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Biomedical subjects

A Heerschap

Publications and source records attributed to A Heerschap.

At least 19 recordsLinked to original sources
PubMed2007

Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium-DTPA-enhanced MRI and localized 19F MRS pharmacokinetic studies of 5-fluorouracil.

Systemic chemotherapy is effective in only a subset of patients with metastasized colorectal cancer. Therefore, early selection of patients who are most likely to benefit from chemotherapy is desirable. Response to treatment may be determined by the delivery of the drug to the tumor, retention of the drug in the tumor and by the amount of intracellular uptake, metabolic activation and catabolism, as well as other factors. The first aim of this study was to investigate the predictive value of DCE-MRI with the contrast agent Gd-DTPA for tumor response to first-line chemotherapy in patients with liver metastases of colorectal cancer. The second aim was to investigate the predictive value of 5-fluorouracil (FU) uptake, retention and catabolism as measured by localized (19)F MRS for tumor response to FU therapy. Since FU uptake, retention and metabolism may depend on tumor vascularization, the relationship between (19)F MRS and the DCE-MRI parameters k(ep), K(trans) and v(e) was also examined (1). In this study, 37 patients were included. The kinetic parameters of DCE-MRI, k(ep), K(trans) and v(e), before start of treatment did not predict tumor response after 2 months, suggesting that the delivery of chemotherapy by tumor vasculature is not a major factor determining response in first-line treatment. No evident correlations between (19)F MRS parameters and tumor response were found. This suggests that in liver metastases that are not selected on the basis of their tumor diameter, FU uptake and catabolism are not limiting factors for response. The transfer constant K(trans), as measured by DCE-MRI before start of treatment, was negatively correlated with FU half-life in the liver metastases, which suggests that, in metastases with a larger tumor blood flow or permeability surface area product, FU is rapidly washed out from the tumor.

Adult↗
PubMed2006

Fast nosologic imaging of the brain.

Magnetic resonance spectroscopic imaging (MRSI) provides information about the spatial metabolic heterogeneity of an organ in the human body. In this way, MRSI can be used to detect tissue regions with abnormal metabolism, e.g. tumor tissue. The main drawback of MRSI in clinical practice is that the analysis of the data requires a lot of expertise from the radiologists. In this article, we present an automatic method that assigns each voxel of a spectroscopic image of the brain to a histopathological class. The method is based on Canonical Correlation Analysis (CCA), which has recently been shown to be a robust technique for tissue typing. In CCA, the spectral as well as the spatial information about the voxel is used to assign it to a class. This has advantages over other methods that only use spectral information since histopathological classes are normally covering neighbouring voxels. In this paper, a new CCA-based method is introduced in which MRSI and MR imaging information is integrated. The performance of tissue typing is compared for CCA applied to the whole MR spectra and to sets of features obtained from the spectra. Tests on simulated and in vivo MRSI data show that the new method is very accurate in terms of classification and segmentation. The results also show the advantage of combining spectroscopic and imaging data.

Algorithms↗
PubMed2006

Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies.

The blood-brain barrier (BBB) is considered one of the major causes for the low efficacy of cytotoxic compounds against primary brain tumours. The aim of this study was to develop intracranial tumour models in mice featuring intact or locally disrupted BBB properties, which can be used in testing chemotherapy against brain tumours. These tumours were established by intracranial injection of suspensions of different tumour cell lines. All cell lines had been transfected with luciferase to allow non-invasive imaging of tumour development using a super-cooled CCD-camera. Following their implantation, tumours developed which displayed the infiltrative, invasive or expansive growth patterns that are also found in primary brain cancer or brain metastases. Contrast-enhanced magnetic resonance imaging showed that the Mel57, K1735Br2 and RG-2 lesions grow without disruption of the BBB, whereas the BBB was leaky in the U87MG and VEGF-A-transfected Mel57 lesions. This was confirmed by immunohistochemistry. Bioluminescence measurements allowed the visualisation of tumour burden already within 4 days after injection of the tumour cells. The applicability of our models for performing efficacy studies was demonstrated in an experiment using temozolomide as study drug. In conclusion, we have developed experimental brain tumour models with partly disrupted, or completely intact BBB properties. In vivo imaging by luciferase allows convenient follow-up of tumour growth and these models will be useful for chemotherapeutic intervention studies.

Animals↗
PubMed2006

Sensitivity-enhanced 13C MR spectroscopy of the human brain at 3 Tesla.

A new coil design for sensitivity-enhanced 13C MR spectroscopy (MRS) of the human brain is presented. The design includes a quadrature transmit/receive head coil optimized for 13C MR sensitivity. Loss-less blocking circuits inside the coil conductors allow this coil to be used inside a homogeneous circularly polarized 1H B1 field for 1H decoupled 13C MRS. A quadrature 1H birdcage coil optimized for minimal local RF heating makes broadband 1H decoupling in the entire human brain possible at 3 Tesla while remaining well within international safety guidelines for RF absorption. Apart from a substantial increase in sensitivity compared to conventional small linear coils, the quadrature 13C coil combined with the quadrature 1H birdcage coil allows efficient cross polarization (CP) in the brain, resulting in an additional 3.5-fold sensitivity improvement compared to direct 13C measurements without nuclear Overhauser enhancement (NOE) or polarization transfer. Combined with the gain in power efficiency, this setup allows broadband 1H to 13C CP over large areas of the brain. Clear 13C resonances from glutamate (Glu), glutamine (Gln), aspartate (Asp), lactate (Lac), and gamma-aminobutyrate (GABA) carbon spins in the human brain demonstrate the quality of 13C MR spectra obtained in vivo with this coil setup.

Aspartic Acid↗
PubMed2006

Intake of 13C-4 creatine enables simultaneous assessment of creatine and phosphocreatine pools in human skeletal muscle by 13C MR spectroscopy.

The feasibility of a novel method for the noninvasive and local assessment of creatine (Cr) and phosphocreatine (PCr) dynamics in human skeletal muscle based on (13)C magnetic resonance (MR) spectroscopy is presented. A high dose of Cr, labeled at the guanidino C-4 position with (13)C 11% enrichment, was administered orally to a human subject for 5 days. Using a surface coil, (13)C MR spectra of the lower leg were acquired on a 1.5T MR system at regular time intervals during and after Cr supplementation. An almost twofold increase in the intensities of the resolved PCr and Cr (13)C-4 signals was observed during this period. The slow decrease in these signals to normal values after supplementation reflects the slow daily turnover of Cr. The PCr/Cr ratio did not appear to change over the whole measurement period. During exercise of the leg, reversible changes in PCr and Cr signals were observed, reflecting conversion by the Cr kinase reaction.

Carbon Radioisotopes↗
PubMed2006

In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.

The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

Biomarkers, Tumor↗
PubMed2006

Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas.

TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF its biological effect on tumor vasculature should be measured rather than its effect on tumor growth. The aim of this study was to assess the effects of a low dose of NGR-TNF (5 ng/kg) on vascular permeability, tumor hypoxia, perfusion and proliferation in lymphoma bearing mice. MRI measurements with blood pool contrast agent showed an increased leakage of the contrast agent from the vasculature in NGR-TNF treated tumors compared with controls (p < 0.05), suggesting NGR-TNF-induced vascular permeability. Immunohistochemical analysis two hours after NGR-TNF treatment showed a decrease in tumor hypoxia (p < 0.1) and an increase in labeling index of the S-phase marker bromodeoxyuridine (p < 0.1), possibly due to an increase in tumor blood flow after NGR-TNF treatment. Although a decrease in tumor hypoxia and an increase in labeling index could have lead to increased tumor growth, in this experiment after one day a decrease in tumor volume was measured. Possibly, the effects on tumor hypoxia and proliferation two hours after treatment are transient and overruled by other, more longlasting effects. For example, the observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth. A beneficial effect of NGR-TNF in combination with other therapeutical agents may therefore critically depend on the sequence and timing of the regimens. Currently, NGR-TNF is being tested in clinical studies.

Animals↗
PubMed2006

Effects of pioglitazone in familial combined hyperlipidaemia.

OBJECTIVES: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. DESIGN: Double blind, randomized, cross-over study. SUBJECTS: Seventeen FCH patients. INTERVENTIONS: Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. MAIN OUTCOME MEASUREMENTS: Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. RESULTS: Pioglitazone improved insulin sensitivity (M value 37.7 +/- 3.6 micromol min(-1) kg(-1) vs. 33.0 +/- 3.3 micromol min(-1) kg(-1) during placebo, P < 0.05) and LDL composition by increasing the K value (-0.11 +/- 0.06 vs. -0.20 +/- 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). CONCLUSION: Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL.

Alanine Transaminase↗
PubMed2005

Echo-time independent signal modulations using PRESS sequences: a new approach to spectral editing of strongly coupled AB spin systems.

In clinical MR spectroscopy, double spin-echo point resolved spectroscopy (PRESS) sequences are routinely used for volume selection. For strongly coupled AB spin systems under PRESS excitation, the dependence of the signal on the echo time TE has been thoroughly investigated, whereas less attention has been paid to the signal modulation which occurs at constant TE with varying interpulse delays. A substantial TE-independent J modulation is here predicted from analytical solutions of the Liouville equation and density matrix simulations, and verified with experiments on citrate at 1.5 and 3T. It is also shown that this modulation effect could be exploited for editing of strongly coupled AB resonances or for removal of singlets in spectra-by means of difference spectroscopy-just using a standard PRESS sequence. The applicability in vivo of this new spectral editing approach is also demonstrated, with selective detection of citrate resonances in the human prostate. This novel approach has the advantages of being simple, and directly applicable on standard clinical MR scanners, provided that the exact behavior of the resonance is known.

Citric Acid↗
PubMed2005

Lower force and impaired performance during high-intensity electrical stimulation in skeletal muscle of GAMT-deficient knockout mice.

Force characteristics of skeletal muscle of knockout mice lacking creatine (Cr) due to a deletion of guanidinoacetate methyltransferase (GAMT) were studied in situ. Medial gastrocnemius muscles of anesthetized GAMT-deficient (GAMT-/-) and control (Con) littermates were stimulated at optimum length via the sciatic nerve at different stimulation frequencies (60-250 Hz). GAMT-/- mice showed reduced maximal tetanic and twitch force, reduced relative force at 60 Hz, and increased relaxation times. High-intensity fatigue protocols consisting of 30 successive isometric or dynamic contractions showed a strong reduction in force at the beginning of the series in GAMT-/- mice, followed by a smaller reduction compared with Con littermates toward the end of the series. Cr supplementation for 2 days in GAMT-/- animals (GAMT(Cr)-/-) resulted in normalization to Con values for relaxation times, relative force at lower stimulation frequencies, and relative force during 30 isometric contractions. Force per muscle mass, however, remained decreased. Furthermore,GAMT(Cr)-/- mice showed differences compared with both Con and unsupplemented animals in maximal rates of force rise and relaxation times during the isometric protocol as well as in force during the dynamic protocol. Our results show that the absence of Cr plays a direct role in relaxation times, maximal rate of force rise, and force production during high-intensity fatigue protocols. The lower force per muscle mass, however, is probably caused by other factors; i.e., high intracellular guanidinoacetate concentrations.

Animals↗
PubMed2005

MRS assessment of glutamate clearance in a novel masticatory muscle pain model.

The injection of 1.0 M glutamate into the masseter (jaw-closer) muscle results in a short period of muscle pain (5-10 min) and a prolonged period of mechanical sensitization (> 30 min). It is unclear, however, whether there is a temporal relationship between intramuscular glutamate concentration and either muscle pain or mechanical sensitization. In the present study, (1)H MRS and electrophysiological recording of masticatory muscle nerve fibers were performed in order to monitor glutamate clearance and nerve fiber activity, respectively, after injection of glutamate into rat masticatory muscles. Glutamate signal amplitude was found to decay rapidly (half-life t 1/2 = 108 +/- 42 s), and became indistinguishable from the baseline 10 min after the injection. Glutamate-evoked nerve fiber activity was also found to decay rapidly (t 1/2 = 76 +/- 28 s). These results suggest that glutamate clearance correlates well with the time course of glutamate-evoked muscle pain fiber discharge.

Animals↗
PubMed2005

The use of multivariate MR imaging intensities versus metabolic data from MR spectroscopic imaging for brain tumour classification.

This study investigated the value of information from both magnetic resonance imaging and magnetic resonance spectroscopic imaging (MRSI) to automated discrimination of brain tumours. The influence of imaging intensities and metabolic data was tested by comparing the use of MR spectra from MRSI, MR imaging intensities, peak integration values obtained from the MR spectra and a combination of the latter two. Three classification techniques were objectively compared: linear discriminant analysis, least squares support vector machines (LS-SVM) with a linear kernel as linear techniques and LS-SVM with radial basis function kernel as a nonlinear technique. Classifiers were evaluated over 100 stratified random splittings of the dataset into training and test sets. The area under the receiver operating characteristic (ROC) curve (AUC) was used as a global performance measure on test data. In general, all techniques obtained a high performance when using peak integration values with or without MR imaging intensities. For example for low- versus high-grade tumours, low- versus high-grade gliomas and gliomas versus meningiomas, the mean test AUC was higher than 0.91, 0.94, and 0.99, respectively, when both MR imaging intensities and peak integration values were used. The use of metabolic data from MRSI significantly improved automated classification of brain tumour types compared to the use of MR imaging intensities solely.

Brain Chemistry↗
PubMed2005

Modulation of hypoxia in murine liver metastases of colon carcinoma by nicotinamide and carbogen.

There is increasing evidence that modulation of tumor hypoxia may improve therapy outcome. However, most preclinical data are derived from subcutaneous rather than orthotopic tumor models. We investigated the effect of the hypoxia-modulating agents nicotinamide and carbogen on tumor hypoxia, tumor blood perfusion, and proliferative activity in liver metastases of the murine colon carcinoma line C26a. In untreated C26a liver metastases, we observed a considerable amount of hypoxia, similar to the amount in liver metastases of patients with colorectal cancer. Compared to untreated mice, we observed a significantly smaller hypoxic fraction in the liver metastases of mice treated with nicotinamide and carbogen breathing as single treatments or in combination. In the group of mice that underwent carbogen breathing, perfusion was significantly lower than in the untreated group, but the decrease was only marginal. The proliferative activity was similar in all groups. In C26a subcutaneous tumors, a similar effect on hypoxia has been observed that was, however, combined with a decrease in proliferative activity. The different effects of nicotinamide and carbogen on parameters of the tumor microenvironment in liver metastases and subcutaneous tumors suggest that the host tissue influences the mechanism by which nicotinamide and carbogen exert their effects. Since tumor hypoxia may be a clinical problem in colorectal liver metastases, our results open possibilities for further research on the effect of hypoxia modifiers on colorectal liver metastases to improve therapy outcome.

Animals↗
PubMed2004

Characterization of late radiation effects in the rat thoracolumbar spinal cord by MR imaging using USPIO.

The aim of this study was to detect late radiation effects in the rat spinal cord using MR imaging with ultra-small particles of iron oxide (USPIO) contrast agent to better understand the development of late radiation damage with emphasis on the period preceding neurological signs. Additionally, the role of an inflammatory reaction was assessed by measuring macrophages that internalized USPIO. T2-weighted spin echo MR measurements were performed at 7T in six rats before paresis was expected (130-150 days post-irradiation, early group), and in six paretic rats (150-190 days post-irradiation, late group). Measurements were performed before, directly after and, only in the early group, 40 h after USPIO administration and compared with histology. In the early group, MR images showed focal regions in grey matter (GM) and white matter (WM) with signal intensity reduction after USPIO injection. Larger lesions with contrast enhancement were located in and around edematous GM of three animals of the early group and five of the late group. Forty hours after injection, additional lesions in WM, GM and nerve roots appeared in animals with GM edema. In the late paretic group, MR imaging showed WM necrosis adjacent to areas with large contrast enhancement. In conclusion, detection of early focal lesions was improved by contrast administration. In the animals with extended radiation damage, large hypo-intense regions appeared due to USPIO, which might be attributed to blood spinal cord barrier breakdown, but the involvement of blood-derived iron-loaded macrophages could not be excluded.

Animals↗
PubMed2004

Measurements of T1 and T2 relaxation times of colon cancer metastases in rat liver at 7 T.

The purpose of this study was to investigate the magnetic resonance imaging (MRI) characteristics of colon cancer metastases in rat liver at 7 T. A dedicated RF microstrip coil of novel design was built in order to increase the signal-to-noise ratio and, in combination with respiratory triggering, to minimize motion artifacts. T1- and T2-weighted MR imaging was performed to follow tumor growth. T1-weighted images provided a good anatomical delineation of the liver structure, while the best contrast between metastases and normal liver tissue was achieved with T2-weighted images. Measurements of T1 and T2 relaxation times were performed with inversion recovery FLASH and Carr-Purcell-Meiboom-Gill and inversion recovery FLASH imaging sequences, respectively, for quantitative MR characterization of metastases. Both the T1 and T2 of the metastases were significantly higher than those of normal liver tissue. Further, an increase in the T1 relaxation time of the metastases was observed with tumor growth. These findings suggest that quantitative in vivo MR characterization provides information on tumor development and possibly response to therapy, though additional studies are needed to elucidate the correlation between the changes in relaxation times and tumor microenvironment.

Animals↗
PubMed2004

Transmit/receive headcoil for optimal 1H MR spectroscopy of the brain in paediatric patients at 3T.

(1)H magnetic resonance (MR) spectroscopy is a useful tool to obtain metabolic information from the brain in paediatric patients. To detect signals of metabolites at low concentrations or from small volumes, the signal-to-noise ratio (SNR) has to be optimized. The SNR can be increased by going to higher field strengths. However, this leads to higher spectral bandwidths, which increases the chemical shift artefact. Here we present a transmit/receive headcoil which is adapted to the dimensions of the paediatric head and enables PRESS localization with high radio-frequency (RF) bandwidths that minimize the chemical shift displacement to only 5%. In addition, since the pulse lengths are shorter with higher RF bandwidths, the echo time can be reduced to 10 ms improving SNR as well.

Brain↗
PubMed2004

Methodological standardization for a multi-institutional in vivo trial of localized 31P MR spectroscopy in human cancer research. In vitro and normal volunteer studies.

A multi-institutional group has been created to demonstrate the utility of in vivo 31P magnetic resonance spectroscopy (31P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of 31P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual 1H/31P tuned radiofrequency probe, quality control procedures, routine use of 1H irradiation while acquiring 31P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized 31P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting.

Biomarkers, Tumor↗