes greater than 14-17% in a cohort of 16 patients. Pixel analyses slightly improve reproducibility estimates and retain information about spatial heterogeneity. Reproducibility studies are recommended when treatment effects are being monitored.

CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.

CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

18 F-FDG PET is often used to monitor tumor response in multicenter oncology clinical trials. This study assessed the repeatability of several semiquantitative standardized uptake values (mean SUV [SUV mean ], maximum SUV [SUV max ], peak SUV [SUV peak ], and the 3-dimensional isocontour at 70% of the maximum pixel value [SUV 70% ]) as measured by repeated baseline 18 F-FDG PET studies in a multicenter phase I oncology trial. Methods: Double-baseline 18 F-FDG PET studies were acquired for 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUV mean , SUV max , SUV peak , and SUV 70% . The effect on SUV repeatability of compliance with recommended image-acquisition guidelines and quality assurance (QA) standards was assessed. Summary statistics for absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients and for a subgroup that passed QA, in both a multi-and a single-observer setting. Intrasubject precision of baseline measurements was assessed by repeatability coefficients, intrasubject coefficients of variation (CV), and confidence intervals on mean baseline differences for all SUV parameters. Results: The mean differences between the 2 SUV baseline measurements were small, varying from 22.1% to 1.9%, and the 95% confidence intervals for these mean differences had a maximum half-width of about 5.6% across the SUV parameters assessed. For SUV max , the intrasubject CV varied from 10.7% to 12.8% for the QA multiand single-observer datasets and was 16% for the full dataset. The 95% repeatability coefficients ranged from 228.4% to 39.6% for the QA datasets and up to 234.3% to 52.3% for the full dataset. Conclusion: Repeatability results of doublebaseline 18 F-FDG PET scans were similar for all SUV parameters assessed, for both the full and the QA datasets, in both the multi-and the single-observer settings. Centralized quality assurance and analysis of data improved intrasubject CV from 15.9% to 10.7% for averaged SUV max . Thresholds for metabolic response in the multicenter multiobserver non-QA settings were 234% and 52% and in the range of 226% to 39% with centralized QA. These results support the use of 18 F-FDG PET for tumor assessment in multicenter oncology clinical trials. PET,wi th the tracer 18 F-FDG, is used for tumor detection, staging, and follow-up studies for multiple neoplasms (1) and is increasingly becoming an integral part of multicenter clinical trials in oncology for the assessment of treatment effect. Accurate quantitative assessment of response as measured by changes in standardized uptake value (SUV) parameters over the course of treatment serves as an early surrogate for clinical benefit and facilitates drug development in oncology (2).For the accurate assessment of tumor response using 18 F-FDG PET, it is crucial to know the intrasubject variation in the measurement of semiquantitative parameters before the initiation of treatment (3). This study focused on the repeatability of 18 F-FDG PET in a mul...

SPRYCEL (dasatinib; Bristol-Myers Squibb, Princeton, NJ) is a multiple kinase inhibitor that potently inhibits Bcr-Abl, Src family (Src, Lck, Yes, Fyn), c-Kit, EPHA2, and platelet-derived growth factor receptor ␤ kinases (Lombardo et al., 2004;Shah et al., 2004;Das et al., 2006). It is currently approved in the United States and European Union to treat chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec, Novartis, Basel, Switzerland). Unlike imatinib mesylate, which binds to the closed confirmation of Bcr-Abl kinase, dasatinib was designed to bind to both the open and closed form of the enzyme (Shah et al., 2004;Tokarski et al., 2006). Because of this binding property and the ability to inhibit multiple kinases, including Src, dasatinib is effective in tumors that are resistant to imatinib mesylate (O'Hare et al., 2005;Schittenhelm et al., 2006). Clinical studies have shown that dasatinib shows clinical response in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate treatment Hochhaus et al., 2006;Talpaz et al., 2006;Quintas-Cardama et al., 2007).Numerous in vitro and in vivo studies have been conducted with dasatinib in nonclinical species to understand its absorption, distribution, metabolism, and excretion (ADME) properties and gauge the suitability of these species as toxicological models Kamath et al., 2008). The metabolic profiles from in vitro studies in liver microsomes, and hepatocytes showed good correlation with the in vivo profiles generated after a single p.o. dose of [14 C]dasatinib to rats and monkeys. The primary metabolites of dasatinib Article, publication date, and citation information can be found at

DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.

The purpose of this phase I, dose-escalation study was to determine the toxicity, maximum tolerated dose, pharmacokinetics, and pharmacodynamic end points of 5,6-dimethylxanthenone acetic acid (DMXAA). In all, 46 patients received a total of 247 infusions of DMXAA over 15 dose levels ranging from 6 to 4900 mg m À2 . The maximum tolerated dose was established at 3700 mg m À2 ; doselimiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg m À2 ). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 mM and 3.2 mM h, respectively, at 6 mg m À2 to 1290 mM and 7600 mM h at 3700 mg m À2 , while clearance declined from 7.4 to 1.7 l h À1 m À2 over the same dose range. The terminal half-life was 8.174.3 h. More than 99% of the drug was protein bound at doses up to 320 mg m À2 ; at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg m À2 . Dosedependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg m À2 and above. There was one unconfirmed partial response at 1300 mg m À2 . In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 10% to 13% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR) CD4 and CD8 T cells with concomitant decreases in naive CD4 and CD8 T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS CD4 T cells, but not in ICOS CD8 T cells or in FoxP3 CD4 regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.