The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy.
A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr)  = 50-79 ml min(-1) ], moderate [CLcr  = 30-49 ml min(-1) ], severe [CLcr <30 ml min(-1) ]).
Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m(-2) day(-1) , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m(-2) day(-1) for patients with moderate renal impairment (suggested dose 1.9 mg m(-2) day(-1) for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m(-2) day(-1) in this cohort.
Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.
© 2015 The British Pharmacological Society.

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The MAGE-A3 recombinant protein combined with AS15 immunostimulant (MAGE-A3 Cancer Immunotherapeutic) is under development by GlaxoSmithKline for the treatment of lung cancer and melanoma. We performed non-clinical safety studies evaluating potential local and systemic toxic effects induced by MAGE-A3 Cancer Immunotherapeutic in rabbits (study 1) and cynomolgus monkeys (study 2). Animals were allocated to two groups to receive a single (rabbits) or 25 repeated (every 2 weeks) injections (monkeys) of MAGE-A3 Cancer Immunotherapeutic (treatment groups) or saline (control groups). All rabbits were sacrificed 3 days post-injection and monkeys 3 days following last injection (3/5 per gender per group) or after a 3-month treatment-free period (2/5 per gender per group). Local and systemic reactions and MAGE-A3-specific immune responses (monkeys) were assessed. Macroscopic and microscopic (for rabbits, injection site only) post-mortem examinations were performed on all animals. No systemic toxicity or unscheduled mortalities were recorded. Single (rabbits) and repeated (monkeys; up to four times at the same site) injections were well tolerated. Following five to seven repeated injections, limb circumferences increased up to 26% (5 h post-injection), but returned to normal after 1-8 days. Three days after the last injection, enlargements of iliac, popliteal, axillary and inguinal lymph nodes, and increased incidence or severity of mononuclear inflammatory cell infiltrates was observed in injected muscles of treated monkeys. No treatment-related macroscopic findings were recorded after the treatment-free period. MAGE-A3-specific antibody and T-cell responses were raised in all treated monkeys, confirming test item exposure. Single or repeated intramuscular injections of MAGE-A3 Cancer Immunotherapeutic were well tolerated in rabbits and monkeys.
Copyright © 2014 GlaxoSmithKline Vaccines. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.

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Twenty-two patients with pathologically confirmed glioblastoma who had received concurrent CCRT with TMZ underwent conventional MRI including T1-weighted imaging(T1WI), T2-weighted imaging(T2WI), fluid attenuated inversion recovery(FLAIR)and contrast-enhanced T1WI(T1Ce). Five GLCM texture maps of contrast, energy, entropy, correlation and homogeneity were generated for each MRI series. Of the aforementioned 5 texture features, the most significant features were contrast and correlation on T2WI with areas under ROC curve of 0.883 and 0.892, respectively, and they had the same sensitivity of 75%, specificity of 100%, accuracy of 86.4%, PPV of 100% and NPV of 76.9% in differentiation true progression from pseudoprogression.
Copyright © 2015. Published by Elsevier Inc.

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The purpose of this study was to implement and evaluate the utility of a multi-echo sequence at 7 Tesla (T) for simultaneous time-of-flight (TOF) MR-angiography (MRA) and susceptibility-weighted imaging (SWI) of radiation-induced cerebral microbleeds (CMBs), intracranial arteries, and veins.
A four-echo gradient-echo sequence was implemented on a 7T scanner. The first echo was used to create TOF-MRA images, while the remaining echoes were combined to visualize CMBs and veins on SWI images. The sequence was evaluated on eight brain tumor patients with known radiation-induced CMBs. Single-echo images were also acquired to visually and quantitatively compare the contrast-to-noise ratio (CNR) of small- and intermediate-vessels between acquisitions. The number of CMBs detected with each acquisition was also quantified. Statistical significance was determined using a Wilcoxon signed-rank test.
Compared with the single-echo sequences, the CNR of small and intermediate arteries increased 7.6% (P < 0.03) and 9.5% (P = 0.06), respectively, while the CNR of small and intermediate veins were not statistically different between sequences (P = 0.95 and P = 0.46, respectively). However, these differences were not discernible by visual inspection. Also the multi-echo sequence detected 18.3% more CMBs (P < 0.008) due to higher slice resolution.
The proposed 7T multi-echo sequence depicts arteries, veins, and CMBs on a single image to facilitate quantitative evaluation of radiation-induced vascular injury.
© 2014 Wiley Periodicals, Inc.

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(129) Xe-blood NMR was performed over the full blood oxygenation range to evaluate (129) Xe relaxation and exchange dynamics in human blood.
Hyperpolarized (129) Xe was equilibrated with blood and isolated plasma, and NMR was performed at 1.5 T.
The (129) Xe relaxation rate was found to increase nonlinearly with decreasing blood oxygenation. Three constants were extrapolated: rsO2 =  11.1, a "relaxivity index" characterizing the rate of change of (129) Xe relaxation as a function of blood oxygenation, and 1/T1oHb  =  0.13 s(-1) and 1/T1dHb = 0.42 s(-1) , the (129) Xe relaxation rates in oxygenated blood and deoxygenated blood, respectively. In addition, rate constants, ka =  0.022 ms(-1) and kb =  0.062 ms(-1) , were determined for xenon diffusing between red blood cells (RBCs) and plasma (hematocrit  =  48%). The (129) Xe-O2 relaxivity in plasma, rO2 = 0.075 s(-1) mM(-1) , and the (129) Xe relaxation rate in isolated plasma (without dissolved O2 ), 1/T1,b0 = 0.046 s(-1) , were also calculated. Finally, intrinsic (129) Xe-RBC relaxation rates, 1/T1,aoHb = 0.19 s(-1) and 1/T1,adHb = 0.84 s(-1) , in oxygenated blood and deoxygenated blood, respectively, were calculated.
The relaxation and exchange analysis performed in this study should provide a sound experimental basis upon which to design future MR experiments for dissolved xenon transport from the lungs to distal tissues.
© 2014 Wiley Periodicals, Inc.

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