Tom W. J. Scheenen

Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy

The success of cellular therapies will depend in part on accurate delivery of cells to target organs. In dendritic cell therapy, in particular, delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. We show here that in vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information. Autologous dendritic cells were labeled with a clinical superparamagnetic iron oxide formulation or 111In-oxine and were co-injected intranodally in melanoma patients under ultrasound guidance. In contrast to scintigraphic imaging, magnetic resonance imaging (MRI) allowed assessment of the accuracy of dendritic cell delivery and of inter- and intra-nodal cell migration patterns. MRI cell tracking using iron oxides appears clinically safe and well suited to monitor cellular therapy in humans.

Relationship between Apparent Diffusion Coefficients at 3.0-T MR Imaging and Gleason Grade in Peripheral Zone Prostate Cancer

PURPOSE To retrospectively determine the relationship between apparent diffusion coefficients (ADCs) obtained with 3.0-T diffusion-weighted (DW) magnetic resonance (MR) imaging and Gleason grades in peripheral zone prostate cancer. MATERIALS AND METHODS The requirement to obtain institutional review board approval was waived. Fifty-one patients with prostate cancer underwent MR imaging before prostatectomy, including DW MR imaging with b values of 0, 50, 500, and 800 sec/mm(2). In prostatectomy specimens, separate slice-by-slice determinations of Gleason grade groups were performed according to primary, secondary, and tertiary Gleason grades. In addition, tumors were classified into qualitative grade groups (low-, intermediate-, or high-grade tumors). ADC maps were aligned to step-sections and regions of interest annotated for each tumor slice. The median ADC of tumors was related to qualitative grade groups with linear mixed-model regression analysis. The accuracy of the median ADC in the most aggressive tumor component in the differentiation of low- from combined intermediate- and high-grade tumors was summarized by using the area under the receiver operating characteristic (ROC) curve (A(z)). RESULTS In 51 prostatectomy specimens, 62 different tumors and 251 step-section tumor lesions were identified. The median ADC in the tumors showed a negative relationship with Gleason grade group, and differences among the three qualitative grade groups were statistically significant (P < .001). Overall, with an increase of one qualitative grade group, the median ADC (±standard deviation) decreased 0.18 × 10(-3) mm(2)/sec ± 0.02. Low-, intermediate-, and high-grade tumors had a median ADC of 1.30 × 10(-3) mm(2)/sec ± 0.30, 1.07 × 10(-3) mm(2)/sec ± 0.30, and 0.94 × 10(-3) mm(2)/sec ± 0.30, respectively. ROC analysis showed a discriminatory performance of A(z) = 0.90 in discerning low-grade from combined intermediate- and high-grade lesions. CONCLUSION ADCs at 3.0 T showed an inverse relationship to Gleason grades in peripheral zone prostate cancer. A high discriminatory performance was achieved in the differentiation of low-, intermediate-, and high-grade cancer.

Prospective Assessment of Prostate Cancer Aggressiveness Using 3-T Diffusion-Weighted Magnetic Resonance Imaging–Guided Biopsies Versus a Systematic 10-Core Transrectal Ultrasound Prostate Biopsy Cohort

BACKGROUND Accurate pretreatment assessment of prostate cancer (PCa) aggressiveness is important in decision making. Gleason grade is a critical predictor of the aggressiveness of PCa. Transrectal ultrasound-guided biopsies (TRUSBxs) show substantial undergrading of Gleason grades found after radical prostatectomy (RP). Diffusion-weighted magnetic resonance imaging (MRI) has been shown to be a biomarker of tumour aggressiveness. OBJECTIVE To improve pretreatment assessment of PCa aggressiveness, this study prospectively evaluated MRI-guided prostate biopsies (MR-GBs) of abnormalities determined on diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) maps. The results were compared with a 10-core TRUSBx cohort. RP findings served as the gold standard. DESIGN, SETTING, AND PARTICIPANTS A 10-core TRUSBx (n=64) or MR-GB (n=34) was used for PCa diagnosis before RP in 98 patients. MEASUREMENTS Using multiparametric 3-T MRI: T2-weighted, dynamic contrast-enhanced imaging, and DWI were performed to identify tumour-suspicious regions in patients with a negative TRUSBx. The regions with the highest restriction on ADC maps within the suspicions regions were used to direct MR-GB. A 10-core TRUSBx was used in a matched cohort. Following RP, the highest Gleason grades (HGGs) in biopsies and RP specimens were identified. Biopsy and RP Gleason grade results were evaluated using chi-square analysis. RESULTS AND LIMITATIONS No significant differences on RP were observed for proportions of patients having a HGG of 3 (35% vs 28%; p=0.50), 4 (32% vs 41%; p=0.51), and 5 (32% vs 31%; p=0.61) for the MR-GB and TRUSBx cohort, respectively. MR-GB showed an exact performance with RP for overall HGG: 88% (30 of 34); for TRUS-GB it was 55% (35 of 64; p=0.001). In the MR-GB cohort, an exact performance with HGG 3 was 100% (12 of 12); for HGG 4, 91% (10 of 11); and for HGG 5, 73% (8 of 11). The corresponding performance rates for TRUSBx were 94% (17 of 18; p=0.41), 46% (12 of 26; p=0.02), and 30% (6 of 20; p=0.01), respectively. CONCLUSIONS This study shows prospectively that DWI-directed MR-GBs significantly improve pretreatment risk stratification by obtaining biopsies that are representative of true Gleason grade.

Short echo time 1H‐MRSI of the human brain at 3T with minimal chemical shift displacement errors using adiabatic refocusing pulses

The chemical shift displacement error (CSDE) is an often‐underestimated problem in slice selection for localized proton spectroscopy at higher fields. With the proposed semi‐localized by adiabatic selective refocusing (LASER) pulse sequence, this problem is dealt with by using RF pulses with bandwidths in the order of 5 kHz. A combination of conventional nonadiabatic slice‐selective excitation of proton spins, together with double slice‐selective refocusing of the spins by two pairs of adiabatic full‐passage (APF) pulses, produces a spin echo in a volume of interest (VOI) at an echo time down to 30 ms. An illustration of the CSDE of conventional point‐resolved spectroscopy (PRESS) and the semi‐LASER sequence is shown with a measurement of the brain of a volunteer at 3T. With one application of the technique to a patient with a glioblastoma multiforme (GBM), its clinical functionality is demonstrated. With sharp selection profiles and a small CSDE, voxels close to the edge of the VOI can also be used for evaluation. With the additional advantage of being relatively insensitive for B1 inhomogeneities, the semi‐LASER technique can be viewed as a superior substitute for conventional PRESS MR spectroscopic imaging (MRSI) at 3T and beyond. Magn Reson Med, 2007.

Fast acquisition-weighted three-dimensional proton MR spectroscopic imaging of the human prostate.

The clinical application of 3D proton spectroscopic imaging (3D SI) of the human prostate requires a robust suppression of periprostatic lipid signal contamination, minimal intervoxel signal contamination, and the shortest possible measurement time. In this work, a weighted elliptical sampling of k‐space, combined with k‐space filtering and pulse repetition time (TR) reduction minimized lipid signals, intervoxel contamination, and measurement time. At 1.5 T, the MR‐visible prostate metabolites citrate, creatine, and choline can now be mapped over the entire human prostate with uncontaminated spherical voxels, with a volume down to 0.37 cm3, in measurement times of 7–15 min. Magn Reson Med 52:80–88, 2004.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

AbstractMany therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines

Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy

The purpose of this study was to implement a quantitative MR imaging method for the determination of muscular and fat content in individual skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD). Turbo Inversion Recovery Magnitude (TIRM) and multiecho MR images were acquired from seven FSHD patients and healthy volunteers. Signal decay in the multiecho MR images was fitted to a biexponential function with fixed relaxation rates for muscle and fat tissue and used to calculate the degree of fatty infiltration in eight muscles in the lower leg. Considerable differences in fatty infiltration between different muscles were observed in FSHD patients, suggesting that this could be used as a biomarker for disease progression. TIRM imaging indicated an inflammatory component of the disease previously only observed in muscle biopsies. Typically, muscle involvement was non-uniform even within one muscle, indicating that MRI can be used as a valuable tool to study pathophysiology and therapy evaluation in FSHD.

The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.

BACKGROUND In the UK, prostate cancer (PC) is the most common cancer in men. A diagnosis can be confirmed only following a prostate biopsy. Many men find themselves with an elevated prostate-specific antigen (PSA) level and a negative biopsy. The best way to manage these men remains uncertain. OBJECTIVES To assess the diagnostic accuracy of magnetic resonance spectroscopy (MRS) and enhanced magnetic resonance imaging (MRI) techniques [dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DW-MRI)] and the clinical effectiveness and cost-effectiveness of strategies involving their use in aiding the localisation of prostate abnormalities for biopsy in patients with prior negative biopsy who remain clinically suspicious for harbouring malignancy. DATA SOURCES Databases searched--MEDLINE (1946 to March 2012), MEDLINE In-Process & Other Non-Indexed Citations (March 2012), EMBASE (1980 to March 2012), Bioscience Information Service (BIOSIS; 1995 to March 2012), Science Citation Index (SCI; 1995 to March 2012), The Cochrane Library (Issue 3 2012), Database of Abstracts of Reviews of Effects (DARE; March 2012), Medion (March 2012) and Health Technology Assessment database (March 2012). REVIEW METHODS Types of studies: direct studies/randomised controlled trials reporting diagnostic outcomes. INDEX TESTS MRS, DCE-MRI and DW-MRI. Comparators: T2-weighted magnetic resonance imaging (T2-MRI), transrectal ultrasound-guided biopsy (TRUS/Bx). Reference standard: histopathological assessment of biopsied tissue. A Markov model was developed to assess the cost-effectiveness of alternative MRS/MRI sequences to direct TRUS-guided biopsies compared with systematic extended-cores TRUS-guided biopsies. A health service provider perspective was adopted and the recommended 3.5% discount rate was applied to costs and outcomes. RESULTS A total of 51 studies were included. In pooled estimates, sensitivity [95% confidence interval (CI)] was highest for MRS (92%; 95% CI 86% to 95%). Specificity was highest for TRUS (imaging test) (81%; 95% CI 77% to 85%). Lifetime costs ranged from £3895 using systematic TRUS-guided biopsies to £4056 using findings on T2-MRI or DCE-MRI to direct biopsies (60-year-old cohort, cancer prevalence 24%). The base-case incremental cost-effectiveness ratio for T2-MRI was <£30,000 per QALY (all cohorts). Probabilistic sensitivity analysis showed high uncertainty surrounding the incremental cost-effectiveness of T2-MRI in moderate prevalence cohorts. The cost-effectiveness of MRS compared with T2-MRI and TRUS was sensitive to several key parameters. LIMITATIONS Non-English-language studies were excluded. Few studies reported DCE-MRI/DW-MRI. The modelling was hampered by limited data on the relative diagnostic accuracy of alternative strategies, the natural history of cancer detected at repeat biopsy, and the impact of diagnosis and treatment on disease progression and health-related quality of life. CONCLUSIONS MRS had higher sensitivity and specificity than T2-MRI. Relative cost-effectiveness of alternative strategies was sensitive to key parameters/assumptions. Under certain circumstances T2-MRI may be cost-effective compared with systematic TRUS. If MRS and DW-MRI can be shown to have high sensitivity for detecting moderate/high-risk cancer, while negating patients with no cancer/low-risk disease to undergo biopsy, their use could represent a cost-effective approach to diagnosis. However, owing to the relative paucity of reliable data, further studies are required. In particular, prospective studies are required in men with suspected PC and elevated PSA levels but previously negative biopsy comparing the utility of the individual and combined components of a multiparametric magnetic resonance (MR) approach (MRS, DCE-MRI and DW-MRI) with both a MR-guided/-directed biopsy session and an extended 14-core TRUS-guided biopsy scheme against a reference standard of histopathological assessment of biopsied tissue obtained via saturation biopsy, template biopsy or prostatectomy specimens. STUDY REGISTRATION PROSPERO number CRD42011001376. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Prostate Cancer Aggressiveness: In Vivo Assessment of MR Spectroscopy and Diffusion-weighted Imaging at 3 T

PURPOSE To determine the individual and combined performance of magnetic resonance (MR) spectroscopic imaging and diffusion-weighted (DW) imaging at 3 T in the in vivo assessment of prostate cancer aggressiveness by using histopathologically defined regions of interest on radical prostatectomy specimens to define the prostate cancer regions to be investigated. MATERIALS AND METHODS The local institutional ethics review board approved this retrospective study and waived the informed consent requirement. Fifty-four patients with biopsy-proved prostate cancer underwent clinical MR spectroscopic imaging followed by prostatectomy. Guided by the histopathologic map, all spectroscopy voxels that contained tumor tissue were selected, and metabolite ratios (choline [Cho] plus creatine [Cr]-to-citrate [Cit] and Cho/Cr ratios) were derived. For each spectroscopic voxel, 25th percentile apparent diffusion coefficient (ADC) of the region corresponding to that voxel was determined, representing the most aberrant tumor part on the ADC map, which was often smaller than spectroscopic imaging voxels. Maximum metabolic ratios and minimum 25th percentile ADC of each tumor were related to tumor aggressiveness and were used to differentiate aggressiveness classes. A logistic regression model (LRM) was used to combine data from both modalities. RESULTS Significant correlation was found between aggressiveness classes and maximum Cho+Cr/Cit ratio (ρ=0.36), maximum Cho/Cr ratio (ρ=0.35), and minimum 25th percentile ADC (ρ=-0.63) in the peripheral zone (PZ). In the transition zone (TZ), the correlation was significant for only Cho+Cr/Cit and Cho/Cr ratios (ρ=0.58 and ρ=0.60, respectively). For differentiation between aggressiveness classes, LRM use did not result in significantly improved differentiation over any individual variables. CONCLUSION These findings enabled confirmation that MR spectroscopic imaging and DW imaging offer potential for in vivo noninvasive assessment of prostate cancer aggressiveness, and both modalities have comparable performance. The combination did not result in better performance. Nonetheless, the better performances of metabolite ratios in the TZ and of ADCs in the PZ suggest that they have complementary value.

Assessment of Prostate Cancer Aggressiveness Using Dynamic Contrast-enhanced Magnetic Resonance Imaging at 3 T

BACKGROUND A challenge in the diagnosis of prostate cancer (PCa) is the accurate assessment of aggressiveness. OBJECTIVE To validate the performance of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of the prostate at 3 tesla (T) for the assessment of PCa aggressiveness, with prostatectomy specimens as the reference standard. DESIGN, SETTINGS, AND PARTICIPANTS A total of 45 patients with PCa scheduled for prostatectomy were included. This study was approved by the institutional review board; the need for informed consent was waived. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Subjects underwent a clinical MRI protocol including DCE-MRI. Blinded to DCE-images, PCa was indicated on T2-weighted images based on histopathology results from prostatectomy specimens with the use of anatomical landmarks for the precise localization of the tumor. PCa was classified as low-, intermediate-, or high-grade, according to Gleason score. DCE-images were used as an overlay on T2-weighted images; mean and quartile values from semi-quantitative and pharmacokinetic model parameters were extracted per tumor region. Statistical analysis included Spearmans ρ, the Kruskal-Wallis test, and a receiver operating characteristics (ROC) analysis. RESULTS AND LIMITATIONS Significant differences were seen for the mean and 75th percentile (p75) values of wash-in (p = 0.024 and p = 0.017, respectively), mean wash-out (p = 0.044), and p75 of transfer constant (K(trans)) (p = 0.035), all between low-grade and high-grade PCa in the peripheral zone. ROC analysis revealed the best discriminating performance between low-grade versus intermediate-grade plus high-grade PCa in the peripheral zone for p75 of wash-in, K(trans), and rate constant (Kep) (area under the curve: 0.72). Due to a limited number of tumors in the transition zone, a definitive conclusion for this region of the prostate could not be drawn. CONCLUSIONS Quantitative parameters (K(trans) and Kep) and semi-quantitative parameters (wash-in and wash-out) derived from DCE-MRI at 3 T have the potential to assess the aggressiveness of PCa in the peripheral zone. P75 of wash-in, K(trans), and Kep offer the best possibility to discriminate low-grade from intermediate-grade plus high-grade PCa.