Jack J. A. van Asten

High resolution magic angle spinning NMR spectroscopy for metabolic assessment of cancer presence and Gleason score in human prostate needle biopsies.

ObjectivesHistopathology of prostate needle biopsies (PNBs) is an important part in the diagnosis, prognosis and treatment evaluation of prostate cancer. The determination of metabolite levels in the same biopsies may have additional clinical value. Here, we demonstrate the use of non-destructive high resolution magic angle spinning (HRMAS) proton NMR Spectroscopy for the assessment of metabolic profiles of prostate tissue in PNBs as commonly obtained in standard clinical practice.Materials and methodsPNBs that were taken routinely from 48 patients suspected of having prostate cancer were subjected to HRMAS proton NMR spectroscopy. Subsequent histopathology of the same biopsies classified the tissue either as cancer (nxa0=xa010) or benign (nxa0=xa030).ResultsSome practical aspects of this assessment were evaluated, such as typical spectral contamination caused by the PNB procedure. Significant metabolic differences were found between malignant and benign tissue using a small set of ratio’s involving signals of choline compounds, citrate and lactate. Moreover, significant correlations were observed between choline, total choline, and citrate over creatine signal ratios and the Gleason scores of tumor in PNBs and of tumor in the whole prostate.ConclusionThis preliminary study indicates that HRMAS NMR of routinely obtained PNBs can provide detailed metabolic information of intact prostate tissue with clinical relevance.

MR spectroscopy of muscle and brain in guanidinoacetate methyltransferase (GAMT)‐deficient mice: Validation of an animal model to study creatine deficiency

As a model for guanidinoacetate methyltransferase (GAMT) deficiency in humans, a gene knockout mouse model was generated. Here we report on several metabolic abnormalities in these mice, observed by in vivo and in vitro MR spectroscopy. In 1H MR spectra of brain and hindleg muscle a clearly reduced signal of creatine (Cr) was observed in GAMT‐deficient (GAMT–/–) animals. Analysis of the 1H MR spectra of GAMT–/– brain indicated little or no increase of a signal for guanidinoacetate (Gua). In proton MR spectra of muscle, a broad signal of low intensity was observed for Gua. However, substantial Gua accumulation in intact muscle tissue was unequivocally confirmed in high‐resolution magic angle spinning spectra, in which the Gua signal was resolved as one clear sharp singlet. In 31P MR analysis of brain and hindleg muscle a strongly reduced phosphocreatine (PCr) content was shown. In addition, a signal of phosphorylated Gua at 0.5 ppm upfield of PCr was observed, with much higher intensity in muscle than in brain. This signal decreased when ischemia was applied to the muscle and recovered after ischemia was released. Overall, the in vivo 31P and 1H MR spectroscopy of GAMT–/– mice is similar to that of human GAMT deficiency. This opens up new avenues for the fundamental study of tissue‐type dependence of creatine synthesis and transport and for diagnostic and therapeutic aspects of creatine deficiencies in humans. Magn Reson Med 50:936–943, 2003.

Gray and white matter degeneration revealed by diffusion in an Alzheimer mouse model.

In patients with Alzheimers disease (AD) the severity of white matter degeneration correlates with the clinical symptoms of the disease. In this study, we performed diffusion-tensor magnetic resonance imaging at ultra-high field in a mouse model for AD (APP(swe)/PS1(dE9)) in combination with a voxel-based approach and tractography to detect changes in water diffusivity in white and gray matter, because these reflect structural alterations in neural tissue. We found substantial changes in water diffusion parallel and perpendicular to axonal tracts in several white matter regions like corpus callosum and fimbria of the hippocampus, that match with previous findings of axonal disconnection and myelin degradation in AD patients. Moreover, we found a significant increase in diffusivity in specific hippocampal subregions, which is supported by neuronal loss as visualized with Klüver-Barrera staining. This work demonstrates the potential of ultra-high field diffusion-tensor magnetic resonance imaging as a noninvasive modality to describe white and gray matter structural changes in mouse models for neurodegenerative disorders, and provides valuable knowledge to assess future AD prevention strategies in translational research.

Phase I Clinical and Magnetic Resonance Imaging Study of the Vascular Agent NGR-hTNF in Patients with Advanced Cancers (European Organization for Research and Treatment of Cancer Study 16041)

Purpose: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors. Experimental Design: NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion. Results: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 μg/m2). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 μg/m2), of which three were infusion related. The MTD was 45 μg/m2. The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks. Conclusions: NGR-hTNF was well tolerated. The MTD was 45 μg/m2 administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs. Clin Cancer Res; 16(4); 1315–23

Short echo time 1H MRSI of the human brain at 3T with adiabatic slice-selective refocusing pulses; reproducibility and variance in a dual center setting

To assess the reproducibility of 1H‐MR spectroscopic imaging (MRSI) of the human brain at 3T with volume selection by a double spin echo sequence for localization with adiabatic refocusing pulses (semi‐LASER).

Chemotherapy Response Monitoring of Colorectal Liver Metastases by Dynamic Gd-DTPA–Enhanced MRI Perfusion Parameters and 18F-FDG PET Metabolic Rate

In this study, we examined the in vivo relationship between functional tumor vasculature, determined by dynamic contrast-enhanced (DCE-) MRI, and tumor metabolism, determined by dynamic 18F-FDG PET, during cytotoxic treatment of patients with colorectal liver metastases. Methods: Twenty-three patients underwent DCE-MRI (using gadolinium dimeglumine) and dynamic 18F-FDG PET at baseline and after 3 treatment cycles, unless treatment was terminated because of toxicity. Parameters for vasculature (rate constant between extravascular extracellular space and blood plasma [kep] and volume transfer constant [Ktrans]), extracellular space (ve), tumor size (the maximal axial diameter of each included lesion [MAD]), and metabolism (glucose metabolic rates [MRglc]) were derived, and changes during treatment were correlated. Overall survival (OS) and progression-free survival (PFS) served as outcome measures for the predictive abilities of pretreatment parameters and of treatment-related parameter changes. Results: Pretreatment MRglc and MAD were individually predictive for OS and PFS. During treatment, Ktrans increased significantly, but this increase could not be confirmed in a lesion-by-lesion analysis. MRglc decreased significantly (P < 0.001). No correlations were found for changes in DCE-MRI parameters and ΔMRglc. No relationship was found between changes in DCE-MRI parameters and OS or PFS. ΔMRglc was able to predict OS (P = 0.008) after correction for confounders. Conclusion: The efficacy of cytotoxic chemotherapy assessed by reduction in tumor metabolism does not depend on pretreatment properties of the tumor vasculature determined by DCE-MRI. Cytotoxic chemotherapy does not alter DCE-MRI–derived properties of tumor vasculature but decreases glucose consumption of tumor cells.

Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose- compared to glucose-fed mice

Fructose consumption has been associated with the surge in obesity and dyslipidemia. This may be mediated by the fructose effects on hepatic lipids and ATP levels. Fructose metabolism provides carbons for de novo lipogenesis (DNL) and stimulates enterocyte secretion of apoB48. Thus, fructose‐induced hepatic triglyceride (HTG) accumulation can be attributed to both DNL stimulation and dietary lipid absorption. The aim of this study was to assess the effects of fructose diet on HTG and ATP content and the contributions of dietary lipids and DNL to HTG. Measurements were performed in vivo in mice by magnetic resonance imaging (MRI) and novel magnetic resonance spectroscopy (MRS) approaches. Abdominal adipose tissue volume and intramyocellular lipid levels were comparable between 8‐wk fructose‐ and glucose‐fed mice. HTG levels were ~1.5‐fold higher in fructose‐fed than in glucose‐fed mice (P<0.05). Metabolic flux analysis by 13C and 2H MRS showed that this was not due to dietary lipid absorption, but due to DNL stimulation. The contribution of oral lipids to HTG was, after 5 h, 1.60 ± 0.23% for fructose and 2.16 ± 0.35% for glucose diets (P=0.26), whereas that of DNL was higher in fructose than in glucose diets (2.55±0.51 vs. 1.13±0.24%, P=0.01). Hepatic energy status, assessed by P MRS, was similar for fructose‐ and glucose‐fed mice. Fructose‐induced HTG accumulation is better explained by DNL and not by dietary lipid uptake, while not compromising ATP homeostasis.—Nunes, P. M., Wright, A. J., Veltien, A., van Asten, J. J. A., Tack, C. J., Jones, J. G., Heerschap, A. Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose‐ compared to glucose‐fed mice. FASEB J. 28, 1988–1997 (2014). www.fasebj.org

In vivo 1 H MR spectroscopic imaging of aggressive prostate cancer: Can we detect lactate?

A semi‐LASER sequence was optimized for in vivo lactate detection in the prostate.

Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy

BackgroundDocetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.MethodologyHigh resolution magic angle spinning (HRMAS) 1H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25xa0mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6xa0ppm.ResultsThe HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6xa0ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.ConclusionsRelative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

Magnetic resonance spectroscopic imaging and volumetric measurements of the brain in patients with postcancer fatigue: a randomized controlled trial

Background Postcancer fatigue is a frequently occurring problem, impairing quality of life. Until now, little is known about (neuro) physiological factors determining postcancer fatigue. For non-cancer patients with chronic fatigue syndrome, certain characteristics of brain morphology and metabolism have been identified in previous studies. We investigated whether these volumetric and metabolic traits are a reflection of fatigue in general and thus also of importance for postcancer fatigue. Methods Fatigued patients were randomly assigned to either the intervention condition (cognitive behavior therapy) or the waiting list condition. Twenty-five patients in the intervention condition and fourteen patients in the waiting list condition were assessed twice, at baseline and six months later. Baseline measurements of 20 fatigued patients were compared with 20 matched non-fatigued controls. All participants had completed treatment of a malignant, solid tumor minimal one year earlier. Global brain volumes, subcortical brain volumes, metabolite tissue concentrations, and metabolite ratios were primary outcome measures. Results Volumetric and metabolic parameters were not significantly different between fatigued and non-fatigued patients. Change scores of volumetric and metabolic parameters from baseline to follow-up were not significantly different between patients in the therapy and the waiting list group. Patients in the therapy group reported a significant larger decrease in fatigue scores than patients in the waiting list group. Conclusions No relation was found between postcancer fatigue and the studied volumetric and metabolic markers. This may suggest that, although postcancer fatigue and chronic fatigue syndrome show strong resemblances as a clinical syndrome, the underlying physiology is different. Trial Registration ClinicalTrials.gov NCT01096641