Evolutionary etiology of high-grade astrocytomas.

Glioblastoma (GBM), the most common brain malignancy, remains fatal with no effective treatment. Analyses of common aberrations in GBM suggest major regulatory pathways associated with disease etiology. However, 90% of GBMs are diagnosed at an advanced stage (primary GBMs), providing no access to early disease stages for assessing disease progression events. As such, both understanding of disease mechanisms and the development of biomarkers and therapeutics for effective disease management are limited. Here, we describe an adult-inducible astrocyte-specific system in genetically engineered mice that queries causation in disease evolution of regulatory networks perturbed in human GBM. Events yielding disease, both engineered and spontaneous, indicate ordered grade-specific perturbations that yield high-grade astrocytomas (anaplastic astrocytomas and GBMs). Impaired retinoblastoma protein RB tumor suppression yields grade II histopathology. Additional activation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) network drives progression to grade III disease, and further inactivation of phosphatase and tensin homolog (PTEN) yields GBM. Spontaneous missense mutation of tumor suppressor Trp53 arises subsequent to KRAS activation, but before grade III progression. The stochastic appearance of mutations identical to those observed in humans, particularly the same spectrum of p53 amino acid changes, supports the validity of engineered lesions and the ensuing interpretations of etiology. Absence of isocitrate dehydrogenase 1 (IDH1) mutation, asymptomatic low grade disease, and rapid emergence of GBM combined with a mesenchymal transcriptome signature reflect characteristics of primary GBM and provide insight into causal relationships.

A phase II study of sagopilone (ZK 219477; ZK-EPO) in patients with breast cancer and brain metastases.

UNLABELLED: Treatments for women with recurrent brain metastases from breast cancer are limited. In this phase II study,we administered sagopilone to patients with breast cancer and brain metastases. We observed modest activity with a central nervous system objective response rate of 13.3%; however, median PFS was disappointing. Further studies should focus on other agents to treat this challenging clinical problem. BACKGROUND: Patients with progressive metastatic breast cancer to the central nervous system (CNS) have limited treatment options. PATIENTS AND METHODS: We conducted a phase II study of sagopilone, an epothilone B analogue that crosses the blood-brain barrier, in patients with breast cancer brain metastases. Women were treated with 16 mg/m(2) or 22 mg/m(2) intravenously every 21 days. The primary endpoint was CNS objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Using modified, high-resolution magnetic resonance angiography (MRA), we also evaluated changes in vessel tortuosity with treatment. RESULTS: Fifteen women were enrolled; all had progressive CNS disease despite whole-brain radiotherapy. Two patients achieved a partial response (ORR, 13.3%) and remained in the study for 6 cycles. Responses were not associated with normalization of tumor-associated vessels on correlative imaging studies. Median PFS and OS were 1.4 months and 5.3 months, respectively. The most common grade 3 toxicities were lymphopenia and fatigue. Enrollment was stopped prematurely because of limited observed activity and slow accrual. CONCLUSIONS: Sagopilone was associated with modest CNS activity in patients with breast cancer; however median PFS was disappointing. Further studies should examine other potentially active agents and/or combinations for this challenging clinical problem.

The effects of healthy aging on intracerebral blood vessels visualized by magnetic resonance angiography.

Histological and magnetic resonance imaging studies have demonstrated that age-associated alterations of the human brain may be at least partially related to vascular alterations. Relatively little information has been published on vascular changes associated with healthy aging, however. The study presented in this paper examined vessels segmented from standardized, high-resolution, magnetic resonance angiograms (MRAs) of 100 healthy volunteers (50 males, 50 females), aged 18-74, without hypertension or other disease likely to affect the vasculature. The subject sample was divided into 5 age groups (n=20/group) with gender equally distributed per group. The anterior cerebral, both middle cerebral, and the posterior circulations were examined for vessel number, vessel radius, and vessel tortuosity. Males exhibited larger vessel radii regardless of age and across all anatomical regions. Both males and females displayed a lower number of MRA-discernible vessels with age, most marked in the posterior circulation. Age-associated tortuosity increases were relatively mild. Our multi-modal image database has been made publicly available for use by other investigators.

Vessel target location estimation during the TIPS procedure.

Creation of a transjugular intrahepatic portosystemic shunt (TIPS) requires passage of a needle toward a moving target that is only seen transiently by X-ray prior to needle passage. Intraoperative, 3D target localization would facilitate target access and improve the safety of the procedure. The clinical assumption is that patients undergoing the TIPS procedure possess rigid, cirrhotic livers that undergo only intraoperative translation without significant deformation or rotation. Based upon this assumption, we hypothesize that the position of any unseen, 3D target point within the liver can be determined intraoperatively by precalculation of the relative positions of the target point to a different 3D point that can be tracked intraoperatively. This paper examines this hypothesis using intraoperatively acquired, biplane, X-ray images of seven patients. In six, we tracked the effects of cardiac and respiratory motion, and in three the effects of needle pressure. Methods involved reconstruction of 3D vessel bifurcation and other trackable intrahepatic points from biplane angiograms, measurement of liver deformation by examining changing distances between these 3D points over time, and comparison of expected to actual displacements of these points with respect to a fixed reference point in the liver. We conclude that, for the rigid livers associated with patients undergoing TIPS, that there is less intraoperative deformation than previously reported by other groups addressing healthy liver deformation, and that the location of an unseen target can be predicted within 3mm accuracy.

White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients.

HIV associated dementia (HAD) is the most advanced stage of central nervous system disease caused by HIV infection. Previous studies have demonstrated that patients with HAD exhibit greater cerebral and basal ganglia atrophy than non-demented HIV+ (HND) patients. However, the extent to which white matter is affected in HAD patients compared to HND patients remains elusive. This study is designed to address the potential white matter abnormalities through the utilization of diffusion tensor imaging (DTI) in both HND and HAD patients. DTI and T1-weighted images were acquired from 18 healthy controls, 21 HND and 8 HAD patients. T1 image-based registration was performed to 1) parcellate the whole brain white matter into major white matter regions, including frontal, parietal, temporal and occipital white matter, corpus callosum and internal capsule for statistical comparisons of the mean DTI values, and 2) warp all DTI parametric images towards the common template space for voxel-based analysis. The statistical comparisons were performed with four DTI parameters including fractional anisotropy (FA), mean (MD), axial (AD), and radial (RD) diffusivities. With Whitney U tests on the mean DTI values, both HND and HAD demonstrated significant differences from the healthy control in multiple white matter regions. In addition, HAD patients exhibited significantly elevated MD and RD in the parietal white matter when compared to HND patients. In the voxel-based analysis, widespread abnormal regions were identified for both HND and HAD patients, although a much larger abnormal volume was observed in HAD patients for all four DTI parameters. Furthermore, both region of interest (ROI) based and voxel-based analyses revealed that RD was affected to a much greater extent than AD by HIV infection, which may suggest that demyelination is the prominent disease progression in white matter.

Simulation of brain tumors in MR images for evaluation of segmentation efficacy.

Obtaining validation data and comparison metrics for segmentation of magnetic resonance images (MRI) are difficult tasks due to the lack of reliable ground truth. This problem is even more evident for images presenting pathology, which can both alter tissue appearance through infiltration and cause geometric distortions. Systems for generating synthetic images with user-defined degradation by noise and intensity inhomogeneity offer the possibility for testing and comparison of segmentation methods. Such systems do not yet offer simulation of sufficiently realistic looking pathology. This paper presents a system that combines physical and statistical modeling to generate synthetic multi-modal 3D brain MRI with tumor and edema, along with the underlying anatomical ground truth, Main emphasis is placed on simulation of the major effects known for tumor MRI, such as contrast enhancement, local distortion of healthy tissue, infiltrating edema adjacent to tumors, destruction and deformation of fiber tracts, and multi-modal MRI contrast of healthy tissue and pathology. The new method synthesizes pathology in multi-modal MRI and diffusion tensor imaging (DTI) by simulating mass effect, warping and destruction of white matter fibers, and infiltration of brain tissues by tumor cells. We generate synthetic contrast enhanced MR images by simulating the accumulation of contrast agent within the brain. The appearance of the the brain tissue and tumor in MRI is simulated by synthesizing texture images from real MR images. The proposed method is able to generate synthetic ground truth and synthesized MR images with tumor and edema that exhibit comparable segmentation challenges to real tumor MRI. Such image data sets will find use in segmentation reliability studies, comparison and validation of different segmentation methods, training and teaching, or even in evaluating standards for tumor size like the RECIST criteria (response evaluation criteria in solid tumors).

Computerized assessment of vessel morphological changes during treatment of glioblastoma multiforme: report of a case imaged serially by MRA over four years.

A patient with glioblastoma multiforme underwent serial computerized analysis of tumor-associated vasculature defined from magnetic resonance angiographic (MRA) scans obtained over almost a four year period. The clinical course included tumor resection with subsequent radiation therapy, a long symptom-free interval, emergence of a new malignant focus, resection of that focus, a stroke, and treatment with chemotherapy and anti-angiogenic therapy. Image analysis methods included segmentation of vessels from each MRA and statistical comparison of vessel morphology over 4 regions of interest (the initial tumor site, the second tumor site, a distant control region, and the entire brain) to the same 4 regions of interest in 50 healthy volunteers (26 females and 24 males; mean age 39 years). Results suggested that following completion of focal radiation therapy (RT) vessel shape abnormalities, if elevated at the time of RT completion, may progressively normalize for months in focal regions, that progressively severe vessel shape abnormalities can precede the emergence of a gadolinium enhancing lesion by months, that lesion resection can produce a dramatic but highly transient drop in abnormal vessel tortuosity both focally and globally, and that treatment with anti-angiogenic agents does not necessarily normalize vessel shape. Quantitative measurements of vessel morphology as defined from MRA may provide useful insights into tumor development and response to therapy.

Constrained data decomposition and regression for analyzing healthy aging from fiber tract diffusion properties.

It has been shown that brain structures in normal aging undergo significant changes attributed to neurodevelopmental and neurodegeneration processes as a lifelong, dynamic process. Modeling changes in healthy aging will be necessary to explain differences to neurodegenerative patterns observed in mental illness and neurological disease. Driving application is the analysis of brain white matter properties as a function of age, given a database of diffusion tensor images (DTI) of 86 subjects well-balanced across adulthood. We present a methodology based on constrained PCA (CPCA) for fitting age-related changes of white matter diffusion of fiber tracts. It is shown that CPCA applied to tract functions of diffusion isolates population noise and retains age as a smooth change over time, well represented by the first principal mode. CPCA is therefore applied to a functional data analysis (FDA) problem. Age regression on tract functions reveals a nonlinear trajectory but also age-related changes varying locally along tracts. Four tracts with four different tensor-derived scalar diffusion measures were analyzed, and leave-one-out validation of data compression is shown.

Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE: One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases. PATIENTS AND METHODS: Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity. RESULTS: Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). CONCLUSION: The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.

Preventing facial recognition when rendering MR images of the head in three dimensions.

In the United States it is not allowed to make public any patient-specific information without the patient's consent. This ruling has led to difficulty for those interested in sharing three-dimensional (3D) images of the head and brain since a patient's face might be recognized from a 3D rendering of the skin surface. Approaches employed to date have included brain stripping and total removal of the face anterior to a cut plane, each of which lose potentially important anatomical information about the skull surface, air sinuses, and orbits. This paper describes a new approach that involves (a) definition of a plane anterior to which the face lies, and (b) an adjustable level of deformation of the skin surface anterior to that plane. On the basis of a user performance study using forced choices, we conclude that approximately 30% of individuals are at risk of recognition from 3D renderings of unaltered images and that truncation of the face below the level of the nose does not preclude facial recognition. Removal of the face anterior to a cut plane may interfere with accurate registration and may delete important anatomical information. Our new method alters little of the underlying anatomy and does not prevent effective registration into a common coordinate system. Although the methods presented here were not fully effective (one subject was consistently recognized under the forced choice study design even at the maximum deformation level employed) this paper may point a way toward solution of a difficult problem that has received little attention in the literature.

Blood vessel morphologic changes depicted with MR angiography during treatment of brain metastases: a feasibility study.

PURPOSE: To prospectively determine if magnetic resonance (MR) angiography can depict intracranial vascular morphologic changes during treatment of brain metastases from breast cancer and if serial quantitative vessel tortuosity measurements can be used to predict tumor treatment response sooner than traditional methods. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Twenty-two women aged 31-61 years underwent brain MR angiography prior to and 2 months after initiation of lapatinib therapy for brain metastases from breast cancer. Vessels were extracted from MR angiograms with a computer program. Changes in vessel number, radius, and tortuosity were calculated mathematically, normalized with values obtained in 34 healthy control subjects (19 women, 15 men; age range, 19-72 years), and compared with subsequent assessments of tumor volume and clinical course. RESULTS: All patients exhibited abnormal vessel tortuosity at baseline. Nineteen (86%) patients did not exhibit improvement in vessel tortuosity at 2-month follow-up, and all patients demonstrated tumor growth at 4-month follow-up. Vessel tortuosity measurements enabled us to correctly predict treatment failure 1-2 months earlier than did traditional methods. Three (14%) patients had quantitative improvement in vessel tortuosity at 2-month follow-up, with drop out of small abnormal vessels and straightening of large vessels. Each of the two patients for whom further follow-up data were available responded to treatment for more than 6 months. CONCLUSION: Study results established the feasibility of using MR angiography to quantify vessel shape changes during therapy. Although further research is required, results suggest that changes in vessel tortuosity might enable early prediction of tumor treatment response.

A review of micro- and macrovascular analyses in the assessment of tumor-associated vasculature as visualized by MR.

There is currently no noninvasive, reliable method of assessing brain tumor malignancy or of monitoring tumor treatment response. Monitoring changes to tumor vasculature might provide an effective means of assessing both tumor aggressiveness and treatment efficacy. To date, most such research has concentrated upon tumor "microvascular" imaging, with permeability and/or perfusion imaging used to assess vessel changes at the subvoxel level. An alternative approach assesses tumor vasculature at the "macroscopic" level, calculating the numbers and shapes of the larger vessels discriminable by magnetic resonance angiography. This paper provides an overview of magnetic resonance (MR) vascular imaging at both the microscopic (dynamic MR perfusion and permeability) and macroscopic (MR angiographic) levels. The two approaches provide different, complementary information and together could provide important insights into cancer growth as well as new methods of assessing malignancy and tumor treatment response.

Multi-modal image set registration and atlas formation.

In this paper, we present a Bayesian framework for both generating inter-subject large deformation transformations between two multi-modal image sets of the brain and for forming multi-class brain atlases. In this framework, the estimated transformations are generated using maximal information about the underlying neuroanatomy present in each of the different modalities. This modality independent registration framework is achieved by jointly estimating the posterior probabilities associated with the multi-modal image sets and the high-dimensional registration transformations mapping these posteriors. To maximally use the information present in all the modalities for registration, Kullback-Leibler divergence between the estimated posteriors is minimized. Registration results for image sets composed of multi-modal MR images of healthy adult human brains are presented. Atlas formation results are presented for a population of five infant human brains.

Tumor therapeutic response and vessel tortuosity: preliminary report in metastatic breast cancer.

No current non-invasive method is capable of assessing the efficacy of brain tumor therapy early during treatment. We outline an approach that evaluates tumor activity via statistical analysis of vessel shape using vessels segmented from MRA. This report is the first to describe the changes in vessel shape that occur during treatment of metastatic brain tumors as assessed by sequential MRA. In this preliminary study of 16 patients undergoing treatment for metastatic breast cancer we conclude that vessel shape may predict tumor response several months in advance of traditional methods.

3D/2D model-to-image registration applied to TIPS surgery.

We have developed a novel model-to-image registration technique which aligns a 3-dimensional model of vasculature with two semiorthogonal fluoroscopic projections. Our vascular registration method is used to intra-operatively initialize the alignment of a catheter and a preoperative vascular model in the context of image-guided TIPS (Transjugular, Intrahepatic, Portosystemic Shunt formation) surgery. Registration optimization is driven by the intensity information from the projection pairs at sample points along the centerlines of the model. Our algorithm shows speed, accuracy and consistency given clinical data.

Vessel tortuosity and brain tumor malignancy: a blinded study.

RATIONALE AND OBJECTIVES: Malignancy provokes regional changes to vessel shape. Characteristic vessel tortuosity abnormalities appear early during tumor development, affect initially healthy vessels, spread beyond the confines of tumor margins, and do not simply mirror tissue perfusion. The ability to detect and quantify tortuosity abnormalities on high-resolution magnetic resonance angiography (MRA) images offers a new approach to the noninvasive diagnosis of malignancy. This report evaluates a computerized, statistical method of analyzing the shapes of vessels extracted from MRA in diagnosing cancer. MATERIALS AND METHODS: The regional vasculature of 34 healthy subjects was compared with the tumor-associated vasculature of 30 brain tumors before surgical resection. The operator performing the analysis was blinded to the diagnosis. Vessels were segmented from an MRA of each subject, a region of interest was defined in each tumor patient and was mapped to all healthy controls, and a statistical analysis of vessel shape measures was then performed over the region of interest. Many difficult cases were included, such as pinpoint, hemorrhagic, and irradiated tumors, as were hypervascular benign tumors. Tumors were identified as benign or malignant on the basis of histological evaluation. RESULTS: A discriminant analysis performed at the study's conclusion successfully classified all but one of the 30 tumors as benign or malignant on the basis of vessel tortuosity. CONCLUSIONS: Quantitative, statistical measures of vessel shape offer a new approach to the diagnosis and staging of disease. Although the methods developed under the current report must be tested against a new series of cases, initial results are promising.

Magnetic resonance angiography visualization of abnormal tumor vasculature in genetically engineered mice.

Previous research on the vasculature of tumor-bearing animals has focused upon the microvasculature. Magnetic resonance angiography (MRA) offers a noninvasive, complementary approach that provides information about larger vessels. Quantitative analysis of MRA images of spontaneous preclinical tumor models has not been previously reported. Eleven TgT121;p53+/- mice, which invariably develop choroid plexus carcinoma (CPC), and nine age-matched healthy controls were imaged using T1, T2, and a high-resolution three-dimensional time-of-flight MRA sequences at 3 T. Tumors and vessels were segmented to determine tumor volume and vascular attributes, including number of terminal branches, vessel count, and the average vessel radii of MRA-visible vessels within the tumor. Differences in the vasculature between tumor-bearing animals and healthy controls were analyzed statistically. Although the spatial resolution of MRA prohibits visualization of capillaries, a high density of intratumor blood vessels was visualized in CPC mice. A significant increase in terminal branch count and vessel count, but not average vessel radius, was observed in CPCs when compared with normal controls. Both terminal branch count and vessel count were highly correlated with tumor volume. This study represents the first MRA analysis of a spontaneous preclinical brain tumor model. Although the spatial resolution of MRA is less than histologic analysis, MRA-obtained vascular attributes provide useful information with full brain coverage. We show that consistent tumor vasculature properties can be determined by MRA. Such methods are critical for developing preclinical therapeutic testing and will help guide the development of human brain tumor analyses.

Comparison of simultaneous and sequential two-view registration for 3D/2D registration of vascular images.

Accurate 3D/2D vessel registration is complicated by issues of image quality, occlusion, and other problems. This study performs a quantitative comparison of 3D/2D vessel registration in which vessels segmented from preoperative CT or MR are registered with biplane x-ray angiograms by either a) simultaneous two-view registration with advance calculation of the relative pose of the two views, or b) sequential registration with each view. We conclude on the basis of phantom studies that, even in the absence of image errors, simultaneous two-view registration is more accurate than sequential registration. In more complex settings, including clinical conditions, the relative accuracy of simultaneous two-view registration is even greater.

Synthetic ground truth for validation of brain tumor MRI segmentation.

Validation and method of comparison for segmentation of magnetic resonance images (MRI) presenting pathology is a challenging task due to the lack of reliable ground truth. We propose a new method for generating synthetic multi-modal 3D brain MRI with tumor and edema, along with the ground truth. Tumor mass effect is modeled using a biomechanical model, while tumor and edema infiltration is modeled as a reaction-diffusion process that is guided by a modified diffusion tensor MRI. We propose the use of warping and geodesic interpolation on the diffusion tensors to simulate the displacement and the destruction of the white matter fibers. We also model the process where the contrast agent tends to accumulate in cortical csf regions and active tumor regions to obtain contrast enhanced T1w MR image that appear realistic. The result is simulated multi-modal MRI with ground truth available as sets of probability maps. The system will be able to generate large sets of simulation images with tumors of varying size, shape and location, and will additionally generate infiltrated and deformed healthy tissue probabilities.