Real-time fMRI-based neurofeedback to restore brain function in substance use disorders: A systematic review of the literature.

INTRODUCTION: Real-time functional magnetic resonance based-neurofeedback (fMRI-neurofeedback) is a neuromodulation tool where individuals self-modulate brain function based on real-time feedback of their brain activity. fMRI-neurofeedback has been used to target brain dysfunction in substance use disorders (SUDs) and to reduce craving, but a systematic synthesis of up-to-date literature is lacking. METHOD: Following PRISMA guidelines, we conducted a systematic review of all the literature that examined the effects of fMRI-neurofeedback on individuals with regular psychoactive substance use (PROSPERO pre-registration = CRD42023401137). RESULTS: The literature included 16 studies comprising 446 participants with SUDs involving alcohol, tobacco, and cocaine. There is consistent between-condition (e.g., fMRI-neurofeedback versus control), less consistent pre-to-post fMRI-neurofeedback, and little intervention-by-time effects on brain function in prefrontal-striatal regions and craving. CONCLUSION: The evidence for changes in brain function/craving was early and inconsistent. More rigorous experiments including repeated measure designs with placebo control conditions, are required to confirm the efficacy of fMRI-neurofeedback in reducing brain alterations and craving in SUDs.

[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

Delineation and agreement of FET PET biological volumes in glioblastoma: results of the nuclear medicine credentialing program from the prospective, multi-centre trial evaluating FET PET In Glioblastoma (FIG) study-TROG 18.06.

PURPOSE: The O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in Glioblastoma (FIG) trial is an Australian prospective, multi-centre study evaluating FET PET for glioblastoma patient management. FET PET imaging timepoints are pre-chemoradiotherapy (FET1), 1-month post-chemoradiotherapy (FET2), and at suspected progression (FET3). Before participant recruitment, site nuclear medicine physicians (NMPs) underwent credentialing of FET PET delineation and image interpretation. METHODS: Sites were required to complete contouring and dynamic analysis by ≥ 2 NMPs on benchmarking cases (n = 6) assessing biological tumour volume (BTV) delineation (3 × FET1) and image interpretation (3 × FET3). Data was reviewed by experts and violations noted. BTV definition includes tumour-to-background ratio (TBR) threshold of 1.6 with crescent-shaped background contour in the contralateral normal brain. Recurrence/pseudoprogression interpretation (FET3) required assessment of maximum TBR (TBRmax), dynamic analysis (time activity curve [TAC] type, time to peak), and qualitative assessment. Intraclass correlation coefficient (ICC) assessed volume agreement, coefficient of variation (CoV) compared maximum/mean TBR (TBRmax/TBRmean) across cases, and pairwise analysis assessed spatial (Dice similarity coefficient [DSC]) and boundary agreement (Hausdorff distance [HD], mean absolute surface distance [MASD]). RESULTS: Data was accrued from 21 NMPs (10 centres, n ≥ 2 each) and 20 underwent review. The initial pass rate was 93/119 (78.2%) and 27/30 requested resubmissions were completed. Violations were found in 25/72 (34.7%; 13/12 minor/major) of FET1 and 22/74 (29.7%; 14/8 minor/major) of FET3 reports. The primary reasons for resubmission were as follows: BTV over-contour (15/30, 50.0%), background placement (8/30, 26.7%), TAC classification (9/30, 30.0%), and image interpretation (7/30, 23.3%). CoV median and range for BTV, TBRmax, and TBRmean were 21.53% (12.00-30.10%), 5.89% (5.01-6.68%), and 5.01% (3.37-6.34%), respectively. BTV agreement was moderate to excellent (ICC = 0.82; 95% CI, 0.63-0.97) with good spatial (DSC = 0.84 ± 0.09) and boundary (HD = 15.78 ± 8.30 mm; MASD = 1.47 ± 1.36 mm) agreement. CONCLUSION: The FIG study credentialing program has increased expertise across study sites. TBRmax and TBRmean were robust, with considerable variability in BTV delineation and image interpretation observed.

Systematic Review: Quantitative Susceptibility Mapping (QSM) of Brain Iron Profile in Neurodegenerative Diseases.

Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique, quantitative susceptibility mapping (QSM), has enabled for the more comprehensive investigation of iron distribution in the brain. The aim of this systematic review was to provide a synthesis of the findings from existing QSM studies in neurodegenerative diseases. We identified 80 records by searching MEDLINE, Embase, Scopus, and PsycInfo databases. The disorders investigated in these studies included Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, Huntington's disease, Friedreich's ataxia, spinocerebellar ataxia, Fabry disease, myotonic dystrophy, pantothenate-kinase-associated neurodegeneration, and mitochondrial membrane protein-associated neurodegeneration. As a general pattern, QSM revealed increased magnetic susceptibility (suggestive of increased iron content) in the brain regions associated with the pathology of each disorder, such as the amygdala and caudate nucleus in Alzheimer's disease, the substantia nigra in Parkinson's disease, motor cortex in amyotrophic lateral sclerosis, basal ganglia in Huntington's disease, and cerebellar dentate nucleus in Friedreich's ataxia. Furthermore, the increased magnetic susceptibility correlated with disease duration and severity of clinical features in some disorders. Although the number of studies is still limited in most of the neurodegenerative diseases, the existing evidence suggests that QSM can be a promising tool in the investigation of neurodegeneration.

Seven-tesla quantitative magnetic resonance spectroscopy of glutamate, γ-aminobutyric acid, and glutathione in the posterior cingulate cortex/precuneus in patients with epilepsy.

OBJECTIVE: The posterior cingulate cortex (PCC)/precuneus is a key hub of the default mode network, whose function is known to be altered in epilepsy. Glutamate and γ-aminobutyric acid (GABA) are the main excitatory and inhibitory neurotransmitters in the central nervous system, respectively. Glutathione (GSH) is the most important free radical scavenging compound in the brain. Quantification of these molecules by magnetic resonance spectroscopy (MRS) up to 4 T is limited by overlapping resonances from other molecules. In this study, we used ultra-high-field (7 T) MRS to quantify their concentrations in patients with different epilepsy syndromes. METHODS: Nineteen patients with temporal lobe epilepsy (TLE) and 16 with idiopathic generalized epilepsy (IGE) underwent magnetic resonance imaging scans using a 7-T research scanner. Single-voxel (8 cm3 ) MRS, located in the PCC/precuneus, was acquired via stimulated echo acquisition mode. Their results were compared to 10 healthy volunteers. RESULTS: Mean concentrations of glutamate, GABA, and the glutamate/GABA ratio did not differ between the IGE, TLE, and healthy volunteer groups. The mean ± SD concentration of GSH was 1.9 ± 0.3 mmol·L-1 in healthy controls, 2.0 ± 0.2 mmol·L-1 in patients with TLE, and 2.2 ± 0.4 mmol·L-1 in patients with IGE. One-way analysis of variance with post hoc Tukey-Kramer test revealed a significant difference in the concentration of GSH between patients with IGE and controls (P = .03). Short-term seizure freedom in patients with epilepsy was predicted by an elevated concentration of glutamate in the PCC/precuneus (P = .01). In patients with TLE, the concentration of GABA declined with age (P = .03). SIGNIFICANCE: Patients with IGE have higher concentrations of GSH in the PCC/precuneus than healthy controls. There is no difference in the concentrations of glutamate and GABA, or their ratio, in the PCC/precuneus between patients with IGE, patients with TLE, and healthy controls. Measuring the concentration of glutamate in the PCC/precuneus may assist with predicting drug response.

Glutamate weighted imaging contrast in gliomas with 7 Tesla magnetic resonance imaging.

INTRODUCTION: Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively. METHODS: We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns. RESULTS: Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113). CONCLUSION: This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.

Nano-assemblies of cationic mPEG brush block copolymers with gadolinium polyoxotungstate [Gd(W5O18)2]9- form stable, high relaxivity MRI contrast agents.

Polyoxometalates (POMs) incorporating paramagnetic ions, such as gadolinium, show promise as contrast agents for application in magnetic resonance imaging (MRI). Specifically, [Gd(W5O18)2]9- (denoted as GdWO) has been reported to have a higher relaxivity than commercially available contrast agents, but it's clinical utility has been limited by the intrinsic instability of POMs at physiological pH (7.4). In the current report we present a stability study on neat GdWO and nano-assemblies of block copolymers with GdWO in the pH range 5.0-7.4 to assess their suitability as MRI contrast agents. Neat GdWO only maintained structural stability between pH 5.4 and 6.4, and demonstrated poor MRI contrast at pH 7.4. To address this pH instability, GdWO was self-assembled with cationic mPEG brush block copolymers containing 20 or 40 units derived from the cationic monomer, 2-dimethylaminoethyl methacrylate (DMAEMA). Nano-assemblies with different charge ratios were synthesised and characterised according to their size, stability, contrasting properties and toxicity. The longitudinal relaxivity (r1) of the nano-assemblies was found to be dependent on the charge ratio, but not on the length of the cationic polymer block. Further investigation of PDMAEMA20 nano-assemblies demonstrated that they were stable over the pH range 5.0-7.4, exhibiting a higher r1 than either neat GdWO (2.77 s-1 mM-1) or clinical MRI contrast agent Gd-DTPA (4.1 s-1 mM-1) at pH 7.4. Importantly, the nano-assembly with the lowest charge ratio (0.2), showed the highest r1 (12.1 s-1 mM-1) whilst, stabilising GdWO over the pH range studied, eliciting low toxicity with MDA-MB231 cells.

Comparison between site and central radiological assessments for patients with recurrent glioblastoma on a clinical trial.

AIM: Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. METHODS: MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. RESULTS: Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 patients continued on trial without site-determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date. CONCLUSION: While the difference between site and central PFS dates was statistically significant, the 0.3-month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an individual.

Emotional reactivity following surgery to the prefrontal cortex.

We aimed to elicit emotion in patients with surgically circumscribed lesions of the prefrontal cortex (PFC) in order to elucidate the precise functional roles in emotion processing of the discrete subregions comprising the ventromedial PFC, including the medial PFC and orbitofrontal cortex (OFC). Three components of emotional reactivity were measured: subjective experience, behaviour, and physiological response. These included measures of self-reported emotion, observer-rated facial expression of emotion and measurements of heart rate and heart rate variability (HRV) during film viewing, and a measure of subjective emotional change since surgery. Patients with lesions to the ventromedial PFC demonstrated significant differences compared with controls in HRV during the film clips, suggesting a shift to greater dominance of sympathetic input. In contrast, patients with lesions restricted to the OFC showed significant differences in HRV suggesting reduced sympathetic input. They also showed less facial expression of emotion during positive film clips, and reported more subjective emotional change since surgery compared with controls. This human lesion study is important for refining theoretical models of emotion processing by the ventromedial PFC, which until now have primarily been based on anatomical connectivity, animal lesion, and human functional neuroimaging research. Such theories have implications for the treatment of a wide variety of emotional disorders.

An Objective Measurement of Lacunar Infarct Location from the Middle Cerebral Artery Stem.

BACKGROUND: There is emerging interest in the relationship between neuroimaging location of lacunar infarcts and underlying stroke risk factors. Recent methods used for localization of lacunar infarcts are affected by high inter-rater variability. We used a novel algorithm-driven method that provided quantitative assessment of the distance of the lacunar infarct from the origins of the lenticulostriate arteries. METHODS: We conducted a retrospective analysis of patients who presented with lacunar infarcts between 2007 and 2011. Diffusion-weighted imaging and magnetic resonance angiography were used to manually mark the infarct lesion and the ipsilateral origins of lenticulostriate arteries. A 3-dimensional distance formula computed the distance between the infarct and the arterial region of interest. All distances were adjusted for brain volumes. Agreement testing using 2 blinded assessors was used to determine reproducibility of this method. RESULTS: One hundred and ten patients were included in our study, with a median age of 72 years (interquartile range 58-81); 67 (61%) were male and 33 (30%) had hypertension and other vascular risk factors including hypercholesterolemia 45 (41%), smoking 33 (30%), diabetes 24 (22%), ischemic heart disease 18 (16%), and atrial fibrillation 9 (8%). The agreement test for 33 patients demonstrated an intraclass correlation of .89 and Lin's correlation coefficient of .89 (95% confidence interval .816-.963). The median distance for the study cohort was 24.5 mm, with shorter median distances of 13.7 mm observed in patients with atrial fibrillation (P value < .005). CONCLUSION: Our study used a novel method to calculate a distance measurement, which has high inter-rater correlation.

Early perfusion MRI predicts survival outcome in patients with recurrent glioblastoma treated with bevacizumab and carboplatin.

Bevacizumab, an anti-angiogenic agent, is FDA-approved for use in patients with recurrent glioblastoma multiforme (rGBM). The radiologic evaluation of tumor response to bevacizumab is complex and there is no validated method of monitoring tumor vascularity during therapy. We evaluated perfusion-weighted MR imaging (PWI) in our cohort of patients enrolled in the CABARET trial, which examined the effectiveness of bevacizumab with or without carboplatin in patients with rGBM. Pre-treatment and early follow-up (4- and 8-week) PWI were used to calculate relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing and FLAIR hyperintense tumor volumes. A novel rCBV measurement (load) was developed to estimate the total volume of perfused tumor blood vessels. Changes in all rCBV measures were examined for correlations with progression-free (PFS) and overall survival (OS). All of our 15 patients enrolled in the CABARET trial were included. Median PFS and OS were 23 and 45 weeks respectively. Kaplan-Meier analysis of pre-treatment PWI revealed an 18 week reduction in median OS in patients with high tumor rCBV (p = 0.031). Changes in rCBV measures, especially load, correlated significantly with PFS and OS at both follow-up time-points. Patients with the greatest reduction in rCBVload by 8-weeks of therapy had a significantly increased median OS (30 weeks; p = 0.013). PWI may be of significant clinical utility in managing patients with rGBM, particularly those treated with anti-angiogenic agents such as bevacizumab. These findings need to be confirmed prospectively in larger studies.

Preoperative biomarkers of tumour vascularity are elevated in patients with glioblastoma multiforme.

We investigated the correlation between the circulating and imaging biomarkers of tumour vascularity, and examined whether they are prognostic of outcomes in patients with glioblastoma multiforme (GBM). Despite the increasing use of anti-angiogenic agents within neuro-oncology, there are still no validated biomarkers to monitor for a treatment response or relapse. The pre- and postoperative circulating endothelial cell (CEC) and progenitor cell (CEP) levels were assessed. Preoperative perfusion-weighted MRI (PWI) was also performed, and the relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing tumour were analysed. A novel PWI parameter (rCBVload) was developed to estimate the total volume of perfused tumour vessels, and it was hypothesised that this parameter would correlate with CEC and CEP concentrations. In total, 24 GBM patients were included. The mean preoperative CEC concentration was significantly higher in GBM patients than the controls (p=0.019), and it then declined significantly postoperatively (p=0.009). The preoperative CEP levels were significantly correlated with the median tumour rCBV (Spearman rank-order coefficient=0.526; p=0.039). Neither CEC nor CEP was correlated with the total tumour vessel volume, as measured by rCBVload. None of the biomarkers that were investigated showed a significant correlation with progression-free or overall survival. We conclude that CEC are potentially useful biomarkers to monitor GBM patients during treatment. We found that CEC are increased in the presence of GBM, and that CEP levels appear to be proportional to tumour vascularity, as measured on PWI. However, in this study, none of the biomarkers of GBM vascularity were highly prognostic of patient outcomes.

Probabilistic MRI tractography of the optic radiation using constrained spherical deconvolution: a feasibility study.

BACKGROUND AND PURPOSE: Imaging the optic radiation (OR) is of considerable interest in studying diseases affecting the visual pathway and for pre-surgical planning of temporal lobe resections. The purpose of this study was to investigate the clinical feasibility of using probabilistic diffusion tractography based on constrained spherical deconvolution (CSD) to image the optic radiation. It was hypothesized that CSD would provide improved tracking of the OR compared with the widely used ball-and-stick model. METHODS: Diffusion weighted MRI (30 directions) was performed on twenty patients with no known visual deficits. Tractography was performed using probabilistic algorithms based on fiber orientation distribution models of local white matter trajectories. The performance of these algorithms was evaluated by comparing computational times and receiver operating characteristic results, and by correlation of anatomical landmark distances to dissection estimates. RESULTS: The results showed that it was consistently feasible to reconstruct individual optic radiations from clinically practical (4.5 minute acquisition) diffusion weighted imaging data sets using CSD. Tractography based on the CSD model resulted in significantly shorter computational times, improved receiver operating characteristic results, and shorter Meyer's loop to temporal pole distances (in closer agreement with dissection studies) when compared to the ball-and-stick based algorithm. CONCLUSIONS: Accurate tractography of the optic radiation can be accomplished using diffusion MRI data collected within a clinically practical timeframe. CSD based tractography was faster, more accurate and had better correlation with known anatomical landmarks than ball-and-stick tractography.

Colloidally stabilized magnetic carbon nanotubes providing MRI contrast in mouse liver tumors.

The use of medical imaging contrast agents may lead to improved patient prognosis by potentially enabling an earlier detection of diseases and therefore an earlier initiation of treatments. In this study, we fabricated superparamagnetic iron oxide (SPIO) nanoparticles within the inner cavity of multiwalled carbon nanotubes (MWCNTs) for the first time; thereby ensuring high mechanical stability of the nanoparticles. A simple, but effective, self-assembled coating with RAFT diblock copolymers ensured the SPIO-MWCNTs have a high dispersion stability under physiological conditions. In vivo acute tolerance testing in mice showed a high tolerance dose up to 100 mg kg(-1). Most importantly, after administration of the material a 55% increase in tumor to liver contrast ratio was observed with in vivo MRI measurements compared to the preinjection image enhancing the detection of the tumor.

Nitroxide-loaded hexosomes provide MRI contrast in vivo.

The purpose of this work was to synthesize and screen, for their effectiveness to act as T1-enhancing magnetic resonance imaging (MRI) contrast agents, a small library of nitroxide lipids incorporated into cubic-phase lipid nanoparticles (cubosomes). The most effective nitroxide lipid was then formulated into lower-toxicity lipid nanoparticles (hexosomes), and effective MR contrast was observed in the aorta and spleen of live rats in vivo. This new class of lower-toxicity lipid nanoparticles allowed for higher relaxivities on the order of those of clinically used gadolinium complexes. The new hexosome formulation presented herein was significantly lower in toxicity and higher in relaxivity than cubosome formulations previously reported by us.

Water-dispersible magnetic carbon nanotubes as T2-weighted MRI contrast agents.

An efficient MRI T2-weighted contrast agent incorporating a potential liver targeting functionality was synthesized via the combination of superparamagnetic iron oxide (SPIO) nanoparticles with multiwalled carbon nanotubes (MWCNTs). Poly(diallyldimethylammonium chloride) (PDDA) was coated on the surface of acid treated MWCNTs via electrostatic interactions and SPIO nanoparticles modified with a potential targeting agent, lactose-glycine adduct (Lac-Gly), were subsequently immobilized on the surface of the PDDA-MWCNTs. A narrow magnetic hysteresis loop indicated that the product displayed superparamagnetism at room temperature which was further confirmed by ZFC (zero field cooling)/FC (field cooling) curves measured by SQUID. The multifunctional MWCNT-based magnetic nanocomposites showed low cytotoxicity in vitro to HEK293 and Huh7 cell lines. Enhanced T2 relaxivities were observed for the hybrid material (186 mM(-1) s(-1)) in comparison with the pure magnetic nanoparticles (92 mM(-1) s(-1)) due to the capacity of the MWCNTs to "carry" more nanoparticles as clusters. More importantly, after administration of the composite material to an in vivo liver cancer model in mice, a significant increase in tumor to liver contrast ratio (277%) was observed in T2 weighted magnetic resonance images.

Evaluation of treatment-associated inflammatory response on diffusion-weighted magnetic resonance imaging and 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography imaging biomarkers.

PURPOSE: Functional imaging biomarkers of cancer treatment response offer the potential for early determination of outcome through the assessment of biochemical, physiologic, and microenvironmental readouts. Cell death may result in an immunologic response, thus complicating the interpretation of biomarker readouts. This study evaluated the temporal effect of treatment-associated inflammatory activity on diffusion magnetic resonance imaging and 2-[(18)F]-fluoro-2-deoxy-D-glucose-positron emission tomography imaging (FDG-PET) biomarkers to delineate the effects of the inflammatory response on imaging readouts. EXPERIMENTAL DESIGN: Rats with intracerebral 9L gliosarcomas were separated into four groups consisting of control, an immunosuppressive agent dexamethasone (Dex), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and BCNU+Dex. Animals were imaged using diffusion-weighted magnetic resonance imaging and FDG-PET at 0, 3, and 7 days posttreatment. RESULTS: In the BCNU- and BCNU+Dex-treated animal groups, diffusion values increased progressively over the 7-day study period to approximately 23% over baseline. The FDG percentage change of standard uptake value decreased at day 3 (-30.9%) but increased over baseline levels at day 7 (+20.1%). FDG-PET of BCNU+Dex-treated animals were found to have percentage of standard uptake value reductions of -31.4% and -24.7% at days 3 and 7, respectively, following treatment. Activated macrophages were observed on day 7 in the BCNU treatment group with much fewer found in the BCNU+Dex group. CONCLUSIONS: Results revealed that treatment-associated inflammatory response following tumor therapy resulted in the accentuation of tumor diffusion response along with a corresponding increase in tumor FDG uptake due to the presence of glucose-consuming activated macrophages. The dynamics and magnitude of potential inflammatory response should be considered when interpreting imaging biomarker results.

Advanced MRI: translation from animal to human in brain tumor research.

Advanced magnetic resonance imaging (MRI) techniques, such as magnetic resonance spectroscopy, diffusion MRI, and perfusion MRI, allow for a diverse range of multidimensional information regarding brain tumor physiology to be obtained in addition to the traditional anatomic images. Although it is well documented that MRI of rodent brain tumor models plays an important role in the basic research and drug discovery process of new brain tumor therapies, the role that animal models have played in translating these methodologies is rarely discussed in such articles. Even in consensus reports outlining the pathway to validation of these techniques, the use of animal models is given scant regard. This is despite that the use of rodent cancer models to test advanced MRI techniques predates and was integral to the development of clinical MRI. This article highlights just how integral preclinical imaging is to the discovery, development, and validation of advanced MRI techniques for imaging brain neoplasms.

Substantiating in vivo magnetic brain tumor targeting of cationic iron oxide nanocarriers via adsorptive surface masking.

Cationic magnetic nanoparticles are attractive as potential vehicles for tumor drug delivery due to their favorable interactions with both the tumor milieu and the therapeutic cargo. However, systemic delivery of these nanoparticles to the tumor site is compromised by their rapid plasma clearance. We developed a simple method for in vivo protection of cationic nanocarriers, using non-covalent surface masking with a conjugate of low molecular weight heparin and polyethylene glycol. Surface masking resulted in a 11-fold increase in plasma AUC and a 2-fold increase in the magnetic capture of systemically injected nanoparticles in orthotopic rodent brain tumors. Overall, the described methodology could expand the prospective applications for cationic magnetic nanoparticles in magnetically mediated gene/drug delivery.

A feasibility study of parametric response map analysis of diffusion-weighted magnetic resonance imaging scans of head and neck cancer patients for providing early detection of therapeutic efficacy.

The parametric response map (PRM) was evaluated as an early surrogate biomarker for monitoring treatment-induced tissue alterations in patients with head and neck squamous cell carcinoma (HNSCC). Diffusion-weighted magnetic resonance imaging (DW-MRI) was performed on 15 patients with HNSCC at baseline and 3 weeks after treatment initiation of a nonsurgical organ preservation therapy (NSOPT) using concurrent radiation and chemotherapy. PRM was applied on serial apparent diffusion coefficient (ADC) maps that were spatially aligned using a deformable image registration algorithm to measure the tumor volume exhibiting significant changes in ADC (PRM(ADC)). Pretherapy and midtherapy ADC maps, quantified from the DWIs, were analyzed by monitoring the percent change in whole-tumor mean ADC and the PRM metric. The prognostic values of percentage change in tumor volume and mean ADC and PRM(ADC) as a treatment response biomarker were assessed by correlating with tumor control at 6 months. Pixel-wise differences as part of PRM(ADC) analysis revealed regions where water mobility increased. Analysis of the tumor ADC histograms also showed increases in mean ADC as early as 3 weeks into therapy in patients with a favorable outcome. Nevertheless, the percentage change in mean ADC was found to not correlate with tumor control at 6 months. In contrast, significant differences in PRM(ADC) and percentage change in tumor volume were observed between patients with pathologically different outcomes. Observations from this study have found that diffusion MRI, when assessed by PRM(ADC), has the potential to provide both prognostic and spatial information during NSOPT of head and neck cancer.