Objectives. The last decade has seen an increasing interest in the method of magnet resonance spectroscopy (MRS) since this is the only research tool that allows a non-invasive in vivo assessment of neurochemical aspects of ADHD without employing ionising radiation. In this paper we review published MRS results with respect to childhood, adolescence and adult ADHD. Method. We searched the Medline (Pub Med) database using the key words ADHD, attention-deficit/hyperactivity disorder, magnet resonance spectroscopy, MRS and spectroscopy. Citations of identified articles were also searched for relevant studies. Meta-analyses were performed for the measured metabolites and regions of assessment. Results. Sixteen studies could be identified that used MRS to investigate the neurobiology of ADHD. Two regions could be identified as the focus of spectroscopic investigations – the frontal lobe including anterior cingulate cortex and parts of prefrontal cortex and the basal ganglia, mostly striatum, alongside the fronto-striato-thalamo-frontal circuits. As for metabolites, in the majority of studies the ratios to creatine and not absolute concentrations of metabolites were estimated. Choline compounds, N-acetyl-aspartate and glutamate/glutamine (to creatine ratios) could be identified as being altered in several studies in ADHD. The meta-analysis showed increased choline compounds in several researched regions. Discussion. MRS is a promising tool for the non-invasive in vivo assessment of the cerebral neurochemistry in ADHD. More regions of interest (ROI) like amygdala, hippocampus, thalamus and cerebellum should be assessed in future studies. Further methodological improvements of MRS are desirable in order to assess the absolute metabolite concentration of several ROIs at the same time. Such developments will open novel perspectives in spectroscopic investigations of ADHD.

To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti–PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug’s activity. PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257

Background Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling pathways. In patients with advanced colorectal cancer and liver metastases, the effect of vandetanib on tumor vasculature was assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods Eligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC 60and K trans) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57. Results Twenty-two patients received vandetanib ( n= 10, 100 mg; n= 12, 300 mg). Baseline measurements of iAUC 60and K transwere reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Estimates of mean % changes from baseline were -3.4% (100 mg) and -4.6% (300 mg) for iAUC 60, and -4.6% (100 mg) and -2.7% (300 mg) for K trans; these changes were not significantly different between doses. The exploratory T2* measurement showed a significant increase at 300 mg versus 100 mg ( P= 0.006). Both doses of vandetanib were generally well tolerated; common toxicities were fatigue, rash and diarrhea (majority CTC grade 1 or 2). The pharmacokinetic profile of vandetanib was similar to that observed previously. There were no RECIST-defined objective responses; five patients experienced stable disease ≥8 weeks. Conclusion In this study in patients with advanced colorectal cancer, vandetanib did not modulate gadolinium uptake in tumor vasculature and tissue measured by the DCE-MRI parameters iAUC 60and K trans. Trial registration NCT00496509(ClinicalTrials.gov); D4200C00050 (AstraZeneca)