Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2001-05-18
2004-10-19
Robinson, Daniel (Department: 3742)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S419000
Reexamination Certificate
active
06807441
ABSTRACT:
BACKGROUND OF THE INVENTION
The field of the invention is magnetic resonance imaging (MRI), and particularly, the imaging of tumors in the human brain.
In the United states, approximately 17,000 new patients are diagnosed each year with a primary intracranial neoplasm. Approximately 60% of these tumors are malignant, and gliomas are the most common type. Although there is a wide variability in life expectancy for patients with the various subtypes of gliomas, their prognosis is generally poor. This is especially true for those with high-grade gliomas, in spite of treatment modalities such as surgery, radiation therapy and chemotherapy. The most aggressive gliomas are those characterized by angiogenesis, a process of new vessel growth essential for the progression of the tumor from low-grade to high-grade. There is also a clear correlation between increased vascularity of the tumor and increased malignancy. Given the vascular nature of these tumors and the lack of success with standard cancer treatments, there is both a great need and hope for therapies that inhibit angiogenesis. Now that several of these agents are entering clinical trials an assessment of their ability to inhibit angiogenesis is crucial to evaluating their clinical potential.
Contrast-enhanced conventional MRI methods have become the imaging standard for the depiction and detection of brain tumors. However, these post-contrast, steady-state methods do not provide reliable information about tumor angiogenesis. The tumor signal enhancement volume that is measured by these prior methods depends on the status of the blood-brain barrier, which is affected by both tumor type and prior treatments for the disease. In addition, a tumor's response to an anti-angiogenic therapy can occur before effects on tumor volume can be detected, or may even occur with increases in tumor volume that result from the evolution of local necroses. Finally, an anti-angiogenic therapy may be judged successful, not necessarily because it results in tumor shrinkage, but because it stabilizes the tumor or returns it to a dormant state. For these reasons, non-invasive methods that can more specifically monitor vessel growth and regression in tumors are needed for the evaluation of anti-angiogenic therapies.
In an effort to provide more direct measures of tumor angiogenesis, relative cerebral blood volume (rCBV) information from dynamic susceptibility-contrast studies have been acquired using MRI methods. Preliminary findings suggest that MRI-acquired rCBV may better differentiate histologic tumor types than prior conventional MRI methods and provide information to predict glial tumor grade. In these rCBV studies, either gradient-echo (GE) or spin-echo (SE) pulse sequences are used to monitor the MR signal intensity during the passage of contrast agent. Each method is sensitive to a different population of blood vessels. Specifically, while GE transverse magnetization relaxation rate changes are sensitive to blood vessels of all sizes, SE transverse magnetization relaxation rate changes are more sensitive to capillary-sized blood vessels. Microvessel density is a recognized marker of tumor angiogenesis in invasive human cancers such as breast and prostate and it has a demonstrated prognostic value in brain tumors. It has been suggested, therefore, that SE-derived rCBV may best correlate with brain tumor angiogenesis.
A difficulty with using first pass contrast-enhanced MRI rCBV techniques to study brain tumors is the leakage which occurs when small molecular weight Gd agents are used. When acquiring data during the first pass of such a Gd contrast agent, the susceptibility effect dominates the signal if the Gd contrast agent remains contained in the vasculature. This is the case when the blood brain barrier is intact. However, with significant blood brain barrier disruption, as if often the case with brain tumors, contrast agent leaks out of the vasculature into the brain or tumor tissue resulting in enhanced T1 relaxation effects outside the vasculature. The resulting MRI signal increase due to T1 effects masks signal decrease due to T2 effects leading to an underestimation of rCBV.
SUMMARY OF THE INVENTION
The present invention relates to the production of MR images which correlate with brain tumor angiogenesis. More particularly, images are acquired during first passage of a contrast agent using a pulse sequence which acquires both gradient-echo NMR signals and spin-echo NMR signals, calculating a relative cerebral blood volume image (rCBV) using images reconstructed with both the gradient-echo and spin-echo NMR signals, and correcting the rCBV image for leakage of contrast agent out of the imaged vasculature. Another aspect of the invention is the production of a T
2
relaxation rate image (&Dgr;R2*) from the gradient-echo NMR signals, producing a T
2
relaxation rate image (&Dgr;R2) from the spin-echo NMR signals, and producing a ratio map image by calculating the ratio &Dgr;R2*/&Dgr;R2 of corresponding pixels in the respective &Dgr;R2* and &Dgr;R2 images.
A general object of the invention is to produce images with which the progression of brain tumors from low grade to high grade can be measured. It has been discovered that the corrected rCBV images derived from the gradient-echo and spin-echo NMR signals as well as the ratio map image (&Dgr;R2*/&Dgr;R2) correlate strongly with tumor grade.
The foregoing and other objects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred embodiment of the invention. Such embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims herein for interpreting the scope of the invention.
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Quarles & Brady LLP
Robinson Daniel
The MCW Research Foundation Inc.
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