Analysis of heterogeneity in T2-weighted MR images can differentiate pseudoprogression from progression in glioblastoma.

PURPOSE: To develop an image analysis technique that distinguishes pseudoprogression from true progression by analyzing tumour heterogeneity in T2-weighted images using topological descriptors of image heterogeneity called Minkowski functionals (MFs). METHODS: Using a retrospective patient cohort (n = 50), and blinded to treatment response outcome, unsupervised feature estimation was performed to investigate MFs for the presence of outliers, potential confounders, and sensitivity to treatment response. The progression and pseudoprogression groups were then unblinded and supervised feature selection was performed using MFs, size and signal intensity features. A support vector machine model was obtained and evaluated using a prospective test cohort. RESULTS: The model gave a classification accuracy, using a combination of MFs and size features, of more than 85% in both retrospective and prospective datasets. A different feature selection method (Random Forest) and classifier (Lasso) gave the same results. Although not apparent to the reporting radiologist, the T2-weighted hyperintensity phenotype of those patients with progression was heterogeneous, large and frond-like when compared to those with pseudoprogression. CONCLUSION: Analysis of heterogeneity, in T2-weighted MR images, which are acquired routinely in the clinic, has the potential to detect an earlier treatment response allowing an early change in treatment strategy. Prospective validation of this technique in larger datasets is required.

Analysis of image heterogeneity using 2D Minkowski functionals detects tumor responses to treatment.

PURPOSE: The acquisition of ever increasing volumes of high resolution magnetic resonance imaging (MRI) data has created an urgent need to develop automated and objective image analysis algorithms that can assist in determining tumor margins, diagnosing tumor stage, and detecting treatment response. METHODS: We have shown previously that Minkowski functionals, which are precise morphological and structural descriptors of image heterogeneity, can be used to enhance the detection, in T1 -weighted images, of a targeted Gd(3+) -chelate-based contrast agent for detecting tumor cell death. We have used Minkowski functionals here to characterize heterogeneity in T2 -weighted images acquired before and after drug treatment, and obtained without contrast agent administration. RESULTS: We show that Minkowski functionals can be used to characterize the changes in image heterogeneity that accompany treatment of tumors with a vascular disrupting agent, combretastatin A4-phosphate, and with a cytotoxic drug, etoposide. CONCLUSIONS: Parameterizing changes in the heterogeneity of T2 -weighted images can be used to detect early responses of tumors to drug treatment, even when there is no change in tumor size. The approach provides a quantitative and therefore objective assessment of treatment response that could be used with other types of MR image and also with other imaging modalities.

Cardiac phenotype induced by a dysfunctional α 1C transgene: a general problem for the transgenic approach.

Based on stable integration of recombinant DNA into a host genome, transgenic technology has become an important genetic engineering methodology. An organism whose genetic characteristics have been altered by the insertion of foreign DNA is supposed to exhibit a new phenotype associated with the function of the transgene. However, successful insertion may not be sufficient to achieve specific modification of function. In this study we describe a strain of transgenic mouse, G7-882, generated by incorporation into the mouse genome of human CaV 1.2 α(1C) cDNA deprived of 3'-UTR to exclude transcription. We found that, in response to chronic infusion of isoproterenol, G7-882 develops dilated cardiomyopathy, a misleading "transgenic artifact" compatible with the expected function of the incorporated "correct" transgene. Specifically, using magnetic resonance imaging (MRI), we found that chronic ß-adrenergic stimulation of G7-882 mice caused left ventricular hypertrophy and aggravated development of dilated cardiomyopathy, although no significant changes in the kinetics, density and voltage dependence of the calcium current were observed in G7-882 cardiomyocytes as compared to cells from wild type mice. This result illustrates the possibility that even when a functional transgene is expressed, an observed change in phenotype may be due to the artifact of "incidental incorporation" leading to misleading conclusions. To exclude this possibility and thus provide a robust tool for exploring biological function, the new transgenic phenotype must be replicated in several independently generated transgenic strains.

Characterization of image heterogeneity using 2D Minkowski functionals increases the sensitivity of detection of a targeted MRI contrast agent.

A targeted Gd(3+)-based contrast agent has been developed that detects tumor cell death by binding to the phosphatidylserine (PS) exposed on the plasma membrane of dying cells. Although this agent has been used to detect tumor cell death in vivo, the differences in signal intensity between treated and untreated tumors was relatively small. As cell death is often spatially heterogeneous within tumors, we investigated whether an image analysis technique that parameterizes heterogeneity could be used to increase the sensitivity of detection of this targeted contrast agent. Two-dimensional (2D) Minkowski functionals (MFs) provided an automated and reliable method for parameterization of image heterogeneity, which does not require prior assumptions about the number of regions or features in the image, and were shown to increase the sensitivity of detection of the contrast agent as compared to simple signal intensity analysis.

Optimal methods for the preservation of cartilage samples in MRI and correlative biochemical studies.

MRI studies of cartilage require the prevention of sample degradation before and during scanning and during shipment for correlative studies. Methods to achieve this include immersion in protease inhibitors (PIs), refrigeration, and freezing. In this study, bovine nasal cartilage (BNC) samples were stored in Dulbecco's phosphate-buffered saline (DPBS), DPBS with standard PIs, or PI solution with GM6001, a potent metalloproteinase inhibitor. For each buffer, three samples were scanned at +4 degrees C and stored at +4 degrees C or at -20 degrees C with thawing prior to imaging. T2 and magnetization transfer (MT) rate, km, were measured weekly over 4 months, after which time water and glycosaminoglycan (GAG) contents were compared with those of matching tissue excised pre-storage. Samples in DPBS exhibited increased T2 (+33.6% after 1 month at +4 degrees C, P = 0.040) and decreased km (-20.6%, P = 0.004), while refrigeration in DPBS with PI and GM6001 yielded good stability (T2: +2.7%, P = 0.874; km: -4.2%, P = 0.654 after 108 days at +4 degrees C). Water content increased while GAG content markedly decreased in all samples. Thus, stability in cartilage MRI parameters can be optimized with appropriate storage conditions, but storage time should nonetheless be minimized.

Tendon and neurovascular bundle displacement in the palm with hand flexion and extension: an MRI and gross anatomy correlative study.

This study evaluated the correlative use of MRI methods and gross anatomy to monitor tendon displacement in the central region of the palm at rest and during flexion and extension of the metacarpophalangeal and interphalangeal joints with respect to the corresponding neurovascular bundles (NVBs). In all of the samples the neutral and extended positions showed the NVB to be palmar with respect to the flexor tendons, while during flexion tendon displacement caused the NVB to be dorsal to both the flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) tendons. T1-weighted MR images correlated with gross anatomical slides demonstrated that significant changes occur in the relative positions of the flexor tendons and associated NVBs of the palm upon flexion and extension.