Glioma grading using apparent diffusion coefficient map: application of histogram analysis based on automatic segmentation

The accurate diagnosis of glioma subtypes is critical for appropriate treatment, but conventional histopathologic diagnosis often exhibits significant intra‐observer variability and sampling error. The aim of this study was to investigate whether histogram analysis using an automatically segmented region of interest (ROI), excluding cystic or necrotic portions, could improve the differentiation between low‐grade and high‐grade gliomas. Thirty‐two patients (nine low‐grade and 23 high‐grade gliomas) were included in this retrospective investigation. The outer boundaries of the entire tumors were manually drawn in each section of the contrast‐enhanced T₁‐weighted MR images. We excluded cystic or necrotic portions from the entire tumor volume. The histogram analyses were performed within the ROI on normalized apparent diffusion coefficient (ADC) maps. To evaluate the contribution of the proposed method to glioma grading, we compared the area under the receiver operating characteristic (ROC) curves. We found that an ROI excluding cystic or necrotic portions was more useful for glioma grading than was an entire tumor ROI. In the case of the fifth percentile values of the normalized ADC histogram, the area under the ROC curve for the tumor ROIs excluding cystic or necrotic portions was significantly higher than that for the entire tumor ROIs (p < 0.005). The automatic segmentation of a cystic or necrotic area probably improves the ability to differentiate between high‐ and low‐grade gliomas on an ADC map. Copyright © 2014 John Wiley & Sons, Ltd.     

Hierarchical non‐negative matrix factorization to characterize brain tumor heterogeneity using multi‐parametric MRI

Tissue characterization in brain tumors and, in particular, in high‐grade gliomas is challenging as a result of the co‐existence of several intra‐tumoral tissue types within the same region and the high spatial heterogeneity. This study presents a method for the detection of the relevant tumor substructures (i.e. viable tumor, necrosis and edema), which could be of added value for the diagnosis, treatment planning and follow‐up of individual patients. Twenty‐four patients with glioma [10 low‐grade gliomas (LGGs), 14 high‐grade gliomas (HGGs)] underwent a multi‐parametric MRI (MP‐MRI) scheme, including conventional MRI (cMRI), perfusion‐weighted imaging (PWI), diffusion kurtosis imaging (DKI) and short‐TE ¹H MRSI. MP‐MRI parameters were derived: T₂, T₁ + contrast, fluid‐attenuated inversion recovery (FLAIR), relative cerebral blood volume (rCBV), mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and the principal metabolites lipids (Lip), lactate (Lac), N‐acetyl‐aspartate (NAA), total choline (Cho), etc. Hierarchical non‐negative matrix factorization (hNMF) was applied to the MP‐MRI parameters, providing tissue characterization on a patient‐by‐patient and voxel‐by‐voxel basis. Tissue‐specific patterns were obtained and the spatial distribution of each tissue type was visualized by means of abundance maps. Dice scores were calculated by comparing tissue segmentation derived from hNMF with the manual segmentation by a radiologist. Correlation coefficients were calculated between each pathologic tissue source and the average feature vector within the corresponding tissue region. For the patients with HGG, mean Dice scores of 78%, 85% and 83% were obtained for viable tumor, the tumor core and the complete tumor region. The mean correlation coefficients were 0.91 for tumor, 0.97 for necrosis and 0.96 for edema. For the patients with LGG, a mean Dice score of 85% and mean correlation coefficient of 0.95 were found for the tumor region. hNMF was also applied to reduced MRI datasets, showing the added value of individual MRI modalities. Copyright © 2015 John Wiley & Sons, Ltd.     

Correlative assessment of tumor microcirculation using contrast‐enhanced perfusion MRI and intravoxel incoherent motion diffusion‐weighted MRI: is there a link between them?

The purpose of this study was to correlate intravoxel incoherent motion (IVIM) imaging with classical perfusion‐weighted MRI metrics in human gliomas. Parametric images for slow diffusion coefficient (D), fast diffusion coefficient (D*), and fractional perfusion‐related volume (f) in patients with high‐grade gliomas were generated. Maps of F_p (plasma flow), v_p (vascular plasma volume), PS (permeability surface–area product), v_e (extravascular, extracellular volume), E (extraction ratio), k_e (influx ratio into the interstitium), and t_c (vascular transit time) from dynamic contrast‐enhanced (DCE) and dynamic susceptibility contrast‐enhanced (DSC) MRI were also generated. A region‐of‐interest analysis on the contralateral healthy white matter and on the tumor areas was performed and the extracted parameter values were tested for any significant differences among tumor grades or any correlations. Only f could be significantly correlated to DSC‐derived v_p and t_c in healthy brain tissue. Concerning the tumor regions, F_p was significantly positively correlated with D* and inversely correlated with f in DSC measurements. The D*, f, and f × D* values in the WHO grade III gliomas were non‐significantly different from those in the grade IV gliomas. There was a trend to significant negative correlations between f and PS as well as between f × D* and k_e in DCE experiments. Presumably due to different theoretical background, tracer properties and modeling of the tumor vasculature in the IVIM theory, there is no clearly evident link between D*, f and DSC‐ and DCE‐derived metrics. Copyright © 2014 John Wiley & Sons, Ltd.     

Multi‐centre reproducibility of diffusion MRI parameters for clinical sequences in the brain

The purpose of this work was to assess the reproducibility of diffusion imaging, and in particular the apparent diffusion coefficient (ADC), intra‐voxel incoherent motion (IVIM) parameters and diffusion tensor imaging (DTI) parameters, across multiple centres using clinically available protocols with limited harmonization between sequences. An ice–water phantom and nine healthy volunteers were scanned across fives centres on eight scanners (four Siemens 1.5T, four Philips 3T). The mean ADC, IVIM parameters (diffusion coefficient D and perfusion fraction f) and DTI parameters (mean diffusivity MD and fractional anisotropy FA), were measured in grey matter, white matter and specific brain sub‐regions. A mixed effect model was used to measure the intra‐ and inter‐scanner coefficient of variation (CV) for each of the five parameters. ADC, D, MD and FA had a good intra‐ and inter‐scanner reproducibility in both grey and white matter, with a CV ranging between 1% and 7.4%; mean 2.6%. Other brain regions also showed high levels of reproducibility except for small structures such as the choroid plexus. The IVIM parameter f had a higher intra‐scanner CV of 8.4% and inter‐scanner CV of 24.8%. No major difference in the inter‐scanner CV for ADC, D, MD and FA was observed when analysing the 1.5T and 3T scanners separately. ADC, D, MD and FA all showed good intra‐scanner reproducibility, with the inter‐scanner reproducibility being comparable or faring slightly worse, suggesting that using data from multiple scanners does not have an adverse effect compared with using data from the same scanner. The IVIM parameter f had a poorer inter‐scanner CV when scanners of different field strengths were combined, and the parameter was also affected by the scan acquisition resolution. This study shows that the majority of diffusion MRI derived parameters are robust across 1.5T and 3T scanners and suitable for use in multi‐centre clinical studies and trials. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd.     

Interstitial fluid pressure correlates with intravoxel incoherent motion imaging metrics in a mouse mammary carcinoma model

The effective delivery of a therapeutic drug to the core of a tumor is often impeded by physiological barriers, such as the interstitial fluid pressure (IFP). There are a number of therapies that can decrease IFP and induce tumor vascular normalization. However, a lack of a noninvasive means to measure IFP hinders the utilization of such a window of opportunity for the maximization of the treatment response. Thus, the purpose of this study was to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion parameters as noninvasive imaging biomarkers for IFP. Mice bearing the 4T1 mammary carcinoma model were studied using diffusion‐weighted imaging (DWI), immediately followed by wick‐in‐needle IFP measurement. Voxelwise analysis was conducted with a conventional monoexponential diffusion model, as well as a biexponential model taking IVIM into account. There was no significant correlation of IFP with either the median apparent diffusion coefficient from the monoexponential model (r = 0.11, p = 0.78) or the median tissue diffusivity from the biexponential model (r = 0.30, p = 0.44). However, IFP was correlated with the median pseudo‐diffusivity (D_p) of apparent vascular voxels (r = 0.76, p = 0.02) and with the median product of the perfusion fraction and pseudo‐diffusivity (f_pD_p) of apparent vascular voxels (r = 0.77, p = 0.02). Although the effect of IVIM in tumors has been reported previously, to our knowledge, this study represents the first direct comparison of IVIM metrics with IFP, with the results supporting the feasibility of the use of IVIM DWI metrics as noninvasive biomarkers for tumor IFP. Copyright © 2011 John Wiley & Sons, Ltd.     

Characterization of clear cell renal cell carcinoma with diffusion kurtosis imaging: correlation between diffusion kurtosis parameters and tumor cellularity

The aim of this study was to evaluate the role of diffusion kurtosis imaging (DKI) in the characterization of clear cell renal cell carcinoma (ccRCC) and to correlate DKI parameters with tumor cellularity. Fifty‐nine patients with pathologically diagnosed ccRCCs were evaluated by DKI on a 3‐T scanner. Regions of interest were drawn on the maps of the mean diffusion coefficient (MD) and mean diffusion kurtosis (MK). All ccRCCs were histologically graded according to the Fuhrman classification system. Tumor cellularity was measured by the nuclear‐to‐cytoplasm (N/C) ratio and the number of tumor cell nuclei (NTCN). ccRCCs were classified as grade 1 (n = 23), grade 2 (n = 24), grade 3 (n = 10) and grade 4 (n = 3). Both MD and MK could readily discriminate between normal renal parenchyma and ccRCCs (p < 0.001), and receiver operating characteristic (ROC) curve analysis showed that MK exhibited a better performance with an area under the ROC curve of 0.874 and sensitivity/specificity of 68.33%/100% (p < 0.001). Further, MD and MK were significantly different between grade 1 and grades 3 and 4 (p = 0.01, p < 0.001) and between grade 2 and grades 3 and 4 (p = 0.015, p < 0.005), respectively. However, no significant difference was found between grade 1 and grade 2 (p > 0.05) for both MD and MK. With regard to NTCN, no significant difference was found between any two grades (p > 0.05), and the N/C ratio changed significantly with grade (p < 0.01, between any two grades). Negative correlations were found between MK and MD (r = –0.56, p < 0.001), and between MD and N/C ratio (r = –0.36, p < 0.005), whereas MK and the N/C ratio were positively correlated (r = 0.45, p = 0.003). DKI could quantitatively characterize ccRCC with different grades by probing non‐Gaussian diffusion properties related to changes in the tumor microenvironment or tissue complexities in the tumor. Copyright © 2016 John Wiley & Sons, Ltd.     

Diffusion‐weighted imaging of the abdomen: Impact of b‐values on texture analysis features

The purpose of this work was to systematically assess the impact of the b‐value on texture analysis in MR diffusion‐weighted imaging (DWI) of the abdomen. In eight healthy male volunteers, echo‐planar DWI sequences at 16 b‐values ranging between 0 and 1000 s/mm² were acquired at 3 T. Three different apparent diffusion coefficient (ADC) maps were computed (0, 750/100, 390, 750 s/mm²/all b‐values). Texture analysis of rectangular regions of interest in the liver, kidney, spleen, pancreas, paraspinal muscle and subcutaneous fat was performed on DW images and the ADC maps, applying 19 features computed from the histogram, grey‐level co‐occurrence matrix (GLCM) and grey‐level run‐length matrix (GLRLM). Correlations between b‐values and texture features were tested with a linear and an exponential model; the best fit was determined by the smallest sum of squared residuals. Differences between the ADC maps were assessed with an analysis of variance. A Bonferroni‐corrected p‐value less than 0.008 (=0.05/6) was considered statistically significant. Most GLCM and GLRLM‐derived texture features (12–18 per organ) showed significant correlations with the b‐value. Four texture features correlated significantly with changing b‐values in all organs (p < 0.008). Correlation coefficients varied between 0.7 and 1.0. The best fit varied across different structures, with fat exhibiting mostly exponential (17 features), muscle mostly linear (12 features) and the parenchymatous organs mixed feature alterations. Two GLCM features showed significant variability in the different ADC maps. Several texture features vary systematically in healthy tissues at different b‐values, which needs to be taken into account if DWI data with different b‐values are analyzed. Histogram and GLRLM‐derived texture features are stable on ADC maps computed from different b‐values.     

Differentiating the histologic grades of gliomas preoperatively using amide proton transfer‐weighted (APTW) and intravoxel incoherent motion MRI

The purpose of this work was to investigate the diagnostic performance of amide proton transfer‐weighted (APTW) and intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in the preoperative grading of gliomas. Fifty‐one patients with suspected gliomas were recruited and underwent a preoperative MRI examination that included APTW and IVIM sequences. All cases were confirmed by postsurgical histopathology. APTW signal intensity, true diffusion coefficient (D), perfusion fraction (f) and pseudo‐diffusion coefficient (D*) were applied to assess the solid tumor component and contralateral normal‐appearing white matter. The relative APTW signal intensity (rAPTW) was also used. Independent‐sample and paired‐sample t‐tests were used to compare differences in MRI parameters between low‐grade glioma (LGG) and high‐grade glioma (HGG) groups. The diagnostic performance was assessed with the receiver operating characteristic curve. Twenty‐six patients were pathologically diagnosed with LGG and 25 were diagnosed with HGG. APTW, rAPTW and f values were significantly higher (all p < 0.001), whereas D values were significantly lower (p < 0.001) in the HGG group than in the LGG group. There was no significant difference between D* values for the two groups. rAPTW had an area under the curve (AUC) of 0.957, with a sensitivity of 100% and a specificity of 84.6%, followed by APTW, f, D and D*. The combined use of APTW and IVIM showed the best diagnostic performance, with an AUC of 0.986. In conclusion, APTW and IVIM, as two promising supplementary sequences for routine MRI, could be valuable in differentiating LGGs from HGGs.     

Invasive ductal carcinoma: correlation of apparent diffusion coefficient value with pathological prognostic factors

The aim of this study was to correlate the apparent diffusion coefficient (ADC) value of invasive ductal carcinoma with pathological prognostic factors. A prospective study was conducted on 59 untreated female patients (mean age 46 years) with invasive ductal carcinoma. All patients were examined at 1.5 Tesla using dedicated bilateral breast coil. They underwent diffusion weighted MR imaging of the breast using a single shot echo planar imaging with a b‐factor of 200 and 400 sec/mm2. Apparent diffusion coefficient (ADC) maps were reconstructed. The ADC value of the breast cancer was calculated and correlated with the pathologic prognostic factors (tumor size, grade and lymph nodes). The mean ADC values of invasive ductal carcinoma were significantly lower in patients with high grade, large breast cancer as well as those with axillary lymph nodes metastasis in a statistically significant way (p = 0.001 for the three factors). The mean ADC value of invasive ductal carcinoma was correlated with histologic grade (r = ?0.675, p = 0.001), tumor size (r = 0.504, p = 0.001) and showed lower ADC values with positive lymph node metastasis. Apparent diffusion coefficient value is correlated with pathological parameters of invasive ductal carcinoma. The lower ADC values are associated with higher histological grade, larger tumor size and presence of axillary lymph nodes. So, the ADC value can be considered as a promising prognostic parameter that may identify highly aggressive breast cancer. Copyright © 2010 John Wiley & Sons, Ltd.     

Relationship between diffusion parameters derived from intravoxel incoherent motion MRI and perfusion measured by dynamic contrast‐enhanced MRI of soft tissue tumors

Our aim was to evaluate the link between diffusion parameters measured by intravoxel incoherent motion (IVIM) diffusion‐weighted imaging (DWI) and the perfusion metrics obtained with dynamic contrast‐enhanced (DCE) MRI in soft tissue tumors (STTs). Twenty‐eight patients affected by histopathologically confirmed STT were included in a prospective study. All patients underwent both DCE MRI and IVIM DWI. The perfusion fraction f, diffusion coefficient D and perfusion‐related diffusion coefficient D* were estimated using a bi‐exponential function to fit the DWI data. DCE MRI was acquired with a temporal resolution of 3–5 s. Maps of the initial area under the gadolinium concentration curve (IAUGC), time to peak (TTP) and maximum slope of increase (MSI) were derived using commercial software. The relationships between the DCE MRI and IVIM DWI measurements were assessed by Spearman's test. To exclude false positive results under multiple testing, the false discovery rate (FDR) procedure was applied. The Mann–Whitney test was used to evaluate the differences between all variables in patients with non‐myxoid and myxoid STT. No significant relationship was found between IVIM parameters and any DCE MRI parameters. Higher f and D*f values were found in non‐myxoid tumors compared with myxoid tumors (p = 0.004 and p = 0.003, respectively). MSI was significantly higher in non‐myxoid tumors than in myxoid tumors (p = 0.029). From the visual assessments of single clinical cases, both f and D*f maps were in satisfactory agreement with DCE maps in the extreme cases of an avascular mass and a highly vascularized mass, whereas, for tumors with slight vascularity or with a highly heterogeneous perfusion pattern, this association was not straightforward. Although IVIM DWI was demonstrated to be feasible in STT, our data did not support evident relationships between perfusion‐related IVIM parameters and perfusion measured by DCE MRI. Copyright © 2015 John Wiley & Sons, Ltd.     

DCE and DW-MRI monitoring of vascular disruption following VEGF-Trap treatment of a rat glioma model

Vascular‐targeted therapies have shown promise as adjuvant cancer treatment. As these agents undergo clinical evaluation, sensitive imaging biomarkers are needed to assess drug target interaction and treatment response. In this study, dynamic contrast enhanced MRI (DCE‐MRI) and diffusion‐weighted MRI (DW‐MRI) were evaluated for detecting response of intracerebral 9 L gliosarcomas to the antivascular agent VEGF‐Trap, a fusion protein designed to bind all forms of Vascular Endothelial Growth Factor‐A (VEGF‐A) and Placental Growth Factor (PGF). Rats with 9 L tumors were treated twice weekly for two weeks with vehicle or VEGF‐Trap. DCE‐ and DW‐MRI were performed one day prior to treatment initiation and one day following each administered dose. Kinetic parameters (K^trans, volume transfer constant; k_ep, efflux rate constant from extravascular/extracellular space to plasma; and v_p, blood plasma volume fraction) and the apparent diffusion coefficient (ADC) over the tumor volumes were compared between groups. A significant decrease in kinetic parameters was observed 24 hours following the first dose of VEGF‐Trap in treated versus control animals (p < 0.05) and was accompanied by a decline in ADC values. In addition to the significant hemodynamic effect, VEGF‐Trap treated animals exhibited significantly longer tumor doubling times (p < 0.05) compared to the controls. Histological findings were found to support imaging response metrics. In conclusion, kinetic MRI parameters and change in ADC have been found to serve as sensitive and early biomarkers of VEGF‐Trap anti‐vascular targeted therapy. Copyright © 2011 John Wiley & Sons, Ltd.     

Response of HT29 colorectal xenograft model to cediranib assessed with 18F‐fluoromisonidazole positron emission tomography,dynamic contrast‐enhanced and diffusion‐weighted MRI

Cediranib is a small‐molecule pan‐vascular endothelial growth factor receptor inhibitor. The tumor response to short‐term cediranib treatment was studied using dynamic contrast‐enhanced and diffusion‐weighted MRI at 7 T, as well as ¹⁸F‐fluoromisonidazole positron emission tomography and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline; they then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow‐up imaging performed 2 h after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, the endothelial cell marker CD31, smooth muscle actin, intercapillary distance and tumor necrosis. Dynamic contrast‐enhanced MRI‐derived parameters decreased significantly in cediranib‐treated tumors relative to pretreatment values [the muscle‐normalized initial area under the gadolinium concentration curve decreased by 48% (p = 0.002), the enhancing fraction by 43% (p = 0.003) and K^trans by 57% (p = 0.003)], but remained unchanged in controls. No change between the pre‐ and post‐treatment tumor apparent diffusion coefficients in either the cediranib‐ or vehicle‐treated group was observed over the course of this study. The ¹⁸F‐fluoromisonidazole mean standardized uptake value decreased by 33% (p = 0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31‐positive vessels (59 per mm²), the fraction of smooth muscle actin‐positive vessels (80–87%) and the intercapillary distance (0.17 mm) were similar in cediranib‐ and vehicle‐treated groups. The fraction of perfused blood vessels in cediranib‐treated tumors (81 ± 7%) was lower than that in vehicle controls (91 ± 3%, p = 0.02). The necrotic fraction was slightly higher in cediranib‐treated rats (34 ± 12%) than in controls (26 ± 10%, p = 0.23). These findings suggest that short‐term treatment with cediranib causes a decrease in tumor perfusion/permeability across the tumor cross‐section, but changes in vascular morphology, vessel density or tumor cellularity are not manifested at this early time point. Copyright © 2012 John Wiley & Sons, Ltd.     

Congenital tumors of the central nervous system: an institutional review of 64 cases with emphasis on tumors with unique histologic and molecular characteristics

Congenital brain tumors are rare accounting for 0.5%–1.9% of all pediatric brain tumors. While different criteria have been used to classify a tumor as congenital, those diagnosed prior to 6 months of age are considered to be “probably” congenital in origin. We performed an institutional review of all central nervous system (CNS) tumors (surgical and autopsy specimens from 1990 to 2019) in patients less than 6 months old. Sixty‐four unique cases were identified, and these accounted for 2.0% of all CNS tumor specimens at our institution. The most common tumor types were high‐grade gliomas, low‐grade gliomas and medulloblastomas. Atypical teratoid rhabdoid tumors, choroid plexus tumors and germ cell tumors also accounted for a significant portion of the cohort. Seven tumors were diagnosed prenatally. The most common clinical presentation at diagnosis was increased head circumference. At the conclusion of the study, over half of the patients were alive including all patients with WHO grade I and II tumors. Ninety‐two percent of cases were classifiable using the 2016 WHO system, and when available, molecular findings supported the histologic diagnoses. However, several gliomas had unusual histologic features and did not correspond to a well‐defined entity. Molecular testing was essential for accurate classification of a subset of these tumors, and several high‐grade gliomas exhibited fusions considered unique to infantile gliomas, including those involving the MET, ALK and NTRK genes. To our knowledge, this cohort represents the largest single‐institution study of congenital CNS tumors and highlights many ways in which congenital CNS tumors are distinct from CNS tumors of older pediatric patients and adults.     

Diffusion-weighted MRI in early chemotherapy response evaluation of patients with diffuse large B-cell lymphoma--a pilot study: comparison with 2-deoxy-2-fluoro- D-glucose-positron emission tomography/computed tomography

To determine the feasibility of diffusion‐weighted MRI (DWI) in the evaluation of the early chemotherapeutic response in patients with aggressive non‐Hodgkin's lymphoma (NHL), eight patients with histologically proven diffuse large B‐cell lymphoma were imaged by MRI, including DWI, and positron emission tomography/computed tomography (PET/CT) before treatment (E1), and after 1 week (E2) and two cycles (E3) of chemotherapy. In all patients, whole‐body screening using T₁‐ and T₂‐weighted images in the coronal plane was performed. To quantitatively evaluate the chemotherapeutic response, axial images including DWI were acquired. Apparent diffusion coefficient (ADC) maps were reconstructed, and the ADC value of the tumor was measured. In addition, the tumor volume was estimated on axial T₂‐weighted images. The maximum standardized uptake value (SUV_max) and active tumor volume were measured on fused PET/CT images. Lymphomas showed high signal intensity on DW images and low signal intensity on ADC maps, except for necrotic foci. The mean pre‐therapy ADC was 0.71 × 10^?3 mm²/s; it increased by 77% at E2 (p < 0.05) and 24% more at E3 (insignificant); the total increase was 106% (p < 0.05). The mean tumor volume by MRI was 276 mL at baseline; it decreased by 58% at E2 (p < 0.05) and 65% more at E3 (p < 0.05), giving a total decrease of 84% (p < 0.05). All the imaged pre‐therapy tumors were strongly positive on PET/CT, with a mean SUV_max of 20. The SUV_max decreased by 60% at E2 (p < 0.05) and 59% more at E3 (p < 0.05), giving a total decrease of 83% (p < 0.05). The active tumor burden decreased by 66% at E2 (p < 0.05). At baseline, both central and peripheral tumor ADC values correlated inversely with SUV_max (p < 0.05), and also correlated inversely with active tumor burden on PET/CT and with tumor volume on MRI at E2 (p < 0.05). In conclusion, the results of DWI in combination with whole‐body MRI were comparable with those of integrated PET/CT. Copyright © 2011 John Wiley & Sons, Ltd.     

Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd‐DTPA and USPIO‐enhanced imaging

High grade and metastatic brain tumours exhibit considerable spatial variations in proliferation, angiogenesis, invasion, necrosis and oedema. Vascular heterogeneity arising from vascular co‐option in regions of invasive growth (in which the blood–brain barrier remains intact) and neoangiogenesis is a major challenge faced in the assessment of brain tumours by conventional MRI. A multiparametric MRI approach, incorporating native measurements and both Gd‐DTPA (Magnevist) and ultrasmall superparamagnetic iron oxide (P904)‐enhanced imaging, was used in combination with histogram and unsupervised cluster analysis using a k‐means algorithm to examine the spatial distribution of vascular parameters, water diffusion characteristics and invasion in intracranially propagated rat RG2 gliomas and human MDA‐MB‐231 LM2–4 breast adenocarcinomas in mice. Both tumour models presented with higher ΔR₁ (the change in transverse relaxation rate R₁ induced by Gd‐DTPA), fractional blood volume (fBV) and apparent diffusion coefficient than uninvolved regions of the brain. MDA‐MB‐231 LM2–4 tumours were less densely cellular than RG2 tumours and exhibited substantial local invasion, associated with oedema, whereas invasion in RG2 tumours was minimal. These additional features were reflected in the more heterogeneous appearance of MDA‐MB‐231 LM2–4 tumours on T₂‐weighted images and maps of functional MRI parameters. Unsupervised cluster analysis separated subregions with distinct functional properties; areas with a low fBV and relatively impermeable blood vessels (low ΔR₁) were predominantly located at the tumour margins, regions of MDA‐MB‐231 LM2–4 tumours with relatively high levels of water diffusion and low vascular permeability and/or fBV corresponded to histologically identified regions of invasion and oedema, and areas of mismatch between vascular permeability and blood volume were identified. We demonstrate that dual contrast MRI and evaluation of tissue diffusion properties, coupled with cluster analysis, allows for the assessment of heterogeneity within invasive brain tumours and the designation of functionally diverse subregions that may provide more informative predictive biomarkers.     

Reliable estimation of brain intravoxel incoherent motion parameters using denoised diffusion‐weighted MRI

In this study, we evaluate whether diffusion‐weighted magnetic resonance imaging (DW‐MRI) data after denoising can provide a reliable estimation of brain intravoxel incoherent motion (IVIM) perfusion parameters. Brain DW‐MRI was performed in five healthy volunteers on a 3 T clinical scanner with 12 different b‐values ranging from 0 to 1000 s/mm². DW‐MRI data denoised using the proposed method were fitted with a biexponential model to extract perfusion fraction (PF), diffusion coefficient (D) and pseudo‐diffusion coefficient (D*). To further evaluate the accuracy and precision of parameter estimation, IVIM parametric images obtained from one volunteer were used to resimulate the DW‐MRI data using the biexponential model with the same b‐values. Rician noise was added to generate DW‐MRI data with various signal‐to‐noise ratio (SNR) levels. The experimental results showed that the denoised DW‐MRI data yielded precise estimates for all IVIM parameters. We also found that IVIM parameters were significantly different between gray matter and white matter (P < 0.05), except for D* (P = 0.6). Our simulation results show that the proposed image denoising method displays good performance in estimating IVIM parameters (both bias and coefficient of variation were <12% for PF, D and D*) in the presence of different levels of simulated Rician noise (SNR_b=0 = 20‐40). Simulations and experiments show that brain DW‐MRI data after denoising can provide a reliable estimation of IVIM parameters.     

Two-step anomalous diffusion tensor imaging

We extend the formalism of anomalous diffusion imaging to include directional anisotropy of fitted parameters. The resulting technique is termed anomalous diffusion tensor imaging (aDTI), and allows the directional properties of the distributed diffusion coefficient (α) and the anomalous diffusion exponent, (γ) to be analysed using the same analytical techniques as regular diffusion tensor imaging (DTI). Together, these parameters quantify the rate of diffusion (α) and the complexity of the diffusion environment (γ). We generated tensor images for the anomalous exponent tensor (Γ) and distributed diffusivity tensor (A) from in vivo human brain data and present images of eigenvalues, eigenvectors, Trace/3 (Tr), fractional anisotropy (FA) and tensor shape measures. In white matter, A is found to have a median Tr = 0.56 × 10^{? 3}mm²s^{? 1}, FA = 0.58 and Γ Tr = 0.69, FA = 0.13. We observed that white matter shows a similar anisotropic geometry for the distributed diffusion tensor as for the regular diffusion tensor, whereas the anomalous exponent tensor exhibits a different shape characteristic which may be informative of tissue microstructure. Copyright © 2011 John Wiley & Sons, Ltd.     

Analysis of parametric histogram from dynamic contrast‐enhanced MRI: application in evaluating brain tumor response to radiotherapy

Dynamic contrast‐enhanced MRI (DCE MRI) has been used to study tumor response to treatment for many years. In this study, the modified full width at half‐maximum (mFWHM), calculated from the wash‐in slope histogram, is proposed as a parameter for the evaluation of changes in tumor heterogeneity which respond to radiotherapy. Twenty‐five patients with brain tumors were evaluated and divided into the nonresponder group (n = 11) and the responder group (n = 14) according to the Response Evaluation Criteria in Solid Tumors (RECIST). All selected tumors were evaluated by mFWHM ratios of post‐ to pre‐therapy (the ratio was defined as the therapeutic mFWHM ratio, TMR). The changes in kurtosis of the histograms and the averaged K^trans within a tumor were also calculated for comparison. The receiver operating characteristic analysis and Kaplan–Meier curves were used to examine the diagnosis ability. The TMR values were significantly higher in nonresponders than in responders (p < 0.001). When compared with the other two parameters, the proposed method also demonstrated better sensitivity and specificity. When adopting the TMR for the estimation of prognosis after therapy, there was a significant difference between the population survival curves. In conclusion, the derived mFWHM reflects tumor heterogeneity, and the ability to depict patient survival probability from TMR corresponds well with that from RECIST. The results reveal that, in brain tumors, progression may be exhibited not only by tumor size, but also by tumor heterogeneity. Copyright © 2012 John Wiley & Sons, Ltd.     

Genetic Analysis of Diffuse High‐Grade Astrocytomas in Infancy Defines a Novel Molecular Entity

Pediatric high‐grade gliomas are considered to be different when compared to adult high‐grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high‐grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high‐grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe‐dependent amplification (MLPA), pyrosequencing of glioma‐associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high‐grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high‐grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior.