In vitro study to simulate the intracardiac magnetohydrodynamic effect.

PURPOSE: Blood flow causes induced voltages via the magnetohydrodynamic (MHD) effect distorting electrograms (EGMs) made during magnetic resonance imaging. To investigate the MHD effect in this context MHD voltages occurring inside the human heart were simulated in an in vitro model system inside a 1.5 T MR system. METHODS: The model was developed to produce MHD signals similar to those produced by intracardiac flow and to acquire them using standard clinical equipment. Additionally, a new approach to estimate MHD distortions on intracardiac electrograms is proposed based on the analytical calculation of the MHD signal from MR phase contrast data. RESULTS: The recorded MHD signals were similar in magnitude to intracardiac signals that would be measured by an electrogram of the left ventricle. The dependency of MHD signals on magnetic field strength and electrode separation was well reflected by an analytical model. MHD signals reconstructed from MR flow data were in excellent agreement with the MHD signal measured by clinical equipment. CONCLUSION: The in vitro model allows investigation of MHD effects on intracardiac electrograms. A phase contrast MR scan was successfully applied to characterize and estimate the MHD distortion on intracardiac signals allowing correction of these effects.

Improving the robustness of 3D turbo spin echo imaging to involuntary motion.

OBJECTIVE: 3D TSE imaging is very prone to motion artifacts, especially from uncooperative patients, because of the long scan duration. The need to repeat this time-consuming 3D acquisition in the event of large motion artifacts substantially reduces patient comfort and increases the workload of the scanner. MATERIALS AND METHODS: A new sampling strategy enables homogenized collection of k-space data for 3D TSE imaging. It is combined with Frobenius norm-based motion-detection to enable freely stopped acquisition in 3D TSE imaging whenever excessive subject motion is detected. RESULTS: The feasibility and reliability of the proposed method were demonstrated and evaluated in in-vivo experiments. CONCLUSION: It is shown that the additional overhead related to repeat scanning of the 3D TSE sequence as a result of patient motion can be substantially reduced by using the homogenized k-space sampling strategy with automatic scan completion as determined by Frobenius norm-based motion-detection.

An L1-norm phase constraint for half-Fourier compressed sensing in 3D MR imaging.

OBJECTIVE: In most half-Fourier imaging methods, explicit phase replacement is used. In combination with parallel imaging, or compressed sensing, half-Fourier reconstruction is usually performed in a separate step. The purpose of this paper is to report that integration of half-Fourier reconstruction into iterative reconstruction minimizes reconstruction errors. MATERIALS AND METHODS: The L1-norm phase constraint for half-Fourier imaging proposed in this work is compared with the L2-norm variant of the same algorithm, with several typical half-Fourier reconstruction methods. Half-Fourier imaging with the proposed phase constraint can be seamlessly combined with parallel imaging and compressed sensing to achieve high acceleration factors. RESULTS: In simulations and in in-vivo experiments half-Fourier imaging with the proposed L1-norm phase constraint enables superior performance both reconstruction of image details and with regard to robustness against phase estimation errors. CONCLUSION: The performance and feasibility of half-Fourier imaging with the proposed L1-norm phase constraint is reported. Its seamless combination with parallel imaging and compressed sensing enables use of greater acceleration in 3D MR imaging.

Incorporation of image data from a previous examination in 3D serial MR imaging.

OBJECT: We aimed to demonstrate that follow-up scans in longitudinal examinations can be significantly accelerated by using images from previous scans as priors for constrained reconstruction. MATERIALS AND METHODS: In this work, we propose a method for incorporating a prior image to improve the reconstruction of a new acquisition with considerable k-space undersampling, which contains a two-level registration scheme with non-parametric transformation, an adaptive synthesis procedure, and a constrained reconstruction with weighted total variation constraint. The performance of the method is evaluated using simulations, as well as results from volunteer and patient examinations. RESULTS: In vivo experiments with both volunteers and patients show that incorporating a prior image into the constrained reconstruction produces many fewer reconstruction errors compared to the conventional reconstruction using only the highly undersampled k-space data. CONCLUSION: The redundant information in the prior image can be efficiently adopted to improve the reconstruction quality of the new acquisition. When maintaining the image quality, higher acceleration can be achieved with the incorporation of the prior image.

Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis.

BACKGROUND: Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC). METHODS: Patients with advanced CRC who had failed conventional treatment, or for whom no therapy of proven efficacy existed, were treated with nintedanib ranging from 50-450 mg once-daily (n = 14) or 150-250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further courses were permitted in the absence of progression or undue toxicity. The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and expressed as the initial area under the DCE-MRI contrast agent concentration-time curve after 60 seconds (iAUC60) or the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans). RESULTS: Patients received a median of 4.0 courses (range: 1-13). Among 21 evaluable patients, 14 (67%) had a ≥40% reduction from baseline in Ktrans and 13 (62%) had a ≥40% decrease from baseline in iAUC60, representing clinically relevant effects on tumour blood flow and permeability, respectively. A ≥40% reduction from baseline in Ktrans was positively associated with non-progressive tumour status (Fisher's exact: p = 0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 (80%) achieved stable disease lasting ≥8 weeks. Time to tumour progression (TTP) at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 65-114). Common drug-related adverse events (AEs) included nausea (67%), vomiting (53%) and diarrhoea (40%); three patients experienced drug-related AEs ≥ grade 3. Four patients treated with nintedanib once-daily had an alanine aminotransferase and/or aspartate aminotransferase increase ≥ grade 3. No increases > grade 2 were seen in the twice-daily group. CONCLUSIONS: Nintedanib modulates tumour blood flow and permeability in patients with advanced, refractory CRC, while achieving antitumour activity and maintaining an acceptable safety profile.

Whole-body MRI-based fat quantification: a comparison to air displacement plethysmography.

PURPOSE: To demonstrate the feasibility of an algorithm for MRI whole-body quantification of internal and subcutaneous fat and quantitative comparison of total adipose tissue to air displacement plethysmography (ADP). MATERIALS AND METHODS: For comparison with ADP, whole-body MR data of 11 volunteers were obtained using a continuously moving table Dixon sequence. Resulting fat images were corrected for B1 related intensity inhomogeneities before fat segmentation. RESULTS: The performed MR measurements of the whole body provided a direct comparison to ADP measurements. The segmentation of subcutaneous and internal fat in the abdomen worked reliably with an accuracy of 98%. Depending on the underlying model for fat quantification, the resultant MR fat masses represent an upper and a lower limit for the true fat masses. In comparison to ADP, the results were in good agreement with ρ ≥ 0.97, P < 0.0001. CONCLUSION: Whole-body fat quantities derived noninvasively by using a continuously moving table Dixon acquisition were directly compared with ADP. The accuracy of the method and the high reproducibility of results indicate its potential for clinical applications.

FOLFIRI and sunitinib as first-line treatment in metastatic colorectal cancer patients with liver metastases--a CESAR phase II study including pharmacokinetic, biomarker, and imaging data.

BACKGROUND: The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. METHODS: mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal. RESULTS: 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. CONCLUSIONS: Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.

Imaging Markers Derived From MRI-Based Automated Kidney Segmentation.

BACKGROUND: Population-wide research on potential new imaging biomarkers of the kidney depends on accurate automated segmentation of the kidney and its compartments (cortex, medulla, and sinus). METHODS: We developed a robust deep-learning framework for kidney (sub-)segmentation based on a hierarchical, three-dimensional convolutional neural network (CNN) that was optimized for multiscale problems of combined localization and segmentation. We applied the CNN to abdominal magnetic resonance images from the population-based German National Cohort (NAKO) study. RESULTS: There was good to excellent agreement between the model predictions and manual segmentations. The median values for the body-surface normalized total kidney, cortex, medulla, and sinus volumes of 9934 persons were 158, 115, 43, and 24 mL/m2. Distributions of these markers are provided both for the overall study population and for a subgroup of persons without kidney disease or any associated conditions. Multivariable adjusted regression analyses revealed that diabetes, male sex, and a higher estimated glomerular filtration rate (eGFR) are important predictors of higher total and cortical volumes. Each increase of eGFR by one unit (i.e., 1 mL/min per 1.73 m2 body surface area) was associated with a 0.98 mL/m2 increase in total kidney volume, and this association was significant. Volumes were lower in persons with eGFR-defined chronic kidney disease. CONCLUSION: The extraction of image-based biomarkers through CNN-based renal sub-segmentation using data from a population-based study yields reliable results, forming a solid foundation for future investigations.

Radiomics workflow definition & challenges - German priority program 2177 consensus statement on clinically applied radiomics.

OBJECTIVES: Achieving a consensus on a definition for different aspects of radiomics workflows to support their translation into clinical usage. Furthermore, to assess the perspective of experts on important challenges for a successful clinical workflow implementation. MATERIALS AND METHODS: The consensus was achieved by a multi-stage process. Stage 1 comprised a definition screening, a retrospective analysis with semantic mapping of terms found in 22 workflow definitions, and the compilation of an initial baseline definition. Stages 2 and 3 consisted of a Delphi process with over 45 experts hailing from sites participating in the German Research Foundation (DFG) Priority Program 2177. Stage 2 aimed to achieve a broad consensus for a definition proposal, while stage 3 identified the importance of translational challenges. RESULTS: Workflow definitions from 22 publications (published 2012-2020) were analyzed. Sixty-nine definition terms were extracted, mapped, and semantic ambiguities (e.g., homonymous and synonymous terms) were identified and resolved. The consensus definition was developed via a Delphi process. The final definition comprising seven phases and 37 aspects reached a high overall consensus (> 89% of experts "agree" or "strongly agree"). Two aspects reached no strong consensus. In addition, the Delphi process identified and characterized from the participating experts' perspective the ten most important challenges in radiomics workflows. CONCLUSION: To overcome semantic inconsistencies between existing definitions and offer a well-defined, broad, referenceable terminology, a consensus workflow definition for radiomics-based setups and a terms mapping to existing literature was compiled. Moreover, the most relevant challenges towards clinical application were characterized. CRITICAL RELEVANCE STATEMENT: Lack of standardization represents one major obstacle to successful clinical translation of radiomics. Here, we report a consensus workflow definition on different aspects of radiomics studies and highlight important challenges to advance the clinical adoption of radiomics. KEY POINTS: Published radiomics workflow terminologies are inconsistent, hindering standardization and translation. A consensus radiomics workflow definition proposal with high agreement was developed. Publicly available result resources for further exploitation by the scientific community.

Everolimus in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth. METHODS: In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months. RESULTS: Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups. CONCLUSIONS: Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; ClinicalTrials.gov number, NCT00414440.)

Magnetic resonance spectroscopy of the anterior cingulate cortex in eating disorders.

The anterior cingulate cortex plays a key role in eating disorders (ED), but it remains an open question whether there are deviations of the neurochemistry of this region in patients with ED. Seventeen adult female patients with ED (10 with bulimia nervosa, 7 with anorexia nervosa) were compared to 14 matched female healthy controls using single voxel magnetic resonance spectroscopy of the anterior cingulate cortex. Group comparisons did not reveal any differences between patients and controls, but a positive correlation between glutamate and myo-inositol signals with "drive for thinness" in patients with bulimia nervosa was found in exploratory correlation analyses.

The utility of multiparametric MRI to characterize hypoxic tumor subvolumes in comparison to FMISO PET/CT. Consequences for diagnosis and chemoradiation treatment planning in head and neck cancer.

BACKGROUND AND PURPOSE: Hypoxia is an essential metabolic marker that determines chemo- and radiation resistance in head-and-neck squamous cell carcinoma (HNSCC) patients. Our exploratory analysis aimed to identify multiparametric MRI (mpMRI) parameters linked to hypoxia that might be used as surrogate for [18F]FMISO-PET in diagnosis and chemoradiation treatment (CRT) of HNSCC. MATERIALS AND METHODS: 21 patients undergoing definitive CRT for HNSCC were prospectively imaged with serial [18F]FMISO-PET and 3 Tesla mpMRI for T1- and T2-weighted and dynamic contrast-enhanced perfusion and diffusion-weighted measurements (ktrans, ve, kep, ADC) in weeks 0, 2 and 5 and FDG-PET in week 0. [18F]FMISO-PET-derived hypoxic subvolumes (HSV) and complementary non-hypoxic subvolumes (nonHSV) were created for tumor and lymph nodes and projected on the mpMRI scans after PET/MRI co-registration. MpMRI and [18F]FMISO-PET parameters within HSVs and nonHSVs were statistically compared. RESULTS: FMISO-PET-based HSVs of the primary tumors on MRI were characterized by lower ADC at all time points (p = 0.012 at baseline; p = 0.015 in week 2) and reduced interstitial space volume fraction ve and perfusion ktrans at baseline (p = 0.006, p = 0.047) compared to nonHSVs. Hypoxic lymph nodes were characterized by significantly lower ADC values at baseline (p = 0.039), but not at later time points and a reduction in ktrans-based perfusion at week 2 (p = 0.018). CONCLUSION: MpMRI parameters differ significantly between hypoxic and non-hypoxic tumor regions, defined on FMISO-PET/CT as gold standard and might represent surrogate markers for tumor hypoxia. These findings suggest that mpMRI may be useful in the future as a surrogate modality for hypoxia imaging in order to personalize CRT.

Neurochemical and structural correlates of executive dysfunction in schizophrenia.

BACKGROUND: Executive dysfunction is a core feature of schizophrenia. The neurochemical and structural changes associated with this deficit are, however, largely unclear. This study tested the hypothesis that changes in glutamate, glutamine and N-acetyl-aspartate (NAA) in hippocampal and dorsolateral prefrontal (DLPFC) regions as well as hippocampal, amygdalar and DLPFC volume reductions are associated with executive dysfunction. METHODS: Twenty-nine subjects with schizophrenia and 31 healthy controls were examined by short-echo single voxel magnetic resonance spectroscopy of the left anterior hippocampus and the left DLPFC. Volumes of the hippocampi, amygdalae and DLPFC were measured bilaterally using manual volumetry. Executive functioning was assessed by the Wisconsin Card Sorting Test (WCST). RESULTS: Poor WCST performance was associated with increased hippocampal glutamate concentrations among subjects with schizophrenia, not among healthy controls. Glutamate in the DLPFC as well as NAA or glutamine in the hippocampus or the DLPFC were not related to executive functioning in schizophrenia or healthy controls. Reduced amygdalar volume was associated with impaired executive functioning in subjects with schizophrenia (p=.06) and healthy controls (p=.04). CONCLUSIONS: Altered hippocampal glutamatergic neurotransmission and amygdalar volume loss may be associated with executive dysfunction in schizophrenia.

Frontolimbic glutamate alterations in first episode schizophrenia: evidence from a magnetic resonance spectroscopy study.

Glutamatergic dysfunction has been implicated in the pathophysiology of schizophrenia. In this study we performed absolute-quantification short-echo magnetic resonance spectroscopy (MRS) in nine patients with first episode schizophrenia and 32 group-matched control subjects to test the hypothesis of glutamatergic dysfunction at disease onset. Regions of interest were the left dorsolateral prefrontal cortex and the left hippocampus. In the patient group absolute concentrations of glutamate were significantly higher in the prefrontal cortex and near-significantly higher in the hippocampus. The glutamate signals significantly correlated with rating scores for schizophreniform symptoms. Absolute-quantification [1H]MRS can reveal glutamatergic abnormalities which might play an important role in the pathogenesis and course of schizophrenia.

Correction to: Effect of radiochemotherapy on T2* MRI in HNSCC and its relation to FMISO PET derived hypoxia and FDG PET.

Following the publication of this article [1], the authors noticed that figures 2, 3, 4 and 5 were in the incorrect order and thus had incorrect captions.

Effect of radiochemotherapy on T2* MRI in HNSCC and its relation to FMISO PET derived hypoxia and FDG PET.

BACKGROUND: To assess the effect of radiochemotherapy (RCT) on proposed tumour hypoxia marker transverse relaxation time (T2*) and to analyse the relation between T2* and 18F-misonidazole PET/CT (FMISO-PET) and 18F-fluorodeoxyglucose PET/CT (FDG-PET). METHODS: Ten patients undergoing definitive RCT for squamous cell head-and-neck cancer (HNSCC) received repeat FMISO- and 3 Tesla T2*-weighted MRI at weeks 0, 2 and 5 during treatment and FDG-PET at baseline. Gross tumour volumes (GTV) of tumour (T), lymph nodes (LN) and hypoxic subvolumes (HSV, based on FMISO-PET) and complementary non-hypoxic subvolumes (nonHSV) were generated. Mean values for T2* and SUVmean FDG were determined. RESULTS: During RCT, marked reduction of tumour hypoxia on FMISO-PET was observed (T, LN), while mean T2* did not change significantly. At baseline, mean T2* values within HSV-T (15 ± 5 ms) were smaller compared to nonHSV-T (18 ± 3 ms; p = 0.051), whereas FDG SUVmean (12 ± 6) was significantly higher for HSV-T (12 ± 6) than for nonHSV-T (6 ± 3; p = 0.026) and higher for HSV-LN (10 ± 4) than for nonHSV-LN (5 ± 2; p ≤ 0.011). Correlation between FMISO PET and FDG PET was higher than between FMSIO PET and T2* (R2 for GTV-T (FMISO/FDG) = 0.81, R2 for GTV-T (FMISO/T2*) = 0.32). CONCLUSIONS: Marked reduction of tumour hypoxia between week 0, 2 and 5 found on FMISO PET was not accompanied by a significant T2*change within GTVs over time. These results suggest a relation between tumour oxygenation status and T2* at baseline, but no simple correlation over time. Therefore, caution is warranted when using T2* as a substitute for FMISO-PET to monitor tumour hypoxia during RCT in HNSCC patients. TRIAL REGISTRATION: DRKS, DRKS00003830 . Registered 23.04.2012.

Effects of RF pulse profile and intra-voxel phase dispersion on MR fingerprinting with balanced SSFP readout.

PURPOSE: To investigate possible errors in T1 and T2 quantification via MR fingerprinting with balanced steady-state free precession readout in the presence of intra-voxel phase dispersion and RF pulse profile imperfections, using computer simulations based on Bloch equations. MATERIALS AND METHODS: A pulse sequence with TR changing in a Perlin noise pattern and a nearly sinusoidal pattern of flip angle following an initial 180-degree inversion pulse was employed. Gaussian distributions of off-resonance frequency were assumed for intra-voxel phase dispersion effects. Slice profiles of sinc-shaped RF pulses were computed to investigate flip angle profile influences. Following identification of the best fit between the acquisition signals and those established in the dictionary based on known parameters, estimation errors were reported. In vivo experiments were performed at 3T to examine the results. RESULTS: Slight intra-voxel phase dispersion with standard deviations from 1 to 3Hz resulted in prominent T2 under-estimations, particularly at large T2 values. T1 and off-resonance frequencies were relatively unaffected. Slice profile imperfections led to under-estimations of T1, which became greater as regional off-resonance frequencies increased, but could be corrected by including slice profile effects in the dictionary. Results from brain imaging experiments in vivo agreed with the simulation results qualitatively. CONCLUSION: MR fingerprinting using balanced SSFP readout in the presence of intra-voxel phase dispersion and imperfect slice profile leads to inaccuracies in quantitative estimations of the relaxation times.

Non-Parametric Bayesian Registration (NParBR) of Body Tumors in DCE-MRI Data.

The identification of tumors in the internal organs of chest, abdomen, and pelvis anatomic regions can be performed with the analysis of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) data. The contrast agent is accumulated differently by pathologic and healthy tissues and that results in a temporally varying contrast in an image series. The internal organs are also subject to potentially extensive movements mainly due to breathing, heart beat, and peristalsis. This contributes to making the analysis of DCE-MRI datasets challenging as well as time consuming. To address this problem we propose a novel pairwise non-rigid registration method with a Non-Parametric Bayesian Registration (NParBR) formulation. The NParBR method uses a Bayesian formulation that assumes a model for the effect of the distortion on the joint intensity statistics, a non-parametric prior for the restored statistics, and also applies a spatial regularization for the estimated registration with Gaussian filtering. A minimally biased intra-dataset atlas is computed for each dataset and used as reference for the registration of the time series. The time series registration method has been tested with 20 datasets of liver, lungs, intestines, and prostate. It has been compared to the B-Splines and to the SyN methods with results that demonstrate that the proposed method improves both accuracy and efficiency.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.

PURPOSE: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. PATIENTS AND METHODS: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. RESULTS: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P =.01 for oral dose; P =.0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P =.004%; and 51%, P =.006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. CONCLUSION: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK, for further clinical development.

Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study.

BACKGROUND: Glutamatergic dysfunction has been implicated in the pathophysiology of schizophrenia. However, so far there is limited direct evidence of altered in vivo glutamate concentrations in the brains of patients with schizophrenia. To test the hypothesis that altered glutamatergic neurotransmission might play a role in the pathogenesis of schizophrenia, we measured glutamate and glutamine concentrations in the prefrontal cortex and the hippocampus of patients with chronic schizophrenia using high-field magnetic resonance spectroscopy. METHODS: Twenty-one patients with schizophrenia and 32 healthy volunteers were examined clinically and by means of short echo time single voxel magnetic resonance spectroscopy of the dorsolateral prefrontal cortex and the hippocampus. Absolute concentrations of neurometabolites were calculated. RESULTS: Absolute concentrations of glutamate were significantly higher in the prefrontal cortex and the hippocampus in the patient group. Factorial analysis of variance (ANOVA) revealed no significant interactions between duration of schizophrenia, number of hospitalizations, or type of antipsychotic medication and glutamate concentrations. Increased prefrontal glutamate concentrations were associated with poorer global mental functioning. CONCLUSIONS: This is the first study that reports increased levels of glutamate in prefrontal and limbic areas in patients with schizophrenia. Our data support the hypothesis of glutamatergic dysfunction in schizophrenia.